Spironolactone: Difference between revisions

Spironolactone
Clinical data
Pronunciation	/ˌspaɪrənoʊˈlæktoʊn/ SPYE-rə-noh-LAK-tohn, /ˌspɪər-/ SPEER-
Trade names	Aldactone, Spiractin, Verospiron, many others; combinations: Aldactazide (+HCTZTooltip hydrochlorothiazide), Aldactide (+HFMZTooltip hydroflumethiazide), Aldactazine (+altizide), others
Other names	SC-9420; NSC-150339; 7α-Acetylthiospirolactone; 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
AHFS/Drugs.com	Monograph
MedlinePlus	a682627
Pregnancy; category	AU: B3; ;
Routes of; administration	By mouth, topical
Drug class	Antimineralocorticoid; Antiandrogen
ATC code	C03DA01 (WHO) ;
Legal status
Legal status	UK: POM (Prescription only); US: WARNINGRx-only;
Pharmacokinetic data
Bioavailability	60–90%
Protein binding	Spironolactone: 88% (to albumin and AGPTooltip alpha-1-acid glycoprotein equivalently); Canrenone: 99.2% (to albumin)
Metabolism	Liver (deacetylation, dethioacetylation, hydroxylation)
Metabolites	7α-TMSTooltip 7α-thiomethylspironolactone, 6β-OH-7α-TMSTooltip 6β-hydroxy-7α-thiomethylspironolactone, canrenone, others; (All three active)
Elimination half-life	Spironolactone: 1.4 hours; 7α-TMSTooltip 7α-thiomethylspironolactone: 13.8 hours; 6β-OH-7α-TMSTooltip 6β-hydroxy-7α-thiomethylspironolactone: 15.0 hours; Canrenone: 16.5 hours
Excretion	Urine, bile
Identifiers
	IUPAC name S-[(7R,8R,9S,10R,13S,14S,17R)-10,13-Dimethyl-3,5'-dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-17,2'-oxolane]-7-yl] ethanethioate;
CAS Number	52-01-7 ;
PubChem CID	5833;
IUPHAR/BPS	2875;
DrugBank	DB00421 ;
ChemSpider	5628 ;
UNII	27O7W4T232;
KEGG	D00443 ;
ChEBI	CHEBI:9241 ;
ChEMBL	ChEMBL1393 ;
CompTox Dashboard (EPA)	DTXSID6034186 ;
ECHA InfoCard	100.000.122
Chemical and physical data
Formula	C24H32O4S
Molar mass	416.574 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C5O[C@@]4([C@@]3([C@H]([C@@H]2[C@H](SC(=O)C)C/C1=C/C(=O)CC[C@]1(C)[C@H]2CC3)CC4)C)CC5;
	InChI InChI=1S/C24H32O4S/c1-14(25)29-19-13-15-12-16(26)4-8-22(15,2)17-5-9-23(3)18(21(17)19)6-10-24(23)11-7-20(27)28-24/h12,17-19,21H,4-11,13H2,1-3H3/t17-,18-,19+,21+,22-,23-,24+/m0/s1 ; Key:LXMSZDCAJNLERA-ZHYRCANASA-N ;
	(verify)

Browse history interactively

← Previous edit Next edit →

Content deleted Content added

VisualWikitext

Inline

Revision as of 16:51, 8 September 2017

Spironolactone, marketed under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease.^[3] It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early-onset puberty, and acne and excessive hair growth in women.^[3]^[12] It is also used for hormone therapy in transgender women.^[13] Spironolactone is taken by mouth.^[3]

Common side effects include electrolyte abnormalities, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex.^[3] In those with liver or kidney problems, extra care should be taken.^[3] Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy.^[14] It is a steroid that blocks the effects of the hormones aldosterone and testosterone and has some estrogen and progesterone-like effects.^[15]^[3] Spironolactone belongs to a class of medications known as potassium-sparing diuretics.^[3]

Spironolactone was introduced in 1959.^[16]^[17] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.^[18] It is available as a generic medication.^[3] The wholesale cost in the developing world as of 2014 is between US$0.02 and US$0.12 per day.^[19] In the United States it costs about US$0.50 per day.^[3]

Medical uses

Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis), and Conn's syndrome (primary hyperaldosteronism). On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy.

Spironolactone directly blocks androgen signaling and also acts as an inhibitor of androgen production. Due to the antiandrogenic effects that result from these actions, it is frequently used off-label to treat a variety of dermatological conditions in which androgens, such as testosterone and dihydrotestosterone (DHT), play a role. Some of these uses include androgenic alopecia in men (either at low doses or as a topical formulation) and women, and hirsutism (excessive hair growth), acne, and seborrhea in women.^[20] Spironolactone is the most commonly used drug in the treatment of hirsutism in the United States.^[21] Higher doses of spironolactone are not recommended in males due to the high risk of feminization and other side effects. Similarly, it is also commonly used to treat symptoms of hyperandrogenism in polycystic ovary syndrome.^[22]

High blood pressure

About one person in one hundred with hypertension has elevated levels of aldosterone; in these people, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives since it targets the primary cause of the elevated blood pressure. However, a Cochrane review found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure.^[23] There is no evidence of person-oriented outcome at any dose in this group.^[23]

Heart failure

While loop diuretics remain first-line for most people with heart failure, spironolactone has shown to reduce both morbidity and mortality in numerous studies and remains an important agent for treating fluid retention, edema, and symptoms of heart failure. Current recommendations from the American Heart Association are to use spironolactone in patients with NYHA Class II-IV heart failure who have a left ventricular ejection fraction of <35%.^[24]

In a randomized evaluation which studied people with severe congestive heart failure, people treated with spironolactone were found to have a relative risk of death of 0.70 or an overall 30% relative risk reduction compared to the placebo group, indicating a significant death and morbidity benefit of the drug. Patients in the study's intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently.^[25] Likewise, it has shown benefit for and is recommended in patients who recently suffered a heart attack and have an ejection fraction less than 40%, who develop symptoms consistent with heart failure, or have a history of diabetes mellitus. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on ACE inhibitors and beta-blockers.^[24] Of note, a recent randomized, double-blinded study of spironolactone in patients with symptomatic heart failure with "preserved" ejection fraction (i.e. >45%) found no reduction in death from cardiovascular events, aborted cardiac arrest, or hospitalizations when spironolactone was compared to placebo.^[26]

It is recommended that alternatives to spironolactone be considered if serum creatinine is >2.5 mg/dL (221µmol/L) in males or >2 mg/dL (176.8 µmol/L) in females, if glomerular filtration rate is below 30mL/min or with a serum potassium of >5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of renal function as well.^[24]

According to systematic review, in heart failure with preserved ejection fraction, treatment with spironolactone did not improve patient outcomes. This is based on the TOPCAT Trial examining this issue, which found that of those treated with placebo had a 20.4% incidence of negative outcome vs 18.6% incidence of negative outcome with spironolactone. However, because the p-value of the study was 0.14, and the unadjusted hazard ratio was 0.89 with a 95% confidence interval of 0.77 to 1.04, it is determined the finding had no statistical significance. Hence the finding that patient outcomes are not improved with use of spironolactone.^[27] More recently, when blood samples from 366 patients in the TOPCAT study were analyzed for presence of canrenone (an active metabolite of spironolactone), 30% of blood samples from Russia lacked detectable residues of canrenone. This led to the conclusion that the TOPCAT trial results in Russia don't reflect actual clinical experience with spironolactone in patients with preserved ejection fraction.^[28] The TOPCAT study results are now considered to have been invalidated. The study's prime investigator and other prominent research cardiologists are now advising physicians treating heart failure with preserved ejection fraction to consider prescribing spironolactone pending outcome of two multicenter trials of newer medications.^[29]

Due to its antiandrogen properties, spironolactone can cause effects associated with low androgen levels and hypogonadism in males. For this reason, men are typically not prescribed spironolactone for any longer than a short period of time, e.g., for an acute exacerbation of heart failure. A newer drug, eplerenone, has been approved by the U.S. Food and Drug Administration for the treatment of heart failure, and lacks the antiandrogen effects of spironolactone. As such, it is far more suitable for men for whom long-term medication is being chosen. However, eplerenone may not be as effective as spironolactone or the related drug canrenone in reducing mortality from heart failure.^[30]

The clinical benefits of spironolactone as a diuretic are typically not seen until 2–3 days after dosing begins. Likewise, the maximal antihypertensive effect may not be seen for 2–3 weeks.

Unlike with some other diuretics, potassium supplementation should not be administered while taking spironolactone, as this may cause dangerous elevations in serum potassium levels resulting in hyperkalemia and potentially deadly abnormal heart rhythms.

Skin and hair conditions

Androgens like testosterone and DHT play a critical role in the pathogenesis of a number of dermatological conditions including acne, seborrhea, hirsutism (excessive facial/body hair growth in women), and pattern hair loss (androgenic alopecia).^[31] In demonstration of this, women with complete androgen insensitivity syndrome (CAIS) do not produce sebum or develop acne and have little to no body, pubic, or axillary hair.^[32]^[33] Moreover, men with congenital 5α-reductase type II deficiency 5α-reductase being an enzyme that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty facial hair, reduced body hair, and reportedly no incidence of male pattern hair loss.^[34]^[35]^[36]^[37]^[38] Conversely, hyperandrogenism in women, for instance due to polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH), is commonly associated with acne and hirsutism as well as virilization (masculinization) in general.^[31] In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.^[39]^[40]

Because of the antiandrogen activity of spironolactone, it can be quite effective in treating acne in women,^[41] and also reduces oil that is naturally produced in the skin.^[42]^[43] Though not the primary intended purpose of the medication, the ability of spironolactone to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful.^[42]^[43] Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill.^[42]^[43] Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months.^[42]^[43] Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication.^[44] Spironolactone can be used in the treatment of female pattern hair loss (FPHL).^[45] There is tentative low quality evidence supporting its use for this indication.^[46] Although apparently effective, it should be noted that not all cases of FHPL are dependent on androgens.^[47]

Antiandrogens like spironolactone are male-specific teratogens which can feminize male fetuses due to their antiandrogen effects (see below).^[39]^[48]^[49] For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception.^[39]^[48]^[49] Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose.^[39] Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.^[39]^[50]

Spironolactone is not generally used in men for the treatment of androgen-dependent dermatological conditions because of its feminizing side effects, but it is effective for such indications in men similarly.^[45] This is evidenced by the usefulness of spironolactone as an antiandrogen in transgender women.^[51]^[52]^[53]

Transgender hormone therapy

Spironolactone is frequently used as a component of hormone replacement therapy in transgender women, especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen.^[51]^[52]^[53] Spironolactone significantly depresses plasma testosterone levels, reducing them to female/castrate levels at sufficient doses and in combination with estrogen. The clinical response consists of, among other effects, decreased male pattern body hair, the induction of breast development, feminization in general, and lack of spontaneous erections.^[53]

Comparison with other antiandrogens

There are few available options for antiandrogen therapy. Spironolactone, cyproterone acetate, and flutamide are some of the most well-known and widely used drugs.^[54] Compared to cyproterone acetate, spironolactone is considerably less potent as an antiandrogen by weight and binding affinity.^[55]^[56] However, despite this, at the doses of which they are typically used, spironolactone and cyproterone acetate have been found to be generally about equivalent in terms of effectiveness for a variety of androgen-related conditions,^[57] though, cyproterone acetate has shown a slight though non-statistically-significant advantage in some studies.^[58]^[59] Also, it has been suggested that cyproterone acetate could be more effective in cases where androgen levels are more pronounced, though this has not been proven.^[57]

Flutamide, another frequently used antiandrogen which is nonsteroidal and a pure androgen blocker, though much less potent by weight and binding affinity than either spironolactone or cyproterone acetate,^[60]^[61] has been found to be more effective than either of them as an antiandrogen when it is used at the typical treatment doses.^[55]^[62]^[63] Unfortunately, the uses of both cyproterone acetate and flutamide have been associated with hepatotoxicity, which can be severe with flutamide and has resulted in cyproterone acetate never being approved in the United States. Bicalutamide is a more potent, safer, and more tolerable alternative to flutamide, but is relatively little-studied in the treatment of androgen-dependent conditions aside from prostate cancer, though it has been used to treat hirsutism with success. Gonadotropin-releasing hormone (GnRH) analogues are another very effective option for antiandrogen therapy, but have not been widely employed for this purpose due to their high cost and limited insurance coverage despite many now being available as generics.^[52] As such, spironolactone may be the only practical, safe, available, and well-supported antiandrogen option in some cases.

In a study of the predictive markers for transgender women requesting breast augmentation, there was a significantly higher rate of those treated with spironolactone requesting breast augmentation compared to other antiandrogens such as cyproterone acetate or GnRH analogues, which was interpreted by the study authors as being potentially indicative that spironolactone may result in poorer breast development in comparison.^[64] This may be related to the fact that spironolactone has been regarded as a comparatively weak antiandrogen relative to other options.^[65]

Available forms

Spironolactone is usually used in the form of oral tablets.^[66]^[67]^[68] The drug has also been marketed in the form of 2% and 5% topical cream in Italy for the treatment of acne and hirsutism under the brand name Spiroderm, although this product is no longer available.^[69]^[4] Spironolactone has poor water solubility, and for this reason, only oral and topical formulations have been developed and other routes of administration such as intravenous injection are not employed.^[6]

Contraindications

Contraindications of spironolactone include renal disease and hyperkalemia (high levels of potassium), among others.^{[citation needed]}

Side effects

The most common side effect of spironolactone is urinary frequency. Other general side effects include dehydration, hyponatremia (low sodium levels), mild hypotension (low blood pressure),^[70] ataxia (muscle incoordination), drowsiness, dizziness,^[70] dry skin, and rashes. Because it reduces androgen levels and directly blocks androgen signaling, spironolactone can, in men, cause breast tenderness, gynecomastia (breast development), and feminization in general, as well as testicular atrophy, reversibly reduced fertility, and sexual dysfunction including loss of libido and erectile dysfunction.^[71] In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement.^[20]^[72]

The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening. Hyperkalemia in these patients can present as a non anion-gap metabolic acidosis. Spironolactone may put patients at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis. In addition, there has been some evidence suggesting an association between use of the drug and bleeding from the stomach and duodenum, though a causal relationship between the two has not been established.^[73] Also, spironolactone has been shown to be immunosuppressive in the treatment of sarcoidosis.^[74]

Hyperkalemia

Spironolactone can cause hyperkalemia, which can, rarely, be fatal.^[75] Of those prescribed typical doses, 10% to 15% developed hyperkalemia,^[75] and in 6%, it was severe.^[75] An increase in the rates of hospitalization (from 0.2% to 11%) and death (from 0.3 per 1,000 to 2.0 per 1,000) due to hyperkalemia from 1994 to 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone following the publication of the RALES study.^[75] The risk of hyperkalemia with spironolactone treatment is greatest in the elderly, in people with renal impairment, and in people simultaneously taking potassium supplements or ACE inhibitors.^[75]

Although spironolactone poses an important risk of hyperkalemia in the elderly, those with renal or cardiovascular disease, or those taking drugs or supplements which increase circulating potassium levels, the rate of hyperkalemia in young women without such characteristics treated with spironolactone for dermatological conditions has been found not to differ from that of controls.^[76]^[42]^[43] This suggests that hyperkalemia is not a significant risk in such patients and that routine monitoring of circulating potassium levels is unnecessary in this population.^[76]^[42]^[43]

Breast effects

In women, spironolactone is commonly associated with breast pain and breast enlargement,^[77]^[78] "probably because of [indirect] estrogenic effects on target tissue."^[75] Breast enlargement may occur in 26% of women and is described as mild,^[70] while breast tenderness is reported to occur in up to 40% of women taking high dosages of the drug.^[79] Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men.^[80]^[81]^[82]^[77] At low dosages, the rate is only 5–10%,^[82] but at high dosages, up to or exceeding 50% of men may develop gynecomastia.^[81]^[80]^[77] The severity of the gynecomastia varies considerably, but is usually mild.^[80] As with women, gynecomastia associated with spironolactone is commonly although inconsistently accompanied by breast tenderness.^[80] Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the drug.^[80]

Menstrual disturbances

In women, menstrual disturbances are common during spironolactone treatment, with 10 to 50% of women experiencing them at moderate doses and almost all experiencing them at a high doses.^[70]^[75] Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation.^[75] Spironolactone produces an irregular, anovulatory pattern of menstrual cycles.^[70] It is also associated with metrorrhagia and menorrhagia (or menometrorrhagia) in a large percentage of women.^[78] It has no birth control effect.^[83] It has been suggested that the weak progestogenic activity of spironolactone is responsible for these effects, although this has not been established and spironolactone has been shown to possess insignificant progestogenic and antiprogestogenic activity even at high dosages in women.^[70]^[84]^[85] An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels.^[80]

The menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with an oral contraceptive.^[70]

Infertility

At high dosages, spironolactone has been associated with semen abnormalities such as decreased sperm count and motility in men.^[80]

Depression

Increased glucocorticoid activity in the body is associated with depression.^[86]^[87] As such, it is thought that there may be a risk of depression with spironolactone treatment.^[86]^[88]^[89] Some clinical research supports this notion.^[64]^[90]^[91]

Rare reactions

Spironolactone may rarely cause more severe side effects such as anaphylaxis, renal failure, hepatitis (two reported cases, neither serious),^[92] agranulocytosis, DRESS syndrome, Stevens-Johnson Syndrome or toxic epidermal necrolysis.^[93]^[94] Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported.^[75]^[82] It should also be used with caution in people with some neurological disorders, anuria, acute kidney injury, or significant impairment of renal excretory function with risk of hyperkalemia.^[95]

Spironolactone bodies

Long-term administration of spironolactone gives the histologic characteristic of spironolactone bodies in the adrenal cortex. Spironolactone bodies are eosinophilic, round, concentrically laminated cytoplasmic inclusions surrounded by clear halos in preparations stained with hematoxylin and eosin.^[96]

Pregnancy and breastfeeding

Spironolactone is considered Pregnancy Category C meaning that it is unclear if it is safe for use during pregnancy.^[3] It is able to cross the placenta.^[78] Likewise, it has been found to be present in the breast milk of lactating mothers and, while the effects of spironolactone or its metabolites have not been extensively studied in breastfeeding infants, it is generally recommended that women also not take the drug while nursing.^[95] However, only very small amounts of spironolactone and its metabolite canrenone enter breast milk, and the amount received by an infant during breastfeeding (<0.5% of the mother's dose) is considered to be insignificant.^[97]

A study found that spironolactone was not associated with teratogenicity in the offspring of rats.^[98]^[99]^[100] Because it is an antiandrogen however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses.^[98]^[99] In accordance, a subsequent study found that partial feminization of the genitalia occurred in the male offspring of rats that received doses of spironolactone that were five times higher than those normally used in humans (200 mg/kg per day).^[98]^[100] Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day).^[100]

In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.^[98]^[99]^[101]^[102] Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific birth defects.^[102] A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy; there was no feminization in the boy.^[102] In addition, spironolactone has been used at high doses to treat pregnant women with Bartter's syndrome, and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants.^[98]^[97] There are similar findings, albeit also limited, for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human abnormalities (including feminization of male fetuses) at both a low dose of 2 mg/day or high doses of 50 to 100 mg/day).^[102] In any case, spironolactone is nonetheless not recommended during pregnancy due to theoretical concerns relating to feminization of males and also to potential alteration of fetal potassium levels.^[98]^[103]

Interactions

Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this drug avoid potassium supplements and salt substitutes containing potassium.^[104] Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne.^[105]

Research has suggested that spironolactone may be able to interfere with the effectiveness of antidepressant treatment. As the drug acts as an antimineralocorticoid, it is thought that it may reduce the effectiveness of certain antidepressants by interfering with normalization of the hypothalamic–pituitary–adrenal axis and increasing glucocorticoid levels.^[106]^[107] However, other research contradicts this hypothesis and has suggested that spironolactone may actually produce antidepressant-like effects in animals.^[108]

Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications.^[95] Spironolactone together with trimethoprim/sulfamethoxazole increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.^[109]

Spironolactone has been reported to induce the enzyme CYP3A4, which can result in interactions with various drugs.^[110] However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4.^[111]

Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found in studies to inhibit the antimineralocorticoid effects of spironolactone.^[112]^[113]^[114] Moreover, the addition of licorice to spironolactone has been found to reduce the antimineralocorticoid side effects of spironolactone in women treated with the drug for hyperandrogenism, and licorice may hence be used to reduce these side effects in women treated with spironolactone as an antiandrogen who are bothered by them.^[112]^[113] On the opposite end of the spectrum, spironolactone is clinically useful in reversing licorice-induced hypokalemia.^[115]^[116]

Aspirin and other nonsteroidal anti-inflammatory drugs have been found to attenuate the diuresis and natriuresis induced by spironolactone therapy but not to affect its antihypertensive effect.^[117]^[118]

Pharmacology

Binding profiles of spironolactone and eplerenone
^[119]	Spironolactone	Eplerenone
hMR (IC₅₀)	2 nM	81 nM
hAR (IC₅₀)	13 nM	4827 nM
hPR (EC₅₀)	2619 nM	>100 μM
hGR (IC₅₀)	2899 nM	>100 μM
hMR (IC₅₀): 50% inhibition of activation by 0.5 nM aldosterone hAR (IC₅₀): 50% inhibition of activation by 10 nM dihydrotestosterone hPR (EC₅₀): 50% activation compared to 5 nM progesterone hGR (IC₅₀): 50% inhibition of activation by 5 nM dexamethasone

Spironolactone is known to possess the following biological activity:^[120]

Mineralocorticoid receptor (MR) antagonist
Androgen receptor (AR) antagonist/very weak partial agonist
Estrogen receptor (ER) mixed agonist/antagonist^[121]^[122]
Progesterone receptor (PR) agonist
Glucocorticoid receptor (GR) antagonist
Pregnane X receptor (PXR) agonist (and thus CYP3A4^[123] and P-glycoprotein inducer)^[124]^[125]^[126]
Steroid 11β-hydroxylase, aldosterone synthase, and 17α-hydroxylase/17,20-lyase inhibitor

There is also evidence that spironolactone may block voltage-dependent Ca²⁺ channels.^[127]^[128]

Although spironolactone is known to possess the above activities, it should be noted that the drug is a prodrug, with active metabolites such as 7α-thiomethylspironolactone (7α-TMS) and canrenone being responsible for its clinical effects. For this reason, the actual in vivo clinical profile of spironolactone may differ from the activities and effective and inhibitory concentrations described above and to the right. In any case, interaction with both the MR and AR have been observed for metabolites of spironolactone.^[129]^[130] On the other hand, spironolactone itself has only very low affinity for the ER, suggesting that its metabolites may be responsible for this activity.^[121]^[122]

Antimineralocorticoid activity

Spironolactone inhibits the effects of mineralocorticoids, namely, aldosterone, by displacing them from MR in the cortical collecting duct of renal nephrons. This decreases the reabsorption of sodium and water while limiting the excretion of potassium (A K+ sparing diuretic). The drug has a slightly delayed onset of action, and so it takes several days for diuresis to occur. This is because the MR is a nuclear receptor which works through regulating gene transcription and gene expression, in this case, to decrease the production and expression of ENaC and ROMK electrolyte channels in the distal nephrons. In addition to direct antagonism of the MRs, the antimineralocorticoid effects of spironolactone may also in part be mediated by direct inactivation of steroid 11β-hydroxylase and aldosterone synthase (18-hydroxylase), enzymes involved in the biosynthesis of mineralocorticoids. If levels of mineralocorticoids are decreased then there are lower circulating levels to compete with spironolactone to influence gene expression as mentioned above.^[131] The onset of action of the antimineralocorticoid effects of spironolactone is relatively slow, with the peak effect sometimes occurring 48 hours or more after the first dose.^[6]^[7]

Antiandrogenic activity

Spironolactone is a potent and direct antagonist of the AR, blocking androgens like testosterone from binding to and activating the receptor.^[132]^[80] The AR antagonism of spironolactone mostly underlies its antiandrogen activity and is responsible for its therapeutic benefits in the treatment of androgen-dependent conditions like acne, hirsutism, and pattern hair loss and its usefulness in hormone therapy for transgender women.^[132] In addition, the AR antagonism of spironolactone is involved in its feminizing side effects like gynecomastia in men.^[132]

Spironolactone, similarly to other steroidal antiandrogens such as cyproterone acetate, is actually not a pure, or silent, antagonist of the AR, but rather is a weak partial agonist with the capacity for both antagonistic and agonistic effects.^[133]^[134]^[135] However, in the presence of sufficiently high levels of potent full agonists like testosterone and DHT (the cases in which spironolactone is usually used even with regards to the "lower" relative levels present in females),^[135] spironolactone will behave more similarly to a pure antagonist. Nonetheless, there may still be a potential for spironolactone to produce androgenic effects in the body at sufficiently high dosages and/or in those with very low endogenous androgen concentrations. As an example, one condition in which spironolactone is contraindicated is prostate cancer in men being treated with androgen deprivation therapy,^[136] as spironolactone has been shown in vitro to significantly accelerate carcinoma growth in the absence of any other androgens.^[133] In accordance, two case reports have described significant worsening of prostate cancer with spironolactone treatment in patients with the disease, leading the authors to conclude that spironolactone has the potential for androgenic effects in some contexts and that it should perhaps be considered to be a selective androgen receptor modulator (SARM), albeit with mostly antagonistic effects.^[137]^[138]

Estrogenic activity

Spironolactone has been found to directly interact with the ER.^[121] Although a study found that spironolactone did not interact with the human ER at the concentration range tested,^[139] a subsequent study found that the drug did interact with the human ER at higher concentrations, albeit with very low (micromolar) affinity (inhibition constant = 2 × 10⁻⁵).^[121] In the same study, spironolactone was administered to rats and found to produce mixed estrogenic and antiestrogenic or selective estrogen receptor modulator (SERM)-like effects that were described as very similar to those of tamoxifen.^[121] In spite of the fact that tamoxifen had three orders of magnitude higher affinity for the ER than did spironolactone, the two drugs showed similar potency in vivo.^[121] It has been said that the likelihood of spironolactone interacting with the ER itself is remote in consideration of its very low affinity for the receptor in vitro.^[122] However, metabolism of spironolactone may result in metabolites with greater ER affinity, which could thus account for the activity.^[121]^[122]

The authors of the study concluded that direct interaction of spironolactone (and/or its metabolites) with the ER could be involved in the gynecomastia, feminization, and effects on gonadotropin levels that the drug is associated with.^[121] Subsequently, it has also been suggested that, as a SERM-like drug, ER agonistic activity of spironolactone in the pituitary gland could be responsible for its antigonadotropic effects while ER antagonstic activity of spironolactone in the endometrium could be responsible for the menstrual disturbances that are associated with it.^[122] Such actions might explain these effects of spironolactone in light of the finding that it is not significantly progestogenic or antiprogestogenic in women even at high dosages.^[122]^[84]^[85]

In accordance, a study found that in women treated with a GnRH analogue, spironolactone therapy almost completely prevented the bone loss that is associated with these drugs, whereas treatment with the selective AR antagonist flutamide had no such effect.^[140]^[141] Other studies have also found an inverse relationship between spironolactone and decreased bone mineral density and bone fractures in men.^[142]^[143] Estrogens are well known for maintaining and having positive effects on bone, and it has been suggested that the estrogenic activity of spironolactone may be involved in its positive effects on bone mineral density.^[140]^[141]^[144] However, it should also be noted that high levels of aldosterone have been associated with adverse bone changes, and so the antimineralocorticoid activity of spironolactone might partially or fully be responsible for these effects as a potential alternative explanation.^[143]

In addition to direct interaction with the ER, spironolactone also has some indirect estrogenic activity, which it mediates via several actions, including:

By acting as an antiandrogen, as androgens can suppress both estrogen production and signaling (e.g., in the breasts).^[80]^[145]
Inhibition of the conversion of estradiol to estrone, resulting in an increase in the ratio of circulating estradiol to estrone.^[146] Estradiol is far more potent than estrone as an estrogen, which is comparatively almost inactive.^[147]^[148]
Enhancement of the rate of peripheral conversion of testosterone into estradiol, thus decreasing the ratio of circulating testosterone to estradiol.^[149]

Spironolactone has been found to act as a reversible inhibitor of human 17β-hydroxysteroid dehydrogenase 2 (17β-HSD2), albeit with weak potency (K_i = 0.25–2.4 μM; IC₅₀ = 0.27–1.1 μM).^[150]^[151]^[152]^[153] C7α thioalkyl derivatives of spironolactone like the 7α-thioethyl analogue were found to inhibit the enzyme with greater potency, suggesting that the actual active metabolites of spironolactone like 7α-TMS might be more potent inhibitors.^[150]^[153] 17β-HSD2 is a key enzyme responsible for inactivation of estradiol into estrone in various tissues, and inhibition of 17β-HSD2 by spironolactone may be involved in the gynecomastia and altered ratio of circulating testosterone to estradiol that the drug is associated with.^[146]^[154] Spironolactone has also been associated with positive effects on bone, and it is notable that 17β-HSD2 inhibitors are under investigation as potential novel treatments for osteoporosis due to their ability to prevent estradiol inactivation in this tissue.^[155]^[156]

Other actions

Progestogenic activity

Spironolactone has weak progestogenic activity in bioassays.^[61]^[157] Its actions in this regard are a result of direct agonist activity at the PR, though with a very low half-maximal potency.^[120] Spironolactone's progestogenic activity has been suggested to be involved in some of its side effects,^[158] including the menstrual irregularities seen in women and the undesirable serum lipid profile changes that are seen at higher doses.^[60]^[159]^[160] It has also been suggested to augment the gynecomastia caused by the estrogenic effects of spironolactone,^[161] as progesterone is known to be involved in mammary gland development.^[162]

Although it has been widely stated that the menstrual irregularities associated with spironolactone are due to its progestogenic activity, and although animal studies (involving both rabbits and rhesus monkeys) have shown clear progestogenic effects,^[163] the dosages of spironolactone used in animals to produce progestogenic effects were very high, and no evidence of progestogenic nor antiprogestogenic effects (as assessed by endometrial changes) have been observed in women even with high clinical dosages of spironolactone treatment.^[84]^[85] As such, it has been stated that the progestogenic potency of spironolactone is below the level of clinical significance in humans and that the menstrual abnormalities associated with the drug must have a different cause.^[84]^[85] Other possible mechanisms of the menstrual disturbances associated with spironolactone that have been suggested include interference with the hypothalamic–pituitary–gonadal axis, inhibition of enzymatic steroidogenesis,^[80] and mixed estrogenic and antiestrogenic activity.^[84]^[85]^[122]

Antigonadotropic activity

Pure AR antagonists like flutamide and bicalutamide are potent progonadotropins with indirect estrogenic activity in males.^[164] This is because they block the AR in the pituitary gland and hypothalamus and thereby inhibit the negative feedback of androgens on the hypothalamic–pituitary–gonadal axis.^[164] This, in turn, results in increased gonadotropin secretion, activation of gonadal steroidogenesis, and an up to 2-fold increase in testosterone levels and 2.5-fold increase in estradiol levels.^[165] Conversely, AR antagonists that are also progestogens, like cyproterone acetate, are not progonadotropic, as activation of the PR is antigonadotropic, and, indeed, cyproterone acetate is potently antigonadotropic in clinical practice.^[164]

Although spironolactone is a potent AR antagonist with no significant progestogenic effects in women even at high dosages and hence is a pure-like AR antagonist, many studies have interestingly not found it to be progonadotropic in men, nor to increase testosterone or estradiol levels.^[166]^[71]^[167] Moreover, spironolactone is also said to possess very little or no antigonadotropic activity (in terms of lowering gonadotropin levels to below normal) even at high dosages,^[78]^[168] although some conflicting reports exist.^[72]^[169]^[170] Nonetheless, since spironolactone does not generally increase gonadotropin levels in spite of potent inhibition of androgen signaling, it must have some degree of antigonadotropic activity sufficient to at least keep gonadotropin levels from increasing.^[164] As estrogens are antigonadotropic similarly to progestogens, and as SERM-like activity has been described for spironolactone, the antigonadotropic effects of spironolactone may be due to estrogenic activity.^[122]

Steroidogenesis inhibition

Spironolactone is able to significantly lower testosterone levels at high dosages in spite of not acting as an antigonadotropin, and this is thought to be due to direct enzymatic inhibition of 17α-hydroxylase and 17,20-lyase, enzymes necessary for the biosynthesis of testosterone.^[171]^[172]^[173] Although spironolactone is said to be a relatively weak inhibitor of 17α-hydroxylase and 17,20-lyase,^[61] at least compared to more potent steroidogenesis inhibitors like ketoconazole and abiraterone acetate (which are able to reduce testosterone concentrations to castrate levels), this action is considered to contribute a significant portion of the antiandrogen effects of spironolactone, for instance lowering testosterone levels in women with hyperandrogenism and in transgender women.^[174]^[149]^[175]

There is also mixed/conflicting evidence that spironolactone may inhibit 5α-reductase, and thus the synthesis of the potent androgen DHT from testosterone, to some extent.^[132]^[176]^[177]^[178]^[179] However, the combination of spironolactone and the potent 5α-reductase inhibitor finasteride has been found to have significant improved effectiveness in the treatment of hirsutism relative to spironolactone therapy alone, suggesting that any inhibition of 5α-reductase by spironolactone is only weak or at best incomplete.^[179]

Spironolactone has been found not to have activity as an aromatase inhibitor.^[153]^[146]

Glucocorticoid activity

Spironolactone has been shown to inhibit steroid 11β-hydroxylase, an enzyme that is essential for the production of the glucocorticoid hormone cortisol. Because of this, glucocorticoid levels might be expected to be lowered, and hence, spironolactone might have some antiglucocorticoidic effects. In clinical practice, however, this has not been found to be the case; spironolactone has actually been found to increase cortisol levels, both with acute and chronic administration. Research has shown that this is due to antagonism of the MR, which suppresses negative feedback on the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis positively regulates the secretion of adrenocorticotropic hormone (ACTH), which in turn signals the adrenal glands, the major source of corticosteroid biosynthesis in the body, to increase production of both mineralocorticoids and glucocorticoids. Therefore, by antagonizing the MR, spironolactone causes an increase in ACTH secretion and by extension an indirect rise in cortisol levels.^[180]^[181] As such, any anti-glucocorticoid activity of spironolactone via direct suppression of glucocorticoid synthesis (at the level of the adrenals) appears to be more than fully offset by its concurrent indirect stimulatory effects on glucocorticoid production.

At the same time, spironolactone weakly binds to and acts as an antagonist of the GR, showing antiglucocorticoid properties, but to a significant degree only at very high concentrations that are probably not clinically relevant.^[120]^[182]^[183]

Pharmacokinetics

Absorption

The bioavailability when taken by mouth of spironolactone is 60 to 90%.^[6]^[7]^[8] The bioavailability of the drug improves significantly when it is taken with food.^[184]^[185] Steady-state concentrations of spironolactone are achieved within 8 days of treatment initiation.^[186]

Distribution

Spironolactone and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively.^[6]^[9] Spironolactone is bound equivalently to albumin and α₁-acid glycoprotein, while canrenone is bound only to albumin.^[6]^[9] Spironolactone and its metabolite 7α-thiospironolactone show very low or negligible affinity for sex hormone-binding globulin (SHBG).^[187]^[139] In accordance, a study of high-dosage spironolactone treatment found no change in steroid binding capacity related to SHBG or to corticosteroid-binding globulin (CBG), suggesting that spironolactone does not displace steroid hormones from their carrier proteins.^[188] This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG.^[189]

Metabolism

Pharmacokinetics of spironolactone and metabolites^[190]
Compound	C_max (ng/mL) (day 1)	C_max (ng/mL) (day 15)	AUC (ng•hr/ml) (day 15)	t_1/2 (hr)
Spironolactone	72	80	231	1.4
Canrenone	155	181	2173	16.5
7α-TMSTooltip 7α-Thiomethylspironolactone	359	391	2804	13.8
6β-OH-7α-TMSTooltip 6β-Hydroxy-7α-thiomethylspironolactone	101	125	1727	15.0

Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a short terminal half-life of 1.4 hours.^[6]^[7] The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ⁶-spironolactone),^[6]^[7]^[129] and these metabolites have much longer half-lives in comparison (13.8 hours, 15.0 hours, and 16.5 hours, respectively).^[6]^[7] These metabolites are responsible for the therapeutic effects of spironolactone,^[6]^[7] and for this reason, spironolactone is a prodrug.^[191] Until fairly recently, the 7α-thiomethylated metabolites of spironolactone had not been identified and it was thought that canrenone was the major active metabolite.^[6]^[186]^[129] However, they have since been characterized and 7α-TMS has been identified as the major metabolite of spironolactone.^[190]

It has been determined that 7α-TMS accounts for around 80% of the potassium-sparing effect of spironolactone^[6]^[186]^[129] while canrenone only accounts for the remaining approximate 10 to 25%.^[192] In accordance, 7α-TMS occurs at higher circulating concentrations than does canrenone and has a higher relative affinity for the MR.^[129] Other known but more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.^[10] In addition to the MR, 7α-TS and 7α-TMS have been found to possess approximately equivalent affinity for the rat prostate AR relative to that of spironolactone, thus likely accounting for the retention of the antiandrogenic activity of spironolactone.^[130]

Canrenone is an antagonist of the MR similarly to spironolactone,^[2] but is slightly more potent in comparison.^[7]^[193] In addition, canrenone inhibits steroidogenic enzymes such as 11β-hydroxylase, cholesterol side-chain cleavage enzyme, 17α-hydroxylase, and 21-hydroxylase similarly to spironolactone, but once again is more potent in doing so in comparison.^[194] In vitro, canrenone binds to and blocks the AR.^[80] However, relative to spironolactone, canrenone is described as having very weak affinity to the AR.^[65] In accordance, replacement of spironolactone with canrenone in male patients has been found to reverse spironolactone-induced gynecomastia, suggesting that canrenone is comparatively much less potent in vivo as an antiandrogen.^[80] As such, based on the above, the antiandrogen effects of spironolactone are considered to be largely due to other metabolites rather than due to canrenone.^[80]^[195]^[196]

Spironolactone is not metabolized by CYP3A4, unlike the related drug eplerenone.^[197]

Elimination

The majority of spironolactone is eliminated by the kidneys, while minimal amounts are handled by biliary excretion.^[198]

Chemistry

Spironolactone, also known as 7α-acetylthiospirolactone, is a steroidal 17α-spirolactone, or more simply a spirolactone.^[199] It can most appropriately be conceptualized as a derivative of progesterone (itself also a potent antimineralocorticoid) in which a hydroxyl group has been substituted at the C17α position (as in 17α-hydroxyprogesterone), the acetyl group at the C17β position has been cyclized with the C17α hydroxyl group to form a spiro 21-carboxylic acid γ-lactone ring, and an acetylthio group has been substituted at the C7α position.^[200]^[201]^[202] These structural modifications of progesterone confer increased oral bioavailability and potency,^[203] potent antiandrogenic activity, and greatly reduced progestogenic activity. The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as 7α-thioprogesterone (SC-8365) is a potent antiandrogen with similar affinity to the AR as that of spironolactone.^[130]

Chemical names

Spironolactone is also known by the following equivalent chemical names:^[200]^[201]^[202]

7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone
3-(3-Oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17α-yl)propionic acid lactone
7α-Acetylthio-17α-(2-carboxyethyl)androst-4-en-17β-ol-3-one γ-lactone
7α-Acetylthio-17α-(2-carboxyethyl)testosterone γ-lactone

Analogues

Spironolactone is closely structurally related to other clinically used spirolactones such as canrenone, potassium canrenoate, drospirenone, and eplerenone, as well as to the never-marketed spirolactones SC-5233 (6,7-dihydrocanrenone; 7α-desthioacetylspironolactone), SC-8109 (19-nor-6,7-dihydrocanrenone), spiroxasone, prorenone (SC-23133), mexrenone (SC-25152, ZK-32055), dicirenone (SC-26304), spirorenone (ZK-35973), and mespirenone (ZK-94679).^[199]

History

Spironolactone was first synthesized in 1957,^[161] was patented between 1958 and 1961,^[204]^[205] and was first marketed, as an antimineralocorticoid, in 1959.^[206]^[207] The AR antagonistic (i.e., antiandrogen) activity of spironolactone was first discovered and reported in 1969,^[208] which shortly followed the discovery in 1968 that gynecomastia, a frequent and by that time well-established side effect of spironolactone, is an important and major side effect of AR antagonists.^[209] The drug started to be used as an antiandrogen, for instance in the treatment of hirsutism in women, by the late 1970s and early 1980s,^[210]^[211]^[212]^[112] and has since become the most widely used antiandrogen for dermatological indications in the United States.^[213]^[68]^[214]^[215]

Society and culture

Generic name

The English, French, and generic name of spironolactone is spironolactone (pronounced as /ˌspaɪrənoʊˈlæktoʊn/ SPYE-rə-noh-LAK-tohn^[1] or as /ˌspɪərənoʊˈlæktoʊn/ SPEER-ə-noh-LAK-tohn^[2] according to different sources) and this is its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip Japanese Accepted Name.^[200]^[216]^[69]^[217] Its name is spironolactonum in Latin, spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also its DCITTooltip Denominazione Comune Italiana).^[216]^[69]^[217]

Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.^[200]^[216]^[69]

Brand names

Spironolactone is marketed under a large number of brand names throughout the world.^[216]^[69] The major brand name of spironolactone is Aldactone.^[216]^[69] Other important brand names include Aldactone-A, Berlactone, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone (veterinary), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued),^[4] Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis, Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (veterinary), Uractone, Uractonum, Verospiron, and Vivitar.^[216]^[69]

Spironolactone is also formulated in combination with a variety of other drugs, including with hydrochlorothiazide as Aldactazide, with hydroflumethiazide as Aldactide, Lasilacton, Lasilactone, and Spiromide, with altizide as Aldactacine and Aldactazine, with furosemide as Fruselac, with benazepril as Cardalis (veterinary), with metolazone as Metolactone, with bendroflumethiazide as Sali-Aldopur, and with torasemide as Dytor Plus, Torlactone, and Zator Plus.^[216]

Availability

Spironolactone is marketed widely throughout the world and is available in almost every country, including in the United States, Canada, the United Kingdom, other European countries, Australia, New Zealand, South Africa, Central and South America, and East and Southeast Asia.^[216]^[69]

Research

Benign prostatic hyperplasia

Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia.^[218]^[219]^[220] It was found to be better than placebo in terms of symptom relief following three months of treatment.^[218]^[219] However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared.^[218]^[219]^[220] Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size.^[218]^[219] Gynecomastia was observed in about 5% of people.^[219] On the basis of these results, it has been said that spironolactone has no place in the treatment of benign prostatic hyperplasia.^[219]

Fibromyalgia

Spironolactone has been assessed in a study for the treatment of fibromyalgia in women.^[221]^[222]

Epstein–Barr virus

Spironolactone has been found to block Epstein–Barr virus (EBV) production and that of other human herpesviruses by inhibiting the function of an EBV protein SM, which is essential for infectious virus production.^[223] This effect of spironolactone was determined to be independent of its antimineralocorticoid actions.^[223] Thus, spironolactone or compounds based on it have the potential to yield novel antiviral drugs with a distinct mechanism of action and limited toxicity.^[223]

References

^ ^a ^b Kevin R. Loughlin; Joyce A. Generali (2006). The Guide to Off-label Prescription Drugs: New Uses for FDA-approved Prescription Drugs. Simon and Schuster. pp. 131–. ISBN 978-0-7432-8667-1.
^ ^a ^b ^c Michelle A. Clark; Richard A. Harvey; Richard Finkel; Jose A. Rey; Karen Whalen (15 December 2011). Pharmacology. Lippincott Williams & Wilkins. pp. 286, 337. ISBN 978-1-4511-1314-3.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k "Spironolactone". The American Society of Health-System Pharmacists. Archived from the original on 2015-11-16. Retrieved Oct 24, 2015. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b ^c NADIR R. FARID; Evanthia Diamanti-Kandarakis (27 February 2009). Diagnosis and Management of Polycystic Ovary Syndrome. Springer Science & Business Media. pp. 235–. ISBN 978-0-387-09718-3.
^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r Sica, Domenic A. (2005). "Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis". Heart Failure Reviews. 10 (1): 23–29. doi:10.1007/s10741-005-2345-1. ISSN 1382-4147.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Maron BA, Leopold JA (2008). "Mineralocorticoid receptor antagonists and endothelial function". Curr Opin Investig Drugs. 9 (9): 963–9. PMC 2967484. PMID 18729003.
^ ^a ^b Carone, Laura; Oxberry, Stephen G.; Twycross, Robert; Charlesworth, Sarah; Mihalyo, Mary; Wilcock, Andrew (2017). "Spironolactone". Journal of Pain and Symptom Management. 53 (2): 288–292. doi:10.1016/j.jpainsymman.2016.12.320. ISSN 0885-3924.
^ ^a ^b ^c ^d Takamura, Norito; Maruyama, Toru; Ahmed, Shamim; Suenaga, Ayaka; Otagiri, Masaki (1997). "Interactions of Aldosterone Antagonist Diuretics with Human Serum Proteins". Pharmaceutical Research. 14 (4): 522–526. doi:10.1023/A:1012168020545. ISSN 0724-8741.
^ ^a ^b Gyorgy Szasz; Zsuzsanna Budvari-Barany (19 December 1990). Pharmaceutical Chemistry of Antihypertensive Agents. CRC Press. pp. 91–. ISBN 978-0-8493-4724-5.
^ Theresa A. McDonagh; Roy S. Gardner; Andrew L. Clark; Henry Dargie (14 July 2011). Oxford Textbook of Heart Failure. OUP Oxford. pp. 403–. ISBN 978-0-19-957772-9. Archived from the original on 27 March 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Friedman, Adam J. (1 October 2015). "Spironolactone for Adult Female Acne". Cutis. 96 (4): 216–217. ISSN 2326-6929. PMID 27141564.
^ Maizes, Victoria (2015). Integrative Women's Health (2 ed.). p. 746. ISBN 9780190214807. Archived from the original on 2016-03-05. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ "Spironolactone Pregnancy and Breastfeeding Warnings". Archived from the original on 2 December 2015. Retrieved 29 November 2015. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Prakash C Deedwania (30 January 2014). Drug & Device Selection in Heart Failure. JP Medical Ltd. pp. 47–. ISBN 978-93-5090-723-8.
^ Camille Georges Wermuth (24 July 2008). The Practice of Medicinal Chemistry. Academic Press. p. 34. ISBN 978-0-12-374194-3. Archived from the original on 21 June 2013. Retrieved 27 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Marshall Sittig (1988). Pharmaceutical Manufacturing Encyclopedia. William Andrew. p. 1385. ISBN 978-0-8155-1144-1. Archived from the original on 20 June 2013. Retrieved 27 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived from the original (PDF) on 13 December 2016. Retrieved 8 December 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ "Spironolactone". International Drug Price Indicator Guide. Retrieved 29 November 2015.
^ ^a ^b Hughes BR, Cunliffe WJ (May 1988). "Tolerance of spironolactone". The British Journal of Dermatology. 118 (5): 687–91. doi:10.1111/j.1365-2133.1988.tb02571.x. PMID 2969259.
^ Victor R. Preedy (1 January 2012). Handbook of Hair in Health and Disease. Springer Science & Business Media. pp. 132–. ISBN 978-90-8686-728-8.
^ Loy R, Seibel MM (December 1988). "Evaluation and therapy of polycystic ovarian syndrome". Endocrinology and Metabolism Clinics of North America. 17 (4): 785–813. PMID 3143568.
^ ^a ^b Batterink, J; Stabler, SN; Tejani, AM; Fowkes, CT (4 August 2010). "Spironolactone for hypertension". The Cochrane database of systematic reviews (8): CD008169. doi:10.1002/14651858.CD008169.pub2. PMID 20687095.
^ ^a ^b ^c Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL, American College of Cardiology, Foundation; American Heart Association Task Force on Practice, Guidelines (Oct 15, 2013). "2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Journal of the American College of Cardiology. 62 (16): e147–239. doi:10.1016/j.jacc.2013.05.019. PMID 23747642.
^ Pitt B, Zannad F, Remme W, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (1999). "The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators". N Engl J Med. 341 (10): 709–17. doi:10.1056/NEJM199909023411001. PMID 10471456. Archived from the original on 2006-08-10. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM (Apr 10, 2014). "Spironolactone for heart failure with preserved ejection fraction". The New England Journal of Medicine. 370 (15): 1383–92. doi:10.1056/nejmoa1313731. PMID 24716680.
^ Pitt B.; et al. (2014). "Spironolactone for Heart Failure with Preserved Ejection Fraction". N Engl J Med. 370 (15): 1383–1392. doi:10.1056/NEJMoa1313731. PMID 24716680. {{cite journal}}: Explicit use of et al. in: |author= (help)
^ Pfeffer, Marc; de Denus, Simon; Desai, Akshay; Leclair, Gregoire; Pitt, Bertram; Solomon, Scott; Lavoie, Joel; Rouleau, Jean; O'Meara, Eileen (2017). ""Spironolactone Metabolites in TOPCAT — New Insights into Regional Variation"". N Engl J Med. 376 (17): 1690–1692. doi:10.1056/NEJMc1612601.
^ Husten, Larry (Apr 27, 2017) [2017]. ""Serious Questions Raised About Integrity Of International Trials"". CardioBrief.org.{{cite web}}: CS1 maint: date and year (link)
^ Chatterjee S, Moeller C, Shah N, Bolorunduro O, Lichstein E, Moskovits N, Mukherjee D (2012). "Eplerenone is not superior to older and less expensive aldosterone antagonists". Am. J. Med. 125 (8): 817–25. doi:10.1016/j.amjmed.2011.12.018. PMID 22840667.
^ ^a ^b Zouboulis CC, Degitz K (2004). "Androgen action on human skin -- from basic research to clinical significance". Exp. Dermatol. 13 Suppl 4: 5–10. doi:10.1111/j.1600-0625.2004.00255.x. PMID 15507105.
^ Alan R. Shalita; James Q. Del Rosso; Guy Webster (21 March 2011). Acne Vulgaris. CRC Press. pp. 33–. ISBN 978-1-61631-009-7. Archived from the original on 9 December 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Christos C. Zouboulis; Andreas D. Katsambas; Albert M. Kligman (28 July 2014). Pathogenesis and Treatment of Acne and Rosacea. Springer. pp. 121–. ISBN 978-3-540-69375-8. Archived from the original on 10 December 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Marks LS (2004). "5alpha-reductase: history and clinical importance". Rev Urol. 6 Suppl 9: S11–21. PMC 1472916. PMID 16985920.
^ Ethel Sloane (2002). Biology of Women. Cengage Learning. pp. 160–. ISBN 0-7668-1142-5.
^ Philip M Hanno; Thomas J. Guzzo; S. Bruce Malkowicz; Alan J. Wein (26 January 2014). Penn Clinical Manual of Urology E-Book: Expert Consult - Online. Elsevier Health Sciences. pp. 782–. ISBN 978-0-323-24466-4.
^ Catherine Harper (1 August 2007). Intersex. Berg. pp. 123–. ISBN 978-1-84788-339-1.
^ Ulrike Blume-Peytavi; David A. Whiting; Ralph M. Trüeb (26 June 2008). Hair Growth and Disorders. Springer Science & Business Media. pp. 161–162. ISBN 978-3-540-46911-7.
^ ^a ^b ^c ^d ^e Diamanti-Kandarakis E, Tolis G, Duleba AJ (1995). "Androgens and therapeutic aspects of antiandrogens in women". J. Soc. Gynecol. Investig. 2 (4): 577–92. doi:10.1177/107155769500200401. PMID 9420861.
^ Katsambas AD, Dessinioti C (2010). "Hormonal therapy for acne: why not as first line therapy? facts and controversies". Clin. Dermatol. 28 (1): 17–23. doi:10.1016/j.clindermatol.2009.03.006. PMID 20082945.
^ Kim, Grace; Del Rosso, James (March 2012). "Oral Spironolactone in Post-teenage Female Patients with Acne Vulgaris". J Clinical and Aesthetic Dermatology. 5 (3): 37–50. PMC 3315877. PMID 22468178.
^ ^a ^b ^c ^d ^e ^f Layton AM, Eady EA, Whitehouse H, Del Rosso JQ, Fedorowicz Z, van Zuuren EJ (2017). "Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review". Am J Clin Dermatol. 18 (2): 169–191. doi:10.1007/s40257-016-0245-x. PMC 5360829. PMID 28155090.
^ ^a ^b ^c ^d ^e ^f Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, Bowe WP, Graber EM, Harper JC, Kang S, Keri JE, Leyden JJ, Reynolds RV, Silverberg NB, Stein Gold LF, Tollefson MM, Weiss JS, Dolan NC, Sagan AA, Stern M, Boyer KM, Bhushan R (2016). "Guidelines of care for the management of acne vulgaris". J. Am. Acad. Dermatol. 74 (5): 945–73.e33. doi:10.1016/j.jaad.2015.12.037. PMID 26897386.
^ Somani N, Turvy D (2014). "Hirsutism: an evidence-based treatment update". Am J Clin Dermatol. 15 (3): 247–66. doi:10.1007/s40257-014-0078-4. PMID 24889738.
^ ^a ^b Rathnayake D, Sinclair R (2010). "Use of spironolactone in dermatology". Skinmed. 8 (6): 328–32, quiz 333. PMID 21413648.
^ HARFMANN, KATYA L.; BECHTEL, MARK A. (March 2015). "Hair Loss in Women". Clinical Obstetrics and Gynecology. 58 (1): 185–199. doi:10.1097/GRF.0000000000000081. PMID 25517757.
^ Cousen P, Messenger A (2010). "Female pattern hair loss in complete androgen insensitivity syndrome". Br. J. Dermatol. 162 (5): 1135–7. doi:10.1111/j.1365-2133.2010.09661.x. PMID 20128792.
^ ^a ^b Iswaran TJ, Imai M, Betton GR, Siddall RA (May 1997). "An overview of animal toxicology studies with bicalutamide (ICI 176,334)". The Journal of Toxicological Sciences. 22 (2): 75–88. doi:10.2131/jts.22.2_75. PMID 9198005.
^ ^a ^b Smith, Robert E. (4 April 2013). Medicinal Chemistry – Fusion of Traditional and Western Medicine. Bentham Science Publishers. pp. 306–. ISBN 978-1-60805-149-6. Archived from the original on 29 May 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help); Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
^ Adam Ostrzenski (2002). Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy. Lippincott Williams & Wilkins. pp. 86–. ISBN 978-0-7817-2761-7.
^ ^a ^b The World Professional Association for Transgender Health (WPATH) (2011). "Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People" (PDF). Archived from the original (PDF) on 2012-05-23. Retrieved 2012-05-27. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b ^c Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al. (September 2009). "Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline". The Journal of Clinical Endocrinology and Metabolism. 94 (9): 3132–54. doi:10.1210/jc.2009-0345. PMID 19509099.
^ ^a ^b ^c Prior JC, Vigna YM, Watson D (February 1989). "Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism". Archives of Sexual Behavior. 18 (1): 49–57. doi:10.1007/bf01579291. PMID 2540730.
^ Reismann P, Likó I, Igaz P, Patócs A, Rácz K (August 2009). "Pharmacological options for treatment of hyperandrogenic disorders". Mini Reviews in Medicinal Chemistry. 9 (9): 1113–26. doi:10.2174/138955709788922692. PMID 19689407. Archived from the original on 2013-06-17. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b Robert S. Haber; Dowling Bluford Stough (2006). Hair Transplantation. Elsevier Health Sciences. p. 6. ISBN 978-1-4160-3104-8. Archived from the original on 4 July 2014. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Peter Greaves (12 April 2012). Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation. Academic Press. p. 621. ISBN 978-0-444-53861-1. Archived from the original on 21 June 2013. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b Andrea Dunaif (19 February 2008). Polycystic Ovary Syndrome: Current Controversies, from the Ovary to the Pancreas. Humana Press. p. 301. ISBN 978-1-58829-831-7. Archived from the original on 21 June 2013. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Gökmen O, Senöz S, Gülekli B, Işik AZ (August 1996). "Comparison of four different treatment regimes in hirsutism related to polycystic ovary". Gynecological Endocrinology. 10 (4): 249–55. doi:10.3109/09513599609012316. PMID 8908525.
^ O'Brien RC, Cooper ME, Murray RM, Seeman E, Thomas AK, Jerums G (May 1991). "Comparison of sequential cyproterone acetate/estrogen versus spironolactone/oral contraceptive in the treatment of hirsutism". The Journal of Clinical Endocrinology and Metabolism. 72 (5): 1008–13. doi:10.1210/jcem-72-5-1008. PMID 1827125.
^ ^a ^b Douglas T. Carrell (12 April 2010). Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice. Springer. pp. 162–163. ISBN 978-1-4419-1435-4. Archived from the original on 4 July 2014. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b ^c Desai; Meena P.; Vijayalakshmi Bhatia & P.S.N. Menon (1 January 2001). Pediatric Endocrine Disorders. Orient Blackswan. p. 167. ISBN 978-81-250-2025-7. Archived from the original on 20 June 2013. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Allan H. Goroll; Albert G. Mulley (27 January 2009). Primary Care Medicine: Office Evaluation and Management of the Adult Patient. Lippincott Williams & Wilkins. p. 1264. ISBN 978-0-7817-7513-7. Archived from the original on 4 July 2014. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Grigoriou O, Papadias C, Konidaris S, Antoniou G, Karakitsos P, Giannikos L (April 1996). "Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial". Gynecological Endocrinology. 10 (2): 119–23. doi:10.3109/09513599609097901. PMID 8701785.
^ ^a ^b Seal, L. J.; Franklin, S.; Richards, C.; Shishkareva, A.; Sinclaire, C.; Barrett, J. (2012). "Predictive Markers for Mammoplasty and a Comparison of Side Effect Profiles in Transwomen Taking Various Hormonal Regimens". The Journal of Clinical Endocrinology & Metabolism. 97 (12): 4422–4428. doi:10.1210/jc.2012-2030. ISSN 0021-972X. PMID 23055547.
^ ^a ^b H.J.T. Coelingh Benni; H.M. Vemer (15 December 1990). Chronic Hyperandrogenic Anovulation. CRC Press. pp. 152–. ISBN 978-1-85070-322-8.
^ Mary Lee; Archana Desai (2007). Gibaldi's Drug Delivery Systems in Pharmaceutical Care. ASHP. pp. 312–. ISBN 978-1-58528-136-7.
^ Sarfaraz K. Niazi (19 April 2016). Handbook of Pharmaceutical Manufacturing Formulations, Second Edition: Volume One, Compressed Solid Products. CRC Press. pp. 470–. ISBN 978-1-4200-8117-6.
^ ^a ^b Sarah H. Wakelin; Howard I. Maibach; Clive B. Archer (1 June 2002). Systemic Drug Treatment in Dermatology: A Handbook. CRC Press. pp. 32, 35. ISBN 978-1-84076-013-2.
^ ^a ^b ^c ^d ^e ^f ^g ^h Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 960–. ISBN 978-3-88763-075-1.
^ ^a ^b ^c ^d ^e ^f ^g Bentham Science Publishers (September 1999). Current Pharmaceutical Design. Bentham Science Publishers. p. 711. More often, mild hypotension (11%), breast enlargement (26%) or dizziness (26%) may occur [53]. In most patients, the above side effects are mild and have no clinical significance. [...] Patients frequently experience menstrual disturbances ranging from 10% to 50% [51,94] with the daily dose of 100mg. The weak progestogenic activity of SP may be responsible for the irregular, anovulatory pattern of menstrual cycles but this issue has not been evaluated adequately. Menstrual disturbances are usually well controlled by concomitant use of oral contraceptives [48].
^ ^a ^b "Spironolactone and endocrine dysfunction". Annals of Internal Medicine. 85 (5): 630–6. November 1976. doi:10.7326/0003-4819-85-5-630. PMID 984618.
^ ^a ^b Douglas T. Carrell; C. Matthew Peterson (23 March 2010). Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice. Springer Science & Business Media. pp. 162–. ISBN 978-1-4419-1436-1. Archived from the original on 4 July 2014. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Verhamme K, Mosis G, Dieleman JP, et al. (2006). "Spironolactone and risk of upper gastrointestinal events: population based case-control study". Br Med J. 333 (7563): 330–3. doi:10.1136/bmj.38883.479549.2F. PMC 1539051. PMID 16840442.
^ Wandelt-Freerksen E. (1977). "Aldactone in the treatment of sarcoidosis of the lungs". JZ Erkr Atmungsorgane. 149 (1): 156–9. PMID 607621.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Jeffrey K. Aronson (2 March 2009). Meyler's Side Effects of Cardiovascular Drugs. Elsevier. pp. 253–258. ISBN 978-0-08-093289-7. Spironolactone causes breast tenderness and enlargement, mastodynia, infertility, cholasma, altered vaginal lubrica- tion, and reduced libido in women, probably because of estrogenic effects on target tissue.
^ ^a ^b Plovanich M, Weng QY, Mostaghimi A (2015). "Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne". JAMA Dermatol. 151 (9): 941–4. doi:10.1001/jamadermatol.2015.34. PMID 25796182.
^ ^a ^b ^c Costas Tsioufis; Roland Schmieder; Giuseppe Mancia (15 August 2016). Interventional Therapies for Secondary and Essential Hypertension. Springer. p. 44. ISBN 978-3-319-34141-5. Gynecomastia is dose related and reaches almost 50% with high spironolactone doses (>150 mg daily), while it is much less common (5–10%) with low doses (25–50 mg spironolactone daily) [135].
^ ^a ^b ^c ^d Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. p. 777,1087, 1196. ISBN 978-0-7817-1750-2. Archived from the original on 2014-06-28. Spironolactone also is both an antiandrogen and a progestagen, and this explains many of its distressing side effects;" decreased libido, mastodynia, and gynecomastia may occur in 50% or more of men, and menometrorrhagia and mastodynia may occur in an equally large number of women taking the drug.27 {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Conn, Jennifer J.; Jacobs, Howard S. (1998). "Managing hirsutism in gynaecological practice". BJOG: An International Journal of Obstetrics and Gynaecology. 105 (7): 687–696. doi:10.1111/j.1471-0528.1998.tb10197.x. ISSN 1470-0328. Breast tenderness is not uncommon and is recorded in up to 40% of women taking higher doses63.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Donald W. Seldin; Gerhard H. Giebisch (23 September 1997). Diuretic Agents: Clinical Physiology and Pharmacology. Academic Press. pp. 630–632. ISBN 978-0-08-053046-8. Archived from the original on 4 July 2014. The incidence of spironolactone in men is dose related. It is estimated that 50% of men treated with ≥150 mg/day of spironolactone will develop gynecomastia. The degree of gynecomastia varies considerably from patient to patient but in most instances causes mild symptoms. Associated breast tenderness is common but an inconsistent feature. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Elsevier Science. 1 December 2014. p. 293. ISBN 978-0-444-63391-0. It is well known that gynecomastia is a side effect of spironolactone in men and occurs in a dose-dependent manner in ~7% of cases with doses of <50 mg per day, and up to 50% of cases with doses of >150 mg per day [40,41].
^ ^a ^b ^c Gordon T. McInnes (2008). Clinical Pharmacology and Therapeutics of Hypertension. Elsevier. p. 125. ISBN 978-0-444-51757-9. Spironolactone lacks specificty for mineralocorticoid receptors and binds to both progesterone and dihydrotestosterone receptors. This can lead to various endocrine side effects that can limit the use of spironolactone. In females spironolactone can induce menstrual disturbances, breast enlargement and breast tenderness.78 In men spironolactone can induce gynecomastia and impotence. In RALES gynaecomastia or breast pain was reported by 10% of the men in the spironolactone group and 1% of the men in the placebo group (p<0.001), causing more patients in the spironolactone group than in the placebo group to discontinue treatment, despite a mean spironolactone dose of 26 mg.18
^ Rabe, T.; Grunwald, K.; Feldmann, K.; Runnebaum, B. (2009). "Treatment of hyperandrogenism in women". Gynecological Endocrinology. 10 (sup3): 1–44. doi:10.3109/09513599609045658. ISSN 0951-3590.
^ ^a ^b ^c ^d ^e McMullen GR, Van Herle AJ (1993). "Hirsutism and the effectiveness of spironolactone in its management". J. Endocrinol. Invest. 16 (11): 925–32. doi:10.1007/BF03348960. PMID 8144871.
^ ^a ^b ^c ^d ^e Nakajima ST, Brumsted JR, Riddick DH, Gibson M (1989). "Absence of progestational activity of oral spironolactone". Fertil. Steril. 52 (1): 155–8. doi:10.1016/s0015-0282(16)60807-5. PMID 2744183.
^ ^a ^b T. Steckler; N. H. Kalin; J. M. H. M. Reul (2005). Handbook of Stress and the Brain: Stress: integrative and clinical aspects. Elsevier. pp. 440–. ISBN 978-0-444-51823-1. Archived from the original on 2017-09-08. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Robert G. Lahita (9 June 2004). Systemic Lupus Erythematosus. Academic Press. pp. 797–. ISBN 978-0-08-047454-0. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H (2003). "Mineralocorticoid receptor function in major depression". Arch. Gen. Psychiatry. 60 (1): 24–8. doi:10.1001/archpsyc.60.1.24. PMID 12511169.
^ Heuser I, Deuschle M, Weber B, Stalla GK, Holsboer F (2000). "Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralocorticoid receptor antagonist spironolactone". Psychoneuroendocrinology. 25 (5): 513–8. doi:10.1016/s0306-4530(00)00006-8. PMID 10818284.
^ Macdonald, J E (2004). "Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment". Heart. 90 (7): 765–770. doi:10.1136/hrt.2003.017368. ISSN 0007-0769.
^ Holsboer, F (2000). "The Corticosteroid Receptor Hypothesis of Depression". Neuropsychopharmacology. 23 (5): 477–501. doi:10.1016/S0893-133X(00)00159-7. ISSN 0893-133X.
^ Thai, Keng-Ee; Sinclair, Rodney D (2001). "Spironolactone-induced hepatitis". Australasian Journal of Dermatology. 42 (3): 180–182. doi:10.1046/j.1440-0960.2001.00510.x. ISSN 0004-8380.
^ "Archived copy". Archived from the original on 2015-03-10. Retrieved 2014-03-03. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)
^ online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7699#f_adverse-reactions
^ ^a ^b ^c "Archived copy" (PDF). Archived from the original (PDF) on 2013-08-22. Retrieved 2014-04-17. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)
^ Aiba M, Suzuki H, Kageyama K, et al. (June 1981). "Spironolactone bodies in aldosteronomas and in the attached adrenals. Enzyme histochemical study of 19 cases of primary aldosteronism and a case of aldosteronism due to bilateral diffuse hyperplasia of the zona glomerulosa". Am. J. Pathol. 103 (3): 404–10. PMC 1903848. PMID 7195152.
^ ^a ^b Sean B. Ainsworth (10 November 2014). Neonatal Formulary: Drug Use in Pregnancy and the First Year of Life. John Wiley & Sons. pp. 486–. ISBN 978-1-118-81959-3. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b ^c ^d ^e ^f Bertis Little (29 September 2006). Drugs and Pregnancy: A Handbook. CRC Press. pp. 63–. ISBN 978-0-340-80917-4. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b ^c Peter C. Rubin; Margaret Ramsey (30 April 2008). Prescribing in Pregnancy. John Wiley & Sons. pp. 83–. ISBN 978-0-470-69555-5. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b ^c Gerald G. Briggs; Roger K. Freeman; Sumner J. Yaffe (2011). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins. pp. 1349–. ISBN 978-1-60831-708-0. Archived from the original on 2017-09-08. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Uri Elkayam; Norbert Gleicher (23 June 1998). Cardiac Problems in Pregnancy: Diagnosis and Management of Maternal and Fetal Heart Disease. John Wiley & Sons. pp. 353–. ISBN 978-0-471-16358-9. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b ^c ^d Christof Schaefer (2001). Drugs During Pregnancy and Lactation: Handbook of Prescription Drugs and Comparative Risk Assessment. Gulf Professional Publishing. pp. 115, 143. ISBN 978-0-444-50763-1. Archived from the original on 2017-09-08. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Jonathan Upfal (2006). Australian Drug Guide. Black Inc. pp. 671–. ISBN 978-1-86395-174-6. Archived from the original on 2017-09-08. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ "Advisory Statement" (PDF). Klinge Chemicals / LoSalt. Archived from the original (pdf) on 2006-11-15. Retrieved 2007-03-15. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Plovanich M, Weng QY, Mostaghimi A (2015). "Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne". JAMA Dermatology. 151: 941–4. doi:10.1001/jamadermatol.2015.34. PMID 25796182. Archived from the original on 2015-03-30. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).
^ Otte C, Hinkelmann K, Moritz S, et al. (April 2010). "Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study". J Psychiatr Res. 44 (6): 339–46. doi:10.1016/j.jpsychires.2009.10.006. PMID 19909979.
^ Mostalac-Preciado CR, de Gortari P, López-Rubalcava C (September 2011). "Antidepressant-like effects of mineralocorticoid but not glucocorticoid antagonists in the lateral septum: interactions with the serotonergic system". Behav. Brain Res. 223 (1): 88–98. doi:10.1016/j.bbr.2011.04.008. PMID 21515309.
^ Juvet T, Gourineni V, Ravi S, Zarich S (September 2013). "Life-threatening hyperkalemia: a potentially lethal drug combination". Connecticut Medicine. 77 (8): 491–493.
^ Mellar P. Davis (28 May 2009). Opioids in Cancer Pain. OUP Oxford. pp. 222–. ISBN 978-0-19-923664-0.
^ Stephen E. Wolverton (8 March 2007). Comprehensive Dermatologic Drug Therapy. Elsevier Health Sciences. pp. 2677–. ISBN 1-4377-2070-6.
^ ^a ^b ^c Armanini D, Andrisani A, Bordin L, Sabbadin C (2016). "Spironolactone in the treatment of polycystic ovary syndrome". Expert Opin Pharmacother. 17 (13): 1713–5. doi:10.1080/14656566.2016.1215430. PMID 27450358.
^ ^a ^b Armanini D, Castello R, Scaroni C, Bonanni G, Faccini G, Pellati D, Bertoldo A, Fiore C, Moghetti P (2007). "Treatment of polycystic ovary syndrome with spironolactone plus licorice". Eur. J. Obstet. Gynecol. Reprod. Biol. 131 (1): 61–7. doi:10.1016/j.ejogrb.2006.10.013. PMID 17113210.
^ SALASSA RM, MATTOX VR, ROSEVEAR JW (1962). "Inhibition of the "mineralocorticoid" activity of licorice by spironolactone". J. Clin. Endocrinol. Metab. 22: 1156–9. doi:10.1210/jcem-22-11-1156. PMID 13991036.
^ Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, Yerramadha MR, Ali Y, Helal E, Camporesi EM (2012). "Licorice abuse: time to send a warning message". Ther Adv Endocrinol Metab. 3 (4): 125–38. doi:10.1177/2042018812454322. PMC 3498851. PMID 23185686.
^ Lin SH, Yang SS, Chau T, Halperin ML (2003). "An unusual cause of hypokalemic paralysis: chronic licorice ingestion". Am. J. Med. Sci. 325 (3): 153–6. doi:10.1097/00000441-200303000-00008. PMID 12640291.
^ Parthasarathy HK, MacDonald TM (2007). "Mineralocorticoid receptor antagonists". Curr. Hypertens. Rep. 9 (1): 45–52. doi:10.1007/s11906-007-0009-3. PMID 17362671.
^ Rainer F. Greger; H. Knauf; E. Mutschler (6 December 2012). Diuretics. Springer Science & Business Media. pp. 352–. ISBN 978-3-642-79565-7.
^ Garthwaite, Susan M; McMahon, Ellen G (2004). "The evolution of aldosterone antagonists". Molecular and Cellular Endocrinology. 217 (1–2): 27–31. doi:10.1016/j.mce.2003.10.005. ISSN 0303-7207.
^ ^a ^b ^c Fagart J, Hillisch A, Huyet J, et al. (September 2010). "A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule". The Journal of Biological Chemistry. 285 (39): 29932–40. doi:10.1074/jbc.M110.131342. PMC 2943305. PMID 20650892.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b ^c ^d ^e ^f ^g ^h Levy J, Burshell A, Marbach M, Afllalo L, Glick SM (1980). "Interaction of spironolactone with oestradiol receptors in cytosol". J. Endocrinol. 84 (3): 371–9. doi:10.1677/joe.0.0840371. PMID 7391714.
^ ^a ^b ^c ^d ^e ^f ^g ^h Sabbadin C, Andrisani A, Zermiani M, Donà G, Bordin L, Ragazzi E, Boscaro M, Ambrosini G, Armanini D (2016). "Spironolactone and intermenstrual bleeding in polycystic ovary syndrome with normal BMI". J. Endocrinol. Invest. 39 (9): 1015–21. doi:10.1007/s40618-016-0466-0. PMID 27072668.
^ Pelkonen O, Mäenpää J, Taavitsainen P, Rautio A, Raunio H (1998). "Inhibition and induction of human cytochrome P450 (CYP) enzymes" (PDF). Xenobiotica. 28 (12): 1203–53. doi:10.1080/004982598238886. PMID 9890159. Archived from the original (PDF) on 2015-09-24. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Rigalli JP, Ruiz ML, Perdomo VG, Villanueva SS, Mottino AD, Catania VA (July 2011). "Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells". Toxicology. 285 (1–2): 18–24. doi:10.1016/j.tox.2011.03.015. PMID 21459122.
^ Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (September 1998). "The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions". J. Clin. Invest. 102 (5): 1016–23. doi:10.1172/JCI3703. PMC 508967. PMID 9727070.
^ Christians U, Schmitz V, Haschke M (December 2005). "Functional interactions between P-glycoprotein and CYP3A in drug metabolism". Expert Opin Drug Metab Toxicol. 1 (4): 641–54. doi:10.1517/17425255.1.4.641. PMID 16863430.
^ Sorrentino R, Autore G, Cirino G, d'Emmanuele de Villa Bianca R, Calignano A, Vanasia M, et al. (2000). "Effect of spironolactone and its metabolites on contractile property of isolated rat aorta rings". J Cardiovasc Pharmacol. 36 (2): 230–235. doi:10.1097/00005344-200008000-00013. PMID 10942165. Archived from the original on 2013-06-20. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Bendtzen, K.; Hansen, P. R.; Rieneck, K. (2003). "Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis". Clinical and Experimental Immunology. 134 (1): 151158. doi:10.1046/j.1365-2249.2003.02249.x. ISSN 0009-9104.
^ ^a ^b ^c ^d ^e Agusti, Géraldine; Bourgeois, Sandrine; Cartiser, Nathalie; Fessi, Hatem; Le Borgne, Marc; Lomberget, Thierry (2013). "A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone". Steroids. 78 (1): 102–107. doi:10.1016/j.steroids.2012.09.005. ISSN 0039-128X. PMID 23063964.
^ ^a ^b ^c Cutler GB, Pita JC, Rifka SM, Menard RH, Sauer MA, Loriaux DL (1978). "SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate". J. Clin. Endocrinol. Metab. 47 (1): 171–5. doi:10.1210/jcem-47-1-171. PMID 263288.
^ Cheng SC, Suzuki K, Sadee W, Harding BW (October 1976). "Effects of spironolactone, canrenone and canrenoate-K on cytochrome P450, and 11beta- and 18-hydroxylation in bovine and human adrenal cortical mitochondria". Endocrinology. 99 (4): 1097–106. doi:10.1210/endo-99-4-1097. PMID 976190.
^ ^a ^b ^c ^d Corvol P, Michaud A, Menard J, Freifeld M, Mahoudeau J (July 1975). "Antiandrogenic effect of spirolactones: mechanism of action". Endocrinology. 97 (1): 52–8. doi:10.1210/endo-97-1-52. PMID 166833.
^ ^a ^b Luthy IA, Begin DJ, Labrie F (November 1988). "Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture". Journal of Steroid Biochemistry. 31 (5): 845–52. doi:10.1016/0022-4731(88)90295-6. PMID 2462135.
^ Térouanne B, Tahiri B, Georget V, et al. (February 2000). "A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects". Molecular and Cellular Endocrinology. 160 (1–2): 39–49. doi:10.1016/S0303-7207(99)00251-8. PMID 10715537.
^ ^a ^b Marc A. Fritz; Leon Speroff (20 December 2010). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. p. 80. ISBN 978-0-7817-7968-5. Archived from the original on 4 July 2014. Retrieved 27 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Attard G, Reid AH, Olmos D, de Bono JS (June 2009). "Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven". Cancer Research. 69 (12): 4937–40. doi:10.1158/0008-5472.CAN-08-4531. PMID 19509232.
^ Sundar S, Dickinson PD (2012). "Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate". BMJ Case Rep. 2012: bcr1120115238. doi:10.1136/bcr.11.2011.5238. PMC 3291010. PMID 22665559.
^ Flynn T, Guancial EA, Kilari M, Kilari D (2016). "Case Report: Spironolactone Withdrawal Associated With a Dramatic Response in a Patient With Metastatic Castrate-Resistant Prostate Cancer". Clin Genitourin Cancer. doi:10.1016/j.clgc.2016.08.006. PMID 27641657.
^ ^a ^b Rifka SM, Pita JC, Vigersky RA, Wilson YA, Loriaux DL (1978). "Interaction of digitalis and spironolactone with human sex steroid receptors". J. Clin. Endocrinol. Metab. 46 (2): 338–44. doi:10.1210/jcem-46-2-338. PMID 86546.
^ ^a ^b Moghetti P, Castello R, Zamberlan N, Rossini M, Gatti D, Negri C, Tosi F, Muggeo M, Adami S (1999). "Spironolactone, but not flutamide, administration prevents bone loss in hyperandrogenic women treated with gonadotropin-releasing hormone agonist". J. Clin. Endocrinol. Metab. 84 (4): 1250–4. doi:10.1210/jcem.84.4.5606. PMID 10199763.
^ ^a ^b Doggrell SA, Brown L (2001). "The spironolactone renaissance". Expert Opin Investig Drugs. 10 (5): 943–54. doi:10.1517/13543784.10.5.943. PMID 11322868.
^ Carbone LD, Cross JD, Raza SH, Bush AJ, Sepanski RJ, Dhawan S, Khan BQ, Gupta M, Ahmad K, Khouzam RN, Dishmon DA, Nesheiwat JP, Hajjar MA, Chishti WA, Nasser W, Khan M, Womack CR, Cho T, Haskin AR, Weber KT (2008). "Fracture risk in men with congestive heart failure risk reduction with spironolactone". J. Am. Coll. Cardiol. 52 (2): 135–8. doi:10.1016/j.jacc.2008.03.039. PMID 18598893.
^ ^a ^b Ghosh M, Majumdar SR (2014). "Antihypertensive medications, bone mineral density, and fractures: a review of old cardiac drugs that provides new insights into osteoporosis". Endocrine. 46 (3): 397–405. doi:10.1007/s12020-014-0167-4. PMID 24504763.
^ Moghetti, Paolo; Castello, Roberto; Zamberlan, Nicoletta; Rossini, Maurizio; Gatti, Davide; Negri, Carlo; Tosi, Flavia; Muggeo, Michele; Adami, Silvano (1999). "Authors' Response: Spironolactone But Not Flutamide Administration Prevents Bone Loss in Hyperandrogenic Women Treated with Gonadotropin-Releasing Hormone Agonist". The Journal of Clinical Endocrinology & Metabolism. 84 (12): 4747-b–4747. doi:10.1210/jcem.84.12.4747b. ISSN 0021-972X.
^ Zhou J, Ng S, Adesanya-Famuiya O, Anderson K, Bondy CA (September 2000). "Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression". FASEB Journal. 14 (12): 1725–30. doi:10.1096/fj.99-0863com. PMID 10973921.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b ^c Satoh T, Itoh S, Seki T, Itoh S, Nomura N, Yoshizawa I (October 2002). "On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production". The Journal of Steroid Biochemistry and Molecular Biology. 82 (2–3): 209–16. doi:10.1016/S0960-0760(02)00154-1. PMID 12477487.
^ Ruggiero RJ, Likis FE (2002). "Estrogen: physiology, pharmacology, and formulations for replacement therapy". Journal of Midwifery & Women's Health. 47 (3): 130–8. doi:10.1016/s1526-9523(02)00233-7. PMID 12071379.
^ Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947. Archived from the original (PDF) on 2016-08-22. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b Rose LI, Underwood RH, Newmark SR, Kisch ES, Williams GH (October 1977). "Pathophysiology of spironolactone-induced gynecomastia". Annals of Internal Medicine. 87 (4): 398–403. doi:10.7326/0003-4819-87-4-398. PMID 907238.
^ ^a ^b Poirier D (2003). "Inhibitors of 17 beta-hydroxysteroid dehydrogenases". Curr. Med. Chem. 10 (6): 453–77. doi:10.2174/0929867033368222. PMID 12570693.
^ Poirier D (2009). "Advances in development of inhibitors of 17beta hydroxysteroid dehydrogenases". Anticancer Agents Med Chem. 9 (6): 642–60. doi:10.2174/187152009788680000. PMID 19601747.
^ Sam KM, Auger S, Luu-The V, Poirier D (1995). "Steroidal spiro-gamma-lactones that inhibit 17 beta-hydroxysteroid dehydrogenase activity in human placental microsomes". J. Med. Chem. 38 (22): 4518–28. doi:10.1021/jm00022a018. PMID 7473580.
^ ^a ^b ^c Tremblay MR, Luu-The V, Leblanc G, Noël P, Breton E, Labrie F, Poirier D (1999). "Spironolactone-related inhibitors of type II 17beta-hydroxysteroid dehydrogenase: chemical synthesis, receptor binding affinities, and proliferative/antiproliferative activities". Bioorg. Med. Chem. 7 (6): 1013–23. doi:10.1016/s0968-0896(98)00260-0. PMID 10428369.
^ Biggar RJ, Andersen EW, Wohlfahrt J, Melbye M (2013). "Spironolactone use and the risk of breast and gynecologic cancers". Cancer Epidemiol. 37 (6): 870–5. doi:10.1016/j.canep.2013.10.004. PMID 24189467.
^ Marchais-Oberwinkler S, Henn C, Möller G, Klein T, Negri M, Oster A, Spadaro A, Werth R, Wetzel M, Xu K, Frotscher M, Hartmann RW, Adamski J (2011). "17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development". J. Steroid Biochem. Mol. Biol. 125 (1–2): 66–82. doi:10.1016/j.jsbmb.2010.12.013. PMID 21193039.
^ Soubhye J, Alard IC, van Antwerpen P, Dufrasne F (2015). "Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis". Future Med Chem. 7 (11): 1431–56. doi:10.4155/fmc.15.74. PMID 26230882.
^ Schane, H. P.; Potts, G. O. (1978). "Oral Progestational Activity of Spironolactone". Journal of Clinical Endocrinology & Metabolism. 47 (3): 691694. doi:10.1210/jcem-47-3-691. ISSN 0021-972X. PMID 95623.
^ Delyani, John A (2000). "Mineralocorticoid receptor antagonists: The evolution of utility and pharmacology". Kidney International. 57 (4): 1408–1411. doi:10.1046/j.1523-1755.2000.00983.x. ISSN 0085-2538. PMID 10760075.
^ Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (31 May 2011). Williams Textbook of Endocrinology E-Book: Expert Consult. Elsevier Health Sciences. p. 2057. ISBN 978-1-4377-3600-7. Archived from the original on 21 June 2013. Retrieved 27 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Nakhjavani M, Hamidi S, Esteghamati A, Abbasi M, Nosratian-Jahromi S, Pasalar P (October 2009). "Short term effects of spironolactone on blood lipid profile: a 3-month study on a cohort of young women with hirsutism". British Journal of Clinical Pharmacology. 68 (4): 634–7. doi:10.1111/j.1365-2125.2009.03483.x. PMC 2780289. PMID 19843067.
^ ^a ^b Eckhard Ottow; Hilmar Weinmann (9 July 2008). Nuclear Receptors As Drug Targets. John Wiley & Sons. p. 410. ISBN 978-3-527-62330-3. Archived from the original on 21 June 2013. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Anderson E (2002). "The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis". Breast Cancer Research : BCR. 4 (5): 197–201. PMC 138744. PMID 12223124. Archived from the original on 2013-02-18. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Schane HP, Potts GO (1978). "Oral progestational activity of spironolactone". J. Clin. Endocrinol. Metab. 47 (3): 691–4. doi:10.1210/jcem-47-3-691. PMID 95623.
^ ^a ^b ^c ^d Iversen P, Melezinek I, Schmidt A (January 2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU International. 87 (1): 47–56. doi:10.1046/j.1464-410x.2001.00988.x. PMID 11121992.
^ Mahler C, Verhelst J, Denis L (May 1998). "Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer". Clinical Pharmacokinetics. 34 (5): 405–17. doi:10.2165/00003088-199834050-00005. PMID 9592622.
^ Shlomo Melmed (2016). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 626–. ISBN 978-0-323-29738-7.
^ Stripp B, Taylor AA, Bartter FC, Gillette JR, Loriaux DL, Easley R, Menard RH (1975). "Effect of spironolactone on sex hormones in man". J. Clin. Endocrinol. Metab. 41 (4): 777–81. doi:10.1210/jcem-41-4-777. PMID 1176584.
^ Drapier-Faure, Evelyne; Faure, Michel (2006). "Antiandrogens". Hidradenitis Suppurativa: 124–127. doi:10.1007/978-3-540-33101-8_16.
^ Israel Journal of Medical Sciences. Israel Medical Association, National Council for Research and Development. July 1984.
^ Jerry Shapiro (12 November 2012). Hair Disorders: Current Concepts in Pathophysiology, Diagnosis and Management, An Issue of Dermatologic Clinics. Elsevier Health Sciences. pp. 186–. ISBN 1-4557-7169-4.
^ Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (30 November 2015). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 743–. ISBN 978-0-323-29738-7.
^ Sengupta (1 January 2007). Gynaecology For Postgraduate And Practitioners. Elsevier India. pp. 172–. ISBN 978-81-312-0436-8.
^ Bruce R. Carr; Richard E. Blackwell (1998). Textbook of Reproductive Medicine. McGraw-Hill Professional Publishing. p. 261. ISBN 978-0-8385-8893-2.
^ Masahashi T, Wu MC, Ohsawa M, et al. (January 1986). "Spironolactone therapy for hyperandrogenic anovulatory women--clinical and endocrinological study". Nihon Sanka Fujinka Gakkai Zasshi. 38 (1): 95–101. PMID 3950464.
^ Haynes BA, Mookadam F (August 2009). "Male gynecomastia". Mayo Clinic Proceedings. Mayo Clinic. 84 (8): 672. doi:10.4065/84.8.672. PMC 2719518. PMID 19648382.
^ Serafini PC, Catalino J, Lobo RA (August 1985). "The effect of spironolactone on genital skin 5 alpha-reductase activity". Journal of Steroid Biochemistry. 23 (2): 191–4. doi:10.1016/0022-4731(85)90236-5. PMID 4033118.
^ Wong IL, Morris RS, Chang L, Spahn MA, Stanczyk FZ, Lobo RA (January 1995). "A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women". The Journal of Clinical Endocrinology and Metabolism. 80 (1): 233–8. doi:10.1210/jcem.80.1.7829618. PMID 7829618.
^ Miles RA, Cassidenti DL, Carmina E, Gentzschein E, Stanczyk FZ, Lobo RA (October 1992). "Cutaneous application of an androstenedione gel as an in vivo test of 5 alpha-reductase activity in women". Fertility and Sterility. 58 (4): 708–12. PMID 1426314.
^ ^a ^b Keleştimur F, Everest H, Unlühizarci K, Bayram F, Sahin Y (March 2004). "A comparison between spironolactone and spironolactone plus finasteride in the treatment of hirsutism". European Journal of Endocrinology / European Federation of Endocrine Societies. 150 (3): 351–4. doi:10.1530/eje.0.1500351. PMID 15012621.
^ Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H (September 1998). "The role of mineralocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation in humans". The Journal of Clinical Endocrinology and Metabolism. 83 (9): 3339–45. doi:10.1210/jcem.83.9.5077. PMID 9745451.
^ Otte C, Moritz S, Yassouridis A, et al. (January 2007). "Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition". Neuropsychopharmacology. 32 (1): 232–8. doi:10.1038/sj.npp.1301217. PMID 17035932. Archived from the original on 2008-10-11. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Campen TJ, Fanestil DD (1982). "Spironolactone: a glucocorticoid agonist or antagonist?". Clin Exp Hypertens A. 4 (9–10): 1627–36. PMID 6128090.
^ Couette B, Marsaud V, Baulieu EE, Richard-Foy H, Rafestin-Oblin ME (1992). "Spironolactone, an aldosterone antagonist, acts as an antiglucocorticosteroid on the mouse mammary tumor virus promoter". Endocrinology. 130 (1): 430–6. doi:10.1210/endo.130.1.1309341. PMID 1309341.
^ Overdiek HW, Merkus FW (November 1986). "Influence of food on the bioavailability of spironolactone". Clinical Pharmacology and Therapeutics. 40 (5): 531–6. doi:10.1038/clpt.1986.219. PMID 3769384.
^ Melander A, Danielson K, Scherstén B, Thulin T, Wåhlin E (July 1977). "Enhancement by food of canrenone bioavailability from spironolactone". Clinical Pharmacology and Therapeutics. 22 (1): 100–3. PMID 872489.
^ ^a ^b ^c International Agency for Research on Cancer; World Health Organization (2001). Some Thyrotropic Agents. World Health Organization. pp. 325–. ISBN 978-92-832-1279-9.
^ Pugeat MM, Dunn JF, Nisula BC (1981). "Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma". J. Clin. Endocrinol. Metab. 53 (1): 69–75. doi:10.1210/jcem-53-1-69. PMID 7195405.
^ Kaulhausen H, Rohner HG, Siedek M, Lafosse M, Breuer H (1980). "[Binding capacity of sex hormone binding globulin and corticosteroid binding globulin in serum of male patients with liver cirrhosis (author's transl)]". J. Clin. Chem. Clin. Biochem. (in German). 18 (2): 137–43. PMID 7189544.
^ Kirby I. Bland; Edward M. Copeland III (9 September 2009). The Breast: Comprehensive Management of Benign and Malignant Diseases. Elsevier Health Sciences. pp. 161–. ISBN 1-4377-1121-9.
^ ^a ^b Gardiner P, Schrode K, Quinlan D, Martin BK, Boreham DR, Rogers MS, Stubbs K, Smith M, Karim A (1989). "Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites". J Clin Pharmacol. 29 (4): 342–7. doi:10.1002/j.1552-4604.1989.tb03339.x. PMID 2723123.
^ Oxford Textbook of Medicine: Vol. 1. Oxford University Press. 2003. pp. 1–. ISBN 978-0-19-262922-7.
^ Pere Ginés; Vicente Arroyo; Juan Rodés; Robert W. Schrier (15 April 2008). Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. John Wiley & Sons. p. 229. ISBN 978-1-4051-4370-7.
^ Juruena MF, Pariante CM, Papadopoulos AS, Poon L, Lightman S, Cleare AJ (2013). "The role of mineralocorticoid receptor function in treatment-resistant depression". J. Psychopharmacol. (Oxford). 27 (12): 1169–79. doi:10.1177/0269881113499205. PMID 23904409.
^ Colby HD (1981). "Chemical suppression of steroidogenesis". Environ. Health Perspect. 38: 119–27. doi:10.1289/ehp.8138119. PMC 1568425. PMID 6786868.
^ Armanini D, Karbowiak I, Goi A, Mantero F, Funder JW (1985). "In-vivo metabolites of spironolactone and potassium canrenoate: determination of potential anti-androgenic activity by a mouse kidney cytosol receptor assay". Clin. Endocrinol. 23 (4): 341–7. doi:10.1111/j.1365-2265.1985.tb01090.x. PMID 4064345.
^ Andriulli A, Arrigoni A, Gindro T, Karbowiak I, Buzzetti G, Armanini D (1989). "Canrenone and androgen receptor-active materials in plasma of cirrhotic patients during long-term K-canrenoate or spironolactone therapy". Digestion. 44 (3): 155–62. doi:10.1159/000199905. PMID 2697627.
^ Blaine T. Smith; Paramount Wellness Institute Brian Luke Seaward, Ph.D.; Visiting Professor University of Oklahoma College of Pharmacy Blaine T Smith (1 November 2014). Pharmacology for Nurses. Jones & Bartlett Publishers. pp. 169–. ISBN 978-1-4496-8940-7.
^ Harry G. Brittain (26 November 2002). Analytical Profiles of Drug Substances and Excipients. Academic Press. p. 309. ISBN 978-0-12-260829-2. Archived from the original on 21 June 2013. Retrieved 27 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b Kolkhof P, Bärfacker L (2017). "30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development". J. Endocrinol. 234 (1): T125–T140. doi:10.1530/JOE-16-0600. PMC 5488394. PMID 28634268.
^ ^a ^b ^c ^d J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. p. 1111. ISBN 978-1-4757-2085-3. Archived from the original on 15 February 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ ^a ^b "Archived copy". Archived from the original on 2016-06-30. Retrieved 2017-07-04. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)
^ ^a ^b http://www.chemspider.com/Chemical-Structure.5628.html?rid=b578a389-d64b-4ec2-ae20-309e5f3abd11
^ Simon JA (1995). "Micronized progesterone: vaginal and oral uses". Clin Obstet Gynecol. 38 (4): 902–14. doi:10.1097/00003081-199538040-00024. PMID 8616985.
^ Jürgen Engel; Axel Kleemann; Bernhard Kutscher; Dietmar Reichert (14 May 2014). Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs. Thieme. pp. 1279–1280. ISBN 978-3-13-179275-4.
^ Ralph Landau; Basil Achilladelis; Alexander Scriabine (1999). Pharmaceutical Innovation: Revolutionizing Human Health. Chemical Heritage Foundation. pp. 198–. ISBN 978-0-941901-21-5. Spironolactone was patented in 1961 and has been used since then to treat heart failure, liver cirrhosis, and nephrotic syndrome.
^ Bodh I. Jugdutt (19 February 2014). Aging and Heart Failure: Mechanisms and Management. Springer Science & Business Media. pp. 175–. ISBN 978-1-4939-0268-2.
^ Camille Georges Wermuth (2 May 2011). The Practice of Medicinal Chemistry. Academic Press. pp. 34–. ISBN 978-0-08-056877-5. Archived from the original on 21 June 2013. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
^ Steelman SL, Brooks JR, Morgan ER, Patanelli DJ (1969). "Anti-androgenic activity of spironolactone". Steroids. 14 (4): 449–50. doi:10.1016/s0039-128x(69)80007-3. PMID 5344274.
^ Neill, J. D., Johansson, E. D. B., Datta, J. K., & Knobil, E. (1968). Endocrinology: Relationship Between the Plasma Levels of Luteinizing Hormone and Progesterone During the Normal Menstrual Cycle. Obstetrical & Gynecological Survey, 23(3), 271-277. Quote: "17a-methyl-B-nortestosterone (Benorterone) (SKF-7690) has satis- factorily undergone extensive pharmacologic and toxicologic studies in animals, plus preliminary clinical studies in humans with somewhat encouraging results. It was therefore subjected to further clinical trials, especially in relation to the treatment of acne vulgaris. This communication reports the promptly reversible development of gynecomastia in 12 of 13 postpuberal males who participated in such a clinical study. It is believed that this complication has not been reported previously with a nonestrogenic antiandrogenic agent."
^ Ober KP, Hennessy JF (1978). "Spironolactone therapy for hirsutism in a hyperandrogenic woman". Ann. Intern. Med. 89 (5 Pt 1): 643–4. PMID 717935.
^ Boisselle A, Tremblay RR (1979). "New therapeutic approach to the hirsute patient". Fertil. Steril. 32 (3): 276–9. doi:10.1016/s0015-0282(16)44232-9. PMID 488407.
^ Shapiro G, Evron S (1980). "A novel use of spironolactone: treatment of hirsutism". J. Clin. Endocrinol. Metab. 51 (3): 429–32. doi:10.1210/jcem-51-3-429. PMID 7410528.
^ Duru Shah; R. K. Bhathena; Safala Shroff (2004). The Polycystic Ovary Syndrome. Orient Blackswan. pp. 78–. ISBN 978-81-250-2633-4.
^ Paula J. Adams Hillard (29 March 2013). Practical Pediatric and Adolescent Gynecology. John Wiley & Sons. pp. 371–. ISBN 978-1-118-53857-9.
^ Michele Curtis (2014). Glass' Office Gynecology. Lippincott Williams & Wilkins. pp. 47–. ISBN 978-1-60831-820-9.
^ ^a ^b ^c ^d ^e ^f ^g ^h "Archived copy". Archived from the original on 2016-12-02. Retrieved 2016-12-01. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)
^ ^a ^b I.K. Morton; Judith M. Hall (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 261–. ISBN 978-0-7514-0499-9.
^ ^a ^b ^c ^d Benign Prostatic Hypertrophy. Springer Science & Business Media. 6 December 2012. pp. 266–. ISBN 978-1-4612-5476-8.
^ ^a ^b ^c ^d ^e ^f Matzkin H, Braf Z (1991). "Endocrine treatment of benign prostatic hypertrophy: current concepts". Urology. 37 (1): 1–16. doi:10.1016/0090-4295(91)80069-j. PMID 1702565.
^ ^a ^b Castro JE, Griffiths HJ, Edwards DE (1971). "A double-blind, controlled, clinical trial of spironolactone for benign prostatic hypertrophy". Br J Surg. 58 (7): 485–9. doi:10.1002/bjs.1800580703. PMID 4104441.
^ Wernze, Heinrich; Herdegen, Thomas (2014). "Long-term efficacy of spironolactone on pain, mood, and quality of life in women with fibromyalgia: An observational case series". Scandinavian Journal of Pain. 5 (2): 63–71. doi:10.1016/j.sjpain.2013.12.003. ISSN 1877-8860.
^ Kalso, Eija (2014). "From patient observation to potential new therapies—Is old spironolactone a new analgesic?". Scandinavian Journal of Pain. 5 (2): 61–62. doi:10.1016/j.sjpain.2014.02.006. ISSN 1877-8860.
^ ^a ^b ^c Verma D, Thompson J, Swaninathan S (2016). "Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function". Proceedings of the National Academy of Sciences. 113: 3609–3614. doi:10.1073/pnas.1523686113. PMC 4822607. PMID 26976570. Archived from the original on 2016-03-24. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

External links

[LoughlinGenerali2006-1] Kevin R. Loughlin; Joyce A. Generali (2006). The Guide to Off-label Prescription Drugs: New Uses for FDA-approved Prescription Drugs. Simon and Schuster. pp. 131–. ISBN 978-0-7432-8667-1.

[ClarkHarvey2011-2] Michelle A. Clark; Richard A. Harvey; Richard Finkel; Jose A. Rey; Karen Whalen (15 December 2011). Pharmacology. Lippincott Williams & Wilkins. pp. 286, 337. ISBN 978-1-4511-1314-3.

[AHFS2015-3] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k "Spironolactone". The American Society of Health-System Pharmacists. Archived from the original on 2015-11-16. Retrieved Oct 24, 2015. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[FARIDDiamanti-Kandarakis2009-4] NADIR R. FARID; Evanthia Diamanti-Kandarakis (27 February 2009). Diagnosis and Management of Polycystic Ovary Syndrome. Springer Science & Business Media. pp. 235–. ISBN 978-0-387-09718-3.

[FDA-AllBoxedWarnings-5] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.

[Sica2005-6] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r Sica, Domenic A. (2005). "Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis". Heart Failure Reviews. 10 (1): 23–29. doi:10.1007/s10741-005-2345-1. ISSN 1382-4147.

[pmid18729003-7] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Maron BA, Leopold JA (2008). "Mineralocorticoid receptor antagonists and endothelial function". Curr Opin Investig Drugs. 9 (9): 963–9. PMC 2967484. PMID 18729003.

[CaroneOxberry2017-8] Carone, Laura; Oxberry, Stephen G.; Twycross, Robert; Charlesworth, Sarah; Mihalyo, Mary; Wilcock, Andrew (2017). "Spironolactone". Journal of Pain and Symptom Management. 53 (2): 288–292. doi:10.1016/j.jpainsymman.2016.12.320. ISSN 0885-3924.

[TakamuraMaruyama1997-9] Takamura, Norito; Maruyama, Toru; Ahmed, Shamim; Suenaga, Ayaka; Otagiri, Masaki (1997). "Interactions of Aldosterone Antagonist Diuretics with Human Serum Proteins". Pharmaceutical Research. 14 (4): 522–526. doi:10.1023/A:1012168020545. ISSN 0724-8741.

[SzaszBudvari-Barany1990-10] Gyorgy Szasz; Zsuzsanna Budvari-Barany (19 December 1990). Pharmaceutical Chemistry of Antihypertensive Agents. CRC Press. pp. 91–. ISBN 978-0-8493-4724-5.

[McDonaghGardner2011-11] Theresa A. McDonagh; Roy S. Gardner; Andrew L. Clark; Henry Dargie (14 July 2011). Oxford Textbook of Heart Failure. OUP Oxford. pp. 403–. ISBN 978-0-19-957772-9. Archived from the original on 27 March 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[12] Friedman, Adam J. (1 October 2015). "Spironolactone for Adult Female Acne". Cutis. 96 (4): 216–217. ISSN 2326-6929. PMID 27141564.

[13] Maizes, Victoria (2015). Integrative Women's Health (2 ed.). p. 746. ISBN 9780190214807. Archived from the original on 2016-03-05. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[14] "Spironolactone Pregnancy and Breastfeeding Warnings". Archived from the original on 2 December 2015. Retrieved 29 November 2015. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Deedwania2014-15] Prakash C Deedwania (30 January 2014). Drug & Device Selection in Heart Failure. JP Medical Ltd. pp. 47–. ISBN 978-93-5090-723-8.

[Wermuth2008-16] Camille Georges Wermuth (24 July 2008). The Practice of Medicinal Chemistry. Academic Press. p. 34. ISBN 978-0-12-374194-3. Archived from the original on 21 June 2013. Retrieved 27 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Sittig1988-17] Marshall Sittig (1988). Pharmaceutical Manufacturing Encyclopedia. William Andrew. p. 1385. ISBN 978-0-8155-1144-1. Archived from the original on 20 June 2013. Retrieved 27 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[WHO19th-18] "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived from the original (PDF) on 13 December 2016. Retrieved 8 December 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[19] "Spironolactone". International Drug Price Indicator Guide. Retrieved 29 November 2015.

[pmid2969259-20] Hughes BR, Cunliffe WJ (May 1988). "Tolerance of spironolactone". The British Journal of Dermatology. 118 (5): 687–91. doi:10.1111/j.1365-2133.1988.tb02571.x. PMID 2969259.

[Preedy2012-21] Victor R. Preedy (1 January 2012). Handbook of Hair in Health and Disease. Springer Science & Business Media. pp. 132–. ISBN 978-90-8686-728-8.

[pmid3143568-22] Loy R, Seibel MM (December 1988). "Evaluation and therapy of polycystic ovarian syndrome". Endocrinology and Metabolism Clinics of North America. 17 (4): 785–813. PMID 3143568.

[Bat2010-23] Batterink, J; Stabler, SN; Tejani, AM; Fowkes, CT (4 August 2010). "Spironolactone for hypertension". The Cochrane database of systematic reviews (8): CD008169. doi:10.1002/14651858.CD008169.pub2. PMID 20687095.

[Yancy_e147-239-24] Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL, American College of Cardiology, Foundation; American Heart Association Task Force on Practice, Guidelines (Oct 15, 2013). "2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Journal of the American College of Cardiology. 62 (16): e147–239. doi:10.1016/j.jacc.2013.05.019. PMID 23747642.

[25] Pitt B, Zannad F, Remme W, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (1999). "The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators". N Engl J Med. 341 (10): 709–17. doi:10.1056/NEJM199909023411001. PMID 10471456. Archived from the original on 2006-08-10. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[26] Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM (Apr 10, 2014). "Spironolactone for heart failure with preserved ejection fraction". The New England Journal of Medicine. 370 (15): 1383–92. doi:10.1056/nejmoa1313731. PMID 24716680.

[27] Pitt B.; et al. (2014). "Spironolactone for Heart Failure with Preserved Ejection Fraction". N Engl J Med. 370 (15): 1383–1392. doi:10.1056/NEJMoa1313731. PMID 24716680. {{cite journal}}: Explicit use of et al. in: |author= (help)

[Pfeffer_posthoc-28] Pfeffer, Marc; de Denus, Simon; Desai, Akshay; Leclair, Gregoire; Pitt, Bertram; Solomon, Scott; Lavoie, Joel; Rouleau, Jean; O'Meara, Eileen (2017). ""Spironolactone Metabolites in TOPCAT — New Insights into Regional Variation"". N Engl J Med. 376 (17): 1690–1692. doi:10.1056/NEJMc1612601.

[CardioBrief-29] Husten, Larry (Apr 27, 2017) [2017]. ""Serious Questions Raised About Integrity Of International Trials"". CardioBrief.org.{{cite web}}: CS1 maint: date and year (link)

[pmid22840667-30] Chatterjee S, Moeller C, Shah N, Bolorunduro O, Lichstein E, Moskovits N, Mukherjee D (2012). "Eplerenone is not superior to older and less expensive aldosterone antagonists". Am. J. Med. 125 (8): 817–25. doi:10.1016/j.amjmed.2011.12.018. PMID 22840667.

[pmid15507105-31] Zouboulis CC, Degitz K (2004). "Androgen action on human skin -- from basic research to clinical significance". Exp. Dermatol. 13 Suppl 4: 5–10. doi:10.1111/j.1600-0625.2004.00255.x. PMID 15507105.

[ShalitaRosso2011-32] Alan R. Shalita; James Q. Del Rosso; Guy Webster (21 March 2011). Acne Vulgaris. CRC Press. pp. 33–. ISBN 978-1-61631-009-7. Archived from the original on 9 December 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[ZouboulisKatsambas2014-33] Christos C. Zouboulis; Andreas D. Katsambas; Albert M. Kligman (28 July 2014). Pathogenesis and Treatment of Acne and Rosacea. Springer. pp. 121–. ISBN 978-3-540-69375-8. Archived from the original on 10 December 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid16985920-34] Marks LS (2004). "5alpha-reductase: history and clinical importance". Rev Urol. 6 Suppl 9: S11–21. PMC 1472916. PMID 16985920.

[Sloane2002-35] Ethel Sloane (2002). Biology of Women. Cengage Learning. pp. 160–. ISBN 0-7668-1142-5.

[HannoGuzzo2014-36] Philip M Hanno; Thomas J. Guzzo; S. Bruce Malkowicz; Alan J. Wein (26 January 2014). Penn Clinical Manual of Urology E-Book: Expert Consult - Online. Elsevier Health Sciences. pp. 782–. ISBN 978-0-323-24466-4.

[Harper2007-37] Catherine Harper (1 August 2007). Intersex. Berg. pp. 123–. ISBN 978-1-84788-339-1.

[Blume-PeytaviWhiting2008-38] Ulrike Blume-Peytavi; David A. Whiting; Ralph M. Trüeb (26 June 2008). Hair Growth and Disorders. Springer Science & Business Media. pp. 161–162. ISBN 978-3-540-46911-7.

[pmid9420861-39] Diamanti-Kandarakis E, Tolis G, Duleba AJ (1995). "Androgens and therapeutic aspects of antiandrogens in women". J. Soc. Gynecol. Investig. 2 (4): 577–92. doi:10.1177/107155769500200401. PMID 9420861.

[pmid20082945-40] Katsambas AD, Dessinioti C (2010). "Hormonal therapy for acne: why not as first line therapy? facts and controversies". Clin. Dermatol. 28 (1): 17–23. doi:10.1016/j.clindermatol.2009.03.006. PMID 20082945.

[pmid22468178-41] Kim, Grace; Del Rosso, James (March 2012). "Oral Spironolactone in Post-teenage Female Patients with Acne Vulgaris". J Clinical and Aesthetic Dermatology. 5 (3): 37–50. PMC 3315877. PMID 22468178.

[pmid28155090-42] ^ ^a ^b ^c ^d ^e ^f Layton AM, Eady EA, Whitehouse H, Del Rosso JQ, Fedorowicz Z, van Zuuren EJ (2017). "Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review". Am J Clin Dermatol. 18 (2): 169–191. doi:10.1007/s40257-016-0245-x. PMC 5360829. PMID 28155090.

[pmid26897386-43] ^ ^a ^b ^c ^d ^e ^f Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, Bowe WP, Graber EM, Harper JC, Kang S, Keri JE, Leyden JJ, Reynolds RV, Silverberg NB, Stein Gold LF, Tollefson MM, Weiss JS, Dolan NC, Sagan AA, Stern M, Boyer KM, Bhushan R (2016). "Guidelines of care for the management of acne vulgaris". J. Am. Acad. Dermatol. 74 (5): 945–73.e33. doi:10.1016/j.jaad.2015.12.037. PMID 26897386.

[pmid24889738-44] Somani N, Turvy D (2014). "Hirsutism: an evidence-based treatment update". Am J Clin Dermatol. 15 (3): 247–66. doi:10.1007/s40257-014-0078-4. PMID 24889738.

[pmid21413648-45] Rathnayake D, Sinclair R (2010). "Use of spironolactone in dermatology". Skinmed. 8 (6): 328–32, quiz 333. PMID 21413648.

[46] HARFMANN, KATYA L.; BECHTEL, MARK A. (March 2015). "Hair Loss in Women". Clinical Obstetrics and Gynecology. 58 (1): 185–199. doi:10.1097/GRF.0000000000000081. PMID 25517757.

[pmid20128792-47] Cousen P, Messenger A (2010). "Female pattern hair loss in complete androgen insensitivity syndrome". Br. J. Dermatol. 162 (5): 1135–7. doi:10.1111/j.1365-2133.2010.09661.x. PMID 20128792.

[IswaranImai1997-48] Iswaran TJ, Imai M, Betton GR, Siddall RA (May 1997). "An overview of animal toxicology studies with bicalutamide (ICI 176,334)". The Journal of Toxicological Sciences. 22 (2): 75–88. doi:10.2131/jts.22.2_75. PMID 9198005.

[Smith2013-49] Smith, Robert E. (4 April 2013). Medicinal Chemistry – Fusion of Traditional and Western Medicine. Bentham Science Publishers. pp. 306–. ISBN 978-1-60805-149-6. Archived from the original on 29 May 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help); Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)

[Ostrzenski2002-50] Adam Ostrzenski (2002). Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy. Lippincott Williams & Wilkins. pp. 86–. ISBN 978-0-7817-2761-7.

[WPATH2011-51] The World Professional Association for Transgender Health (WPATH) (2011). "Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People" (PDF). Archived from the original (PDF) on 2012-05-23. Retrieved 2012-05-27. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid19509099-52] Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al. (September 2009). "Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline". The Journal of Clinical Endocrinology and Metabolism. 94 (9): 3132–54. doi:10.1210/jc.2009-0345. PMID 19509099.

[pmid2540730-53] Prior JC, Vigna YM, Watson D (February 1989). "Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism". Archives of Sexual Behavior. 18 (1): 49–57. doi:10.1007/bf01579291. PMID 2540730.

[pmid19689407-54] Reismann P, Likó I, Igaz P, Patócs A, Rácz K (August 2009). "Pharmacological options for treatment of hyperandrogenic disorders". Mini Reviews in Medicinal Chemistry. 9 (9): 1113–26. doi:10.2174/138955709788922692. PMID 19689407. Archived from the original on 2013-06-17. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[HaberStough2006-55] Robert S. Haber; Dowling Bluford Stough (2006). Hair Transplantation. Elsevier Health Sciences. p. 6. ISBN 978-1-4160-3104-8. Archived from the original on 4 July 2014. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Greaves2012-56] Peter Greaves (12 April 2012). Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation. Academic Press. p. 621. ISBN 978-0-444-53861-1. Archived from the original on 21 June 2013. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Dunaif2008-57] Andrea Dunaif (19 February 2008). Polycystic Ovary Syndrome: Current Controversies, from the Ovary to the Pancreas. Humana Press. p. 301. ISBN 978-1-58829-831-7. Archived from the original on 21 June 2013. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid8908525-58] Gökmen O, Senöz S, Gülekli B, Işik AZ (August 1996). "Comparison of four different treatment regimes in hirsutism related to polycystic ovary". Gynecological Endocrinology. 10 (4): 249–55. doi:10.3109/09513599609012316. PMID 8908525.

[pmid1827125-59] O'Brien RC, Cooper ME, Murray RM, Seeman E, Thomas AK, Jerums G (May 1991). "Comparison of sequential cyproterone acetate/estrogen versus spironolactone/oral contraceptive in the treatment of hirsutism". The Journal of Clinical Endocrinology and Metabolism. 72 (5): 1008–13. doi:10.1210/jcem-72-5-1008. PMID 1827125.

[Carrell2010-60] Douglas T. Carrell (12 April 2010). Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice. Springer. pp. 162–163. ISBN 978-1-4419-1435-4. Archived from the original on 4 July 2014. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[DesaiP.2001-61] Desai; Meena P.; Vijayalakshmi Bhatia & P.S.N. Menon (1 January 2001). Pediatric Endocrine Disorders. Orient Blackswan. p. 167. ISBN 978-81-250-2025-7. Archived from the original on 20 June 2013. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[GorollMulley2009-62] Allan H. Goroll; Albert G. Mulley (27 January 2009). Primary Care Medicine: Office Evaluation and Management of the Adult Patient. Lippincott Williams & Wilkins. p. 1264. ISBN 978-0-7817-7513-7. Archived from the original on 4 July 2014. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid8701785-63] Grigoriou O, Papadias C, Konidaris S, Antoniou G, Karakitsos P, Giannikos L (April 1996). "Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial". Gynecological Endocrinology. 10 (2): 119–23. doi:10.3109/09513599609097901. PMID 8701785.

[SealFranklin2012-64] Seal, L. J.; Franklin, S.; Richards, C.; Shishkareva, A.; Sinclaire, C.; Barrett, J. (2012). "Predictive Markers for Mammoplasty and a Comparison of Side Effect Profiles in Transwomen Taking Various Hormonal Regimens". The Journal of Clinical Endocrinology & Metabolism. 97 (12): 4422–4428. doi:10.1210/jc.2012-2030. ISSN 0021-972X. PMID 23055547.

[BenniVemer1990-65] H.J.T. Coelingh Benni; H.M. Vemer (15 December 1990). Chronic Hyperandrogenic Anovulation. CRC Press. pp. 152–. ISBN 978-1-85070-322-8.

[LeeDesai2007-66] Mary Lee; Archana Desai (2007). Gibaldi's Drug Delivery Systems in Pharmaceutical Care. ASHP. pp. 312–. ISBN 978-1-58528-136-7.

[Niazi2016-67] Sarfaraz K. Niazi (19 April 2016). Handbook of Pharmaceutical Manufacturing Formulations, Second Edition: Volume One, Compressed Solid Products. CRC Press. pp. 470–. ISBN 978-1-4200-8117-6.

[WakelinMaibach2002-68] Sarah H. Wakelin; Howard I. Maibach; Clive B. Archer (1 June 2002). Systemic Drug Treatment in Dermatology: A Handbook. CRC Press. pp. 32, 35. ISBN 978-1-84076-013-2.

[IndexNominum2000-69] ^ ^a ^b ^c ^d ^e ^f ^g ^h Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 960–. ISBN 978-3-88763-075-1.

[Publishers1999-70] ^ ^a ^b ^c ^d ^e ^f ^g Bentham Science Publishers (September 1999). Current Pharmaceutical Design. Bentham Science Publishers. p. 711. More often, mild hypotension (11%), breast enlargement (26%) or dizziness (26%) may occur [53]. In most patients, the above side effects are mild and have no clinical significance. [...] Patients frequently experience menstrual disturbances ranging from 10% to 50% [51,94] with the daily dose of 100mg. The weak progestogenic activity of SP may be responsible for the irregular, anovulatory pattern of menstrual cycles but this issue has not been evaluated adequately. Menstrual disturbances are usually well controlled by concomitant use of oral contraceptives [48].

[pmid984618-71] "Spironolactone and endocrine dysfunction". Annals of Internal Medicine. 85 (5): 630–6. November 1976. doi:10.7326/0003-4819-85-5-630. PMID 984618.

[CarrellPeterson2010-72] Douglas T. Carrell; C. Matthew Peterson (23 March 2010). Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice. Springer Science & Business Media. pp. 162–. ISBN 978-1-4419-1436-1. Archived from the original on 4 July 2014. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[73] Verhamme K, Mosis G, Dieleman JP, et al. (2006). "Spironolactone and risk of upper gastrointestinal events: population based case-control study". Br Med J. 333 (7563): 330–3. doi:10.1136/bmj.38883.479549.2F. PMC 1539051. PMID 16840442.

[74] Wandelt-Freerksen E. (1977). "Aldactone in the treatment of sarcoidosis of the lungs". JZ Erkr Atmungsorgane. 149 (1): 156–9. PMID 607621.

[Aronson2009-75] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Jeffrey K. Aronson (2 March 2009). Meyler's Side Effects of Cardiovascular Drugs. Elsevier. pp. 253–258. ISBN 978-0-08-093289-7. Spironolactone causes breast tenderness and enlargement, mastodynia, infertility, cholasma, altered vaginal lubrica- tion, and reduced libido in women, probably because of estrogenic effects on target tissue.

[pmid25796182-76] Plovanich M, Weng QY, Mostaghimi A (2015). "Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne". JAMA Dermatol. 151 (9): 941–4. doi:10.1001/jamadermatol.2015.34. PMID 25796182.

[TsioufisSchmieder2016-77] Costas Tsioufis; Roland Schmieder; Giuseppe Mancia (15 August 2016). Interventional Therapies for Secondary and Essential Hypertension. Springer. p. 44. ISBN 978-3-319-34141-5. Gynecomastia is dose related and reaches almost 50% with high spironolactone doses (>150 mg daily), while it is much less common (5–10%) with low doses (25–50 mg spironolactone daily) [135].

[Becker2001-78] Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. p. 777,1087, 1196. ISBN 978-0-7817-1750-2. Archived from the original on 2014-06-28. Spironolactone also is both an antiandrogen and a progestagen, and this explains many of its distressing side effects;" decreased libido, mastodynia, and gynecomastia may occur in 50% or more of men, and menometrorrhagia and mastodynia may occur in an equally large number of women taking the drug.27 {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[ConnJacobs1998-79] Conn, Jennifer J.; Jacobs, Howard S. (1998). "Managing hirsutism in gynaecological practice". BJOG: An International Journal of Obstetrics and Gynaecology. 105 (7): 687–696. doi:10.1111/j.1471-0528.1998.tb10197.x. ISSN 1470-0328. Breast tenderness is not uncommon and is recorded in up to 40% of women taking higher doses63.

[SeldinGiebisch1997-80] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Donald W. Seldin; Gerhard H. Giebisch (23 September 1997). Diuretic Agents: Clinical Physiology and Pharmacology. Academic Press. pp. 630–632. ISBN 978-0-08-053046-8. Archived from the original on 4 July 2014. The incidence of spironolactone in men is dose related. It is estimated that 50% of men treated with ≥150 mg/day of spironolactone will develop gynecomastia. The degree of gynecomastia varies considerably from patient to patient but in most instances causes mild symptoms. Associated breast tenderness is common but an inconsistent feature. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Elsevier2014-81] Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Elsevier Science. 1 December 2014. p. 293. ISBN 978-0-444-63391-0. It is well known that gynecomastia is a side effect of spironolactone in men and occurs in a dose-dependent manner in ~7% of cases with doses of <50 mg per day, and up to 50% of cases with doses of >150 mg per day [40,41].

[McInnes2008-82] Gordon T. McInnes (2008). Clinical Pharmacology and Therapeutics of Hypertension. Elsevier. p. 125. ISBN 978-0-444-51757-9. Spironolactone lacks specificty for mineralocorticoid receptors and binds to both progesterone and dihydrotestosterone receptors. This can lead to various endocrine side effects that can limit the use of spironolactone. In females spironolactone can induce menstrual disturbances, breast enlargement and breast tenderness.78 In men spironolactone can induce gynecomastia and impotence. In RALES gynaecomastia or breast pain was reported by 10% of the men in the spironolactone group and 1% of the men in the placebo group (p<0.001), causing more patients in the spironolactone group than in the placebo group to discontinue treatment, despite a mean spironolactone dose of 26 mg.18

[RabeGrunwald2009-83] Rabe, T.; Grunwald, K.; Feldmann, K.; Runnebaum, B. (2009). "Treatment of hyperandrogenism in women". Gynecological Endocrinology. 10 (sup3): 1–44. doi:10.3109/09513599609045658. ISSN 0951-3590.

[pmid8144871-84] McMullen GR, Van Herle AJ (1993). "Hirsutism and the effectiveness of spironolactone in its management". J. Endocrinol. Invest. 16 (11): 925–32. doi:10.1007/BF03348960. PMID 8144871.

[pmid2744183-85] Nakajima ST, Brumsted JR, Riddick DH, Gibson M (1989). "Absence of progestational activity of oral spironolactone". Fertil. Steril. 52 (1): 155–8. doi:10.1016/s0015-0282(16)60807-5. PMID 2744183.

[StecklerKalin2005-86] T. Steckler; N. H. Kalin; J. M. H. M. Reul (2005). Handbook of Stress and the Brain: Stress: integrative and clinical aspects. Elsevier. pp. 440–. ISBN 978-0-444-51823-1. Archived from the original on 2017-09-08. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Lahita2004-87] Robert G. Lahita (9 June 2004). Systemic Lupus Erythematosus. Academic Press. pp. 797–. ISBN 978-0-08-047454-0. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid12511169-88] Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H (2003). "Mineralocorticoid receptor function in major depression". Arch. Gen. Psychiatry. 60 (1): 24–8. doi:10.1001/archpsyc.60.1.24. PMID 12511169.

[pmid10818284-89] Heuser I, Deuschle M, Weber B, Stalla GK, Holsboer F (2000). "Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralocorticoid receptor antagonist spironolactone". Psychoneuroendocrinology. 25 (5): 513–8. doi:10.1016/s0306-4530(00)00006-8. PMID 10818284.

[Macdonald2004-90] Macdonald, J E (2004). "Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment". Heart. 90 (7): 765–770. doi:10.1136/hrt.2003.017368. ISSN 0007-0769.

[Holsboer2000-91] Holsboer, F (2000). "The Corticosteroid Receptor Hypothesis of Depression". Neuropsychopharmacology. 23 (5): 477–501. doi:10.1016/S0893-133X(00)00159-7. ISSN 0893-133X.

[ThaiSinclair2001-92] Thai, Keng-Ee; Sinclair, Rodney D (2001). "Spironolactone-induced hepatitis". Australasian Journal of Dermatology. 42 (3): 180–182. doi:10.1046/j.1440-0960.2001.00510.x. ISSN 0004-8380.

[93] "Archived copy". Archived from the original on 2015-03-10. Retrieved 2014-03-03. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)

[94] .lexi.com/lco/action/doc/retrieve/docid/patch_f/7699#f_adverse-reactions

[FDA2008-95] "Archived copy" (PDF). Archived from the original (PDF) on 2013-08-22. Retrieved 2014-04-17. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)

[96] Aiba M, Suzuki H, Kageyama K, et al. (June 1981). "Spironolactone bodies in aldosteronomas and in the attached adrenals. Enzyme histochemical study of 19 cases of primary aldosteronism and a case of aldosteronism due to bilateral diffuse hyperplasia of the zona glomerulosa". Am. J. Pathol. 103 (3): 404–10. PMC 1903848. PMID 7195152.

[Ainsworth2014-97] Sean B. Ainsworth (10 November 2014). Neonatal Formulary: Drug Use in Pregnancy and the First Year of Life. John Wiley & Sons. pp. 486–. ISBN 978-1-118-81959-3. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Little2006-98] ^ ^a ^b ^c ^d ^e ^f Bertis Little (29 September 2006). Drugs and Pregnancy: A Handbook. CRC Press. pp. 63–. ISBN 978-0-340-80917-4. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[RubinRamsey2008-99] Peter C. Rubin; Margaret Ramsey (30 April 2008). Prescribing in Pregnancy. John Wiley & Sons. pp. 83–. ISBN 978-0-470-69555-5. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[BriggsFreeman2011-100] Gerald G. Briggs; Roger K. Freeman; Sumner J. Yaffe (2011). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins. pp. 1349–. ISBN 978-1-60831-708-0. Archived from the original on 2017-09-08. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[ElkayamGleicher1998-101] Uri Elkayam; Norbert Gleicher (23 June 1998). Cardiac Problems in Pregnancy: Diagnosis and Management of Maternal and Fetal Heart Disease. John Wiley & Sons. pp. 353–. ISBN 978-0-471-16358-9. Archived from the original on 8 September 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Schaefer2001-102] Christof Schaefer (2001). Drugs During Pregnancy and Lactation: Handbook of Prescription Drugs and Comparative Risk Assessment. Gulf Professional Publishing. pp. 115, 143. ISBN 978-0-444-50763-1. Archived from the original on 2017-09-08. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Upfal2006-103] Jonathan Upfal (2006). Australian Drug Guide. Black Inc. pp. 671–. ISBN 978-1-86395-174-6. Archived from the original on 2017-09-08. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[104] "Advisory Statement" (PDF). Klinge Chemicals / LoSalt. Archived from the original (pdf) on 2006-11-15. Retrieved 2007-03-15. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[105] Plovanich M, Weng QY, Mostaghimi A (2015). "Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne". JAMA Dermatology. 151: 941–4. doi:10.1001/jamadermatol.2015.34. PMID 25796182. Archived from the original on 2015-03-30. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[106] Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).

[pmid19909979-107] Otte C, Hinkelmann K, Moritz S, et al. (April 2010). "Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study". J Psychiatr Res. 44 (6): 339–46. doi:10.1016/j.jpsychires.2009.10.006. PMID 19909979.

[pmid21515309-108] Mostalac-Preciado CR, de Gortari P, López-Rubalcava C (September 2011). "Antidepressant-like effects of mineralocorticoid but not glucocorticoid antagonists in the lateral septum: interactions with the serotonergic system". Behav. Brain Res. 223 (1): 88–98. doi:10.1016/j.bbr.2011.04.008. PMID 21515309.

[109] Juvet T, Gourineni V, Ravi S, Zarich S (September 2013). "Life-threatening hyperkalemia: a potentially lethal drug combination". Connecticut Medicine. 77 (8): 491–493.

[Davis2009-110] Mellar P. Davis (28 May 2009). Opioids in Cancer Pain. OUP Oxford. pp. 222–. ISBN 978-0-19-923664-0.

[Wolverton2007-111] Stephen E. Wolverton (8 March 2007). Comprehensive Dermatologic Drug Therapy. Elsevier Health Sciences. pp. 2677–. ISBN 1-4377-2070-6.

[pmid27450358-112] Armanini D, Andrisani A, Bordin L, Sabbadin C (2016). "Spironolactone in the treatment of polycystic ovary syndrome". Expert Opin Pharmacother. 17 (13): 1713–5. doi:10.1080/14656566.2016.1215430. PMID 27450358.

[pmid17113210-113] Armanini D, Castello R, Scaroni C, Bonanni G, Faccini G, Pellati D, Bertoldo A, Fiore C, Moghetti P (2007). "Treatment of polycystic ovary syndrome with spironolactone plus licorice". Eur. J. Obstet. Gynecol. Reprod. Biol. 131 (1): 61–7. doi:10.1016/j.ejogrb.2006.10.013. PMID 17113210.

[pmid13991036-114] SALASSA RM, MATTOX VR, ROSEVEAR JW (1962). "Inhibition of the "mineralocorticoid" activity of licorice by spironolactone". J. Clin. Endocrinol. Metab. 22: 1156–9. doi:10.1210/jcem-22-11-1156. PMID 13991036.

[pmid23185686-115] Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, Yerramadha MR, Ali Y, Helal E, Camporesi EM (2012). "Licorice abuse: time to send a warning message". Ther Adv Endocrinol Metab. 3 (4): 125–38. doi:10.1177/2042018812454322. PMC 3498851. PMID 23185686.

[pmid12640291-116] Lin SH, Yang SS, Chau T, Halperin ML (2003). "An unusual cause of hypokalemic paralysis: chronic licorice ingestion". Am. J. Med. Sci. 325 (3): 153–6. doi:10.1097/00000441-200303000-00008. PMID 12640291.

[pmid17362671-117] Parthasarathy HK, MacDonald TM (2007). "Mineralocorticoid receptor antagonists". Curr. Hypertens. Rep. 9 (1): 45–52. doi:10.1007/s11906-007-0009-3. PMID 17362671.

[GregerKnauf2012-118] Rainer F. Greger; H. Knauf; E. Mutschler (6 December 2012). Diuretics. Springer Science & Business Media. pp. 352–. ISBN 978-3-642-79565-7.

[GarthwaiteMcMahon2004-119] Garthwaite, Susan M; McMahon, Ellen G (2004). "The evolution of aldosterone antagonists". Molecular and Cellular Endocrinology. 217 (1–2): 27–31. doi:10.1016/j.mce.2003.10.005. ISSN 0303-7207.

[pmid20650892-120] Fagart J, Hillisch A, Huyet J, et al. (September 2010). "A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule". The Journal of Biological Chemistry. 285 (39): 29932–40. doi:10.1074/jbc.M110.131342. PMC 2943305. PMID 20650892.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[pmid7391714-121] ^ ^a ^b ^c ^d ^e ^f ^g ^h Levy J, Burshell A, Marbach M, Afllalo L, Glick SM (1980). "Interaction of spironolactone with oestradiol receptors in cytosol". J. Endocrinol. 84 (3): 371–9. doi:10.1677/joe.0.0840371. PMID 7391714.

[pmid27072668-122] ^ ^a ^b ^c ^d ^e ^f ^g ^h Sabbadin C, Andrisani A, Zermiani M, Donà G, Bordin L, Ragazzi E, Boscaro M, Ambrosini G, Armanini D (2016). "Spironolactone and intermenstrual bleeding in polycystic ovary syndrome with normal BMI". J. Endocrinol. Invest. 39 (9): 1015–21. doi:10.1007/s40618-016-0466-0. PMID 27072668.

[pmid9890159-123] Pelkonen O, Mäenpää J, Taavitsainen P, Rautio A, Raunio H (1998). "Inhibition and induction of human cytochrome P450 (CYP) enzymes" (PDF). Xenobiotica. 28 (12): 1203–53. doi:10.1080/004982598238886. PMID 9890159. Archived from the original (PDF) on 2015-09-24. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid21459122-124] Rigalli JP, Ruiz ML, Perdomo VG, Villanueva SS, Mottino AD, Catania VA (July 2011). "Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells". Toxicology. 285 (1–2): 18–24. doi:10.1016/j.tox.2011.03.015. PMID 21459122.

[pmid9727070-125] Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (September 1998). "The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions". J. Clin. Invest. 102 (5): 1016–23. doi:10.1172/JCI3703. PMC 508967. PMID 9727070.

[pmid16863430-126] Christians U, Schmitz V, Haschke M (December 2005). "Functional interactions between P-glycoprotein and CYP3A in drug metabolism". Expert Opin Drug Metab Toxicol. 1 (4): 641–54. doi:10.1517/17425255.1.4.641. PMID 16863430.

[pmid10942165-127] Sorrentino R, Autore G, Cirino G, d'Emmanuele de Villa Bianca R, Calignano A, Vanasia M, et al. (2000). "Effect of spironolactone and its metabolites on contractile property of isolated rat aorta rings". J Cardiovasc Pharmacol. 36 (2): 230–235. doi:10.1097/00005344-200008000-00013. PMID 10942165. Archived from the original on 2013-06-20. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[BendtzenHansen2003-128] Bendtzen, K.; Hansen, P. R.; Rieneck, K. (2003). "Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis". Clinical and Experimental Immunology. 134 (1): 151158. doi:10.1046/j.1365-2249.2003.02249.x. ISSN 0009-9104.

[AgustiBourgeois2013-129] Agusti, Géraldine; Bourgeois, Sandrine; Cartiser, Nathalie; Fessi, Hatem; Le Borgne, Marc; Lomberget, Thierry (2013). "A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone". Steroids. 78 (1): 102–107. doi:10.1016/j.steroids.2012.09.005. ISSN 0039-128X. PMID 23063964.

[pmid263288-130] Cutler GB, Pita JC, Rifka SM, Menard RH, Sauer MA, Loriaux DL (1978). "SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate". J. Clin. Endocrinol. Metab. 47 (1): 171–5. doi:10.1210/jcem-47-1-171. PMID 263288.

[pmid976190-131] Cheng SC, Suzuki K, Sadee W, Harding BW (October 1976). "Effects of spironolactone, canrenone and canrenoate-K on cytochrome P450, and 11beta- and 18-hydroxylation in bovine and human adrenal cortical mitochondria". Endocrinology. 99 (4): 1097–106. doi:10.1210/endo-99-4-1097. PMID 976190.

[pmid166833-132] Corvol P, Michaud A, Menard J, Freifeld M, Mahoudeau J (July 1975). "Antiandrogenic effect of spirolactones: mechanism of action". Endocrinology. 97 (1): 52–8. doi:10.1210/endo-97-1-52. PMID 166833.

[pmid2462135-133] Luthy IA, Begin DJ, Labrie F (November 1988). "Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture". Journal of Steroid Biochemistry. 31 (5): 845–52. doi:10.1016/0022-4731(88)90295-6. PMID 2462135.

[pmid10715537-134] Térouanne B, Tahiri B, Georget V, et al. (February 2000). "A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects". Molecular and Cellular Endocrinology. 160 (1–2): 39–49. doi:10.1016/S0303-7207(99)00251-8. PMID 10715537.

[FritzSperoff2010-135] Marc A. Fritz; Leon Speroff (20 December 2010). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. p. 80. ISBN 978-0-7817-7968-5. Archived from the original on 4 July 2014. Retrieved 27 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid19509232-136] Attard G, Reid AH, Olmos D, de Bono JS (June 2009). "Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven". Cancer Research. 69 (12): 4937–40. doi:10.1158/0008-5472.CAN-08-4531. PMID 19509232.

[pmid22665559-137] Sundar S, Dickinson PD (2012). "Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate". BMJ Case Rep. 2012: bcr1120115238. doi:10.1136/bcr.11.2011.5238. PMC 3291010. PMID 22665559.

[pmid27641657-138] Flynn T, Guancial EA, Kilari M, Kilari D (2016). "Case Report: Spironolactone Withdrawal Associated With a Dramatic Response in a Patient With Metastatic Castrate-Resistant Prostate Cancer". Clin Genitourin Cancer. doi:10.1016/j.clgc.2016.08.006. PMID 27641657.

[pmid86546-139] Rifka SM, Pita JC, Vigersky RA, Wilson YA, Loriaux DL (1978). "Interaction of digitalis and spironolactone with human sex steroid receptors". J. Clin. Endocrinol. Metab. 46 (2): 338–44. doi:10.1210/jcem-46-2-338. PMID 86546.

[pmid10199763-140] Moghetti P, Castello R, Zamberlan N, Rossini M, Gatti D, Negri C, Tosi F, Muggeo M, Adami S (1999). "Spironolactone, but not flutamide, administration prevents bone loss in hyperandrogenic women treated with gonadotropin-releasing hormone agonist". J. Clin. Endocrinol. Metab. 84 (4): 1250–4. doi:10.1210/jcem.84.4.5606. PMID 10199763.

[pmid11322868-141] Doggrell SA, Brown L (2001). "The spironolactone renaissance". Expert Opin Investig Drugs. 10 (5): 943–54. doi:10.1517/13543784.10.5.943. PMID 11322868.

[pmid18598893-142] Carbone LD, Cross JD, Raza SH, Bush AJ, Sepanski RJ, Dhawan S, Khan BQ, Gupta M, Ahmad K, Khouzam RN, Dishmon DA, Nesheiwat JP, Hajjar MA, Chishti WA, Nasser W, Khan M, Womack CR, Cho T, Haskin AR, Weber KT (2008). "Fracture risk in men with congestive heart failure risk reduction with spironolactone". J. Am. Coll. Cardiol. 52 (2): 135–8. doi:10.1016/j.jacc.2008.03.039. PMID 18598893.

[pmid24504763-143] Ghosh M, Majumdar SR (2014). "Antihypertensive medications, bone mineral density, and fractures: a review of old cardiac drugs that provides new insights into osteoporosis". Endocrine. 46 (3): 397–405. doi:10.1007/s12020-014-0167-4. PMID 24504763.

[MoghettiCastello1999-144] Moghetti, Paolo; Castello, Roberto; Zamberlan, Nicoletta; Rossini, Maurizio; Gatti, Davide; Negri, Carlo; Tosi, Flavia; Muggeo, Michele; Adami, Silvano (1999). "Authors' Response: Spironolactone But Not Flutamide Administration Prevents Bone Loss in Hyperandrogenic Women Treated with Gonadotropin-Releasing Hormone Agonist". The Journal of Clinical Endocrinology & Metabolism. 84 (12): 4747-b–4747. doi:10.1210/jcem.84.12.4747b. ISSN 0021-972X.

[pmid10973921-145] Zhou J, Ng S, Adesanya-Famuiya O, Anderson K, Bondy CA (September 2000). "Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression". FASEB Journal. 14 (12): 1725–30. doi:10.1096/fj.99-0863com. PMID 10973921.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[pmid12477487-146] Satoh T, Itoh S, Seki T, Itoh S, Nomura N, Yoshizawa I (October 2002). "On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production". The Journal of Steroid Biochemistry and Molecular Biology. 82 (2–3): 209–16. doi:10.1016/S0960-0760(02)00154-1. PMID 12477487.

[pmid12071379-147] Ruggiero RJ, Likis FE (2002). "Estrogen: physiology, pharmacology, and formulations for replacement therapy". Journal of Midwifery & Women's Health. 47 (3): 130–8. doi:10.1016/s1526-9523(02)00233-7. PMID 12071379.

[pmid16112947-148] Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947. Archived from the original (PDF) on 2016-08-22. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid907238-149] Rose LI, Underwood RH, Newmark SR, Kisch ES, Williams GH (October 1977). "Pathophysiology of spironolactone-induced gynecomastia". Annals of Internal Medicine. 87 (4): 398–403. doi:10.7326/0003-4819-87-4-398. PMID 907238.

[pmid12570693-150] Poirier D (2003). "Inhibitors of 17 beta-hydroxysteroid dehydrogenases". Curr. Med. Chem. 10 (6): 453–77. doi:10.2174/0929867033368222. PMID 12570693.

[pmid19601747-151] Poirier D (2009). "Advances in development of inhibitors of 17beta hydroxysteroid dehydrogenases". Anticancer Agents Med Chem. 9 (6): 642–60. doi:10.2174/187152009788680000. PMID 19601747.

[pmid7473580-152] Sam KM, Auger S, Luu-The V, Poirier D (1995). "Steroidal spiro-gamma-lactones that inhibit 17 beta-hydroxysteroid dehydrogenase activity in human placental microsomes". J. Med. Chem. 38 (22): 4518–28. doi:10.1021/jm00022a018. PMID 7473580.

[pmid10428369-153] Tremblay MR, Luu-The V, Leblanc G, Noël P, Breton E, Labrie F, Poirier D (1999). "Spironolactone-related inhibitors of type II 17beta-hydroxysteroid dehydrogenase: chemical synthesis, receptor binding affinities, and proliferative/antiproliferative activities". Bioorg. Med. Chem. 7 (6): 1013–23. doi:10.1016/s0968-0896(98)00260-0. PMID 10428369.

[pmid24189467-154] Biggar RJ, Andersen EW, Wohlfahrt J, Melbye M (2013). "Spironolactone use and the risk of breast and gynecologic cancers". Cancer Epidemiol. 37 (6): 870–5. doi:10.1016/j.canep.2013.10.004. PMID 24189467.

[pmid21193039-155] Marchais-Oberwinkler S, Henn C, Möller G, Klein T, Negri M, Oster A, Spadaro A, Werth R, Wetzel M, Xu K, Frotscher M, Hartmann RW, Adamski J (2011). "17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development". J. Steroid Biochem. Mol. Biol. 125 (1–2): 66–82. doi:10.1016/j.jsbmb.2010.12.013. PMID 21193039.

[pmid26230882-156] Soubhye J, Alard IC, van Antwerpen P, Dufrasne F (2015). "Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis". Future Med Chem. 7 (11): 1431–56. doi:10.4155/fmc.15.74. PMID 26230882.

[SchanePotts1978-157] Schane, H. P.; Potts, G. O. (1978). "Oral Progestational Activity of Spironolactone". Journal of Clinical Endocrinology & Metabolism. 47 (3): 691694. doi:10.1210/jcem-47-3-691. ISSN 0021-972X. PMID 95623.

[Delyani2000-158] Delyani, John A (2000). "Mineralocorticoid receptor antagonists: The evolution of utility and pharmacology". Kidney International. 57 (4): 1408–1411. doi:10.1046/j.1523-1755.2000.00983.x. ISSN 0085-2538. PMID 10760075.

[MelmedPolonsky2011-159] Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (31 May 2011). Williams Textbook of Endocrinology E-Book: Expert Consult. Elsevier Health Sciences. p. 2057. ISBN 978-1-4377-3600-7. Archived from the original on 21 June 2013. Retrieved 27 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid19843067-160] Nakhjavani M, Hamidi S, Esteghamati A, Abbasi M, Nosratian-Jahromi S, Pasalar P (October 2009). "Short term effects of spironolactone on blood lipid profile: a 3-month study on a cohort of young women with hirsutism". British Journal of Clinical Pharmacology. 68 (4): 634–7. doi:10.1111/j.1365-2125.2009.03483.x. PMC 2780289. PMID 19843067.

[OttowWeinmann2008-161] Eckhard Ottow; Hilmar Weinmann (9 July 2008). Nuclear Receptors As Drug Targets. John Wiley & Sons. p. 410. ISBN 978-3-527-62330-3. Archived from the original on 21 June 2013. Retrieved 28 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid12223124-162] Anderson E (2002). "The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis". Breast Cancer Research : BCR. 4 (5): 197–201. PMC 138744. PMID 12223124. Archived from the original on 2013-02-18. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid95623-163] Schane HP, Potts GO (1978). "Oral progestational activity of spironolactone". J. Clin. Endocrinol. Metab. 47 (3): 691–4. doi:10.1210/jcem-47-3-691. PMID 95623.

[pmid11121992-164] Iversen P, Melezinek I, Schmidt A (January 2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU International. 87 (1): 47–56. doi:10.1046/j.1464-410x.2001.00988.x. PMID 11121992.

[pmid9592622-165] Mahler C, Verhelst J, Denis L (May 1998). "Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer". Clinical Pharmacokinetics. 34 (5): 405–17. doi:10.2165/00003088-199834050-00005. PMID 9592622.

[Melmed2016-166] Shlomo Melmed (2016). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 626–. ISBN 978-0-323-29738-7.

[pmid1176584-167] Stripp B, Taylor AA, Bartter FC, Gillette JR, Loriaux DL, Easley R, Menard RH (1975). "Effect of spironolactone on sex hormones in man". J. Clin. Endocrinol. Metab. 41 (4): 777–81. doi:10.1210/jcem-41-4-777. PMID 1176584.

[Drapier-FaureFaure2006-168] Drapier-Faure, Evelyne; Faure, Michel (2006). "Antiandrogens". Hidradenitis Suppurativa: 124–127. doi:10.1007/978-3-540-33101-8_16.

[169] Israel Journal of Medical Sciences. Israel Medical Association, National Council for Research and Development. July 1984.

[Shapiro2012-170] Jerry Shapiro (12 November 2012). Hair Disorders: Current Concepts in Pathophysiology, Diagnosis and Management, An Issue of Dermatologic Clinics. Elsevier Health Sciences. pp. 186–. ISBN 1-4557-7169-4.

[MelmedPolonsky2015-171] Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (30 November 2015). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 743–. ISBN 978-0-323-29738-7.

[Sengupta2007-172] Sengupta (1 January 2007). Gynaecology For Postgraduate And Practitioners. Elsevier India. pp. 172–. ISBN 978-81-312-0436-8.

[CarrBlackwell1998-173] Bruce R. Carr; Richard E. Blackwell (1998). Textbook of Reproductive Medicine. McGraw-Hill Professional Publishing. p. 261. ISBN 978-0-8385-8893-2.

[pmid3950464-174] Masahashi T, Wu MC, Ohsawa M, et al. (January 1986). "Spironolactone therapy for hyperandrogenic anovulatory women--clinical and endocrinological study". Nihon Sanka Fujinka Gakkai Zasshi. 38 (1): 95–101. PMID 3950464.

[pmid19648382-175] Haynes BA, Mookadam F (August 2009). "Male gynecomastia". Mayo Clinic Proceedings. Mayo Clinic. 84 (8): 672. doi:10.4065/84.8.672. PMC 2719518. PMID 19648382.

[pmid4033118-176] Serafini PC, Catalino J, Lobo RA (August 1985). "The effect of spironolactone on genital skin 5 alpha-reductase activity". Journal of Steroid Biochemistry. 23 (2): 191–4. doi:10.1016/0022-4731(85)90236-5. PMID 4033118.

[pmid7829618-177] Wong IL, Morris RS, Chang L, Spahn MA, Stanczyk FZ, Lobo RA (January 1995). "A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women". The Journal of Clinical Endocrinology and Metabolism. 80 (1): 233–8. doi:10.1210/jcem.80.1.7829618. PMID 7829618.

[pmid1426314-178] Miles RA, Cassidenti DL, Carmina E, Gentzschein E, Stanczyk FZ, Lobo RA (October 1992). "Cutaneous application of an androstenedione gel as an in vivo test of 5 alpha-reductase activity in women". Fertility and Sterility. 58 (4): 708–12. PMID 1426314.

[pmid15012621-179] Keleştimur F, Everest H, Unlühizarci K, Bayram F, Sahin Y (March 2004). "A comparison between spironolactone and spironolactone plus finasteride in the treatment of hirsutism". European Journal of Endocrinology / European Federation of Endocrine Societies. 150 (3): 351–4. doi:10.1530/eje.0.1500351. PMID 15012621.

[pmid9745451-180] Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H (September 1998). "The role of mineralocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation in humans". The Journal of Clinical Endocrinology and Metabolism. 83 (9): 3339–45. doi:10.1210/jcem.83.9.5077. PMID 9745451.

[pmid17035932-181] Otte C, Moritz S, Yassouridis A, et al. (January 2007). "Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition". Neuropsychopharmacology. 32 (1): 232–8. doi:10.1038/sj.npp.1301217. PMID 17035932. Archived from the original on 2008-10-11. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid6128090-182] Campen TJ, Fanestil DD (1982). "Spironolactone: a glucocorticoid agonist or antagonist?". Clin Exp Hypertens A. 4 (9–10): 1627–36. PMID 6128090.

[pmid1309341-183] Couette B, Marsaud V, Baulieu EE, Richard-Foy H, Rafestin-Oblin ME (1992). "Spironolactone, an aldosterone antagonist, acts as an antiglucocorticosteroid on the mouse mammary tumor virus promoter". Endocrinology. 130 (1): 430–6. doi:10.1210/endo.130.1.1309341. PMID 1309341.

[pmid3769384-184] Overdiek HW, Merkus FW (November 1986). "Influence of food on the bioavailability of spironolactone". Clinical Pharmacology and Therapeutics. 40 (5): 531–6. doi:10.1038/clpt.1986.219. PMID 3769384.

[pmid872489-185] Melander A, Danielson K, Scherstén B, Thulin T, Wåhlin E (July 1977). "Enhancement by food of canrenone bioavailability from spironolactone". Clinical Pharmacology and Therapeutics. 22 (1): 100–3. PMID 872489.

[CancerOrganization2001-186] International Agency for Research on Cancer; World Health Organization (2001). Some Thyrotropic Agents. World Health Organization. pp. 325–. ISBN 978-92-832-1279-9.

[pmid7195405-187] Pugeat MM, Dunn JF, Nisula BC (1981). "Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma". J. Clin. Endocrinol. Metab. 53 (1): 69–75. doi:10.1210/jcem-53-1-69. PMID 7195405.

[pmid7189544-188] Kaulhausen H, Rohner HG, Siedek M, Lafosse M, Breuer H (1980). "[Binding capacity of sex hormone binding globulin and corticosteroid binding globulin in serum of male patients with liver cirrhosis (author's transl)]". J. Clin. Chem. Clin. Biochem. (in German). 18 (2): 137–43. PMID 7189544.

[BlandIII2009-189] Kirby I. Bland; Edward M. Copeland III (9 September 2009). The Breast: Comprehensive Management of Benign and Malignant Diseases. Elsevier Health Sciences. pp. 161–. ISBN 1-4377-1121-9.

[pmid2723123-190] Gardiner P, Schrode K, Quinlan D, Martin BK, Boreham DR, Rogers MS, Stubbs K, Smith M, Karim A (1989). "Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites". J Clin Pharmacol. 29 (4): 342–7. doi:10.1002/j.1552-4604.1989.tb03339.x. PMID 2723123.

[Oxford2003-191] Oxford Textbook of Medicine: Vol. 1. Oxford University Press. 2003. pp. 1–. ISBN 978-0-19-262922-7.

[GinésArroyo2008-192] Pere Ginés; Vicente Arroyo; Juan Rodés; Robert W. Schrier (15 April 2008). Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. John Wiley & Sons. p. 229. ISBN 978-1-4051-4370-7.

[pmid23904409-193] Juruena MF, Pariante CM, Papadopoulos AS, Poon L, Lightman S, Cleare AJ (2013). "The role of mineralocorticoid receptor function in treatment-resistant depression". J. Psychopharmacol. (Oxford). 27 (12): 1169–79. doi:10.1177/0269881113499205. PMID 23904409.

[pmid6786868-194] Colby HD (1981). "Chemical suppression of steroidogenesis". Environ. Health Perspect. 38: 119–27. doi:10.1289/ehp.8138119. PMC 1568425. PMID 6786868.

[pmid4064345-195] Armanini D, Karbowiak I, Goi A, Mantero F, Funder JW (1985). "In-vivo metabolites of spironolactone and potassium canrenoate: determination of potential anti-androgenic activity by a mouse kidney cytosol receptor assay". Clin. Endocrinol. 23 (4): 341–7. doi:10.1111/j.1365-2265.1985.tb01090.x. PMID 4064345.

[pmid2697627-196] Andriulli A, Arrigoni A, Gindro T, Karbowiak I, Buzzetti G, Armanini D (1989). "Canrenone and androgen receptor-active materials in plasma of cirrhotic patients during long-term K-canrenoate or spironolactone therapy". Digestion. 44 (3): 155–62. doi:10.1159/000199905. PMID 2697627.

[SmithPh.D.2014-197] Blaine T. Smith; Paramount Wellness Institute Brian Luke Seaward, Ph.D.; Visiting Professor University of Oklahoma College of Pharmacy Blaine T Smith (1 November 2014). Pharmacology for Nurses. Jones & Bartlett Publishers. pp. 169–. ISBN 978-1-4496-8940-7.

[Brittain2002-198] Harry G. Brittain (26 November 2002). Analytical Profiles of Drug Substances and Excipients. Academic Press. p. 309. ISBN 978-0-12-260829-2. Archived from the original on 21 June 2013. Retrieved 27 May 2012. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid28634268-199] Kolkhof P, Bärfacker L (2017). "30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development". J. Endocrinol. 234 (1): T125–T140. doi:10.1530/JOE-16-0600. PMC 5488394. PMID 28634268.

[Elks2014-200] J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. p. 1111. ISBN 978-1-4757-2085-3. Archived from the original on 15 February 2017. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[PubChem-201] "Archived copy". Archived from the original on 2016-06-30. Retrieved 2017-07-04. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)

[ChemSpider-202] ttp://www.chemspider.com/Chemical-Structure.5628.html?rid=b578a389-d64b-4ec2-ae20-309e5f3abd11

[pmid8616985-203] Simon JA (1995). "Micronized progesterone: vaginal and oral uses". Clin Obstet Gynecol. 38 (4): 902–14. doi:10.1097/00003081-199538040-00024. PMID 8616985.

[EngelKleemann2014-204] Jürgen Engel; Axel Kleemann; Bernhard Kutscher; Dietmar Reichert (14 May 2014). Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs. Thieme. pp. 1279–1280. ISBN 978-3-13-179275-4.

[LandauAchilladelis1999-205] Ralph Landau; Basil Achilladelis; Alexander Scriabine (1999). Pharmaceutical Innovation: Revolutionizing Human Health. Chemical Heritage Foundation. pp. 198–. ISBN 978-0-941901-21-5. Spironolactone was patented in 1961 and has been used since then to treat heart failure, liver cirrhosis, and nephrotic syndrome.

[Jugdutt2014-206] Bodh I. Jugdutt (19 February 2014). Aging and Heart Failure: Mechanisms and Management. Springer Science & Business Media. pp. 175–. ISBN 978-1-4939-0268-2.

[Wermuth2011-207] Camille Georges Wermuth (2 May 2011). The Practice of Medicinal Chemistry. Academic Press. pp. 34–. ISBN 978-0-08-056877-5. Archived from the original on 21 June 2013. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[pmid5344274-208] Steelman SL, Brooks JR, Morgan ER, Patanelli DJ (1969). "Anti-androgenic activity of spironolactone". Steroids. 14 (4): 449–50. doi:10.1016/s0039-128x(69)80007-3. PMID 5344274.

[NeillJohansson1968-209] Neill, J. D., Johansson, E. D. B., Datta, J. K., & Knobil, E. (1968). Endocrinology: Relationship Between the Plasma Levels of Luteinizing Hormone and Progesterone During the Normal Menstrual Cycle. Obstetrical & Gynecological Survey, 23(3), 271-277. Quote: "17a-methyl-B-nortestosterone (Benorterone) (SKF-7690) has satis- factorily undergone extensive pharmacologic and toxicologic studies in animals, plus preliminary clinical studies in humans with somewhat encouraging results. It was therefore subjected to further clinical trials, especially in relation to the treatment of acne vulgaris. This communication reports the promptly reversible development of gynecomastia in 12 of 13 postpuberal males who participated in such a clinical study. It is believed that this complication has not been reported previously with a nonestrogenic antiandrogenic agent."

[pmid717935-210] Ober KP, Hennessy JF (1978). "Spironolactone therapy for hirsutism in a hyperandrogenic woman". Ann. Intern. Med. 89 (5 Pt 1): 643–4. PMID 717935.

[pmid488407-211] Boisselle A, Tremblay RR (1979). "New therapeutic approach to the hirsute patient". Fertil. Steril. 32 (3): 276–9. doi:10.1016/s0015-0282(16)44232-9. PMID 488407.

[pmid7410528-212] Shapiro G, Evron S (1980). "A novel use of spironolactone: treatment of hirsutism". J. Clin. Endocrinol. Metab. 51 (3): 429–32. doi:10.1210/jcem-51-3-429. PMID 7410528.

[ShahBhathena2004-213] Duru Shah; R. K. Bhathena; Safala Shroff (2004). The Polycystic Ovary Syndrome. Orient Blackswan. pp. 78–. ISBN 978-81-250-2633-4.

[Hillard2013-214] Paula J. Adams Hillard (29 March 2013). Practical Pediatric and Adolescent Gynecology. John Wiley & Sons. pp. 371–. ISBN 978-1-118-53857-9.

[Curtis2014-215] Michele Curtis (2014). Glass' Office Gynecology. Lippincott Williams & Wilkins. pp. 47–. ISBN 978-1-60831-820-9.

[Drugs.com-216] ^ ^a ^b ^c ^d ^e ^f ^g ^h "Archived copy". Archived from the original on 2016-12-02. Retrieved 2016-12-01. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)

[MortonHall1999-217] I.K. Morton; Judith M. Hall (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 261–. ISBN 978-0-7514-0499-9.

[Springer2012-218] Benign Prostatic Hypertrophy. Springer Science & Business Media. 6 December 2012. pp. 266–. ISBN 978-1-4612-5476-8.

[pmid1702565-219] ^ ^a ^b ^c ^d ^e ^f Matzkin H, Braf Z (1991). "Endocrine treatment of benign prostatic hypertrophy: current concepts". Urology. 37 (1): 1–16. doi:10.1016/0090-4295(91)80069-j. PMID 1702565.

[pmid4104441-220] Castro JE, Griffiths HJ, Edwards DE (1971). "A double-blind, controlled, clinical trial of spironolactone for benign prostatic hypertrophy". Br J Surg. 58 (7): 485–9. doi:10.1002/bjs.1800580703. PMID 4104441.

[WernzeHerdegen2014-221] Wernze, Heinrich; Herdegen, Thomas (2014). "Long-term efficacy of spironolactone on pain, mood, and quality of life in women with fibromyalgia: An observational case series". Scandinavian Journal of Pain. 5 (2): 63–71. doi:10.1016/j.sjpain.2013.12.003. ISSN 1877-8860.

[Kalso2014-222] Kalso, Eija (2014). "From patient observation to potential new therapies—Is old spironolactone a new analgesic?". Scandinavian Journal of Pain. 5 (2): 61–62. doi:10.1016/j.sjpain.2014.02.006. ISSN 1877-8860.

[Verma2016-223] Verma D, Thompson J, Swaninathan S (2016). "Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function". Proceedings of the National Academy of Sciences. 113: 3609–3614. doi:10.1073/pnas.1523686113. PMC 4822607. PMID 26976570. Archived from the original on 2016-03-24. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

@@ Line 27: / Line 27: @@
 | protein_bound = Spironolactone: 88% (to [[human serum albumin|albumin]] and {{abbrlink|AGP|alpha-1-acid glycoprotein}} equivalently)<ref name="TakamuraMaruyama1997">{{cite journal|last1=Takamura|first1=Norito|last2=Maruyama|first2=Toru|last3=Ahmed|first3=Shamim|last4=Suenaga|first4=Ayaka|last5=Otagiri|first5=Masaki |title=Interactions of Aldosterone Antagonist Diuretics with Human Serum Proteins |journal=Pharmaceutical Research|volume=14|issue=4|year=1997|pages=522–526|issn=0724-8741 |doi=10.1023/A:1012168020545}}</ref><br />Canrenone: 99.2% (to albumin)<ref name="TakamuraMaruyama1997" />
 | metabolism = [[Liver]] ([[deacetylation]], [[dacetylation|dethioacetylation]], [[hydroxylation]])<ref name="Sica2005" /><ref name="pmid18729003" />
-| metabolites = {{abbrlink|7α-TMS|7α-thiomethylspironolactone}}, {{abbrlink|6β-OH-7α-TMS|6β-hydroxy-7α-thiomethylspironolactone}}, [[canrenone]], others<ref name="Sica2005" /><ref name="pmid18729003" /><ref name="SzaszBudvari-Barany1990" /><br />(All three active)<ref name="McDonaghGardner2011">{{cite book|author1=Theresa A. McDonagh|author2=Roy S. Gardner|author3=Andrew L. Clark |author4=Henry Dargie|title=Oxford Textbook of Heart Failure|url=https://books.google.com/books?id=KDDCiTQyGLsC&pg=PA403|date=14 July 2011|publisher=OUP Oxford|isbn=978-0-19-957772-9|pages=403–}}</ref>
+| metabolites = {{abbrlink|7α-TMS|7α-thiomethylspironolactone}}, {{abbrlink|6β-OH-7α-TMS|6β-hydroxy-7α-thiomethylspironolactone}}, [[canrenone]], others<ref name="Sica2005" /><ref name="pmid18729003" /><ref name="SzaszBudvari-Barany1990" /><br />(All three active)<ref name="McDonaghGardner2011">{{cite book|author1=Theresa A. McDonagh|author2=Roy S. Gardner|author3=Andrew L. Clark|author4=Henry Dargie|title=Oxford Textbook of Heart Failure|url=https://books.google.com/books?id=KDDCiTQyGLsC&pg=PA403|date=14 July 2011|publisher=OUP Oxford|isbn=978-0-19-957772-9|pages=403–|deadurl=no|archiveurl=https://web.archive.org/web/20170327090209/https://books.google.com/books?id=KDDCiTQyGLsC&pg=PA403|archivedate=27 March 2017|df=}}</ref>
 | elimination_half-life = Spironolactone: 1.4 hours<ref name="Sica2005" /><br />{{abbrlink|7α-TMS|7α-thiomethylspironolactone}}: 13.8 hours<ref name="Sica2005" /><br />{{abbrlink|6β-OH-7α-TMS|6β-hydroxy-7α-thiomethylspironolactone}}: 15.0 hours<ref name="Sica2005" /><br />[[Canrenone]]: 16.5 hours<ref name="Sica2005" />
 | excretion = [[Urine]], [[bile]]<ref name="pmid18729003" />
@@ Line 63: / Line 63: @@
 }}
 <!-- Definition and medical uses -->
-'''Spironolactone''', marketed under the brand name '''Aldactone''' among others, is a [[medication]] that is primarily used to treat [[edema|fluid build-up]] due to [[heart failure]], [[hepatic cirrhosis|liver scarring]], or [[kidney disease]].<ref name=AHFS2015>{{cite web|title=Spironolactone|url=http://www.drugs.com/monograph/spironolactone.html|publisher=The American Society of Health-System Pharmacists|accessdate=Oct 24, 2015}}</ref> It is also used in the treatment of [[hypertension|high blood pressure]], [[hypokalemia|low blood potassium]] that does not improve with [[Potassium#Supplementation|supplementation]], [[precocious puberty|early-onset puberty]], and [[acne]] and [[hirsutism|excessive hair growth]] in women.<ref name=AHFS2015/><ref>{{cite journal|first1=Adam J.|last1=Friedman|title=Spironolactone for Adult Female Acne|journal=Cutis|date=1 October 2015|issn=2326-6929|pages=216–217|volume=96|issue=4|pmid=27141564}}</ref> It is also used for [[hormone replacement therapy (male-to-female)|hormone therapy]] in transgender women.<ref>{{cite book|last1=Maizes|first1=Victoria|title=Integrative Women's Health|date=2015|isbn=9780190214807|page=746|edition=2|url=https://books.google.ca/books?id=uveJCgAAQBAJ&pg=PA746}}</ref> Spironolactone is taken by mouth.<ref name=AHFS2015/>
+'''Spironolactone''', marketed under the brand name '''Aldactone''' among others, is a [[medication]] that is primarily used to treat [[edema|fluid build-up]] due to [[heart failure]], [[hepatic cirrhosis|liver scarring]], or [[kidney disease]].<ref name=AHFS2015>{{cite web|title=Spironolactone|url=http://www.drugs.com/monograph/spironolactone.html|publisher=The American Society of Health-System Pharmacists|accessdate=Oct 24, 2015|deadurl=no|archiveurl=https://web.archive.org/web/20151116054857/http://www.drugs.com/monograph/spironolactone.html|archivedate=2015-11-16|df=}}</ref> It is also used in the treatment of [[hypertension|high blood pressure]], [[hypokalemia|low blood potassium]] that does not improve with [[Potassium#Supplementation|supplementation]], [[precocious puberty|early-onset puberty]], and [[acne]] and [[hirsutism|excessive hair growth]] in women.<ref name=AHFS2015/><ref>{{cite journal|first1=Adam J.|last1=Friedman|title=Spironolactone for Adult Female Acne|journal=Cutis|date=1 October 2015|issn=2326-6929|pages=216–217|volume=96|issue=4|pmid=27141564}}</ref> It is also used for [[hormone replacement therapy (male-to-female)|hormone therapy]] in transgender women.<ref>{{cite book|last1=Maizes|first1=Victoria|title=Integrative Women's Health|date=2015|isbn=9780190214807|page=746|edition=2|url=https://books.google.ca/books?id=uveJCgAAQBAJ&pg=PA746|deadurl=no|archiveurl=https://web.archive.org/web/20160305050257/https://books.google.ca/books?id=uveJCgAAQBAJ&pg=PA746|archivedate=2016-03-05|df=}}</ref> Spironolactone is taken by mouth.<ref name=AHFS2015/>
 <!-- Side effects and mechanism of action -->
-Common [[side effect]]s include [[electrolyte abnormalities]], particularly [[hyperkalemia|high blood potassium]], nausea, vomiting, headache, rashes, and a decreased desire for sex.<ref name=AHFS2015/> In those with liver or kidney problems, extra care should be taken.<ref name=AHFS2015/> Spironolactone has not been well studied in pregnancy and should not be used to treat [[high blood pressure of pregnancy]].<ref>{{cite web|title=Spironolactone Pregnancy and Breastfeeding Warnings|url=http://www.drugs.com/pregnancy/spironolactone.html|accessdate=29 November 2015}}</ref> It is a [[steroid]] that [[receptor antagonist|block]]s the effects of the [[hormone]]s [[aldosterone]] and [[testosterone]] and has some [[estrogen]] and  [[progesterone]]-like effects.<ref name="Deedwania2014">{{cite book|author=Prakash C Deedwania|title=Drug & Device Selection in Heart Failure|url=https://books.google.com/books?id=k8bUAgAAQBAJ&pg=PA47|date=30 January 2014|publisher=JP Medical Ltd|isbn=978-93-5090-723-8|pages=47–}}</ref><ref name=AHFS2015/> Spironolactone belongs to a class of medications known as [[potassium-sparing diuretic]]s.<ref name=AHFS2015/>
+Common [[side effect]]s include [[electrolyte abnormalities]], particularly [[hyperkalemia|high blood potassium]], nausea, vomiting, headache, rashes, and a decreased desire for sex.<ref name=AHFS2015/> In those with liver or kidney problems, extra care should be taken.<ref name=AHFS2015/> Spironolactone has not been well studied in pregnancy and should not be used to treat [[high blood pressure of pregnancy]].<ref>{{cite web|title=Spironolactone Pregnancy and Breastfeeding Warnings|url=http://www.drugs.com/pregnancy/spironolactone.html|accessdate=29 November 2015|deadurl=no|archiveurl=https://web.archive.org/web/20151202081203/http://www.drugs.com/pregnancy/spironolactone.html|archivedate=2 December 2015|df=}}</ref> It is a [[steroid]] that [[receptor antagonist|block]]s the effects of the [[hormone]]s [[aldosterone]] and [[testosterone]] and has some [[estrogen]] and  [[progesterone]]-like effects.<ref name="Deedwania2014">{{cite book|author=Prakash C Deedwania|title=Drug & Device Selection in Heart Failure|url=https://books.google.com/books?id=k8bUAgAAQBAJ&pg=PA47|date=30 January 2014|publisher=JP Medical Ltd|isbn=978-93-5090-723-8|pages=47–}}</ref><ref name=AHFS2015/> Spironolactone belongs to a class of medications known as [[potassium-sparing diuretic]]s.<ref name=AHFS2015/>
 <!-- History, society and culture -->
-Spironolactone was introduced in 1959.<ref name="Wermuth2008">{{cite book | author = Camille Georges Wermuth | title = The Practice of Medicinal Chemistry | url = https://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34 | accessdate = 27 May 2012 | date = 24 July 2008 | publisher = Academic Press | isbn = 978-0-12-374194-3 | page = 34}}</ref><ref name="Sittig1988">{{cite book | author = Marshall Sittig | title = Pharmaceutical Manufacturing Encyclopedia | url = https://books.google.com/books?id=XCsJgUnclbcC&pg=PA1385 | accessdate = 27 May 2012 | year = 1988 | publisher = William Andrew | isbn = 978-0-8155-1144-1 | page = 1385}}</ref> It is on the [[World Health Organization's List of Essential Medicines]], the most effective and safe medicines needed in a [[health system]].<ref name=WHO19th>{{cite web|title=WHO Model List of Essential Medicines (19th List)|url=http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|work=World Health Organization|accessdate=8 December 2016|date=April 2015}}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/> The wholesale cost in the [[developing world]] as of 2014 is between {{US$}}0.02 and {{US$}}0.12 per day.<ref>{{cite web|title=Spironolactone|url=http://erc.msh.org/dmpguide/resultsdetail.cfm?language=english&code=SPI25T&s_year=2014&year=2014&str=25%20mg&desc=Spironolactone&pack=new&frm=TAB-CAP&rte=PO&class_code2=16%2E&supplement=&class_name=%2816%2E%29Diuretics%3Cbr%3E|website=International Drug Price Indicator Guide|accessdate=29 November 2015}}</ref> In the United States it costs about {{US$}}0.50 per day.<ref name=AHFS2015/>
+Spironolactone was introduced in 1959.<ref name="Wermuth2008">{{cite book | author = Camille Georges Wermuth | title = The Practice of Medicinal Chemistry | url = https://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34 | accessdate = 27 May 2012 | date = 24 July 2008 | publisher = Academic Press | isbn = 978-0-12-374194-3 | page = 34 | deadurl = no | archiveurl = https://web.archive.org/web/20130621115634/http://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34 | archivedate = 21 June 2013 | df =  }}</ref><ref name="Sittig1988">{{cite book | author = Marshall Sittig | title = Pharmaceutical Manufacturing Encyclopedia | url = https://books.google.com/books?id=XCsJgUnclbcC&pg=PA1385 | accessdate = 27 May 2012 | year = 1988 | publisher = William Andrew | isbn = 978-0-8155-1144-1 | page = 1385 | deadurl = no | archiveurl = https://web.archive.org/web/20130620225714/http://books.google.com/books?id=XCsJgUnclbcC&pg=PA1385 | archivedate = 20 June 2013 | df =  }}</ref> It is on the [[World Health Organization's List of Essential Medicines]], the most effective and safe medicines needed in a [[health system]].<ref name=WHO19th>{{cite web|title=WHO Model List of Essential Medicines (19th List)|url=http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|work=World Health Organization|accessdate=8 December 2016|date=April 2015|deadurl=no|archiveurl=https://web.archive.org/web/20161213052708/http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|archivedate=13 December 2016|df=}}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/> The wholesale cost in the [[developing world]] as of 2014 is between {{US$}}0.02 and {{US$}}0.12 per day.<ref>{{cite web|title=Spironolactone|url=http://erc.msh.org/dmpguide/resultsdetail.cfm?language=english&code=SPI25T&s_year=2014&year=2014&str=25%20mg&desc=Spironolactone&pack=new&frm=TAB-CAP&rte=PO&class_code2=16%2E&supplement=&class_name=%2816%2E%29Diuretics%3Cbr%3E|website=International Drug Price Indicator Guide|accessdate=29 November 2015}}</ref> In the United States it costs about {{US$}}0.50 per day.<ref name=AHFS2015/>
 {{TOC limit|3}}
@@ Line 84: / Line 84: @@
 While [[loop diuretics]] remain first-line for most people with [[heart failure]], spironolactone has shown to reduce both morbidity and mortality in numerous studies and remains an important agent for treating fluid retention, edema, and symptoms of heart failure. Current recommendations from the [[American Heart Association]] are to use spironolactone in patients with NYHA Class II-IV heart failure who have a left ventricular [[ejection fraction]] of <35%.<ref name="Yancy e147-239">{{cite journal|vauthors=Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL,(( American College of Cardiology, Foundation; American Heart Association Task Force on Practice, Guidelines))|title=2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.|journal=Journal of the American College of Cardiology|date=Oct 15, 2013|volume=62|issue=16|pages=e147–239|pmid=23747642|doi=10.1016/j.jacc.2013.05.019}}</ref>
-In a [[clinical trial|randomized evaluation]] which studied people with severe [[Heart failure|congestive heart failure]], people treated with spironolactone were found to have a [[relative risk]] of death of 0.70 or an overall 30% [[relative risk reduction]] compared to the [[placebo]] group, indicating a significant [[death]] and [[morbidity]] benefit of the drug. Patients in the study's intervention arm also had fewer symptoms of [[heart failure]] and were hospitalized less frequently.<ref>{{cite journal |vauthors=Pitt B, Zannad F, Remme W, Cody R, Castaigne A, Perez A, Palensky J, Wittes J | title = The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators | journal = N Engl J Med | volume = 341 | issue = 10 | pages = 709–17 | year = 1999 | url= http://content.nejm.org/cgi/content/full/341/10/709 | pmid = 10471456 | doi = 10.1056/NEJM199909023411001}}</ref> Likewise, it has shown benefit for and is recommended in patients who recently suffered a [[myocardial infarction|heart attack]] and have an ejection fraction less than 40%, who develop symptoms consistent with heart failure, or have a history of [[diabetes mellitus]]. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on [[ACE inhibitors]] and [[beta-blockers]].<ref name="Yancy e147-239"/> Of note, a recent randomized, double-blinded study of spironolactone in patients with symptomatic heart failure with "preserved" ejection fraction (i.e. >45%) found no reduction in death from cardiovascular events, aborted cardiac arrest, or hospitalizations when spironolactone was compared to [[placebo]].<ref>{{cite journal|vauthors=Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM |title=Spironolactone for heart failure with preserved ejection fraction.|journal=The New England Journal of Medicine|date=Apr 10, 2014|volume=370|issue=15|pages=1383–92|pmid=24716680|doi=10.1056/nejmoa1313731}}</ref>
+In a [[clinical trial|randomized evaluation]] which studied people with severe [[Heart failure|congestive heart failure]], people treated with spironolactone were found to have a [[relative risk]] of death of 0.70 or an overall 30% [[relative risk reduction]] compared to the [[placebo]] group, indicating a significant [[death]] and [[morbidity]] benefit of the drug. Patients in the study's intervention arm also had fewer symptoms of [[heart failure]] and were hospitalized less frequently.<ref>{{cite journal | vauthors = Pitt B, Zannad F, Remme W, Cody R, Castaigne A, Perez A, Palensky J, Wittes J | title = The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators | journal = N Engl J Med | volume = 341 | issue = 10 | pages = 709–17 | year = 1999 | url = http://content.nejm.org/cgi/content/full/341/10/709 | pmid = 10471456 | doi = 10.1056/NEJM199909023411001 | deadurl = no | archiveurl = https://web.archive.org/web/20060810000710/http://content.nejm.org/cgi/content/full/341/10/709 | archivedate = 2006-08-10 | df =  }}</ref> Likewise, it has shown benefit for and is recommended in patients who recently suffered a [[myocardial infarction|heart attack]] and have an ejection fraction less than 40%, who develop symptoms consistent with heart failure, or have a history of [[diabetes mellitus]]. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on [[ACE inhibitors]] and [[beta-blockers]].<ref name="Yancy e147-239"/> Of note, a recent randomized, double-blinded study of spironolactone in patients with symptomatic heart failure with "preserved" ejection fraction (i.e. >45%) found no reduction in death from cardiovascular events, aborted cardiac arrest, or hospitalizations when spironolactone was compared to [[placebo]].<ref>{{cite journal|vauthors=Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM |title=Spironolactone for heart failure with preserved ejection fraction.|journal=The New England Journal of Medicine|date=Apr 10, 2014|volume=370|issue=15|pages=1383–92|pmid=24716680|doi=10.1056/nejmoa1313731}}</ref>
 It is recommended that alternatives to spironolactone be considered if serum [[creatinine]] is >2.5&nbsp;mg/dL (221µmol/L) in males or >2&nbsp;mg/dL (176.8 µmol/L) in females, if [[glomerular filtration rate]] is below 30mL/min or with a serum potassium of >5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of renal function as well.<ref name="Yancy e147-239"/>
@@ Line 97: / Line 97: @@
 ===Skin and hair conditions===
-Androgens like testosterone and DHT play a critical role in the [[pathogenesis]] of a number of [[cutaneous condition|dermatological conditions]] including [[acne]], [[seborrhea]], [[hirsutism]] (excessive facial/body hair growth in women), and [[pattern hair loss]] (androgenic alopecia).<ref name="pmid15507105">{{cite journal | vauthors = Zouboulis CC, Degitz K | title = Androgen action on human skin -- from basic research to clinical significance | journal = Exp. Dermatol. | volume = 13 Suppl 4 | issue = | pages = 5–10 | year = 2004 | pmid = 15507105 | doi = 10.1111/j.1600-0625.2004.00255.x | url = }}</ref> In demonstration of this, women with [[complete androgen insensitivity syndrome]] (CAIS) do not produce [[sebum]] or develop acne and have little to no [[body hair|body]], [[pubic hair|pubic]], or [[axillary hair]].<ref name="ShalitaRosso2011">{{cite book|author1=Alan R. Shalita|author2=James Q. Del Rosso|author3=Guy Webster|title=Acne Vulgaris|url=https://books.google.com/books?id=CIPOBQAAQBAJ&pg=PA33|date=21 March 2011|publisher=CRC Press|isbn=978-1-61631-009-7|pages=33–}}</ref><ref name="ZouboulisKatsambas2014">{{cite book|author1=Christos C. Zouboulis|author2=Andreas D. Katsambas|author3=Albert M. Kligman|title=Pathogenesis and Treatment of Acne and Rosacea|url=https://books.google.com/books?id=vnQqBAAAQBAJ&pg=PA121|date=28 July 2014|publisher=Springer|isbn=978-3-540-69375-8|pages=121–}}</ref> Moreover, men with [[congenital disorder|congenital]] [[5α-reductase deficiency|5α-reductase type II deficiency]] [[5α-reductase]] being an [[enzyme]] that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty [[facial hair]], reduced body hair, and reportedly no incidence of male pattern hair loss.<ref name="pmid16985920">{{cite journal | vauthors = Marks LS | title = 5alpha-reductase: history and clinical importance | journal = Rev Urol | volume = 6 Suppl 9 | issue = | pages = S11–21 | year = 2004 | pmid = 16985920 | pmc = 1472916 | doi = | url = }}</ref><ref name="Sloane2002">{{cite book|author=Ethel Sloane|title=Biology of Women|url=https://books.google.com/books?id=kqcYyk7zlHYC&pg=PA160|year=2002|publisher=Cengage Learning|isbn=0-7668-1142-5|pages=160–}}</ref><ref name="HannoGuzzo2014">{{cite book|author1=Philip M Hanno|author2=Thomas J. Guzzo|author3=S. Bruce Malkowicz|author4=Alan J. Wein|title=Penn Clinical Manual of Urology E-Book: Expert Consult - Online|url=https://books.google.com/books?id=OQTbAgAAQBAJ&pg=PA782|date=26 January 2014|publisher=Elsevier Health Sciences|isbn=978-0-323-24466-4|pages=782–}}</ref><ref name="Harper2007">{{cite book|author=Catherine Harper|title=Intersex|url=https://books.google.com/books?id=fM6vAwAAQBAJ&pg=PA123|date=1 August 2007|publisher=Berg|isbn=978-1-84788-339-1|pages=123–}}</ref><ref name="Blume-PeytaviWhiting2008">{{cite book|author1=Ulrike Blume-Peytavi|author2=David A. Whiting|author3=Ralph M. Trüeb|title=Hair Growth and Disorders|url=https://books.google.com/books?id=pHrX2-huQCoC&pg=PA161|date=26 June 2008|publisher=Springer Science & Business Media|isbn=978-3-540-46911-7|pages=161–162}}</ref> Conversely, [[hyperandrogenism]] in women, for instance due to [[polycystic ovary syndrome]] (PCOS) or [[congenital adrenal hyperplasia]] (CAH), is commonly associated with acne and hirsutism as well as [[virilization]] (masculinization) in general.<ref name="pmid15507105" /> In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned [[androgen-dependent condition|androgen-dependent]] skin and hair conditions.<ref name="pmid9420861">{{cite journal | vauthors = Diamanti-Kandarakis E, Tolis G, Duleba AJ | title = Androgens and therapeutic aspects of antiandrogens in women | journal = J. Soc. Gynecol. Investig. | volume = 2 | issue = 4 | pages = 577–92 | year = 1995 | pmid = 9420861 | doi = 10.1177/107155769500200401| url = }}</ref><ref name="pmid20082945">{{cite journal | vauthors = Katsambas AD, Dessinioti C | title = Hormonal therapy for acne: why not as first line therapy? facts and controversies | journal = Clin. Dermatol. | volume = 28 | issue = 1 | pages = 17–23 | year = 2010 | pmid = 20082945 | doi = 10.1016/j.clindermatol.2009.03.006 | url = }}</ref>
+Androgens like testosterone and DHT play a critical role in the [[pathogenesis]] of a number of [[cutaneous condition|dermatological conditions]] including [[acne]], [[seborrhea]], [[hirsutism]] (excessive facial/body hair growth in women), and [[pattern hair loss]] (androgenic alopecia).<ref name="pmid15507105">{{cite journal | vauthors = Zouboulis CC, Degitz K | title = Androgen action on human skin -- from basic research to clinical significance | journal = Exp. Dermatol. | volume = 13 Suppl 4 | issue = | pages = 5–10 | year = 2004 | pmid = 15507105 | doi = 10.1111/j.1600-0625.2004.00255.x | url = }}</ref> In demonstration of this, women with [[complete androgen insensitivity syndrome]] (CAIS) do not produce [[sebum]] or develop acne and have little to no [[body hair|body]], [[pubic hair|pubic]], or [[axillary hair]].<ref name="ShalitaRosso2011">{{cite book|author1=Alan R. Shalita|author2=James Q. Del Rosso|author3=Guy Webster|title=Acne Vulgaris|url=https://books.google.com/books?id=CIPOBQAAQBAJ&pg=PA33|date=21 March 2011|publisher=CRC Press|isbn=978-1-61631-009-7|pages=33–|deadurl=no|archiveurl=https://web.archive.org/web/20161209210819/https://books.google.com/books?id=CIPOBQAAQBAJ&pg=PA33|archivedate=9 December 2016|df=}}</ref><ref name="ZouboulisKatsambas2014">{{cite book|author1=Christos C. Zouboulis|author2=Andreas D. Katsambas|author3=Albert M. Kligman|title=Pathogenesis and Treatment of Acne and Rosacea|url=https://books.google.com/books?id=vnQqBAAAQBAJ&pg=PA121|date=28 July 2014|publisher=Springer|isbn=978-3-540-69375-8|pages=121–|deadurl=no|archiveurl=https://web.archive.org/web/20161210040108/https://books.google.com/books?id=vnQqBAAAQBAJ&pg=PA121|archivedate=10 December 2016|df=}}</ref> Moreover, men with [[congenital disorder|congenital]] [[5α-reductase deficiency|5α-reductase type II deficiency]] [[5α-reductase]] being an [[enzyme]] that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty [[facial hair]], reduced body hair, and reportedly no incidence of male pattern hair loss.<ref name="pmid16985920">{{cite journal | vauthors = Marks LS | title = 5alpha-reductase: history and clinical importance | journal = Rev Urol | volume = 6 Suppl 9 | issue = | pages = S11–21 | year = 2004 | pmid = 16985920 | pmc = 1472916 | doi = | url = }}</ref><ref name="Sloane2002">{{cite book|author=Ethel Sloane|title=Biology of Women|url=https://books.google.com/books?id=kqcYyk7zlHYC&pg=PA160|year=2002|publisher=Cengage Learning|isbn=0-7668-1142-5|pages=160–}}</ref><ref name="HannoGuzzo2014">{{cite book|author1=Philip M Hanno|author2=Thomas J. Guzzo|author3=S. Bruce Malkowicz|author4=Alan J. Wein|title=Penn Clinical Manual of Urology E-Book: Expert Consult - Online|url=https://books.google.com/books?id=OQTbAgAAQBAJ&pg=PA782|date=26 January 2014|publisher=Elsevier Health Sciences|isbn=978-0-323-24466-4|pages=782–}}</ref><ref name="Harper2007">{{cite book|author=Catherine Harper|title=Intersex|url=https://books.google.com/books?id=fM6vAwAAQBAJ&pg=PA123|date=1 August 2007|publisher=Berg|isbn=978-1-84788-339-1|pages=123–}}</ref><ref name="Blume-PeytaviWhiting2008">{{cite book|author1=Ulrike Blume-Peytavi|author2=David A. Whiting|author3=Ralph M. Trüeb|title=Hair Growth and Disorders|url=https://books.google.com/books?id=pHrX2-huQCoC&pg=PA161|date=26 June 2008|publisher=Springer Science & Business Media|isbn=978-3-540-46911-7|pages=161–162}}</ref> Conversely, [[hyperandrogenism]] in women, for instance due to [[polycystic ovary syndrome]] (PCOS) or [[congenital adrenal hyperplasia]] (CAH), is commonly associated with acne and hirsutism as well as [[virilization]] (masculinization) in general.<ref name="pmid15507105" /> In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned [[androgen-dependent condition|androgen-dependent]] skin and hair conditions.<ref name="pmid9420861">{{cite journal | vauthors = Diamanti-Kandarakis E, Tolis G, Duleba AJ | title = Androgens and therapeutic aspects of antiandrogens in women | journal = J. Soc. Gynecol. Investig. | volume = 2 | issue = 4 | pages = 577–92 | year = 1995 | pmid = 9420861 | doi = 10.1177/107155769500200401| url = }}</ref><ref name="pmid20082945">{{cite journal | vauthors = Katsambas AD, Dessinioti C | title = Hormonal therapy for acne: why not as first line therapy? facts and controversies | journal = Clin. Dermatol. | volume = 28 | issue = 1 | pages = 17–23 | year = 2010 | pmid = 20082945 | doi = 10.1016/j.clindermatol.2009.03.006 | url = }}</ref>
 Because of the antiandrogen activity of spironolactone, it can be quite effective in treating acne in women,<ref name="pmid22468178">{{cite journal|last1=Kim|first1=Grace|last2=Del Rosso|first2=James|title=Oral Spironolactone in Post-teenage Female Patients with Acne Vulgaris|journal=J Clinical and Aesthetic Dermatology|date=March 2012|volume=5|issue=3|pages=37–50|pmid=22468178|pmc=3315877}}</ref> and also reduces oil that is naturally produced in the skin.<ref name="pmid28155090" /><ref name="pmid26897386" /> Though not the primary intended purpose of the medication, the ability of spironolactone to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful.<ref name="pmid28155090" /><ref name="pmid26897386" /> Oftentimes, for women treating acne, spironolactone is prescribed and paired with a [[combined oral contraceptive pill|birth control pill]].<ref name="pmid28155090" /><ref name="pmid26897386" /> Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months.<ref name="pmid28155090" /><ref name="pmid26897386" /> Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication.<ref name="pmid24889738">{{cite journal | vauthors = Somani N, Turvy D | title = Hirsutism: an evidence-based treatment update | journal = Am J Clin Dermatol | volume = 15 | issue = 3 | pages = 247–66 | year = 2014 | pmid = 24889738 | doi = 10.1007/s40257-014-0078-4 | url = }}</ref> Spironolactone can be used in the treatment of [[female pattern hair loss]] (FPHL).<ref name="pmid21413648">{{cite journal | vauthors = Rathnayake D, Sinclair R | title = Use of spironolactone in dermatology | journal = Skinmed | volume = 8 | issue = 6 | pages = 328–32; quiz 333 | year = 2010 | pmid = 21413648 | doi = | url = }}</ref> There is tentative low quality evidence supporting its use for this indication.<ref>{{cite journal|last1=HARFMANN|first1=KATYA L.|last2=BECHTEL|first2=MARK A.|title=Hair Loss in Women|journal=Clinical Obstetrics and Gynecology|date=March 2015|volume=58|issue=1|pages=185–199|doi=10.1097/GRF.0000000000000081|pmid=25517757}}</ref> Although apparently effective, it should be noted that not all cases of FHPL are dependent on androgens.<ref name="pmid20128792">{{cite journal | vauthors = Cousen P, Messenger A | title = Female pattern hair loss in complete androgen insensitivity syndrome | journal = Br. J. Dermatol. | volume = 162 | issue = 5 | pages = 1135–7 | year = 2010 | pmid = 20128792 | doi = 10.1111/j.1365-2133.2010.09661.x | url = }}</ref>
-Antiandrogens like spironolactone are male-specific [[teratogen]]s which can feminize male [[fetus]]es due to their antiandrogen effects (see [[Spironolactone#Pregnancy and breastfeeding|below]]).<ref name="pmid9420861" /><ref name="IswaranImai1997">{{cite journal | vauthors = Iswaran TJ, Imai M, Betton GR, Siddall RA | title = An overview of animal toxicology studies with bicalutamide (ICI 176,334) | journal = The Journal of Toxicological Sciences | volume = 22 | issue = 2 | pages = 75–88 | date = May 1997 | pmid = 9198005 | doi = 10.2131/jts.22.2_75 }}</ref><ref name="Smith2013">{{cite book |first1=Robert E. |last1=Smith | name-list-format = vanc |title=Medicinal Chemistry – Fusion of Traditional and Western Medicine |url=https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306 |date=4 April 2013 |publisher=Bentham Science Publishers |isbn=978-1-60805-149-6 |pages=306–}}</ref> For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception.<ref name="pmid9420861" /><ref name="IswaranImai1997" /><ref name="Smith2013" /> Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose.<ref name="pmid9420861" /> Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.<ref name="pmid9420861" /><ref name="Ostrzenski2002">{{cite book|author=Adam Ostrzenski|title=Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy|url=https://books.google.com/books?id=TYlZsGdwqrQC&pg=PA86|year=2002|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-2761-7|pages=86–}}</ref>
+Antiandrogens like spironolactone are male-specific [[teratogen]]s which can feminize male [[fetus]]es due to their antiandrogen effects (see [[Spironolactone#Pregnancy and breastfeeding|below]]).<ref name="pmid9420861" /><ref name="IswaranImai1997">{{cite journal | vauthors = Iswaran TJ, Imai M, Betton GR, Siddall RA | title = An overview of animal toxicology studies with bicalutamide (ICI 176,334) | journal = The Journal of Toxicological Sciences | volume = 22 | issue = 2 | pages = 75–88 | date = May 1997 | pmid = 9198005 | doi = 10.2131/jts.22.2_75 }}</ref><ref name="Smith2013">{{cite book |first1=Robert E. |last1=Smith |name-list-format=vanc |title=Medicinal Chemistry – Fusion of Traditional and Western Medicine |url=https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306 |date=4 April 2013 |publisher=Bentham Science Publishers |isbn=978-1-60805-149-6 |pages=306– |deadurl=no |archiveurl=https://web.archive.org/web/20160529034219/https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306 |archivedate=29 May 2016 |df= }}</ref> For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception.<ref name="pmid9420861" /><ref name="IswaranImai1997" /><ref name="Smith2013" /> Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose.<ref name="pmid9420861" /> Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.<ref name="pmid9420861" /><ref name="Ostrzenski2002">{{cite book|author=Adam Ostrzenski|title=Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy|url=https://books.google.com/books?id=TYlZsGdwqrQC&pg=PA86|year=2002|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-2761-7|pages=86–}}</ref>
 Spironolactone is not generally used in men for the treatment of androgen-dependent dermatological conditions because of its feminizing side effects, but it is effective for such indications in men similarly.<ref name="pmid21413648" /> This is evidenced by the usefulness of spironolactone as an antiandrogen in transgender women.<ref name="WPATH2011" /><ref name="pmid19509099" /><ref name="pmid2540730" />
 ===Transgender hormone therapy===
-Spironolactone is frequently used as a component of [[hormone replacement therapy (male-to-female)|hormone replacement therapy]] in [[transgender women]], especially in the [[United States]] (where [[cyproterone acetate]] is not available), usually in addition to an [[estrogen]].<ref name="WPATH2011">{{cite web | url = http://www.wpath.org/documents/Standards%20of%20Care_FullBook_1g-1.pdf | title = Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People | author = The World Professional Association for Transgender Health (WPATH) | year = 2011 | format = PDF | accessdate = 2012-05-27}}</ref><ref name="pmid19509099">{{cite journal  |vauthors=Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, etal | title = Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 94 | issue = 9 | pages = 3132–54 |date=September 2009 | pmid = 19509099 | doi = 10.1210/jc.2009-0345 | url = http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=19509099}}</ref><ref name="pmid2540730">{{cite journal |vauthors=Prior JC, Vigna YM, Watson D | title = Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism | journal = Archives of Sexual Behavior | volume = 18 | issue = 1 | pages = 49–57 |date=February 1989 | pmid = 2540730 | doi = 10.1007/bf01579291| url = }}</ref> Spironolactone significantly depresses plasma testosterone levels, reducing them to female/castrate levels at sufficient doses and in combination with estrogen. The clinical response consists of, among other effects, decreased [[hirsutism|male pattern body hair]], the induction of [[breast development]], [[feminization (biology)|feminization]] in general, and lack of [[spontaneous erection]]s.<ref name="pmid2540730" />
+Spironolactone is frequently used as a component of [[hormone replacement therapy (male-to-female)|hormone replacement therapy]] in [[transgender women]], especially in the [[United States]] (where [[cyproterone acetate]] is not available), usually in addition to an [[estrogen]].<ref name="WPATH2011">{{cite web | url = http://www.wpath.org/documents/Standards%20of%20Care_FullBook_1g-1.pdf | title = Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People | author = The World Professional Association for Transgender Health (WPATH) | year = 2011 | format = PDF | accessdate = 2012-05-27 | deadurl = no | archiveurl = https://web.archive.org/web/20120523064935/http://www.wpath.org/documents/Standards%20of%20Care_FullBook_1g-1.pdf | archivedate = 2012-05-23 | df =  }}</ref><ref name="pmid19509099">{{cite journal  |vauthors=Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, etal | title = Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 94 | issue = 9 | pages = 3132–54 |date=September 2009 | pmid = 19509099 | doi = 10.1210/jc.2009-0345 | url = http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=19509099}}</ref><ref name="pmid2540730">{{cite journal |vauthors=Prior JC, Vigna YM, Watson D | title = Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism | journal = Archives of Sexual Behavior | volume = 18 | issue = 1 | pages = 49–57 |date=February 1989 | pmid = 2540730 | doi = 10.1007/bf01579291| url = }}</ref> Spironolactone significantly depresses plasma testosterone levels, reducing them to female/castrate levels at sufficient doses and in combination with estrogen. The clinical response consists of, among other effects, decreased [[hirsutism|male pattern body hair]], the induction of [[breast development]], [[feminization (biology)|feminization]] in general, and lack of [[spontaneous erection]]s.<ref name="pmid2540730" />
 ===Comparison with other antiandrogens===
-There are few available options for antiandrogen therapy. Spironolactone, [[cyproterone acetate]], and [[flutamide]] are some of the most well-known and widely used drugs.<ref name="pmid19689407">{{cite journal |vauthors=Reismann P, Likó I, Igaz P, Patócs A, Rácz K | title = Pharmacological options for treatment of hyperandrogenic disorders | journal = Mini Reviews in Medicinal Chemistry | volume = 9 | issue = 9 | pages = 1113–26 |date=August 2009 | pmid = 19689407 | doi = 10.2174/138955709788922692| url = http://www.benthamdirect.org/pages/content.php?MRMC/2009/00000009/00000009/0009N.SGM}}</ref> Compared to cyproterone acetate, spironolactone is considerably less potent as an antiandrogen by weight and [[binding affinity]].<ref name="HaberStough2006">{{cite book | author1 = Robert S. Haber | author2 = Dowling Bluford Stough | title = Hair Transplantation | url = https://books.google.com/books?id=PXJMqrbk-fAC&pg=PA6 | accessdate = 28 May 2012 | year = 2006 | publisher = Elsevier Health Sciences | isbn = 978-1-4160-3104-8 | page = 6}}</ref><ref name="Greaves2012">{{cite book | author = Peter Greaves | title = Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation | url = https://books.google.com/books?id=VTeMNWAKqUcC&pg=PA621 | accessdate = 28 May 2012 | date = 12 April 2012 | publisher = Academic Press | isbn = 978-0-444-53861-1 | page = 621}}</ref> However, despite this, at the doses of which they are typically used, spironolactone and cyproterone acetate have been found to be generally about equivalent in terms of effectiveness for a variety of androgen-related conditions,<ref name="Dunaif2008">{{cite book | author = Andrea Dunaif | title = Polycystic Ovary Syndrome: Current Controversies, from the Ovary to the Pancreas | url = https://books.google.com/books?id=xdxqJuE7tSwC&pg=PA301 | accessdate = 28 May 2012 | date = 19 February 2008 | publisher = Humana Press | isbn = 978-1-58829-831-7 | page = 301}}</ref> though, cyproterone acetate has shown a slight though non-[[statistical significance|statistically-significant]] advantage in some studies.<ref name="pmid8908525">{{cite journal |vauthors=Gökmen O, Senöz S, Gülekli B, Işik AZ | title = Comparison of four different treatment regimes in hirsutism related to polycystic ovary | journal = Gynecological Endocrinology | volume = 10 | issue = 4 | pages = 249–55 |date=August 1996 | pmid = 8908525 | doi = 10.3109/09513599609012316| url = }}</ref><ref name="pmid1827125">{{cite journal |vauthors=O'Brien RC, Cooper ME, Murray RM, Seeman E, Thomas AK, Jerums G | title = Comparison of sequential cyproterone acetate/estrogen versus spironolactone/oral contraceptive in the treatment of hirsutism | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 72 | issue = 5 | pages = 1008–13 |date=May 1991 | pmid = 1827125 | doi = 10.1210/jcem-72-5-1008| url = http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=1827125}}</ref> Also, it has been suggested that cyproterone acetate could be more effective in cases where androgen levels are more pronounced, though this has not been proven.<ref name="Dunaif2008" />
+There are few available options for antiandrogen therapy. Spironolactone, [[cyproterone acetate]], and [[flutamide]] are some of the most well-known and widely used drugs.<ref name="pmid19689407">{{cite journal | vauthors = Reismann P, Likó I, Igaz P, Patócs A, Rácz K | title = Pharmacological options for treatment of hyperandrogenic disorders | journal = Mini Reviews in Medicinal Chemistry | volume = 9 | issue = 9 | pages = 1113–26 | date = August 2009 | pmid = 19689407 | doi = 10.2174/138955709788922692 | url = http://www.benthamdirect.org/pages/content.php?MRMC/2009/00000009/00000009/0009N.SGM | deadurl = no | archiveurl = https://web.archive.org/web/20130617021205/http://www.benthamdirect.org/pages/content.php?MRMC%2F2009%2F00000009%2F00000009%2F0009N.SGM | archivedate = 2013-06-17 | df =  }}</ref> Compared to cyproterone acetate, spironolactone is considerably less potent as an antiandrogen by weight and [[binding affinity]].<ref name="HaberStough2006">{{cite book | author1 = Robert S. Haber | author2 = Dowling Bluford Stough | title = Hair Transplantation | url = https://books.google.com/books?id=PXJMqrbk-fAC&pg=PA6 | accessdate = 28 May 2012 | year = 2006 | publisher = Elsevier Health Sciences | isbn = 978-1-4160-3104-8 | page = 6 | deadurl = no | archiveurl = https://web.archive.org/web/20140704201433/http://books.google.com/books?id=PXJMqrbk-fAC&pg=PA6 | archivedate = 4 July 2014 | df =  }}</ref><ref name="Greaves2012">{{cite book | author = Peter Greaves | title = Histopathology of Preclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation | url = https://books.google.com/books?id=VTeMNWAKqUcC&pg=PA621 | accessdate = 28 May 2012 | date = 12 April 2012 | publisher = Academic Press | isbn = 978-0-444-53861-1 | page = 621 | deadurl = no | archiveurl = https://web.archive.org/web/20130621004813/http://books.google.com/books?id=VTeMNWAKqUcC&pg=PA621 | archivedate = 21 June 2013 | df =  }}</ref> However, despite this, at the doses of which they are typically used, spironolactone and cyproterone acetate have been found to be generally about equivalent in terms of effectiveness for a variety of androgen-related conditions,<ref name="Dunaif2008">{{cite book | author = Andrea Dunaif | title = Polycystic Ovary Syndrome: Current Controversies, from the Ovary to the Pancreas | url = https://books.google.com/books?id=xdxqJuE7tSwC&pg=PA301 | accessdate = 28 May 2012 | date = 19 February 2008 | publisher = Humana Press | isbn = 978-1-58829-831-7 | page = 301 | deadurl = no | archiveurl = https://web.archive.org/web/20130621002813/http://books.google.com/books?id=xdxqJuE7tSwC&pg=PA301 | archivedate = 21 June 2013 | df =  }}</ref> though, cyproterone acetate has shown a slight though non-[[statistical significance|statistically-significant]] advantage in some studies.<ref name="pmid8908525">{{cite journal |vauthors=Gökmen O, Senöz S, Gülekli B, Işik AZ | title = Comparison of four different treatment regimes in hirsutism related to polycystic ovary | journal = Gynecological Endocrinology | volume = 10 | issue = 4 | pages = 249–55 |date=August 1996 | pmid = 8908525 | doi = 10.3109/09513599609012316| url = }}</ref><ref name="pmid1827125">{{cite journal |vauthors=O'Brien RC, Cooper ME, Murray RM, Seeman E, Thomas AK, Jerums G | title = Comparison of sequential cyproterone acetate/estrogen versus spironolactone/oral contraceptive in the treatment of hirsutism | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 72 | issue = 5 | pages = 1008–13 |date=May 1991 | pmid = 1827125 | doi = 10.1210/jcem-72-5-1008| url = http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=1827125}}</ref> Also, it has been suggested that cyproterone acetate could be more effective in cases where androgen levels are more pronounced, though this has not been proven.<ref name="Dunaif2008" />
-Flutamide, another frequently used antiandrogen which is [[nonsteroidal]] and a pure androgen blocker, though much less potent by weight and binding affinity than either spironolactone or cyproterone acetate,<ref name="Carrell2010">{{cite book | author = Douglas T. Carrell | title = Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice | url = https://books.google.com/books?id=lcBEheiufVcC&pg=PA163 | accessdate = 28 May 2012 | date = 12 April 2010 | publisher = Springer | isbn = 978-1-4419-1435-4 | pages = 162–163}}</ref><ref name="DesaiP.2001">{{cite book | author1 = Desai | author2 = Meena P. | author3 = Vijayalakshmi Bhatia & P.S.N. Menon | title = Pediatric Endocrine Disorders | url = https://books.google.com/books?id=63naXWOc4NwC&pg=PA167 | accessdate = 28 May 2012 | date = 1 January 2001 | publisher = Orient Blackswan | isbn = 978-81-250-2025-7 | page = 167}}</ref> has been found to be more effective than either of them as an antiandrogen when it is used at the typical treatment doses.<ref name="HaberStough2006" /><ref name="GorollMulley2009">{{cite book | author1 = Allan H. Goroll | author2 = Albert G. Mulley | title = Primary Care Medicine: Office Evaluation and Management of the Adult Patient | url = https://books.google.com/books?id=bIZvJPcSEXMC&pg=PA1264 | accessdate = 28 May 2012 | date = 27 January 2009 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-7513-7 | page = 1264}}</ref><ref name="pmid8701785">{{cite journal |vauthors=Grigoriou O, Papadias C, Konidaris S, Antoniou G, Karakitsos P, Giannikos L | title = Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial | journal = Gynecological Endocrinology | volume = 10 | issue = 2 | pages = 119–23 |date=April 1996 | pmid = 8701785 | doi = 10.3109/09513599609097901| url = }}</ref> Unfortunately, the uses of both cyproterone acetate and flutamide have been associated with [[hepatotoxicity]], which can be severe with flutamide and has resulted in cyproterone acetate never being approved in the United States. [[Bicalutamide]] is a more potent, safer, and more tolerable alternative to flutamide, but is relatively little-studied in the treatment of androgen-dependent conditions aside from [[prostate cancer]], though it has been used to treat hirsutism with success. [[Gonadotropin-releasing hormone]] (GnRH) [[gonadotropin-releasing hormone analogue|analogue]]s are another very effective option for antiandrogen therapy, but have not been widely employed for this purpose due to their high cost and limited insurance coverage despite many now being available as [[generic drug|generics]].<ref name="pmid19509099" /> As such, spironolactone may be the only practical, safe, available, and well-supported antiandrogen option in some cases.
+Flutamide, another frequently used antiandrogen which is [[nonsteroidal]] and a pure androgen blocker, though much less potent by weight and binding affinity than either spironolactone or cyproterone acetate,<ref name="Carrell2010">{{cite book | author = Douglas T. Carrell | title = Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice | url = https://books.google.com/books?id=lcBEheiufVcC&pg=PA163 | accessdate = 28 May 2012 | date = 12 April 2010 | publisher = Springer | isbn = 978-1-4419-1435-4 | pages = 162–163 | deadurl = no | archiveurl = https://web.archive.org/web/20140704201613/http://books.google.com/books?id=lcBEheiufVcC&pg=PA163 | archivedate = 4 July 2014 | df =  }}</ref><ref name="DesaiP.2001">{{cite book | author1 = Desai | author2 = Meena P. | author3 = Vijayalakshmi Bhatia & P.S.N. Menon | title = Pediatric Endocrine Disorders | url = https://books.google.com/books?id=63naXWOc4NwC&pg=PA167 | accessdate = 28 May 2012 | date = 1 January 2001 | publisher = Orient Blackswan | isbn = 978-81-250-2025-7 | page = 167 | deadurl = no | archiveurl = https://web.archive.org/web/20130620234745/http://books.google.com/books?id=63naXWOc4NwC&pg=PA167 | archivedate = 20 June 2013 | df =  }}</ref> has been found to be more effective than either of them as an antiandrogen when it is used at the typical treatment doses.<ref name="HaberStough2006" /><ref name="GorollMulley2009">{{cite book | author1 = Allan H. Goroll | author2 = Albert G. Mulley | title = Primary Care Medicine: Office Evaluation and Management of the Adult Patient | url = https://books.google.com/books?id=bIZvJPcSEXMC&pg=PA1264 | accessdate = 28 May 2012 | date = 27 January 2009 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-7513-7 | page = 1264 | deadurl = no | archiveurl = https://web.archive.org/web/20140704201748/http://books.google.com/books?id=bIZvJPcSEXMC&pg=PA1264 | archivedate = 4 July 2014 | df =  }}</ref><ref name="pmid8701785">{{cite journal |vauthors=Grigoriou O, Papadias C, Konidaris S, Antoniou G, Karakitsos P, Giannikos L | title = Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial | journal = Gynecological Endocrinology | volume = 10 | issue = 2 | pages = 119–23 |date=April 1996 | pmid = 8701785 | doi = 10.3109/09513599609097901| url = }}</ref> Unfortunately, the uses of both cyproterone acetate and flutamide have been associated with [[hepatotoxicity]], which can be severe with flutamide and has resulted in cyproterone acetate never being approved in the United States. [[Bicalutamide]] is a more potent, safer, and more tolerable alternative to flutamide, but is relatively little-studied in the treatment of androgen-dependent conditions aside from [[prostate cancer]], though it has been used to treat hirsutism with success. [[Gonadotropin-releasing hormone]] (GnRH) [[gonadotropin-releasing hormone analogue|analogue]]s are another very effective option for antiandrogen therapy, but have not been widely employed for this purpose due to their high cost and limited insurance coverage despite many now being available as [[generic drug|generics]].<ref name="pmid19509099" /> As such, spironolactone may be the only practical, safe, available, and well-supported antiandrogen option in some cases.
 In a study of the predictive markers for transgender women requesting [[breast augmentation]], there was a significantly higher rate of those treated with spironolactone requesting breast augmentation compared to other antiandrogens such as cyproterone acetate or GnRH analogues, which was interpreted by the study authors as being potentially indicative that spironolactone may result in poorer breast development in comparison.<ref name="SealFranklin2012">{{cite journal|last1=Seal|first1=L. J.|last2=Franklin|first2=S.|last3=Richards|first3=C.|last4=Shishkareva|first4=A.|last5=Sinclaire|first5=C.|last6=Barrett|first6=J.|title=Predictive Markers for Mammoplasty and a Comparison of Side Effect Profiles in Transwomen Taking Various Hormonal Regimens|journal=The Journal of Clinical Endocrinology & Metabolism|volume=97|issue=12|year=2012|pages=4422–4428|issn=0021-972X|doi=10.1210/jc.2012-2030|pmid=23055547}}</ref> This may be related to the fact that spironolactone has been regarded as a comparatively weak antiandrogen relative to other options.<ref name="BenniVemer1990">{{cite book|author1=H.J.T. Coelingh Benni|author2=H.M. Vemer|title=Chronic Hyperandrogenic Anovulation|url=https://books.google.com/books?id=q6zqFrCLUoIC&pg=PA152|date=15 December 1990|publisher=CRC Press|isbn=978-1-85070-322-8|pages=152–}}</ref>
@@ Line 122: / Line 122: @@
 ==Side effects==
-The most common side effect of spironolactone is [[urinary frequency]]. Other general side effects include [[dehydration]], [[hyponatremia]] (low [[sodium]] levels), mild [[hypotension]] (low [[blood pressure]]),<ref name="Publishers1999" /> [[ataxia]] (muscle incoordination), [[drowsiness]], [[dizziness]],<ref name="Publishers1999" /> [[dry skin]], and [[rash]]es. Because it reduces androgen levels and directly blocks androgen signaling, spironolactone can, in men, cause [[breast tenderness]], [[gynecomastia]] (breast development), and [[feminization (biology)|feminization]] in general, as well as [[testicular atrophy]], reversibly [[infertility|reduced fertility]], and [[sexual dysfunction]] including loss of [[libido]] and [[erectile dysfunction]].<ref name="pmid984618">{{cite journal | title = Spironolactone and endocrine dysfunction | journal = Annals of Internal Medicine | volume = 85 | issue = 5 | pages = 630–6 |date=November 1976 | pmid = 984618 | doi = 10.7326/0003-4819-85-5-630| url = }}</ref> In women, spironolactone can cause [[menstrual irregularities]], [[breast tenderness]], and [[mammoplasia|breast enlargement]].<ref name="pmid2969259"/><ref name="CarrellPeterson2010">{{cite book|author1=Douglas T. Carrell|author2=C. Matthew Peterson|title=Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice|url=https://books.google.com/books?id=lcBEheiufVcC&pg=PA162|date=23 March 2010|publisher=Springer Science & Business Media|isbn=978-1-4419-1436-1|pages=162–}}</ref>
+The most common side effect of spironolactone is [[urinary frequency]]. Other general side effects include [[dehydration]], [[hyponatremia]] (low [[sodium]] levels), mild [[hypotension]] (low [[blood pressure]]),<ref name="Publishers1999" /> [[ataxia]] (muscle incoordination), [[drowsiness]], [[dizziness]],<ref name="Publishers1999" /> [[dry skin]], and [[rash]]es. Because it reduces androgen levels and directly blocks androgen signaling, spironolactone can, in men, cause [[breast tenderness]], [[gynecomastia]] (breast development), and [[feminization (biology)|feminization]] in general, as well as [[testicular atrophy]], reversibly [[infertility|reduced fertility]], and [[sexual dysfunction]] including loss of [[libido]] and [[erectile dysfunction]].<ref name="pmid984618">{{cite journal | title = Spironolactone and endocrine dysfunction | journal = Annals of Internal Medicine | volume = 85 | issue = 5 | pages = 630–6 |date=November 1976 | pmid = 984618 | doi = 10.7326/0003-4819-85-5-630| url = }}</ref> In women, spironolactone can cause [[menstrual irregularities]], [[breast tenderness]], and [[mammoplasia|breast enlargement]].<ref name="pmid2969259"/><ref name="CarrellPeterson2010">{{cite book|author1=Douglas T. Carrell|author2=C. Matthew Peterson|title=Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice|url=https://books.google.com/books?id=lcBEheiufVcC&pg=PA162|date=23 March 2010|publisher=Springer Science & Business Media|isbn=978-1-4419-1436-1|pages=162–|deadurl=no|archiveurl=https://web.archive.org/web/20140704224913/http://books.google.com/books?id=lcBEheiufVcC&pg=PA162|archivedate=4 July 2014|df=}}</ref>
 The most important potential side effect of spironolactone is [[hyperkalemia]] (high [[potassium]] levels), which, in severe cases, can be life-threatening. Hyperkalemia in these patients can present as a non anion-gap metabolic acidosis. Spironolactone may put patients at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and [[gastritis]]. In addition, there has been some evidence suggesting an association between use of the drug and [[hemorrhage|bleeding]] from the [[stomach]] and [[duodenum]], though a causal relationship between the two has not been established.<ref>{{cite journal | title=Spironolactone and risk of upper gastrointestinal events: population based case-control study | journal=Br Med J | year=2006  |vauthors=Verhamme K, Mosis G, Dieleman JP, etal | volume=333 | issue=7563 | pages=330&ndash;3 | doi=10.1136/bmj.38883.479549.2F | pmid=16840442 | pmc=1539051 }}</ref> Also, spironolactone has been shown to be [[immunosuppression|immunosuppressive]] in the treatment of [[sarcoidosis]].<ref>{{cite journal | title = Aldactone in the treatment of sarcoidosis of the lungs | journal=JZ Erkr Atmungsorgane. | year=1977 | author=Wandelt-Freerksen E. | volume=149 | pages=156–9 | pmid = 607621 | issue = 1}}</ref>
@@ Line 132: / Line 132: @@
 ===Breast effects===
-In women, spironolactone is commonly associated with [[mastodynia|breast pain]] and [[mammoplasia|breast enlargement]],<ref name="TsioufisSchmieder2016" /><ref name="Becker2001">{{cite book|author=Kenneth L. Becker|title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA777|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|page=777,1087, 1196|quote=Spironolactone also is both an antiandrogen and a progestagen, and this explains many of its distressing side effects;” decreased libido, mastodynia, and gynecomastia may occur in 50% or more of men, and menometrorrhagia and mastodynia may occur in an equally large number of women taking the drug.27}}</ref> "probably because of [indirect] estrogenic effects on target tissue."<ref name="Aronson2009" /> Breast enlargement may occur in 26% of women and is described as mild,<ref name="Publishers1999">{{cite book|author=Bentham Science Publishers|title=Current Pharmaceutical Design|url=https://books.google.com/books?id=9rfNZL6oEO0C&pg=PA711|date=September 1999|publisher=Bentham Science Publishers|page=711|quote=More often, mild hypotension (11%), breast enlargement (26%) or dizziness (26%) may occur [53]. In most patients, the above side effects are mild and have no clinical significance. [...] Patients frequently experience menstrual disturbances ranging from 10% to 50% [51,94] with the daily dose of 100mg. The weak progestogenic activity of SP may be responsible for the irregular, anovulatory pattern of menstrual cycles but this issue has not been evaluated adequately. Menstrual disturbances are usually well controlled by concomitant use of oral contraceptives [48].}}</ref> while breast tenderness is reported to occur in up to 40% of women taking high dosages of the drug.<ref name="ConnJacobs1998">{{cite journal|last1=Conn|first1=Jennifer J.|last2=Jacobs|first2=Howard S.|title=Managing hirsutism in gynaecological practice|journal=BJOG: An International Journal of Obstetrics and Gynaecology|volume=105|issue=7|year=1998|pages=687–696|issn=1470-0328|doi=10.1111/j.1471-0528.1998.tb10197.x|quote=Breast tenderness is not uncommon and is recorded in up to 40% of women taking higher doses63.}}</ref> Spironolactone also commonly and dose-dependently produces [[gynecomastia]] (breast development) as a side effect in men.<ref name="SeldinGiebisch1997">{{cite book|author1=Donald W. Seldin|author2=Gerhard H. Giebisch|title=Diuretic Agents: Clinical Physiology and Pharmacology|url=https://books.google.com/books?id=VHcsrw6unuAC&pg=PA630|date=23 September 1997|publisher=Academic Press|isbn=978-0-08-053046-8|pages=630–632|quote=The incidence of spironolactone in men is dose related. It is estimated that 50% of men treated with ≥150 mg/day of spironolactone will develop gynecomastia. The degree of gynecomastia varies considerably from patient to patient but in most instances causes mild symptoms. Associated breast tenderness is common but an inconsistent feature.}}</ref><ref name="Elsevier2014">{{cite book|title=Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions|url=https://books.google.com/books?id=NfqxAwAAQBAJ&pg=PA293|date=1 December 2014|publisher=Elsevier Science|isbn=978-0-444-63391-0|page=293|quote=It is well known that gynecomastia is a side effect of spironolactone in men and occurs in a dose-dependent manner in ~7% of cases with doses of <50 mg per day, and up to 50% of cases with doses of >150 mg per day [40,41].}}</ref><ref name="McInnes2008">{{cite book|author=Gordon T. McInnes|title=Clinical Pharmacology and Therapeutics of Hypertension|url=https://books.google.com/books?id=9nqP9iz7NNAC&pg=PA125|year=2008|publisher=Elsevier|isbn=978-0-444-51757-9|page=125|quote=Spironolactone lacks specificty for mineralocorticoid receptors and binds to both progesterone and dihydrotestosterone receptors. This can lead to various endocrine side effects that can limit the use of spironolactone. In females spironolactone can induce menstrual disturbances, breast enlargement and breast tenderness.78 In men spironolactone can induce gynecomastia and impotence. In RALES gynaecomastia or breast pain was reported by 10% of the men in the spironolactone group and 1% of the men in the placebo group (p<0.001), causing more patients in the spironolactone group than in the placebo group to discontinue treatment, despite a mean spironolactone dose of 26 mg.18}}</ref><ref name="TsioufisSchmieder2016">{{cite book|author1=Costas Tsioufis|author2=Roland Schmieder|author3=Giuseppe Mancia|title=Interventional Therapies for Secondary and Essential Hypertension|url=https://books.google.com/books?id=MFfYDAAAQBAJ&pg=PA44|date=15 August 2016|publisher=Springer|isbn=978-3-319-34141-5|page=44|quote=Gynecomastia is dose related and reaches almost 50% with high spironolactone doses (>150 mg daily), while it is much less common (5–10%) with low doses (25–50 mg spironolactone daily) [135].}}</ref> At low dosages, the rate is only 5–10%,<ref name="McInnes2008" /> but at high dosages, up to or exceeding 50% of men may develop gynecomastia.<ref name="Elsevier2014" /><ref name="SeldinGiebisch1997" /><ref name="TsioufisSchmieder2016" /> The severity of the gynecomastia varies considerably, but is usually mild.<ref name="SeldinGiebisch1997" /> As with women, gynecomastia associated with spironolactone is commonly although inconsistently accompanied by breast tenderness.<ref name="SeldinGiebisch1997" /> Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the drug.<ref name="SeldinGiebisch1997" />
+In women, spironolactone is commonly associated with [[mastodynia|breast pain]] and [[mammoplasia|breast enlargement]],<ref name="TsioufisSchmieder2016" /><ref name="Becker2001">{{cite book|author=Kenneth L. Becker|title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA777|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|page=777,1087, 1196|quote=Spironolactone also is both an antiandrogen and a progestagen, and this explains many of its distressing side effects;” decreased libido, mastodynia, and gynecomastia may occur in 50% or more of men, and menometrorrhagia and mastodynia may occur in an equally large number of women taking the drug.27|deadurl=no|archiveurl=https://web.archive.org/web/20140628110255/http://books.google.com/books?id=FVfzRvaucq8C|archivedate=2014-06-28|df=}}</ref> "probably because of [indirect] estrogenic effects on target tissue."<ref name="Aronson2009" /> Breast enlargement may occur in 26% of women and is described as mild,<ref name="Publishers1999">{{cite book|author=Bentham Science Publishers|title=Current Pharmaceutical Design|url=https://books.google.com/books?id=9rfNZL6oEO0C&pg=PA711|date=September 1999|publisher=Bentham Science Publishers|page=711|quote=More often, mild hypotension (11%), breast enlargement (26%) or dizziness (26%) may occur [53]. In most patients, the above side effects are mild and have no clinical significance. [...] Patients frequently experience menstrual disturbances ranging from 10% to 50% [51,94] with the daily dose of 100mg. The weak progestogenic activity of SP may be responsible for the irregular, anovulatory pattern of menstrual cycles but this issue has not been evaluated adequately. Menstrual disturbances are usually well controlled by concomitant use of oral contraceptives [48].}}</ref> while breast tenderness is reported to occur in up to 40% of women taking high dosages of the drug.<ref name="ConnJacobs1998">{{cite journal|last1=Conn|first1=Jennifer J.|last2=Jacobs|first2=Howard S.|title=Managing hirsutism in gynaecological practice|journal=BJOG: An International Journal of Obstetrics and Gynaecology|volume=105|issue=7|year=1998|pages=687–696|issn=1470-0328|doi=10.1111/j.1471-0528.1998.tb10197.x|quote=Breast tenderness is not uncommon and is recorded in up to 40% of women taking higher doses63.}}</ref> Spironolactone also commonly and dose-dependently produces [[gynecomastia]] (breast development) as a side effect in men.<ref name="SeldinGiebisch1997">{{cite book|author1=Donald W. Seldin|author2=Gerhard H. Giebisch|title=Diuretic Agents: Clinical Physiology and Pharmacology|url=https://books.google.com/books?id=VHcsrw6unuAC&pg=PA630|date=23 September 1997|publisher=Academic Press|isbn=978-0-08-053046-8|pages=630–632|quote=The incidence of spironolactone in men is dose related. It is estimated that 50% of men treated with ≥150 mg/day of spironolactone will develop gynecomastia. The degree of gynecomastia varies considerably from patient to patient but in most instances causes mild symptoms. Associated breast tenderness is common but an inconsistent feature.|deadurl=no|archiveurl=https://web.archive.org/web/20140704201956/http://books.google.com/books?id=VHcsrw6unuAC&pg=PA630|archivedate=4 July 2014|df=}}</ref><ref name="Elsevier2014">{{cite book|title=Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions|url=https://books.google.com/books?id=NfqxAwAAQBAJ&pg=PA293|date=1 December 2014|publisher=Elsevier Science|isbn=978-0-444-63391-0|page=293|quote=It is well known that gynecomastia is a side effect of spironolactone in men and occurs in a dose-dependent manner in ~7% of cases with doses of <50 mg per day, and up to 50% of cases with doses of >150 mg per day [40,41].}}</ref><ref name="McInnes2008">{{cite book|author=Gordon T. McInnes|title=Clinical Pharmacology and Therapeutics of Hypertension|url=https://books.google.com/books?id=9nqP9iz7NNAC&pg=PA125|year=2008|publisher=Elsevier|isbn=978-0-444-51757-9|page=125|quote=Spironolactone lacks specificty for mineralocorticoid receptors and binds to both progesterone and dihydrotestosterone receptors. This can lead to various endocrine side effects that can limit the use of spironolactone. In females spironolactone can induce menstrual disturbances, breast enlargement and breast tenderness.78 In men spironolactone can induce gynecomastia and impotence. In RALES gynaecomastia or breast pain was reported by 10% of the men in the spironolactone group and 1% of the men in the placebo group (p<0.001), causing more patients in the spironolactone group than in the placebo group to discontinue treatment, despite a mean spironolactone dose of 26 mg.18}}</ref><ref name="TsioufisSchmieder2016">{{cite book|author1=Costas Tsioufis|author2=Roland Schmieder|author3=Giuseppe Mancia|title=Interventional Therapies for Secondary and Essential Hypertension|url=https://books.google.com/books?id=MFfYDAAAQBAJ&pg=PA44|date=15 August 2016|publisher=Springer|isbn=978-3-319-34141-5|page=44|quote=Gynecomastia is dose related and reaches almost 50% with high spironolactone doses (>150 mg daily), while it is much less common (5–10%) with low doses (25–50 mg spironolactone daily) [135].}}</ref> At low dosages, the rate is only 5–10%,<ref name="McInnes2008" /> but at high dosages, up to or exceeding 50% of men may develop gynecomastia.<ref name="Elsevier2014" /><ref name="SeldinGiebisch1997" /><ref name="TsioufisSchmieder2016" /> The severity of the gynecomastia varies considerably, but is usually mild.<ref name="SeldinGiebisch1997" /> As with women, gynecomastia associated with spironolactone is commonly although inconsistently accompanied by breast tenderness.<ref name="SeldinGiebisch1997" /> Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the drug.<ref name="SeldinGiebisch1997" />
 ===Menstrual disturbances===
@@ Line 143: / Line 143: @@
 ===Depression===
-Increased glucocorticoid activity in the body is associated with [[depression (mood)|depression]].<ref name="StecklerKalin2005">{{cite book|author1=T. Steckler|author2=N. H. Kalin|author3=J. M. H. M. Reul|title=Handbook of Stress and the Brain: Stress: integrative and clinical aspects|url=https://books.google.com/books?id=HihP_D6neBQC&pg=PA440|year=2005|publisher=Elsevier|isbn=978-0-444-51823-1|pages=440–}}</ref><ref name="Lahita2004">{{cite book|author=Robert G. Lahita|title=Systemic Lupus Erythematosus|url=https://books.google.com/books?id=FPj1IT9xy2wC&pg=PA797|date=9 June 2004|publisher=Academic Press|isbn=978-0-08-047454-0|pages=797–}}</ref> As such, it is thought that there may be a risk of depression with spironolactone treatment.<ref name="StecklerKalin2005" /><ref name="pmid12511169">{{vcite2 journal | vauthors = Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H | title = Mineralocorticoid receptor function in major depression | journal = Arch. Gen. Psychiatry | volume = 60 | issue = 1 | pages = 24–8 | year = 2003 | pmid = 12511169 | doi = 10.1001/archpsyc.60.1.24| url = }}</ref><ref name="pmid10818284">{{vcite2 journal | vauthors = Heuser I, Deuschle M, Weber B, Stalla GK, Holsboer F | title = Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralocorticoid receptor antagonist spironolactone | journal = Psychoneuroendocrinology | volume = 25 | issue = 5 | pages = 513–8 | year = 2000 | pmid = 10818284 | doi = 10.1016/s0306-4530(00)00006-8| url = }}</ref> Some clinical research supports this notion.<ref name="SealFranklin2012"/><ref name="Macdonald2004">{{cite journal|last1=Macdonald|first1=J E|title=Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment|journal=Heart|volume=90|issue=7|year=2004|pages=765–770|issn=0007-0769|doi=10.1136/hrt.2003.017368}}</ref><ref name="Holsboer2000">{{cite journal|last1=Holsboer|first1=F|title=The Corticosteroid Receptor Hypothesis of Depression|journal=Neuropsychopharmacology|volume=23|issue=5|year=2000|pages=477–501|issn=0893-133X|doi=10.1016/S0893-133X(00)00159-7}}</ref>
+Increased glucocorticoid activity in the body is associated with [[depression (mood)|depression]].<ref name="StecklerKalin2005">{{cite book|author1=T. Steckler|author2=N. H. Kalin|author3=J. M. H. M. Reul|title=Handbook of Stress and the Brain: Stress: integrative and clinical aspects|url=https://books.google.com/books?id=HihP_D6neBQC&pg=PA440|year=2005|publisher=Elsevier|isbn=978-0-444-51823-1|pages=440–|deadurl=no|archiveurl=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=HihP_D6neBQC&pg=PA440|archivedate=2017-09-08|df=}}</ref><ref name="Lahita2004">{{cite book|author=Robert G. Lahita|title=Systemic Lupus Erythematosus|url=https://books.google.com/books?id=FPj1IT9xy2wC&pg=PA797|date=9 June 2004|publisher=Academic Press|isbn=978-0-08-047454-0|pages=797–|deadurl=no|archiveurl=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=FPj1IT9xy2wC&pg=PA797|archivedate=8 September 2017|df=}}</ref> As such, it is thought that there may be a risk of depression with spironolactone treatment.<ref name="StecklerKalin2005" /><ref name="pmid12511169">{{vcite2 journal | vauthors = Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H | title = Mineralocorticoid receptor function in major depression | journal = Arch. Gen. Psychiatry | volume = 60 | issue = 1 | pages = 24–8 | year = 2003 | pmid = 12511169 | doi = 10.1001/archpsyc.60.1.24| url = }}</ref><ref name="pmid10818284">{{vcite2 journal | vauthors = Heuser I, Deuschle M, Weber B, Stalla GK, Holsboer F | title = Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralocorticoid receptor antagonist spironolactone | journal = Psychoneuroendocrinology | volume = 25 | issue = 5 | pages = 513–8 | year = 2000 | pmid = 10818284 | doi = 10.1016/s0306-4530(00)00006-8| url = }}</ref> Some clinical research supports this notion.<ref name="SealFranklin2012"/><ref name="Macdonald2004">{{cite journal|last1=Macdonald|first1=J E|title=Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment|journal=Heart|volume=90|issue=7|year=2004|pages=765–770|issn=0007-0769|doi=10.1136/hrt.2003.017368}}</ref><ref name="Holsboer2000">{{cite journal|last1=Holsboer|first1=F|title=The Corticosteroid Receptor Hypothesis of Depression|journal=Neuropsychopharmacology|volume=23|issue=5|year=2000|pages=477–501|issn=0893-133X|doi=10.1016/S0893-133X(00)00159-7}}</ref>
 ===Rare reactions===
-Spironolactone may rarely cause more severe side effects such as [[anaphylaxis]], [[renal failure]], [[hepatitis]] (two reported cases, neither serious),<ref name="ThaiSinclair2001">{{cite journal|last1=Thai|first1=Keng-Ee|last2=Sinclair|first2=Rodney D|title=Spironolactone-induced hepatitis|journal=Australasian Journal of Dermatology|volume=42|issue=3|year=2001|pages=180–182|issn=0004-8380|doi=10.1046/j.1440-0960.2001.00510.x}}</ref> [[agranulocytosis]], [[DRESS syndrome]], [[Stevens-Johnson Syndrome]] or [[toxic epidermal necrolysis]].<ref>http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258786.htm</ref><ref>online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7699#f_adverse-reactions</ref> Five cases of [[breast cancer]] in patients who took spironolactone for prolonged periods of time have been reported.<ref name="Aronson2009"/><ref name="McInnes2008" /> It should also be used with caution in people with some [[neurological disorders]], [[anuria]], [[acute kidney injury]], or significant impairment of [[renal failure|renal excretory function]] with risk of hyperkalemia.<ref name="FDA2008" />
+Spironolactone may rarely cause more severe side effects such as [[anaphylaxis]], [[renal failure]], [[hepatitis]] (two reported cases, neither serious),<ref name="ThaiSinclair2001">{{cite journal|last1=Thai|first1=Keng-Ee|last2=Sinclair|first2=Rodney D|title=Spironolactone-induced hepatitis|journal=Australasian Journal of Dermatology|volume=42|issue=3|year=2001|pages=180–182|issn=0004-8380|doi=10.1046/j.1440-0960.2001.00510.x}}</ref> [[agranulocytosis]], [[DRESS syndrome]], [[Stevens-Johnson Syndrome]] or [[toxic epidermal necrolysis]].<ref>{{cite web |url=http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258786.htm |title=Archived copy |accessdate=2014-03-03 |deadurl=no |archiveurl=https://web.archive.org/web/20150310163603/http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258786.htm |archivedate=2015-03-10 |df= }}</ref><ref>online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7699#f_adverse-reactions</ref> Five cases of [[breast cancer]] in patients who took spironolactone for prolonged periods of time have been reported.<ref name="Aronson2009"/><ref name="McInnes2008" /> It should also be used with caution in people with some [[neurological disorders]], [[anuria]], [[acute kidney injury]], or significant impairment of [[renal failure|renal excretory function]] with risk of hyperkalemia.<ref name="FDA2008" />
 ===Spironolactone bodies===
@@ Line 155: / Line 155: @@
 Spironolactone is considered [[Pregnancy Category]] C meaning that it is unclear if it is safe for use during pregnancy.<ref name=AHFS2015/> It is able to cross the [[placenta]].<ref name="Becker2001" /> Likewise, it has been found to be present in the breast milk of lactating mothers and, while the effects of spironolactone or its metabolites have not been extensively studied in breastfeeding infants, it is generally recommended that women also not take the drug while [[breast feeding|nursing]].<ref name="FDA2008" /> However, only very small amounts of spironolactone and its metabolite canrenone enter [[breast milk]], and the amount received by an infant during breastfeeding (<0.5% of the mother's dose) is considered to be insignificant.<ref name="Ainsworth2014" />
-A study found that spironolactone was not associated with [[teratogen]]icity in the offspring of rats.<ref name="Little2006">{{cite book|author=Bertis Little|title=Drugs and Pregnancy: A Handbook|url=https://books.google.com/books?id=lnySHcBjXsEC&pg=PA63|date=29 September 2006|publisher=CRC Press|isbn=978-0-340-80917-4|pages=63–}}</ref><ref name="RubinRamsey2008">{{cite book|author1=Peter C. Rubin|author2=Margaret Ramsey|title=Prescribing in Pregnancy|url=https://books.google.com/books?id=2zHGHec53oMC&pg=PA83|date=30 April 2008|publisher=John Wiley & Sons|isbn=978-0-470-69555-5|pages=83–}}</ref><ref name="BriggsFreeman2011">{{cite book|author1=Gerald G. Briggs|author2=Roger K. Freeman|author3=Sumner J. Yaffe|title=Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk|url=https://books.google.com/books?id=OIgTE4aynrMC&pg=PA1349|year=2011|publisher=Lippincott Williams & Wilkins|isbn=978-1-60831-708-0|pages=1349–}}</ref> Because it is an antiandrogen however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses.<ref name="Little2006" /><ref name="RubinRamsey2008" /> In accordance, a subsequent study found that partial feminization of the genitalia occurred in the male offspring of rats that received doses of spironolactone that were five times higher than those normally used in humans (200&nbsp;mg/kg per day).<ref name="Little2006" /><ref name="BriggsFreeman2011" /> Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100&nbsp;mg/kg per day).<ref name="BriggsFreeman2011" />
+A study found that spironolactone was not associated with [[teratogen]]icity in the offspring of rats.<ref name="Little2006">{{cite book|author=Bertis Little|title=Drugs and Pregnancy: A Handbook|url=https://books.google.com/books?id=lnySHcBjXsEC&pg=PA63|date=29 September 2006|publisher=CRC Press|isbn=978-0-340-80917-4|pages=63–|deadurl=no|archiveurl=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=lnySHcBjXsEC&pg=PA63|archivedate=8 September 2017|df=}}</ref><ref name="RubinRamsey2008">{{cite book|author1=Peter C. Rubin|author2=Margaret Ramsey|title=Prescribing in Pregnancy|url=https://books.google.com/books?id=2zHGHec53oMC&pg=PA83|date=30 April 2008|publisher=John Wiley & Sons|isbn=978-0-470-69555-5|pages=83–|deadurl=no|archiveurl=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=2zHGHec53oMC&pg=PA83|archivedate=8 September 2017|df=}}</ref><ref name="BriggsFreeman2011">{{cite book|author1=Gerald G. Briggs|author2=Roger K. Freeman|author3=Sumner J. Yaffe|title=Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk|url=https://books.google.com/books?id=OIgTE4aynrMC&pg=PA1349|year=2011|publisher=Lippincott Williams & Wilkins|isbn=978-1-60831-708-0|pages=1349–|deadurl=no|archiveurl=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=OIgTE4aynrMC&pg=PA1349|archivedate=2017-09-08|df=}}</ref> Because it is an antiandrogen however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses.<ref name="Little2006" /><ref name="RubinRamsey2008" /> In accordance, a subsequent study found that partial feminization of the genitalia occurred in the male offspring of rats that received doses of spironolactone that were five times higher than those normally used in humans (200&nbsp;mg/kg per day).<ref name="Little2006" /><ref name="BriggsFreeman2011" /> Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100&nbsp;mg/kg per day).<ref name="BriggsFreeman2011" />
-In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.<ref name="Little2006" /><ref name="RubinRamsey2008" /><ref name="ElkayamGleicher1998">{{cite book|author1=Uri Elkayam|author2=Norbert Gleicher|title=Cardiac Problems in Pregnancy: Diagnosis and Management of Maternal and Fetal Heart Disease|url=https://books.google.com/books?id=z6E-Hgeu1nYC&pg=PA353|date=23 June 1998|publisher=John Wiley & Sons|isbn=978-0-471-16358-9|pages=353–}}</ref><ref name="Schaefer2001">{{cite book|author=Christof Schaefer|title=Drugs During Pregnancy and Lactation: Handbook of Prescription Drugs and Comparative Risk Assessment|url=https://books.google.com/books?id=CE569saGK70C&pg=PA115|year=2001|publisher=Gulf Professional Publishing|isbn=978-0-444-50763-1|pages=115, 143}}</ref> Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific [[birth defect]]s.<ref name="Schaefer2001" /> A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy; there was no feminization in the boy.<ref name="Schaefer2001" /> In addition, spironolactone has been used at high doses to treat pregnant women with [[Bartter's syndrome]], and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants.<ref name="Little2006" /><ref name="Ainsworth2014">{{cite book|author=Sean B. Ainsworth|title=Neonatal Formulary: Drug Use in Pregnancy and the First Year of Life|url=https://books.google.com/books?id=VOLhBQAAQBAJ&pg=PA486|date=10 November 2014|publisher=John Wiley & Sons|isbn=978-1-118-81959-3|pages=486–}}</ref> There are similar findings, albeit also limited, for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human  abnormalities (including feminization of male fetuses) at both a low dose of 2&nbsp;mg/day or high doses of 50 to 100&nbsp;mg/day).<ref name="Schaefer2001" /> In any case, spironolactone is nonetheless not recommended during pregnancy due to theoretical concerns relating to feminization of males and also to potential alteration of fetal potassium levels.<ref name="Little2006" /><ref name="Upfal2006">{{cite book|author=Jonathan Upfal|title=Australian Drug Guide|url=https://books.google.com/books?id=7O9kiqN2q2YC&pg=PA671|year=2006|publisher=Black Inc.|isbn=978-1-86395-174-6|pages=671–}}</ref>
+In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.<ref name="Little2006" /><ref name="RubinRamsey2008" /><ref name="ElkayamGleicher1998">{{cite book|author1=Uri Elkayam|author2=Norbert Gleicher|title=Cardiac Problems in Pregnancy: Diagnosis and Management of Maternal and Fetal Heart Disease|url=https://books.google.com/books?id=z6E-Hgeu1nYC&pg=PA353|date=23 June 1998|publisher=John Wiley & Sons|isbn=978-0-471-16358-9|pages=353–|deadurl=no|archiveurl=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=z6E-Hgeu1nYC&pg=PA353|archivedate=8 September 2017|df=}}</ref><ref name="Schaefer2001">{{cite book|author=Christof Schaefer|title=Drugs During Pregnancy and Lactation: Handbook of Prescription Drugs and Comparative Risk Assessment|url=https://books.google.com/books?id=CE569saGK70C&pg=PA115|year=2001|publisher=Gulf Professional Publishing|isbn=978-0-444-50763-1|pages=115, 143|deadurl=no|archiveurl=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=CE569saGK70C&pg=PA115|archivedate=2017-09-08|df=}}</ref> Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific [[birth defect]]s.<ref name="Schaefer2001" /> A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy; there was no feminization in the boy.<ref name="Schaefer2001" /> In addition, spironolactone has been used at high doses to treat pregnant women with [[Bartter's syndrome]], and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants.<ref name="Little2006" /><ref name="Ainsworth2014">{{cite book|author=Sean B. Ainsworth|title=Neonatal Formulary: Drug Use in Pregnancy and the First Year of Life|url=https://books.google.com/books?id=VOLhBQAAQBAJ&pg=PA486|date=10 November 2014|publisher=John Wiley & Sons|isbn=978-1-118-81959-3|pages=486–|deadurl=no|archiveurl=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=VOLhBQAAQBAJ&pg=PA486|archivedate=8 September 2017|df=}}</ref> There are similar findings, albeit also limited, for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human  abnormalities (including feminization of male fetuses) at both a low dose of 2&nbsp;mg/day or high doses of 50 to 100&nbsp;mg/day).<ref name="Schaefer2001" /> In any case, spironolactone is nonetheless not recommended during pregnancy due to theoretical concerns relating to feminization of males and also to potential alteration of fetal potassium levels.<ref name="Little2006" /><ref name="Upfal2006">{{cite book|author=Jonathan Upfal|title=Australian Drug Guide|url=https://books.google.com/books?id=7O9kiqN2q2YC&pg=PA671|year=2006|publisher=Black Inc.|isbn=978-1-86395-174-6|pages=671–|deadurl=no|archiveurl=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=7O9kiqN2q2YC&pg=PA671|archivedate=2017-09-08|df=}}</ref>
 ==Interactions==
-Spironolactone often increases serum [[potassium]] levels and can cause [[hyperkalemia]], a very serious condition. Therefore, it is recommended that people using this drug avoid potassium supplements and salt substitutes containing potassium.<ref>{{cite web | title = Advisory Statement | publisher = Klinge Chemicals / LoSalt | url = http://www.losalt.com/docs/lo_salt_web_advice.pdf | format = pdf | accessdate = 2007-03-15 |archiveurl = http://web.archive.org/web/20061115185827/http://www.losalt.com/docs/lo_salt_web_advice.pdf <!-- Bot retrieved archive --> |archivedate = 2006-11-15}}</ref> Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne.<ref>{{cite journal |vauthors=Plovanich M, Weng QY, Mostaghimi A | title = Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne | journal = JAMA Dermatology |year = 2015| url= http://archderm.jamanetwork.com/article.aspx?articleid=2194951 | pmid = 25796182| doi = 10.1001/jamadermatol.2015.34 | volume=151 | pages=941–4}}</ref>
+Spironolactone often increases serum [[potassium]] levels and can cause [[hyperkalemia]], a very serious condition. Therefore, it is recommended that people using this drug avoid potassium supplements and salt substitutes containing potassium.<ref>{{cite web | title = Advisory Statement | publisher = Klinge Chemicals / LoSalt | url = http://www.losalt.com/docs/lo_salt_web_advice.pdf | format = pdf | accessdate = 2007-03-15 | archiveurl = https://web.archive.org/web/20061115185827/http://www.losalt.com/docs/lo_salt_web_advice.pdf | archivedate = 2006-11-15 | deadurl = yes | df =  }}</ref> Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne.<ref>{{cite journal | vauthors = Plovanich M, Weng QY, Mostaghimi A | title = Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne | journal = JAMA Dermatology | year = 2015 | url = http://archderm.jamanetwork.com/article.aspx?articleid=2194951 | pmid = 25796182 | doi = 10.1001/jamadermatol.2015.34 | volume = 151 | pages = 941–4 | deadurl = no | archiveurl = https://web.archive.org/web/20150330174430/http://archderm.jamanetwork.com/article.aspx?articleid=2194951 | archivedate = 2015-03-30 | df =  }}</ref>
 Research has suggested that spironolactone may be able to interfere with the effectiveness of [[antidepressant]] treatment. As the drug acts as an antimineralocorticoid, it is thought that it may reduce the effectiveness of certain antidepressants by interfering with normalization of the [[hypothalamic–pituitary–adrenal axis]] and increasing glucocorticoid levels.<ref>Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).</ref><ref name="pmid19909979">{{cite journal  |vauthors=Otte C, Hinkelmann K, Moritz S, etal | title = Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study | journal = J Psychiatr Res | volume = 44 | issue = 6 | pages = 339–46 |date=April 2010 | pmid = 19909979 | doi = 10.1016/j.jpsychires.2009.10.006 | url = http://linkinghub.elsevier.com/retrieve/pii/S0022-3956(09)00229-5}}</ref> However, other research contradicts this hypothesis and has suggested that spironolactone may actually produce antidepressant-like effects in animals.<ref name="pmid21515309">{{cite journal |vauthors=Mostalac-Preciado CR, de Gortari P, López-Rubalcava C | title = Antidepressant-like effects of mineralocorticoid but not glucocorticoid antagonists in the lateral septum: interactions with the serotonergic system | journal = Behav. Brain Res. | volume = 223 | issue = 1 | pages = 88–98 |date=September 2011 | pmid = 21515309 | doi = 10.1016/j.bbr.2011.04.008 | url = http://linkinghub.elsevier.com/retrieve/pii/S0166-4328(11)00296-8}}</ref>
-Spironolactone can also have numerous other interactions, most commonly with other [[cardiac]] and blood pressure medications.<ref name="FDA2008">http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/012151s062lbl.pdf</ref> Spironolactone together with [[trimethoprim/sulfamethoxazole]] increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.<ref>{{Cite journal |vauthors=Juvet T, Gourineni V, Ravi S, Zarich S | title = Life-threatening hyperkalemia: a potentially lethal drug combination | journal = Connecticut Medicine | date = September 2013 | volume = 77 | issue = 8 | pages = 491–493}}</ref>
+Spironolactone can also have numerous other interactions, most commonly with other [[cardiac]] and blood pressure medications.<ref name="FDA2008">{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/012151s062lbl.pdf |title=Archived copy |accessdate=2014-04-17 |deadurl=no |archiveurl=https://web.archive.org/web/20130822170409/http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/012151s062lbl.pdf |archivedate=2013-08-22 |df= }}</ref> Spironolactone together with [[trimethoprim/sulfamethoxazole]] increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.<ref>{{Cite journal |vauthors=Juvet T, Gourineni V, Ravi S, Zarich S | title = Life-threatening hyperkalemia: a potentially lethal drug combination | journal = Connecticut Medicine | date = September 2013 | volume = 77 | issue = 8 | pages = 491–493}}</ref>
 Spironolactone has been reported to induce the [[enzyme]] [[CYP3A4]], which can result in [[drug interaction|interaction]]s with various drugs.<ref name="Davis2009">{{cite book|author=Mellar P. Davis|title=Opioids in Cancer Pain|url=https://books.google.com/books?id=aEzg6i2nPMQC&pg=PA222|date=28 May 2009|publisher=OUP Oxford|isbn=978-0-19-923664-0|pages=222–}}</ref> However, it has also been reported that metabolites of spironolactone [[irreversible inhibition|irreversibly inhibit]] CYP3A4.<ref name="Wolverton2007">{{cite book|author=Stephen E. Wolverton|title=Comprehensive Dermatologic Drug Therapy|url=https://books.google.com/books?id=AaJwq_X6U6MC&pg=PT2677|date=8 March 2007|publisher=Elsevier Health Sciences|isbn=1-4377-2070-6|pages=2677–}}</ref>
@@ Line 196: / Line 196: @@
 * [[Progesterone receptor]] (PR) [[agonist]]
 * [[Glucocorticoid receptor]] (GR) antagonist
-* [[Pregnane X receptor]] (PXR) agonist (and thus [[CYP3A4]]<ref name="pmid9890159">{{cite journal | vauthors = Pelkonen O, Mäenpää J, Taavitsainen P, Rautio A, Raunio H | title = Inhibition and induction of human cytochrome P450 (CYP) enzymes | journal = Xenobiotica | volume = 28 | issue = 12 | pages = 1203–53 | year = 1998 | pmid = 9890159 | doi = 10.1080/004982598238886 | url = http://www.researchgate.net/profile/Hannu_Raunio/publication/13399265_Inhibition_and_induction_of_human_cytochrome_P450_(CYP)_enzymes/links/0deec521eff4a0e032000000.pdf}}</ref> and [[P-glycoprotein]] inducer)<ref name="pmid21459122">{{cite journal |vauthors=Rigalli JP, Ruiz ML, Perdomo VG, Villanueva SS, Mottino AD, Catania VA | title = Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells | journal = Toxicology | volume = 285 | issue = 1–2 | pages = 18–24 |date=July 2011 | pmid = 21459122 | doi = 10.1016/j.tox.2011.03.015 | url = }}</ref><ref name="pmid9727070">{{cite journal |vauthors=Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = J. Clin. Invest. | volume = 102 | issue = 5 | pages = 1016–23 |date=September 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 | url = }}</ref><ref name="pmid16863430">{{cite journal |vauthors=Christians U, Schmitz V, Haschke M | title = Functional interactions between P-glycoprotein and CYP3A in drug metabolism | journal = Expert Opin Drug Metab Toxicol | volume = 1 | issue = 4 | pages = 641–54 |date=December 2005 | pmid = 16863430 | doi = 10.1517/17425255.1.4.641 | url = }}</ref>
+* [[Pregnane X receptor]] (PXR) agonist (and thus [[CYP3A4]]<ref name="pmid9890159">{{cite journal | vauthors = Pelkonen O, Mäenpää J, Taavitsainen P, Rautio A, Raunio H | title = Inhibition and induction of human cytochrome P450 (CYP) enzymes | journal = Xenobiotica | volume = 28 | issue = 12 | pages = 1203–53 | year = 1998 | pmid = 9890159 | doi = 10.1080/004982598238886 | url = http://www.researchgate.net/profile/Hannu_Raunio/publication/13399265_Inhibition_and_induction_of_human_cytochrome_P450_(CYP)_enzymes/links/0deec521eff4a0e032000000.pdf | deadurl = no | archiveurl = https://web.archive.org/web/20150924131438/http://www.researchgate.net/profile/Hannu_Raunio/publication/13399265_Inhibition_and_induction_of_human_cytochrome_P450_(CYP)_enzymes/links/0deec521eff4a0e032000000.pdf | archivedate = 2015-09-24 | df =  }}</ref> and [[P-glycoprotein]] inducer)<ref name="pmid21459122">{{cite journal |vauthors=Rigalli JP, Ruiz ML, Perdomo VG, Villanueva SS, Mottino AD, Catania VA | title = Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells | journal = Toxicology | volume = 285 | issue = 1–2 | pages = 18–24 |date=July 2011 | pmid = 21459122 | doi = 10.1016/j.tox.2011.03.015 | url = }}</ref><ref name="pmid9727070">{{cite journal |vauthors=Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = J. Clin. Invest. | volume = 102 | issue = 5 | pages = 1016–23 |date=September 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 | url = }}</ref><ref name="pmid16863430">{{cite journal |vauthors=Christians U, Schmitz V, Haschke M | title = Functional interactions between P-glycoprotein and CYP3A in drug metabolism | journal = Expert Opin Drug Metab Toxicol | volume = 1 | issue = 4 | pages = 641–54 |date=December 2005 | pmid = 16863430 | doi = 10.1517/17425255.1.4.641 | url = }}</ref>
 * [[Steroid 11β-hydroxylase]], [[aldosterone synthase]], and [[17α-hydroxylase]]/[[17,20-lyase]] [[enzyme inhibitor|inhibitor]]
-There is also evidence that spironolactone may [[channel blocker|block]] [[voltage-dependent calcium channel|voltage-dependent Ca<sup>2+</sup> channel]]s.<ref name="pmid10942165">{{cite journal  |vauthors=Sorrentino R, Autore G, Cirino G, d'Emmanuele de Villa Bianca R, Calignano A, Vanasia M, etal | title = Effect of spironolactone and its metabolites on contractile property of isolated rat aorta rings. | journal = J Cardiovasc Pharmacol | year = 2000 | volume = 36 | issue = 2 | pages = 230–235 | pmid = 10942165 | url = http://www.ncbi.nlm.nih.gov/pubmed/10942165 | doi=10.1097/00005344-200008000-00013}}</ref><ref name="BendtzenHansen2003">{{cite journal | last1 = Bendtzen | first1 = K. | last2 = Hansen | first2 = P. R. | last3 = Rieneck | first3 = K. | title = Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis | journal = Clinical and Experimental Immunology | volume = 134 | issue = 1 | year = 2003 | page = 151158 | issn = 0009-9104 | doi = 10.1046/j.1365-2249.2003.02249.x}}</ref>
+There is also evidence that spironolactone may [[channel blocker|block]] [[voltage-dependent calcium channel|voltage-dependent Ca<sup>2+</sup> channel]]s.<ref name="pmid10942165">{{cite journal | vauthors = Sorrentino R, Autore G, Cirino G, d'Emmanuele de Villa Bianca R, Calignano A, Vanasia M, etal | title = Effect of spironolactone and its metabolites on contractile property of isolated rat aorta rings. | journal = J Cardiovasc Pharmacol | year = 2000 | volume = 36 | issue = 2 | pages = 230–235 | pmid = 10942165 | url = http://www.ncbi.nlm.nih.gov/pubmed/10942165 | doi = 10.1097/00005344-200008000-00013 | deadurl = no | archiveurl = https://web.archive.org/web/20130620173200/http://www.ncbi.nlm.nih.gov/pubmed/10942165 | archivedate = 2013-06-20 | df =  }}</ref><ref name="BendtzenHansen2003">{{cite journal | last1 = Bendtzen | first1 = K. | last2 = Hansen | first2 = P. R. | last3 = Rieneck | first3 = K. | title = Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis | journal = Clinical and Experimental Immunology | volume = 134 | issue = 1 | year = 2003 | page = 151158 | issn = 0009-9104 | doi = 10.1046/j.1365-2249.2003.02249.x}}</ref>
 Although spironolactone is known to possess the above activities, it should be noted that the drug is a [[prodrug]], with [[active metabolite]]s such as [[7α-thiomethylspironolactone]] (7α-TMS) and [[canrenone]] being responsible for its clinical effects. For this reason, the actual ''in vivo'' clinical profile of spironolactone may differ from the activities and effective and inhibitory concentrations described above and to the right. In any case, interaction with both the MR and AR have been observed for metabolites of spironolactone.<ref name="AgustiBourgeois2013" /><ref name="pmid263288" /> On the other hand, spironolactone itself has only very low affinity for the ER, suggesting that its metabolites may be responsible for this activity.<ref name="pmid7391714" /><ref name="pmid27072668" />
@@ Line 209: / Line 209: @@
 Spironolactone is a potent and direct antagonist of the AR, blocking androgens like testosterone from binding to and activating the receptor.<ref name="pmid166833">{{cite journal |vauthors=Corvol P, Michaud A, Menard J, Freifeld M, Mahoudeau J | title = Antiandrogenic effect of spirolactones: mechanism of action | journal = Endocrinology | volume = 97 | issue = 1 | pages = 52–8 |date=July 1975 | pmid = 166833 | doi = 10.1210/endo-97-1-52| url = http://endo.endojournals.org/cgi/pmidlookup?view=long&pmid=166833}}</ref><ref name="SeldinGiebisch1997" /> The AR antagonism of spironolactone mostly underlies its antiandrogen activity and is responsible for its therapeutic benefits in the treatment of [[androgen-dependent condition]]s like acne, hirsutism, and pattern hair loss and its usefulness in hormone therapy for transgender women.<ref name="pmid166833" /> In addition, the AR antagonism of spironolactone is involved in its feminizing side effects like gynecomastia in men.<ref name="pmid166833" />
-Spironolactone, similarly to other [[steroidal antiandrogen]]s such as [[cyproterone acetate]], is actually not a pure, or ''[[silent antagonist|silent]]'', antagonist of the AR, but rather is a weak [[partial agonist]] with the capacity for both antagonistic and agonistic effects.<ref name="pmid2462135">{{cite journal |vauthors=Luthy IA, Begin DJ, Labrie F | title = Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture | journal = Journal of Steroid Biochemistry | volume = 31 | issue = 5 | pages = 845–52 |date=November 1988 | pmid = 2462135 | doi = 10.1016/0022-4731(88)90295-6| url = }}</ref><ref name="pmid10715537">{{cite journal  |vauthors=Térouanne B, Tahiri B, Georget V, etal | title = A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects | journal = Molecular and Cellular Endocrinology | volume = 160 | issue = 1–2 | pages = 39–49 |date=February 2000 | pmid = 10715537 | doi = 10.1016/S0303-7207(99)00251-8| url = http://linkinghub.elsevier.com/retrieve/pii/S0303-7207(99)00251-8}}</ref><ref name="FritzSperoff2010">{{cite book | author1 = Marc A. Fritz | author2 = Leon Speroff | title = Clinical Gynecologic Endocrinology and Infertility | url = https://books.google.com/books?id=Ll73ZsBKLkwC&pg=PA80 | accessdate = 27 May 2012 | date = 20 December 2010 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-7968-5 | page = 80}}</ref> However, in the presence of sufficiently high levels of potent full agonists like testosterone and DHT (the cases in which spironolactone is usually used even with regards to the "lower" relative levels present in females),<ref name="FritzSperoff2010" /> spironolactone will behave more similarly to a pure antagonist. Nonetheless, there may still be a potential for spironolactone to produce androgenic effects in the body at sufficiently high dosages and/or in those with very low endogenous androgen concentrations. As an example, one condition in which spironolactone is contraindicated is [[prostate cancer]] in men being treated with [[androgen deprivation therapy]],<ref name="pmid19509232">{{cite journal |vauthors=Attard G, Reid AH, Olmos D, de Bono JS | title = Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven | journal = Cancer Research | volume = 69 | issue = 12 | pages = 4937–40 |date=June 2009 | pmid = 19509232 | doi = 10.1158/0008-5472.CAN-08-4531 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19509232}}</ref> as spironolactone has been shown ''[[in vitro]]'' to significantly accelerate [[carcinoma]] growth in the absence of any other androgens.<ref name="pmid2462135" /> In accordance, two [[case report]]s have described significant worsening of prostate cancer with spironolactone treatment in patients with the disease, leading the authors to conclude that spironolactone has the potential for androgenic effects in some contexts and that it should perhaps be considered to be a [[selective androgen receptor modulator]] (SARM), albeit with mostly antagonistic effects.<ref name="pmid22665559">{{vcite2 journal | vauthors = Sundar S, Dickinson PD | title = Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate | journal = BMJ Case Rep | volume = 2012 | issue = | pages = bcr1120115238| year = 2012 | pmid = 22665559 | pmc = 3291010 | doi = 10.1136/bcr.11.2011.5238 | url = }}</ref><ref name="pmid27641657">{{cite journal | vauthors = Flynn T, Guancial EA, Kilari M, Kilari D | title = Case Report: Spironolactone Withdrawal Associated With a Dramatic Response in a Patient With Metastatic Castrate-Resistant Prostate Cancer | journal = Clin Genitourin Cancer | volume = | issue = | pages = | year = 2016 | pmid = 27641657 | doi = 10.1016/j.clgc.2016.08.006 | url = }}</ref>
+Spironolactone, similarly to other [[steroidal antiandrogen]]s such as [[cyproterone acetate]], is actually not a pure, or ''[[silent antagonist|silent]]'', antagonist of the AR, but rather is a weak [[partial agonist]] with the capacity for both antagonistic and agonistic effects.<ref name="pmid2462135">{{cite journal |vauthors=Luthy IA, Begin DJ, Labrie F | title = Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture | journal = Journal of Steroid Biochemistry | volume = 31 | issue = 5 | pages = 845–52 |date=November 1988 | pmid = 2462135 | doi = 10.1016/0022-4731(88)90295-6| url = }}</ref><ref name="pmid10715537">{{cite journal  |vauthors=Térouanne B, Tahiri B, Georget V, etal | title = A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects | journal = Molecular and Cellular Endocrinology | volume = 160 | issue = 1–2 | pages = 39–49 |date=February 2000 | pmid = 10715537 | doi = 10.1016/S0303-7207(99)00251-8| url = http://linkinghub.elsevier.com/retrieve/pii/S0303-7207(99)00251-8}}</ref><ref name="FritzSperoff2010">{{cite book | author1 = Marc A. Fritz | author2 = Leon Speroff | title = Clinical Gynecologic Endocrinology and Infertility | url = https://books.google.com/books?id=Ll73ZsBKLkwC&pg=PA80 | accessdate = 27 May 2012 | date = 20 December 2010 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-7968-5 | page = 80 | deadurl = no | archiveurl = https://web.archive.org/web/20140704202013/http://books.google.com/books?id=Ll73ZsBKLkwC&pg=PA80 | archivedate = 4 July 2014 | df =  }}</ref> However, in the presence of sufficiently high levels of potent full agonists like testosterone and DHT (the cases in which spironolactone is usually used even with regards to the "lower" relative levels present in females),<ref name="FritzSperoff2010" /> spironolactone will behave more similarly to a pure antagonist. Nonetheless, there may still be a potential for spironolactone to produce androgenic effects in the body at sufficiently high dosages and/or in those with very low endogenous androgen concentrations. As an example, one condition in which spironolactone is contraindicated is [[prostate cancer]] in men being treated with [[androgen deprivation therapy]],<ref name="pmid19509232">{{cite journal |vauthors=Attard G, Reid AH, Olmos D, de Bono JS | title = Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven | journal = Cancer Research | volume = 69 | issue = 12 | pages = 4937–40 |date=June 2009 | pmid = 19509232 | doi = 10.1158/0008-5472.CAN-08-4531 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19509232}}</ref> as spironolactone has been shown ''[[in vitro]]'' to significantly accelerate [[carcinoma]] growth in the absence of any other androgens.<ref name="pmid2462135" /> In accordance, two [[case report]]s have described significant worsening of prostate cancer with spironolactone treatment in patients with the disease, leading the authors to conclude that spironolactone has the potential for androgenic effects in some contexts and that it should perhaps be considered to be a [[selective androgen receptor modulator]] (SARM), albeit with mostly antagonistic effects.<ref name="pmid22665559">{{vcite2 journal | vauthors = Sundar S, Dickinson PD | title = Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate | journal = BMJ Case Rep | volume = 2012 | issue = | pages = bcr1120115238| year = 2012 | pmid = 22665559 | pmc = 3291010 | doi = 10.1136/bcr.11.2011.5238 | url = }}</ref><ref name="pmid27641657">{{cite journal | vauthors = Flynn T, Guancial EA, Kilari M, Kilari D | title = Case Report: Spironolactone Withdrawal Associated With a Dramatic Response in a Patient With Metastatic Castrate-Resistant Prostate Cancer | journal = Clin Genitourin Cancer | volume = | issue = | pages = | year = 2016 | pmid = 27641657 | doi = 10.1016/j.clgc.2016.08.006 | url = }}</ref>
 ===Estrogenic activity===
@@ Line 221: / Line 221: @@
 * By acting as an antiandrogen, as androgens can suppress both estrogen production and signaling (e.g., in the breasts).<ref name="SeldinGiebisch1997" /><ref name="pmid10973921">{{cite journal |vauthors=Zhou J, Ng S, Adesanya-Famuiya O, Anderson K, Bondy CA | title = Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression | journal = [[FASEB Journal]] | volume = 14 | issue = 12 | pages = 1725–30 |date=September 2000 | pmid = 10973921 | doi = 10.1096/fj.99-0863com| url = http://www.fasebj.org/cgi/pmidlookup?view=long&pmid=10973921}}</ref>
-* Inhibition of the conversion of estradiol to estrone, resulting in an increase in the ratio of circulating estradiol to estrone.<ref name="pmid12477487">{{cite journal |vauthors=Satoh T, Itoh S, Seki T, Itoh S, Nomura N, Yoshizawa I | title = On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 82 | issue = 2–3 | pages = 209–16 |date=October 2002 | pmid = 12477487 | doi = 10.1016/S0960-0760(02)00154-1| url = http://linkinghub.elsevier.com/retrieve/pii/S0960076002001541}}</ref> Estradiol is far more potent than estrone as an estrogen, which is comparatively almost inactive.<ref name="pmid12071379">{{cite journal |vauthors=Ruggiero RJ, Likis FE | title = Estrogen: physiology, pharmacology, and formulations for replacement therapy | journal = Journal of Midwifery & Women's Health | volume = 47 | issue = 3 | pages = 130–8 | year = 2002 | pmid = 12071379 | doi = 10.1016/s1526-9523(02)00233-7| url = http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1526-9523&date=2002&volume=47&issue=3&spage=130}}</ref><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref>
+* Inhibition of the conversion of estradiol to estrone, resulting in an increase in the ratio of circulating estradiol to estrone.<ref name="pmid12477487">{{cite journal |vauthors=Satoh T, Itoh S, Seki T, Itoh S, Nomura N, Yoshizawa I | title = On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 82 | issue = 2–3 | pages = 209–16 |date=October 2002 | pmid = 12477487 | doi = 10.1016/S0960-0760(02)00154-1| url = http://linkinghub.elsevier.com/retrieve/pii/S0960076002001541}}</ref> Estradiol is far more potent than estrone as an estrogen, which is comparatively almost inactive.<ref name="pmid12071379">{{cite journal |vauthors=Ruggiero RJ, Likis FE | title = Estrogen: physiology, pharmacology, and formulations for replacement therapy | journal = Journal of Midwifery & Women's Health | volume = 47 | issue = 3 | pages = 130–8 | year = 2002 | pmid = 12071379 | doi = 10.1016/s1526-9523(02)00233-7| url = http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1526-9523&date=2002&volume=47&issue=3&spage=130}}</ref><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue =  | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf | deadurl = no | archiveurl = https://web.archive.org/web/20160822055012/http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf | archivedate = 2016-08-22 | df =  }}</ref>
 * Enhancement of the rate of peripheral conversion of testosterone into estradiol, thus decreasing the ratio of circulating testosterone to estradiol.<ref name="pmid907238" />
@@ Line 229: / Line 229: @@
 ====Progestogenic activity====
-Spironolactone has weak [[progestogen]]ic activity in [[bioassay]]s.<ref name="DesaiP.2001" /><ref name="SchanePotts1978">{{cite journal | last1 = Schane | first1 = H. P. | last2 = Potts | first2 = G. O. | title = Oral Progestational Activity of Spironolactone | journal = Journal of Clinical Endocrinology & Metabolism | volume = 47 | issue = 3 | year = 1978 | page = 691694 | issn = 0021-972X | doi = 10.1210/jcem-47-3-691 | pmid=95623}}</ref> Its actions in this regard are a result of direct agonist activity at the PR, though with a very low [[EC50|half-maximal]] potency.<ref name="pmid20650892" /> Spironolactone's progestogenic activity has been suggested to be involved in some of its side effects,<ref name="Delyani2000">{{cite journal|last1=Delyani|first1=John A|title=Mineralocorticoid receptor antagonists: The evolution of utility and pharmacology|journal=Kidney International|volume=57|issue=4|year=2000|pages=1408–1411|issn=0085-2538|doi=10.1046/j.1523-1755.2000.00983.x|pmid=10760075}}</ref> including the [[menstrual disorder|menstrual irregularities]] seen in women and the undesirable [[serum (blood)|serum]] [[lipid]] profile changes that are seen at higher doses.<ref name="Carrell2010" /><ref name="MelmedPolonsky2011">{{cite book | vauthors = Melmed S, Polonsky KS, Larsen PR, Kronenberg HM | title = Williams Textbook of Endocrinology E-Book: Expert Consult | url = https://books.google.com/books?id=nbg1QOAObicC&pg=PT2057 | accessdate = 27 May 2012 | date = 31 May 2011 | publisher = Elsevier Health Sciences | isbn = 978-1-4377-3600-7 | page = 2057}}</ref><ref name="pmid19843067">{{cite journal |vauthors=Nakhjavani M, Hamidi S, Esteghamati A, Abbasi M, Nosratian-Jahromi S, Pasalar P | title = Short term effects of spironolactone on blood lipid profile: a 3-month study on a cohort of young women with hirsutism | journal = British Journal of Clinical Pharmacology | volume = 68 | issue = 4 | pages = 634–7 |date=October 2009 | pmid = 19843067 | pmc = 2780289 | doi = 10.1111/j.1365-2125.2009.03483.x }}</ref> It has also been suggested to augment the [[gynecomastia]] caused by the estrogenic effects of spironolactone,<ref name="OttowWeinmann2008">{{cite book | author1 = Eckhard Ottow | author2 = Hilmar Weinmann | title = Nuclear Receptors As Drug Targets | url = https://books.google.com/books?id=iATfLbPgRugC&pg=PA410 | accessdate = 28 May 2012 | date = 9 July 2008 | publisher = John Wiley & Sons | isbn = 978-3-527-62330-3 | page = 410}}</ref> as progesterone is known to be involved in [[breast development|mammary gland development]].<ref name="pmid12223124">{{cite journal | author = Anderson E | title = The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis | journal = Breast Cancer Research : BCR | volume = 4 | issue = 5 | pages = 197–201 | year = 2002 | pmid = 12223124 | pmc = 138744 | doi = | url = http://breast-cancer-research.com/content/4/5/197}}</ref>
+Spironolactone has weak [[progestogen]]ic activity in [[bioassay]]s.<ref name="DesaiP.2001" /><ref name="SchanePotts1978">{{cite journal | last1 = Schane | first1 = H. P. | last2 = Potts | first2 = G. O. | title = Oral Progestational Activity of Spironolactone | journal = Journal of Clinical Endocrinology & Metabolism | volume = 47 | issue = 3 | year = 1978 | page = 691694 | issn = 0021-972X | doi = 10.1210/jcem-47-3-691 | pmid=95623}}</ref> Its actions in this regard are a result of direct agonist activity at the PR, though with a very low [[EC50|half-maximal]] potency.<ref name="pmid20650892" /> Spironolactone's progestogenic activity has been suggested to be involved in some of its side effects,<ref name="Delyani2000">{{cite journal|last1=Delyani|first1=John A|title=Mineralocorticoid receptor antagonists: The evolution of utility and pharmacology|journal=Kidney International|volume=57|issue=4|year=2000|pages=1408–1411|issn=0085-2538|doi=10.1046/j.1523-1755.2000.00983.x|pmid=10760075}}</ref> including the [[menstrual disorder|menstrual irregularities]] seen in women and the undesirable [[serum (blood)|serum]] [[lipid]] profile changes that are seen at higher doses.<ref name="Carrell2010" /><ref name="MelmedPolonsky2011">{{cite book | vauthors = Melmed S, Polonsky KS, Larsen PR, Kronenberg HM | title = Williams Textbook of Endocrinology E-Book: Expert Consult | url = https://books.google.com/books?id=nbg1QOAObicC&pg=PT2057 | accessdate = 27 May 2012 | date = 31 May 2011 | publisher = Elsevier Health Sciences | isbn = 978-1-4377-3600-7 | page = 2057 | deadurl = no | archiveurl = https://web.archive.org/web/20130621122700/http://books.google.com/books?id=nbg1QOAObicC&pg=PT2057 | archivedate = 21 June 2013 | df =  }}</ref><ref name="pmid19843067">{{cite journal |vauthors=Nakhjavani M, Hamidi S, Esteghamati A, Abbasi M, Nosratian-Jahromi S, Pasalar P | title = Short term effects of spironolactone on blood lipid profile: a 3-month study on a cohort of young women with hirsutism | journal = British Journal of Clinical Pharmacology | volume = 68 | issue = 4 | pages = 634–7 |date=October 2009 | pmid = 19843067 | pmc = 2780289 | doi = 10.1111/j.1365-2125.2009.03483.x }}</ref> It has also been suggested to augment the [[gynecomastia]] caused by the estrogenic effects of spironolactone,<ref name="OttowWeinmann2008">{{cite book | author1 = Eckhard Ottow | author2 = Hilmar Weinmann | title = Nuclear Receptors As Drug Targets | url = https://books.google.com/books?id=iATfLbPgRugC&pg=PA410 | accessdate = 28 May 2012 | date = 9 July 2008 | publisher = John Wiley & Sons | isbn = 978-3-527-62330-3 | page = 410 | deadurl = no | archiveurl = https://web.archive.org/web/20130621121614/http://books.google.com/books?id=iATfLbPgRugC&pg=PA410 | archivedate = 21 June 2013 | df =  }}</ref> as progesterone is known to be involved in [[breast development|mammary gland development]].<ref name="pmid12223124">{{cite journal | author = Anderson E | title = The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis | journal = Breast Cancer Research : BCR | volume = 4 | issue = 5 | pages = 197–201 | year = 2002 | pmid = 12223124 | pmc = 138744 | doi =  | url = http://breast-cancer-research.com/content/4/5/197 | deadurl = no | archiveurl = https://web.archive.org/web/20130218203949/http://breast-cancer-research.com/content/4/5/197 | archivedate = 2013-02-18 | df =  }}</ref>
 Although it has been widely stated that the menstrual irregularities associated with spironolactone are due to its progestogenic activity, and although animal studies (involving both rabbits and [[rhesus monkey]]s) have shown clear progestogenic effects,<ref name="pmid95623">{{cite journal | vauthors = Schane HP, Potts GO | title = Oral progestational activity of spironolactone | journal = J. Clin. Endocrinol. Metab. | volume = 47 | issue = 3 | pages = 691–4 | year = 1978 | pmid = 95623 | doi = 10.1210/jcem-47-3-691 | url = }}</ref> the dosages of spironolactone used in animals to produce progestogenic effects were very high, and no evidence of progestogenic nor antiprogestogenic effects (as assessed by [[endometrium|endometrial]] changes) have been observed in women even with high clinical dosages of spironolactone treatment.<ref name="pmid8144871">{{cite journal | vauthors = McMullen GR, Van Herle AJ | title = Hirsutism and the effectiveness of spironolactone in its management | journal = J. Endocrinol. Invest. | volume = 16 | issue = 11 | pages = 925–32 | year = 1993 | pmid = 8144871 | doi = 10.1007/BF03348960 | url = }}</ref><ref name="pmid2744183">{{cite journal | vauthors = Nakajima ST, Brumsted JR, Riddick DH, Gibson M | title = Absence of progestational activity of oral spironolactone | journal = Fertil. Steril. | volume = 52 | issue = 1 | pages = 155–8 | year = 1989 | pmid = 2744183 | doi = 10.1016/s0015-0282(16)60807-5| url = }}</ref> As such, it has been stated that the progestogenic potency of spironolactone is below the level of clinical significance in humans and that the menstrual abnormalities associated with the drug must have a different cause.<ref name="pmid8144871" /><ref name="pmid2744183" /> Other possible mechanisms of the menstrual disturbances associated with spironolactone that have been suggested include interference with the [[hypothalamic–pituitary–gonadal axis]], inhibition of enzymatic [[steroidogenesis]],<ref name="SeldinGiebisch1997" /> and mixed estrogenic and antiestrogenic activity.<ref name="pmid8144871" /><ref name="pmid2744183" /><ref name="pmid27072668"/>
@@ Line 246: / Line 246: @@
 ====Glucocorticoid activity====
-Spironolactone has been shown to inhibit steroid 11β-hydroxylase, an enzyme that is essential for the production of the [[glucocorticoid]] hormone [[cortisol]]. Because of this, glucocorticoid levels might be expected to be lowered, and hence, spironolactone might have some [[antiglucocorticoid]]ic effects. In clinical practice, however, this has not been found to be the case; spironolactone has actually been found to increase [[cortisol]] levels, both with acute and chronic administration. Research has shown that this is due to antagonism of the MR, which suppresses [[negative feedback]] on the [[hypothalamic–pituitary–adrenal axis|hypothalamic–pituitary–adrenal (HPA) axis]]. The HPA axis positively regulates the [[secretion]] of [[adrenocorticotropic hormone]] (ACTH), which in turn signals the [[adrenal gland]]s, the major source of [[corticosteroid]] biosynthesis in the body, to increase production of both mineralocorticoids and glucocorticoids. Therefore, by antagonizing the MR, spironolactone causes an increase in ACTH secretion and by extension an indirect rise in cortisol levels.<ref name="pmid9745451">{{cite journal |vauthors=Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H | title = The role of mineralocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation in humans | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 83 | issue = 9 | pages = 3339–45 |date=September 1998 | pmid = 9745451 | doi = 10.1210/jcem.83.9.5077| url = http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=9745451}}</ref><ref name="pmid17035932">{{cite journal  |vauthors=Otte C, Moritz S, Yassouridis A, etal | title = Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition | journal = Neuropsychopharmacology | volume = 32 | issue = 1 | pages = 232–8 |date=January 2007 | pmid = 17035932 | doi = 10.1038/sj.npp.1301217 | url = http://dx.doi.org/10.1038/sj.npp.1301217}}</ref> As such, any anti-glucocorticoid activity of spironolactone via direct suppression of glucocorticoid synthesis (at the level of the adrenals) appears to be more than fully offset by its concurrent indirect stimulatory effects on glucocorticoid production.
+Spironolactone has been shown to inhibit steroid 11β-hydroxylase, an enzyme that is essential for the production of the [[glucocorticoid]] hormone [[cortisol]]. Because of this, glucocorticoid levels might be expected to be lowered, and hence, spironolactone might have some [[antiglucocorticoid]]ic effects. In clinical practice, however, this has not been found to be the case; spironolactone has actually been found to increase [[cortisol]] levels, both with acute and chronic administration. Research has shown that this is due to antagonism of the MR, which suppresses [[negative feedback]] on the [[hypothalamic–pituitary–adrenal axis|hypothalamic–pituitary–adrenal (HPA) axis]]. The HPA axis positively regulates the [[secretion]] of [[adrenocorticotropic hormone]] (ACTH), which in turn signals the [[adrenal gland]]s, the major source of [[corticosteroid]] biosynthesis in the body, to increase production of both mineralocorticoids and glucocorticoids. Therefore, by antagonizing the MR, spironolactone causes an increase in ACTH secretion and by extension an indirect rise in cortisol levels.<ref name="pmid9745451">{{cite journal |vauthors=Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H | title = The role of mineralocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation in humans | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 83 | issue = 9 | pages = 3339–45 |date=September 1998 | pmid = 9745451 | doi = 10.1210/jcem.83.9.5077| url = http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=9745451}}</ref><ref name="pmid17035932">{{cite journal | vauthors = Otte C, Moritz S, Yassouridis A, etal | title = Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition | journal = Neuropsychopharmacology | volume = 32 | issue = 1 | pages = 232–8 | date = January 2007 | pmid = 17035932 | doi = 10.1038/sj.npp.1301217 | url = http://dx.doi.org/10.1038/sj.npp.1301217 | deadurl = no | archiveurl = https://web.archive.org/web/20081011132747/http://dx.doi.org/10.1038/sj.npp.1301217 | archivedate = 2008-10-11 | df =  }}</ref> As such, any anti-glucocorticoid activity of spironolactone via direct suppression of glucocorticoid synthesis (at the level of the adrenals) appears to be more than fully offset by its concurrent indirect stimulatory effects on glucocorticoid production.
 At the same time, spironolactone weakly binds to and acts as an antagonist of the GR, showing antiglucocorticoid properties, but to a significant degree only at very high concentrations that are probably not clinically relevant.<ref name="pmid20650892"/><ref name="pmid6128090">{{vcite2 journal | vauthors = Campen TJ, Fanestil DD | title = Spironolactone: a glucocorticoid agonist or antagonist? | journal = Clin Exp Hypertens A | volume = 4 | issue = 9–10 | pages = 1627–36 | year = 1982 | pmid = 6128090 | doi = | url = }}</ref><ref name="pmid1309341">{{vcite2 journal | vauthors = Couette B, Marsaud V, Baulieu EE, Richard-Foy H, Rafestin-Oblin ME | title = Spironolactone, an aldosterone antagonist, acts as an antiglucocorticosteroid on the mouse mammary tumor virus promoter | journal = Endocrinology | volume = 130 | issue = 1 | pages = 430–6 | year = 1992 | pmid = 1309341 | doi = 10.1210/endo.130.1.1309341 | url = }}</ref>
@@ Line 282: / Line 282: @@
 ===Elimination===
-The majority of spironolactone is eliminated by the [[kidney]]s, while minimal amounts are handled by [[bile|biliary]] excretion.<ref name="Brittain2002">{{cite book | author = Harry G. Brittain | title = Analytical Profiles of Drug Substances and Excipients | url = https://books.google.com/books?id=RMN5zMW64ZEC&pg=PA309 | accessdate = 27 May 2012 | date = 26 November 2002 | publisher = Academic Press | isbn = 978-0-12-260829-2 | page = 309}}</ref>
+The majority of spironolactone is eliminated by the [[kidney]]s, while minimal amounts are handled by [[bile|biliary]] excretion.<ref name="Brittain2002">{{cite book | author = Harry G. Brittain | title = Analytical Profiles of Drug Substances and Excipients | url = https://books.google.com/books?id=RMN5zMW64ZEC&pg=PA309 | accessdate = 27 May 2012 | date = 26 November 2002 | publisher = Academic Press | isbn = 978-0-12-260829-2 | page = 309 | deadurl = no | archiveurl = https://web.archive.org/web/20130621104609/http://books.google.com/books?id=RMN5zMW64ZEC&pg=PA309 | archivedate = 21 June 2013 | df =  }}</ref>
 ==Chemistry==
@@ Line 290: / Line 290: @@
 ===Chemical names===
-Spironolactone is also known by the following equivalent chemical names:<ref name="Elks2014" /><ref name="PubChem">https://pubchem.ncbi.nlm.nih.gov/compound/5833</ref><ref name="ChemSpider">http://www.chemspider.com/Chemical-Structure.5628.html?rid=b578a389-d64b-4ec2-ae20-309e5f3abd11</ref>
+Spironolactone is also known by the following equivalent chemical names:<ref name="Elks2014" /><ref name="PubChem">{{cite web |url=https://pubchem.ncbi.nlm.nih.gov/compound/5833 |title=Archived copy |accessdate=2017-07-04 |deadurl=no |archiveurl=https://web.archive.org/web/20160630101052/http://pubchem.ncbi.nlm.nih.gov/compound/5833/ |archivedate=2016-06-30 |df= }}</ref><ref name="ChemSpider">http://www.chemspider.com/Chemical-Structure.5628.html?rid=b578a389-d64b-4ec2-ae20-309e5f3abd11</ref>
 * 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
@@ Line 303: / Line 303: @@
 ==History==
 Spironolactone was first [[chemical synthesis|synthesized]] in 1957,<ref name="OttowWeinmann2008" /> was [[patent]]ed between 1958 and 1961,<ref name="EngelKleemann2014">{{cite book|author1=Jürgen Engel|author2=Axel Kleemann|author3=Bernhard Kutscher |author4=Dietmar Reichert |title=Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs|url=https://books.google.com/books?id=4lCGAwAAQBAJ&pg=PA1279|date=14 May 2014|publisher=Thieme|isbn=978-3-13-179275-4|pages=1279–1280
-}}</ref><ref name="LandauAchilladelis1999">{{cite book|author1=Ralph Landau|author2=Basil Achilladelis|author3=Alexander Scriabine|title=Pharmaceutical Innovation: Revolutionizing Human Health|url=https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA198|year=1999|publisher=Chemical Heritage Foundation|isbn=978-0-941901-21-5|pages=198–|quote=Spironolactone was patented in 1961 and has been used since then to treat heart failure, liver cirrhosis, and nephrotic syndrome.}}</ref> and was first marketed, as an antimineralocorticoid, in 1959.<ref name="Jugdutt2014">{{cite book|author=Bodh I. Jugdutt|title=Aging and Heart Failure: Mechanisms and Management|url=https://books.google.com/books?id=0e23BAAAQBAJ&pg=PA175|date=19 February 2014|publisher=Springer Science & Business Media|isbn=978-1-4939-0268-2|pages=175–}}</ref><ref name="Wermuth2011">{{cite book|author=Camille Georges Wermuth|title=The Practice of Medicinal Chemistry|url=https://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34|date=2 May 2011|publisher=Academic Press|isbn=978-0-08-056877-5|pages=34–}}</ref> The AR antagonistic (i.e., antiandrogen) activity of spironolactone was first discovered and reported in 1969,<ref name="pmid5344274">{{cite journal | vauthors = Steelman SL, Brooks JR, Morgan ER, Patanelli DJ | title = Anti-androgenic activity of spironolactone | journal = Steroids | volume = 14 | issue = 4 | pages = 449–50 | year = 1969 | pmid = 5344274 | doi = 10.1016/s0039-128x(69)80007-3| url = }}</ref> which shortly followed the discovery in 1968 that gynecomastia, a frequent and by that time well-established side effect of spironolactone, is an important and major side effect of AR antagonists.<ref name="NeillJohansson1968">Neill, J. D., Johansson, E. D. B., Datta, J. K., & Knobil, E. (1968). Endocrinology: Relationship Between the Plasma Levels of Luteinizing Hormone and Progesterone During the Normal Menstrual Cycle. ''Obstetrical & Gynecological Survey'', 23(3), 271-277. Quote: "17a-methyl-B-nortestosterone (Benorterone) (SKF-7690) has satis- factorily undergone extensive pharmacologic and toxicologic studies in animals, plus preliminary clinical studies in humans with somewhat encouraging results. It was therefore subjected to further clinical trials, especially in relation to the treatment of acne vulgaris. This communication reports the promptly reversible development of gynecomastia in 12 of 13 postpuberal males who participated in such a clinical study. It is believed that this complication has not been reported previously with a nonestrogenic antiandrogenic agent."</ref> The drug started to be used as an antiandrogen, for instance in the treatment of hirsutism in women, by the late 1970s and early 1980s,<ref name="pmid717935">{{cite journal | vauthors = Ober KP, Hennessy JF | title = Spironolactone therapy for hirsutism in a hyperandrogenic woman | journal = Ann. Intern. Med. | volume = 89 | issue = 5 Pt 1 | pages = 643–4 | year = 1978 | pmid = 717935 | doi = | url = }}</ref><ref name="pmid488407">{{cite journal | vauthors = Boisselle A, Tremblay RR | title = New therapeutic approach to the hirsute patient | journal = Fertil. Steril. | volume = 32 | issue = 3 | pages = 276–9 | year = 1979 | pmid = 488407 | doi = 10.1016/s0015-0282(16)44232-9| url = }}</ref><ref name="pmid7410528">{{cite journal | vauthors = Shapiro G, Evron S | title = A novel use of spironolactone: treatment of hirsutism | journal = J. Clin. Endocrinol. Metab. | volume = 51 | issue = 3 | pages = 429–32 | year = 1980 | pmid = 7410528 | doi = 10.1210/jcem-51-3-429 | url = }}</ref><ref name="pmid27450358">{{cite journal | vauthors = Armanini D, Andrisani A, Bordin L, Sabbadin C | title = Spironolactone in the treatment of polycystic ovary syndrome | journal = Expert Opin Pharmacother | volume = 17 | issue = 13 | pages = 1713–5 | year = 2016 | pmid = 27450358 | doi = 10.1080/14656566.2016.1215430 | url = }}</ref> and has since become the most widely used antiandrogen for dermatological indications in the United States.<ref name="ShahBhathena2004">{{cite book|author1=Duru Shah|author2=R. K. Bhathena|author3=Safala Shroff|title=The Polycystic Ovary Syndrome|url=https://books.google.com/books?id=Jxd03OBIn9wC&pg=PA78|year=2004|publisher=Orient Blackswan|isbn=978-81-250-2633-4|pages=78–}}</ref><ref name="WakelinMaibach2002" /><ref name="Hillard2013">{{cite book|author=Paula J. Adams Hillard|title=Practical Pediatric and Adolescent Gynecology|url=https://books.google.com/books?id=vAA5Z5aqlUQC&pg=PT371|date=29 March 2013|publisher=John Wiley & Sons|isbn=978-1-118-53857-9|pages=371–}}</ref><ref name="Curtis2014">{{cite book|author=Michele Curtis|title=Glass' Office Gynecology|url=https://books.google.com/books?id=w2AGBAAAQBAJ&pg=PA47|year=2014|publisher=Lippincott Williams & Wilkins|isbn=978-1-60831-820-9|pages=47–}}</ref>
+}}</ref><ref name="LandauAchilladelis1999">{{cite book|author1=Ralph Landau|author2=Basil Achilladelis|author3=Alexander Scriabine|title=Pharmaceutical Innovation: Revolutionizing Human Health|url=https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA198|year=1999|publisher=Chemical Heritage Foundation|isbn=978-0-941901-21-5|pages=198–|quote=Spironolactone was patented in 1961 and has been used since then to treat heart failure, liver cirrhosis, and nephrotic syndrome.}}</ref> and was first marketed, as an antimineralocorticoid, in 1959.<ref name="Jugdutt2014">{{cite book|author=Bodh I. Jugdutt|title=Aging and Heart Failure: Mechanisms and Management|url=https://books.google.com/books?id=0e23BAAAQBAJ&pg=PA175|date=19 February 2014|publisher=Springer Science & Business Media|isbn=978-1-4939-0268-2|pages=175–}}</ref><ref name="Wermuth2011">{{cite book|author=Camille Georges Wermuth|title=The Practice of Medicinal Chemistry|url=https://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34|date=2 May 2011|publisher=Academic Press|isbn=978-0-08-056877-5|pages=34–|deadurl=no|archiveurl=https://web.archive.org/web/20130621115634/http://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34|archivedate=21 June 2013|df=}}</ref> The AR antagonistic (i.e., antiandrogen) activity of spironolactone was first discovered and reported in 1969,<ref name="pmid5344274">{{cite journal | vauthors = Steelman SL, Brooks JR, Morgan ER, Patanelli DJ | title = Anti-androgenic activity of spironolactone | journal = Steroids | volume = 14 | issue = 4 | pages = 449–50 | year = 1969 | pmid = 5344274 | doi = 10.1016/s0039-128x(69)80007-3| url = }}</ref> which shortly followed the discovery in 1968 that gynecomastia, a frequent and by that time well-established side effect of spironolactone, is an important and major side effect of AR antagonists.<ref name="NeillJohansson1968">Neill, J. D., Johansson, E. D. B., Datta, J. K., & Knobil, E. (1968). Endocrinology: Relationship Between the Plasma Levels of Luteinizing Hormone and Progesterone During the Normal Menstrual Cycle. ''Obstetrical & Gynecological Survey'', 23(3), 271-277. Quote: "17a-methyl-B-nortestosterone (Benorterone) (SKF-7690) has satis- factorily undergone extensive pharmacologic and toxicologic studies in animals, plus preliminary clinical studies in humans with somewhat encouraging results. It was therefore subjected to further clinical trials, especially in relation to the treatment of acne vulgaris. This communication reports the promptly reversible development of gynecomastia in 12 of 13 postpuberal males who participated in such a clinical study. It is believed that this complication has not been reported previously with a nonestrogenic antiandrogenic agent."</ref> The drug started to be used as an antiandrogen, for instance in the treatment of hirsutism in women, by the late 1970s and early 1980s,<ref name="pmid717935">{{cite journal | vauthors = Ober KP, Hennessy JF | title = Spironolactone therapy for hirsutism in a hyperandrogenic woman | journal = Ann. Intern. Med. | volume = 89 | issue = 5 Pt 1 | pages = 643–4 | year = 1978 | pmid = 717935 | doi = | url = }}</ref><ref name="pmid488407">{{cite journal | vauthors = Boisselle A, Tremblay RR | title = New therapeutic approach to the hirsute patient | journal = Fertil. Steril. | volume = 32 | issue = 3 | pages = 276–9 | year = 1979 | pmid = 488407 | doi = 10.1016/s0015-0282(16)44232-9| url = }}</ref><ref name="pmid7410528">{{cite journal | vauthors = Shapiro G, Evron S | title = A novel use of spironolactone: treatment of hirsutism | journal = J. Clin. Endocrinol. Metab. | volume = 51 | issue = 3 | pages = 429–32 | year = 1980 | pmid = 7410528 | doi = 10.1210/jcem-51-3-429 | url = }}</ref><ref name="pmid27450358">{{cite journal | vauthors = Armanini D, Andrisani A, Bordin L, Sabbadin C | title = Spironolactone in the treatment of polycystic ovary syndrome | journal = Expert Opin Pharmacother | volume = 17 | issue = 13 | pages = 1713–5 | year = 2016 | pmid = 27450358 | doi = 10.1080/14656566.2016.1215430 | url = }}</ref> and has since become the most widely used antiandrogen for dermatological indications in the United States.<ref name="ShahBhathena2004">{{cite book|author1=Duru Shah|author2=R. K. Bhathena|author3=Safala Shroff|title=The Polycystic Ovary Syndrome|url=https://books.google.com/books?id=Jxd03OBIn9wC&pg=PA78|year=2004|publisher=Orient Blackswan|isbn=978-81-250-2633-4|pages=78–}}</ref><ref name="WakelinMaibach2002" /><ref name="Hillard2013">{{cite book|author=Paula J. Adams Hillard|title=Practical Pediatric and Adolescent Gynecology|url=https://books.google.com/books?id=vAA5Z5aqlUQC&pg=PT371|date=29 March 2013|publisher=John Wiley & Sons|isbn=978-1-118-53857-9|pages=371–}}</ref><ref name="Curtis2014">{{cite book|author=Michele Curtis|title=Glass' Office Gynecology|url=https://books.google.com/books?id=w2AGBAAAQBAJ&pg=PA47|year=2014|publisher=Lippincott Williams & Wilkins|isbn=978-1-60831-820-9|pages=47–}}</ref>
 ==Society and culture==
 ===Generic name===
-The [[English language|English]], [[French language|French]], and [[generic drug|generic name]] of spironolactone is ''spironolactone'' (pronounced as {{IPAc-en|ˌ|s|p|aɪ|r|ə|n|oʊ|ˈ|l|æ|k|t|oʊ|n}} {{respell|SPYE|rə-noh|LAK|tohn}}<ref name="LoughlinGenerali2006">{{cite book|author1=Kevin R. Loughlin|author2=Joyce A. Generali|title=The Guide to Off-label Prescription Drugs: New Uses for FDA-approved Prescription Drugs|url=https://books.google.com/books?id=fhEFkBxEtH8C&pg=PA131|year=2006|publisher=Simon and Schuster|isbn=978-0-7432-8667-1|pages=131–}}</ref> or as {{IPAc-en|ˌ|s|p|ɪər|ə|n|oʊ|ˈ|l|æ|k|t|oʊ|n}} {{respell|SPEER|ə-noh|LAK|tohn}}<ref name="ClarkHarvey2011" /> according to different sources) and this is its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014">{{cite book|author=J. Elks|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1111|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|page=1111}}</ref><ref name="Drugs.com">https://www.drugs.com/international/spironolactone.html</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA960|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=960–}}</ref><ref name="MortonHall1999">{{cite book|author1=I.K. Morton|author2=Judith M. Hall|title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA261|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=261–}}</ref> Its name is spironolactonum in [[Latin language|Latin]], spironolacton in [[German language|German]], espironolactona in [[Spanish language|Spanish]] and [[Portuguese language|Portuguese]], and spironolattone in [[Italian language|Italian]] (which is also its {{abbrlink|DCIT|Denominazione Comune Italiana}}).<ref name="Drugs.com" /><ref name="IndexNominum2000" /><ref name="MortonHall1999" />
+The [[English language|English]], [[French language|French]], and [[generic drug|generic name]] of spironolactone is ''spironolactone'' (pronounced as {{IPAc-en|ˌ|s|p|aɪ|r|ə|n|oʊ|ˈ|l|æ|k|t|oʊ|n}} {{respell|SPYE|rə-noh|LAK|tohn}}<ref name="LoughlinGenerali2006">{{cite book|author1=Kevin R. Loughlin|author2=Joyce A. Generali|title=The Guide to Off-label Prescription Drugs: New Uses for FDA-approved Prescription Drugs|url=https://books.google.com/books?id=fhEFkBxEtH8C&pg=PA131|year=2006|publisher=Simon and Schuster|isbn=978-0-7432-8667-1|pages=131–}}</ref> or as {{IPAc-en|ˌ|s|p|ɪər|ə|n|oʊ|ˈ|l|æ|k|t|oʊ|n}} {{respell|SPEER|ə-noh|LAK|tohn}}<ref name="ClarkHarvey2011" /> according to different sources) and this is its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014">{{cite book|author=J. Elks|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1111|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|page=1111|deadurl=no|archiveurl=https://web.archive.org/web/20170215024945/https://books.google.com/books?id=0vXTBwAAQBAJ|archivedate=15 February 2017|df=}}</ref><ref name="Drugs.com">{{cite web |url=https://www.drugs.com/international/spironolactone.html |title=Archived copy |accessdate=2016-12-01 |deadurl=no |archiveurl=https://web.archive.org/web/20161202040938/https://www.drugs.com/international/spironolactone.html |archivedate=2016-12-02 |df= }}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA960|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=960–}}</ref><ref name="MortonHall1999">{{cite book|author1=I.K. Morton|author2=Judith M. Hall|title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA261|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=261–}}</ref> Its name is spironolactonum in [[Latin language|Latin]], spironolacton in [[German language|German]], espironolactona in [[Spanish language|Spanish]] and [[Portuguese language|Portuguese]], and spironolattone in [[Italian language|Italian]] (which is also its {{abbrlink|DCIT|Denominazione Comune Italiana}}).<ref name="Drugs.com" /><ref name="IndexNominum2000" /><ref name="MortonHall1999" />
 Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.<ref name="Elks2014" /><ref name="Drugs.com" /><ref name="IndexNominum2000"/>
@@ Line 329: / Line 329: @@
 ===Epstein–Barr virus===
-Spironolactone has been found to block [[Epstein–Barr virus]] (EBV) production and that of other human [[herpesviruses]] by inhibiting the function of an EBV protein SM, which is essential for infectious virus production.<ref name="Verma2016">{{cite journal |vauthors=Verma D, Thompson J, Swaninathan S | title = Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function | journal = Proceedings of the National Academy of Sciences | volume =  113| issue =  | pages =  3609–3614| year = 2016 | pmid =  26976570| doi = 10.1073/pnas.1523686113| url = http://www.pnas.org/content/early/2016/03/09/1523686113.abstract | pmc=4822607}}</ref> This effect of spironolactone was determined to be independent of its antimineralocorticoid actions.<ref name="Verma2016" /> Thus, spironolactone or compounds based on it have the potential to yield novel [[antiviral drug]]s with a distinct mechanism of action and limited toxicity.<ref name="Verma2016" />
+Spironolactone has been found to block [[Epstein–Barr virus]] (EBV) production and that of other human [[herpesviruses]] by inhibiting the function of an EBV protein SM, which is essential for infectious virus production.<ref name="Verma2016">{{cite journal | vauthors = Verma D, Thompson J, Swaninathan S | title = Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function | journal = Proceedings of the National Academy of Sciences | volume = 113 | issue =  | pages = 3609–3614 | year = 2016 | pmid = 26976570 | doi = 10.1073/pnas.1523686113 | url = http://www.pnas.org/content/early/2016/03/09/1523686113.abstract | pmc = 4822607 | deadurl = no | archiveurl = https://web.archive.org/web/20160324050609/http://www.pnas.org/content/early/2016/03/09/1523686113.abstract | archivedate = 2016-03-24 | df =  }}</ref> This effect of spironolactone was determined to be independent of its antimineralocorticoid actions.<ref name="Verma2016" /> Thus, spironolactone or compounds based on it have the potential to yield novel [[antiviral drug]]s with a distinct mechanism of action and limited toxicity.<ref name="Verma2016" />
 ==References==