Spironolactone

From Wikipedia, the free encyclopedia
  (Redirected from Aldactone)
Jump to navigation Jump to search
Spironolactone
Skeletal formula of spironolactone
Ball-and-stick model of the spironolactone molecule
Clinical data
Pronunciation /ˌsprənˈlæktn/ SPY-rə-noh-LAK-tohn,[3] /ˌspɪər-/ SPEER-[4]
Trade names Aldactone, Spiractin, Verospiron, many others; combinations: Aldactazide (+HCTZ), Aldactide (+HFMZ), Aldactazine (+altizide), others
Synonyms 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
  • US: C (Risk not ruled out)
Routes of
administration
By mouth,[1] topical[2]
Drug class Antimineralocorticoid; Steroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 60–90%[5][6][7]
Protein binding Spironolactone: 88% (to albumin and AGP equivalently)[8]
Canrenone: 99.2% (to albumin)[8]
Metabolism Liver (deacetylation, dethioacetylation, hydroxylation)[5][6]
Metabolites 7α-TMS, 6β-OH-7α-TMS, canrenone, others[5][6][9]
(All three active)[10]
Elimination half-life Spironolactone: 1.4 hours[5]
7α-TMS: 13.8 hours[5]
6β-OH-7α-TMS: 15.0 hours[5]
Canrenone: 16.5 hours[5]
Excretion Urine, bile[6]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.000.122 Edit this at Wikidata
Chemical and physical data
Formula C24H32O4S
Molar mass 416.574 g/mol
3D model (JSmol)
Melting point 134 to 135 °C (273 to 275 °F)
  (verify)

Spironolactone, sold 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.[1] It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women, and as a part of feminizing hormone therapy in transgender women.[1][11][12] Spironolactone is taken by mouth.[1]

Common side effects include electrolyte abnormalities, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex.[1] In those with liver or kidney problems, extra care should be taken.[1] Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy.[13] It is a steroid that blocks the effects of the hormones aldosterone and testosterone and has some estrogen-like effects.[1][14] Spironolactone belongs to a class of medications known as potassium-sparing diuretics.[1]

Spironolactone was discovered in 1957 and was introduced in 1959.[15][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.[1] 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.[1]

Medical uses[edit]

Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, low blood levels of potassium, secondary hyperaldosteronism (such as occurs with liver 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 medication 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[edit]

About 1 in 100 people 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[edit]

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 medication. People 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 greater than 2.5 mg/dL (221 µmol/L) in males or greater than 2 mg/dL (176.8 µmol/L) in females, if glomerular filtration rate is below 30 mL/min or with a serum potassium of greater than 5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of kidney 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 do not 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 medication, 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 medication 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[edit]

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 FPHL 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[edit]

Spironolactone is frequently used as a component of feminizing hormone therapy in transgender women, especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen.[51][52][53] Other clinical effects include decreased male pattern body hair, the induction of breast development, feminization in general, and lack of spontaneous erections.[53]

Doses and forms[edit]

Spironolactone is typically used at a low dosage of 25 to 50 mg/day in the treatment of heart failure,[54][55][56][57] while it is used at low to high dosages of 25 to 200 mg/day in the treatment of essential hypertension,[54][57] and at high dosages of 100 to 400 mg/day for hyperaldosteronism and ascites due to cirrhosis.[58][59][60][61] The medication is typically used at high dosages of 100 to 200 mg/day in the treatment of skin and hair conditions in women,[62][63][64][65][66] and at high dosages of 100 to 400 mg/day in feminizing hormone therapy for transgender women.[67][68][69]

Spironolactone is available in the form of tablets (25 mg, 50 mg, 100 mg) for use by mouth.[70][71][72][73] It 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, but this product is no longer available.[2][74] Spironolactone has poor water solubility, and for this reason, only oral and topical formulations have been developed; other routes of administration such as intravenous injection are not used.[5]

Comparison[edit]

There are few available options for antiandrogen therapy. Spironolactone, cyproterone acetate, and flutamide are some of the most well-known and widely used medications.[75] Compared to cyproterone acetate, spironolactone is considerably less potent as an antiandrogen by weight and binding affinity.[76][77] However, at the doses at which they are typically used, spironolactone and cyproterone acetate have been found to be roughly equivalent in terms of effectiveness for a variety of androgen-related conditions,[78] though cyproterone acetate has shown a slight though non-statistically-significant advantage in some studies.[79][80] 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.[78]

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,[81][82] has been found to be more effective than either of them as an antiandrogen when it is used at the typical treatment doses.[76][83][84] 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.[85] This may be related to the fact that spironolactone has been regarded as a comparatively weak antiandrogen relative to other options.[86]

Contraindications[edit]

Contraindications of spironolactone include end-stage kidney disease and hyperkalemia (high levels of potassium), among others.[citation needed]

Side effects[edit]

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),[87] ataxia (muscle incoordination), drowsiness, dizziness,[87] dry skin, and rashes. Because it reduces androgen levels and directly blocks androgen signaling, spironolactone can, in men, cause breast tenderness, gynecomastia (male breast development), and feminization in general, as well as testicular atrophy, reversibly reduced fertility, and sexual dysfunction including loss of libido and erectile dysfunction.[88] In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement.[20][62]

The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening. Hyperkalemia in these people can present as a non anion-gap metabolic acidosis. Spironolactone may put people 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 medication and bleeding from the stomach and duodenum, though a causal relationship between the two has not been established.[89] Also, spironolactone has been shown to be immunosuppressive in the treatment of sarcoidosis.[90]

Hyperkalemia[edit]

Spironolactone can cause hyperkalemia, or high blood potassium levels.[91] Rarely, this can be fatal.[91] Of people prescribed typical dosages of spironolactone, 10 to 15% have been found to develop some degree of hyperkalemia, and 6% have been found to develop severe hyperkalemia.[91] At a higher dosage, a rate of hyperkalemia of 24% has been observed.[92] An abrupt increase in the rate of hospitalization from 0.2% to 11% and in the rate of death from 0.3 per 1,000 to 2.0 per 1,000 due to hyperkalemia between early 1994 and late 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone upon the publication of the Randomized Aldactone Evaluation Study (RALES) in July 1999.[91][92][93] The risk of hyperkalemia with spironolactone is greatest in the elderly, in people with chronic kidney disease, and in people also taking a potassium supplement or ACE inhibitor.[91]

Although spironolactone poses an important risk of hyperkalemia in the elderly, those with kidney or cardiovascular disease, or those taking medications or supplements which increase circulating potassium levels, the rate of hyperkalemia in young women without such characteristics who have been treated with spironolactone for dermatological conditions has been found not to differ from that of controls.[42][43][94] 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.[42][43][94]

Breast effects[edit]

In women, spironolactone is commonly associated with breast pain and breast enlargement,[95][66] "probably because of [indirect] estrogenic effects on target tissue."[91] Breast enlargement may occur in 26% of women and is described as mild,[87] while breast tenderness is reported to occur in up to 40% of women taking high dosages of the medication.[96] Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men.[95][97][98][99] At low dosages, the rate is only 5–10%,[99] but at high dosages, up to or exceeding 50% of men may develop gynecomastia.[95][97][98] The severity of the gynecomastia varies considerably, but is usually mild.[97] As with women, gynecomastia associated with spironolactone is commonly although inconsistently accompanied by breast tenderness.[97] Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication.[97]

Menstrual disturbances[edit]

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.[87][91] Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation.[91] Spironolactone produces an irregular, anovulatory pattern of menstrual cycles.[87] It is also associated with metrorrhagia and menorrhagia (or menometrorrhagia) in a large percentage of women.[66] It has no birth control effect.[100] 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.[87][101][102] An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels.[97]

The menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with an oral contraceptive.[87]

Infertility[edit]

At high dosages, spironolactone has been associated with semen abnormalities such as decreased sperm count and motility in men.[97]

Depression[edit]

Increased glucocorticoid activity in the body is associated with depression.[103][104] As such, it is thought that there may be a risk of depression with spironolactone treatment.[103][105][106] A small amount of clinical research supports this notion.[85][107][108]

Rare reactions[edit]

Spironolactone may rarely cause more severe side effects such as anaphylaxis, kidney failure, hepatitis (two reported cases, neither serious),[109] agranulocytosis, DRESS syndrome, Stevens-Johnson syndrome or toxic epidermal necrolysis.[110][111] Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported.[91][99] It should also be used with caution in people with some neurological disorders, no urine production, acute kidney injury, or significant impairment of kidney excretory function with risk of hyperkalemia.[112]

Spironolactone bodies[edit]

Micrograph (H&E stain) of an adrenal gland showing 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.[113]

Pregnancy and breastfeeding[edit]

Spironolactone is considered Pregnancy Category C meaning that it is unclear if it is safe for use during pregnancy.[1] It is able to cross the placenta.[66] 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 medication while nursing.[112] 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.[114]

A study found that spironolactone was not associated with teratogenicity in the offspring of rats.[115][116][117] Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses.[115][116] 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).[115][117] Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day).[117]

In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.[115][116][118][119] Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific birth defects.[119] 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.[119] 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.[114][115] 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).[119] 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.[115][120]

Interactions[edit]

Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this medication avoid potassium supplements and salt substitutes containing potassium.[121] 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.[122]

Research has suggested that spironolactone may be able to interfere with the effectiveness of antidepressant treatment. As the medication 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.[123][124] However, other research contradicts this hypothesis and has suggested that spironolactone may actually produce antidepressant-like effects in animals.[125]

Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications.[112] 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.[126]

Spironolactone has been reported to induce the enzyme CYP3A4, which can result in interactions with various medications.[127] However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4.[128]

Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found in studies to inhibit the antimineralocorticoid effects of spironolactone.[129][130][131] Moreover, the addition of licorice to spironolactone has been found to reduce the antimineralocorticoid side effects of spironolactone in women treated with the medication 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.[129][130] On the opposite end of the spectrum, spironolactone is clinically useful in reversing licorice-induced hypokalemia.[132][133]

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to attenuate the diuresis and natriuresis induced by spironolactone therapy but not to affect its antihypertensive effect.[134][135]

Pharmacology[edit]

Pharmacodynamics[edit]

7α-Thiomethylspironolactone, the main active metabolite of spironolactone.
Spironolactone at steroid hormone receptors[136][137]
Site Value (nM) Type Action Species Ref
AR 39.4
120
13–670
>20,000
Ki
IC50a 
IC50b
EC50
Antagonist Human [138]
[139]
[140][141]
[141]
ER >1,100
5,700
Ki
IC50b
Antagonist Human [138]
[140]
ERα >20,000
>20,000
IC50b
EC50
N/A Human [141]
[141]
ERβ >20,000
3,300
IC50b
EC50
Agonist Human [141]
[141]
GR 32.6
1,400
2,900–6,920
>20,000
Ki
IC50a
IC50b
EC50
Antagonist Human [138]
[139]
[140][142]
[141]
MR 2.32
49
2.4–60
17.7
Ki
IC50a
IC50b
Kb
Antagonist Human [138]
[139]
[140][139]
[138]
PR 400
650
>25,000
2,620
Ki
IC50a
IC50b
EC50
Agonist Human [138]
[139]
[140][142]
[140]
PR-B 4,000
>20,000
IC50b
EC50
Antagonist Human [141]
[141]
a = Binding inhibition. b = Functional antagonism.

Spironolactone is known to possess the following biological activity:[143]

There is also evidence that spironolactone may block voltage-dependent Ca2+ channels.[150][151]

Although spironolactone is known to possess the above activities, it should be noted that the medication 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.[152][153] On the other hand, spironolactone itself has only very low affinity for the ER, suggesting that its metabolites may be responsible for this activity.[144][145]

Antimineralocorticoid activity[edit]

Spironolactone inhibits the effects of mineralocorticoids, namely, aldosterone, by displacing them from MR in the cortical collecting duct of kidney nephrons. This decreases the reabsorption of sodium and water while limiting the excretion of potassium (A K+ sparing diuretic). The medication 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.[154] 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.[5][6]

Canrenone is an antagonist of the MR similarly to spironolactone,[4] but is slightly more potent in comparison.[6][155] It has been determined that 7α-TMS accounts for around 80% of the potassium-sparing effect of spironolactone[5][152][156] while canrenone accounts for the remaining approximate 10 to 25%.[58] In accordance, 7α-TMS occurs at higher circulating concentrations than does canrenone in addition to having a higher relative affinity for the MR.[152]

Antiandrogenic activity[edit]

Spironolactone is a potent and direct antagonist of the AR, blocking androgens like testosterone from binding to and activating the receptor.[157][97] 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.[157] In addition, the AR antagonism of spironolactone is involved in its feminizing side effects like gynecomastia in men.[157]

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.[158][159][160] 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),[160] 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,[161] as spironolactone has been shown in vitro to significantly accelerate carcinoma growth in the absence of any other androgens.[158] 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.[162][163]

In vitro, canrenone binds to and blocks the AR.[97] However, relative to spironolactone, canrenone is described as having very weak affinity to the AR.[86] 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.[97] 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.[97][164][165] In accordance, 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.[153]

Estrogenic activity[edit]

Spironolactone has been found to directly interact with the ER.[144] One study found that spironolactone did not interact with the human ER at a specific concentration range tested.[166] However, a subsequent study found that the medication did interact with the human ER at higher concentrations, albeit with very low affinity (Ki = 20 µM).[144] 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.[144] In spite of the fact that tamoxifen had two orders of magnitude higher affinity for the ER than did spironolactone, the two medications showed similar potency in vivo.[144] The likelihood of spironolactone interacting with the ER itself is remote in consideration of its very low affinity for the receptor in vitro.[145] However, metabolism of spironolactone may result in metabolites with greater ER affinity, which might account for the activity.[144][145]

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 medication is associated with.[144] Subsequently, it has also been suggested that, as a SERM-like medication, 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.[145] 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.[101][102][145]

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 medications, whereas treatment with the selective AR antagonist flutamide had no such effect.[167][168] Other studies have also found an inverse relationship between spironolactone and decreased bone mineral density and bone fractures in men.[169][170] 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.[167][168][171] 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.[170]

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).[97][172]
  • Inhibition of the conversion of estradiol to estrone, resulting in an increase in the ratio of circulating estradiol to estrone.[173] Estradiol is far more potent than estrone as an estrogen, which is comparatively almost inactive.[174][175]
  • Enhancement of the rate of peripheral conversion of testosterone into estradiol, thus decreasing the ratio of circulating testosterone to estradiol.[176]

Spironolactone has been found to act as a reversible inhibitor of human 17β-hydroxysteroid dehydrogenase 2 (17β-HSD2), albeit with weak potency (Ki = 0.25–2.4 μM; IC50 = 0.27–1.1 μM).[177][178][179][180] 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.[177][180] 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 associated with the medication.[173][181] 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.[182][183]

Progestogenic activity[edit]

Spironolactone has weak progestogenic activity in bioassays.[82][184] Its actions in this regard are a result of direct agonist activity at the PR, though with a very low half-maximal potency.[143] Spironolactone's progestogenic activity has been suggested to be involved in some of its side effects,[185] including the menstrual irregularities seen in women and the undesirable serum lipid profile changes that are seen at higher doses.[81][186][187] It has also been suggested to augment the gynecomastia caused by the estrogenic effects of spironolactone,[15] as progesterone is known to be involved in mammary gland development.[188]

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,[189] 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.[101][102] 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 medication must have a different cause.[101][102] 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,[97] and mixed estrogenic and antiestrogenic activity.[101][102][145]

Antigonadotropic effects[edit]

Pure AR antagonists like flutamide and bicalutamide are potent progonadotropins with indirect estrogenic activity in males.[190] 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.[190] 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.[191] 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.[190]

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.[88][192][193] 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,[66][194] although some conflicting reports exist.[62][195][196] 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.[190] 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.[145]

Steroidogenesis inhibition[edit]

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.[197][198][199] Although spironolactone is said to be a relatively weak inhibitor of 17α-hydroxylase and 17,20-lyase,[82] at least compared to more potent steroidogenesis inhibitors like ketoconazole and abiraterone acetate (which can reduce testosterone concentrations to castrate levels), this action is considered to contribute a significant portion of the antiandrogenic effects of spironolactone, for instance lowering testosterone levels in women with hyperandrogenism and in transgender women.[200][176][201] Canrenone inhibits steroidogenic enzymes such as 17α-hydroxylase, 17,20-lyase, 11β-hydroxylase, cholesterol side-chain cleavage enzyme, and 21-hydroxylase similarly to spironolactone, but is more potent in doing so in comparison.[202]

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.[157][203][204][205][206] 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.[206] Spironolactone has been found not to have activity as an aromatase inhibitor.[173][180]

Glucocorticoid effects[edit]

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 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.[207][208] As such, any antiglucocorticoid 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.[143][209][210]

Pharmacokinetics[edit]

Pharmacokinetics of 100 mg/day spironolactone[211]
Compound Cmax (day 1) Cmax (day 15) AUC (day 15) t1/2
Spironolactone 72 ng/mL (173 nmol/L) 80 ng/mL (192 nmol/L) 231 ng•hour/mL (555 nmol•hour/L) 1.4 hours
Canrenone 155 ng/mL (455 nmol/L) 181 ng/mL (532 nmol/L) 2,173 ng•hour/mL (6,382 nmol•hour/L) 16.5 hours
7α-TMS 359 ng/mL (924 nmol/L) 391 ng/mL (1,006 nmol/L) 2,804 ng•hour/mL (7,216 nmol•hour/L) 13.8 hours
6β-OH-7α-TMS 101 ng/mL (250 nmol/L) 125 ng/mL (309 nmol/L) 1,727 ng•hour/mL (4,269 nmol•hour/L) 15.0 hours

Absorption[edit]

The bioavailability of spironolactone when taken by mouth is 60 to 90%.[5][6][7] The bioavailability of the medication improves significantly when it is taken with food.[212][213] The relationship between a single dose of spironolactone and plasma levels of canrenone, a major active metabolite of spironolactone, has been found to be linear across a dose range of 25 to 200 mg spironolactone.[63] Steady-state concentrations of spironolactone are achieved within 8 days of treatment initiation.[156]

Little or no systemic absorption has been observed with topical spironolactone.[214]

Distribution[edit]

Spironolactone and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively.[5][8] Spironolactone is bound equivalently to albumin and α1-acid glycoprotein, while canrenone is bound only to albumin.[5][8] Spironolactone and its metabolite 7α-thiospironolactone show very low or negligible affinity for sex hormone-binding globulin (SHBG).[166][215] 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.[216] This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG.[217]

Metabolism[edit]

Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a very short terminal half-life of 1.4 hours.[5][6] Unlike the related medication eplerenone, spironolactone is not metabolized by CYP3A4.[218] The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ6-spironolactone).[5][6][152] These metabolites have much longer elimination half-lives than spironolactone of 13.8 hours, 15.0 hours, and 16.5 hours, respectively, and are responsible for the therapeutic effects of the medication.[5][6] As such, spironolactone is a prodrug.[219] The 7α-thiomethylated metabolites of spironolactone were not known for many years and it was originally thought that canrenone was the major active metabolite of the medication, but subsequent research identified 7α-TMS as the major metabolite.[5][156][152] 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.[9]

Chemical structures of spironolactone and metabolites

Elimination[edit]

The majority of spironolactone is eliminated by the kidneys, while minimal amounts are handled by biliary excretion.[220]

Chemistry[edit]

Spironolactone, also known as 7α-acetylthiospirolactone, is a steroidal 17α-spirolactone, or more simply a spirolactone.[221] It can most appropriately be conceptualized as a derivative of progesterone,[222][223] 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 in at the C7α position.[224][225][226] These structural modifications of progesterone confer increased oral bioavailability and potency,[227] potent antiandrogenic activity, and strongly reduced progestogenic activity.[140] The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as 7α-thioprogesterone (SC-8365), unlike progesterone,[175] is a potent antiandrogen with similar affinity to the AR as that of spironolactone.[153] In addition, the C7α substitution appears to be responsible for the loss of progestogenic activity and good oral bioavailability of spironolactone, as SC-5233, the analogue of spironolactone without a C7α substitution, has potent progestogenic activity but very poor oral bioavailability similarly to progesterone.[228][229][175]

Names[edit]

Spironolactone is also known by the following equivalent chemical names:[224][225][226]

  • 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[edit]

Spironolactone is closely related structurally 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).[221]

Synthesis[edit]

Chemical syntheses of spironolactone and its analogues and derivatives have been described and reviewed.[230]

History[edit]

The natriuretic effects of progesterone were demonstrated in 1955, and the development of spironolactone as a synthetic antimineralocorticoid analogue of progesterone shortly followed this.[222][223][231][232] Spironolactone was first synthesized in 1957,[15][231][232] was patented between 1958 and 1961,[233][234] and was first marketed, as an antimineralocorticoid, in 1959.[235][236] The AR antagonistic (i.e., antiandrogen) activity of spironolactone was first discovered and reported in 1969,[237] 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.[238] The medication started to be used as an antiandrogen, for instance in the treatment of hirsutism in women, by the late 1970s and early 1980s,[239][240][241][129] and has since become the most widely used antiandrogen for dermatological indications in the United States.[242][73][243][244]

Society and culture[edit]

Generic names[edit]

The English, French, and generic name of the medication is spironolactone and this is its INN, USAN, USP, BAN, DCF, and JAN.[224][245][74][246] Its name is spironolactonum in Latin, spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also its DCIT).[245][74][246]

Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.[224][245][74]

Brand names[edit]

Spironolactone is marketed under a large number of brand names throughout the world.[245][74] The major brand name of spironolactone is Aldactone.[245][74] Other important brand names include Aldactone-A, Berlactone, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone (veterinary), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued),[2] Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis, Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (veterinary), Uractone, Uractonum, Verospiron, and Vivitar.[245][74]

Spironolactone is also formulated in combination with a variety of other medications, 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.[245]

Availability[edit]

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.[245][74]

Research[edit]

Benign prostatic hyperplasia[edit]

Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia.[247][248][249] It was found to be better than placebo in terms of symptom relief following three months of treatment.[247][248] However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared.[247][248][249] Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size.[247][248] Gynecomastia was observed in about 5% of people.[248] On the basis of these results, it has been said that spironolactone has no place in the treatment of benign prostatic hyperplasia.[248]

Epstein–Barr virus[edit]

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.[250] This effect of spironolactone was determined to be independent of its antimineralocorticoid actions.[250] Thus, spironolactone or compounds based on it have the potential to yield novel antiviral medications with a distinct mechanism of action and limited toxicity.[250]

Other conditions[edit]

Spironolactone has been studied in fibromyalgia in women.[251][252] It has also been studied in bulimia nervosa in women, but was not found to be effective.[253]

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ a b 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. 
  5. ^ a b c d e f g h i j k l m n o p q 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. 
  6. ^ a b c d e f g h i j Maron BA, Leopold JA (2008). "Mineralocorticoid receptor antagonists and endothelial function". Curr Opin Investig Drugs. 9 (9): 963–9. PMC 2967484Freely accessible. PMID 18729003. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ Friedman, Adam J. (1 October 2015). "Spironolactone for Adult Female Acne". Cutis. 96 (4): 216–217. ISSN 2326-6929. PMID 27141564. 
  12. ^ Maizes, Victoria (2015). Integrative Women's Health (2 ed.). p. 746. ISBN 9780190214807. 
  13. ^ "Spironolactone Pregnancy and Breastfeeding Warnings". Archived from the original on 2 December 2015. Retrieved 29 November 2015. 
  14. ^ Prakash C Deedwania (30 January 2014). Drug & Device Selection in Heart Failure. JP Medical Ltd. pp. 47–. ISBN 978-93-5090-723-8. 
  15. ^ a b c 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. 
  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. 
  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. 
  18. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016. 
  19. ^ "Spironolactone". International Drug Price Indicator Guide. Retrieved 29 November 2015. 
  20. ^ 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. 
  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. 
  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. 
  23. ^ 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. 
  24. ^ 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. 
  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. 
  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. 
  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. 
  29. ^ Husten, Larry (Apr 27, 2017) [2017]. ""Serious Questions Raised About Integrity Of International Trials"". CardioBrief.org. 
  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. 
  31. ^ 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. 
  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. 
  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. 
  34. ^ Marks LS (2004). "5alpha-reductase: history and clinical importance". Rev Urol. 6 Suppl 9: S11–21. PMC 1472916Freely accessible. PMID 16985920. 
  35. ^ Ethel Sloane (2002). Biology of Women. Cengage Learning. pp. 160–. ISBN 0-7668-1142-5. 
  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. 
  37. ^ Catherine Harper (1 August 2007). Intersex. Berg. pp. 123–. ISBN 978-1-84788-339-1. 
  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. 
  39. ^ 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. 
  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. 
  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 3315877Freely accessible. PMID 22468178. 
  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 5360829Freely accessible. PMID 28155090. 
  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. 
  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. 
  45. ^ a b 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. 
  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. 
  48. ^ 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. 
  49. ^ a b Smith RE (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. 
  50. ^ Adam Ostrzenski (2002). Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy. Lippincott Williams & Wilkins. pp. 86–. ISBN 978-0-7817-2761-7. 
  51. ^ 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. 
  52. ^ 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. 
  53. ^ 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. 
  54. ^ a b Joseph L. Izzo; Domenic A. Sica; Henry Richard Black (2008). Hypertension Primer. Lippincott Williams & Wilkins. pp. 444–. ISBN 978-0-7817-8205-0. Table C131.2. Doses of aldosterone antagonists in various clinical conditions. Drug: Spironolactone (Aldactone). Usual dose ranges (total mg/d). Essential hypertension: 25-200. Hyperaldosteronism [(and PCOS)]: 50-200. Heart failure: 25-50. 
  55. ^ David A. Warrell; Edward J. Benz; Timothy M. Cox; John D. Firth (2003). Oxford Textbook of Medicine. Oxford University Press. pp. 1–. ISBN 978-0-19-262922-7. Spironolactone 25 mg/day should be given routinely to all patients with congestive heart failure. [...] It is not known whether higher doses of spironolactone than 25 mg/day are also associated with a beneficial effect on mortality. 
  56. ^ Jeffrey D. Hosenpud; Barry H. Greenberg (2007). Congestive Heart Failure. Lippincott Williams & Wilkins. pp. 483–. ISBN 978-0-7817-6285-4. The first clinical trial demonstrating the benefits of aldosterone receptor blockade in [heart failure] was the Randomized Aldosterone Evaluation Study (RALES), in which 1,633 patients with NYHA Class III-IV chronic [heart failure], already receiving ACEIs, were randomized to spironolactone versus placebo (111). Patients were initiated on 12.5 or 25 mg of spironolactone daily and were titrated to 25 mg daily, with the possibility of increasing to 50 mg. 
  57. ^ a b Punit S. Ramrakha; Punit Ramrakha; Jonathan Hill (23 February 2012). Oxford Handbook of Cardiology. OUP Oxford. pp. 107–. ISBN 978-0-19-964321-9. Table 2.6 Doses for commonly used aldosterone antagonists. Agent: Spironolactone. Heart failure. Starting dose: 25 mg daily. Target dose: 50 mg daily. Hypertension. Starting dose: 100 mg daily. Target dose: 25-200 mg daily. 
  58. ^ a b 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. pp. 229,231. ISBN 978-1-4051-4370-7. The most rational treatment of cirrhotic patients with ascites appears to be the administration of an aldosterone antagonist. A stepwise equential therapy with increasing oral doses of an aldosterone antagonist (up to 400 mg/day) may be effective in mobilizing ascites in 60-80% of non-azotemic cirrhotic patients with ascites who do not respond to bed rest and dietary sodium restriction (11,12,74). The effective dosage of aldosterone antagonists depends on plasma aldosterone levels (75). Patients with moderately increased plasma levels require low doses of those drugs (100-150 mg/day), whereas patients with marked hyperaldosteronism may require as much as 200-400 mg/day. A further increase of the dosage up to 500-600 mg/day is of limited usefulness (11,12). 
  59. ^ C. J. Hawkey; Jaime Bosch; Joel E. Richter; Guadalupe Garcia-Tsao, Francis K. L. Chan (2 March 2012). Textbook of Clinical Gastroenterology and Hepatology. John Wiley & Sons. pp. 739–. ISBN 978-1-118-32142-3. Patients with new onset ascites respond to spironolactone 50-100 mg/day and the dose may be increased progressively if needed. Patients with prior episodes of ascites should receive the combination of spironolactone 100 mg/day with furosemide (20-40 mg/day) [12-14]. If there is no response, compliance with diet and medications should be confirmed and diuretics may then be increased in a stepwise fashion every 5-7 days by doubling doses to a maximal dose of spironolactone of 400 mg/day and a maximal dose of furosemide of 160 mg/day. 
  60. ^ Eugene R. Schiff; Michael F. Sorrell; Willis C. Maddrey (2007). Schiff's Diseases of the Liver. Lippincott Williams & Wilkins. pp. 547–. ISBN 978-0-7817-6040-9. The response to spironolactone depends on the degree of hyperaldosteronism. Patients with a normal or slightly increased plasma concentration of aldosterone usually respond to low doses of spironolactone (100 to 150 mg/day), but as much as 300 to 400 mg/day may be needed to antagonize the tubular effect of aldosterone in patients with marked hyperaldosteronism. The basic drug for the treatment of ascites, therefore, is spironolactone. 
  61. ^ Henry Richard Black; William J. Elliott (M.D.) (1 January 2007). Hypertension: A Companion to Braunwald's Heart Disease. Elsevier Health Sciences. pp. 114–. ISBN 1-4160-3053-0. The hypertension associated with primary aldosteronism is salt and water dependent and is best treated by sustained salt and water depletion (Fig. 9-9).39-41 The usual doses of diuretics are hydrochlorothiazide, 12.5 to 50 mg/day, or furosemide, 80 to 180 mg/day, in combination with either spironolactone, 100 to 200 mg/day, or amiloride, 10 to 20 mg/day. 
  62. ^ a b c 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. A modest improvement in hirsutism can be anticipated in 70-80% of women using even the minimum of 100 mg of spironolactone per day for 6 months [157]. [...] The most common dosage is 100-200 mg per day in a divided dosage. Women treated with 200 mg/day show a greater reduction in hair shaft diameter than women receiving 100 mg/day [159]. [...] Menstrual irregularity (usually metrorrhagia), is the most common side effect of spironolactone and occurs in over 50% of patients with a dosage of 200 mg/day [159]. [...] Patients must be counseled to use contraception while taking spironolactone because it theoretically can feminize a male fetus. 
  63. ^ a b Jashin J. Wu (18 October 2012). Comprehensive Dermatologic Drug Therapy E-Book. Elsevier Health Sciences. pp. 364–. ISBN 1-4557-3801-8. Spironolactone is an aldosterone antagonist and a relatively weak antiandrogen that blocks the AR and inhibits androgen biosynthesis. Spironolactone does not inhibit 5α-reductase. [...] The progestational activity of spironolactone is variable. The drug influences the ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH) by reducing the response of LH to GnRH. [...] In a dose range of 25-200 mg a linear relationship between a single dose of spironolactone and plasma levels of canrenone occurs within 96 hours. [...] Common doses [of spironolactone for dermatological indications] range between 50 and 200 mg daily, with 100 mg daily typically being better tolerated than higher dosages.20 
  64. ^ Alexandre Hohl (30 March 2017). Testosterone: From Basic to Clinical Aspects. Springer. pp. 333–. ISBN 978-3-319-46086-4. Doses [of spironolactone for hirsutism and PCOS] used in clinical studies have varied from 50 to 400 mg daily; although 100-mg/day are usually effective for the treatment of hirsutism, higher doses (200-300 mg/day) may be preferable in extremely hirsute or markedly obese women. Thus, the initial recommended dosage is 100 mg/day, gradually increasing it by increments of 25 mg/day every 3 months up to 200 mg/day on the basis of the response. [...] In patients with normal renal function, hyperkalemia is almost never seen. 
  65. ^ Janet P. Pregler; Alan H. DeCherney (2002). Women's Health: Principles and Clinical Practice. PMPH-USA. pp. 593–. ISBN 978-1-55009-170-0. Effective and safe dosages of spironolactone range between 50 and 400 mg orally daily. However, the most commonly prescribed regimen is 200 mg daily for the initial treatment of hirsutism and 100 mg daily for maintenance therapy. 
  66. ^ a b c d e Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 777,1087,1196. ISBN 978-0-7817-1750-2. Spironolactone has been used successfully in dosages of 100 to 200 mg daily for the treatment of idiopathic hirsutism and hirsutism associated with polycystic ovarian disease (see Chaps. 96 and 101).184 [...] 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 breast pain may occur in an equally large number of women taking the drug.27 
  67. ^ Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, Rosenthal SM, Safer JD, Tangpricha V, T'Sjoen GG (November 2017). "Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline". J. Clin. Endocrinol. Metab. 102 (11): 3869–3903. doi:10.1210/jc.2017-01658. PMID 28945902. Hormone Regimens in Transgender Persons. Transgender females. Antiandrogens. Spironolactone. 100–300 mg/d. 
  68. ^ Wesp LM, Deutsch MB (March 2017). "Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons". Psychiatr. Clin. North Am. 40 (1): 99–111. doi:10.1016/j.psc.2016.10.006. PMID 28159148. Table 3. Recommended antiandrogen dose. Drug: Spironolactone. Initial Dose (mg/d): 100. Maximum Dose (mg/d): 400. Comments: Usually divided into twice daily dosing. Pills come in 25, 50, or 100 mg doses and can be titrated up as tolerated. Taking earlier in day may prevent urinary frequency during night. 
  69. ^ Rebecca Webb; Joshua D. Safer (2019). Chapter 28 – Transgender Hormonal Treatment. Yen & Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management (Eighth Edition). Elsevier Health Sciences. pp. 709–716.e1. doi:10.1016/B978-0-323-47912-7.00028-7. ISBN 978-0-323-58232-2. Spironolactone 100–200 mg/day (up to 400 mg). 
  70. ^ Muller (19 June 1998). European Drug Index: European Drug Registrations, Fourth Edition. CRC Press. pp. 44–. ISBN 978-3-7692-2114-5. 
  71. ^ Mary Lee; Archana Desai (2007). Gibaldi's Drug Delivery Systems in Pharmaceutical Care. ASHP. pp. 312–. ISBN 978-1-58528-136-7. 
  72. ^ 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. 
  73. ^ 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. 
  74. ^ 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. 
  75. ^ 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. 
  76. ^ 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. 
  77. ^ 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. 
  78. ^ 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. 
  79. ^ 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. 
  80. ^ 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. 
  81. ^ 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. 
  82. ^ 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. 
  83. ^ 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. 
  84. ^ 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. 
  85. ^ 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. 
  86. ^ 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. 
  87. ^ 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]. 
  88. ^ 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. 
  89. ^ 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 1539051Freely accessible. PMID 16840442. 
  90. ^ Wandelt-Freerksen E. (1977). "Aldactone in the treatment of sarcoidosis of the lungs". JZ Erkr Atmungsorgane. 149 (1): 156–9. PMID 607621. 
  91. ^ 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. 
  92. ^ a b Lainscak M, Pelliccia F, Rosano G, Vitale C, Schiariti M, Greco C, Speziale G, Gaudio C (2015). "Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone". Int. J. Cardiol. 200: 25–9. doi:10.1016/j.ijcard.2015.05.127. PMID 26404748. 
  93. ^ Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA (2004). "Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study". N. Engl. J. Med. 351 (6): 543–51. doi:10.1056/NEJMoa040135. PMID 15295047. 
  94. ^ 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. 
  95. ^ 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]. 
  96. ^ 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. 
  97. ^ 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. 
  98. ^ 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]. 
  99. ^ 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 
  100. ^ 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. 
  101. ^ 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. 
  102. ^ 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. 
  103. ^ 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. 
  104. ^ 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. 
  105. ^ 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. 
  106. ^ 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. 
  107. ^ 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. PMC 1768327Freely accessible. 
  108. ^ 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. 
  109. ^ 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. 
  110. ^ "Archived copy". Archived from the original on 2015-03-10. Retrieved 2014-03-03. 
  111. ^ online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7699#f_adverse-reactions
  112. ^ a b c "Archived copy" (PDF). Archived (PDF) from the original on 2013-08-22. Retrieved 2014-04-17. 
  113. ^ 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 1903848Freely accessible. PMID 7195152. 
  114. ^ 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. 
  115. ^ 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. 
  116. ^ 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. 
  117. ^ 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. 
  118. ^ 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. 
  119. ^ 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. 
  120. ^ Jonathan Upfal (2006). Australian Drug Guide. Black Inc. pp. 671–. ISBN 978-1-86395-174-6. Archived from the original on 2017-09-08. 
  121. ^ "Advisory Statement" (PDF). Klinge Chemicals / LoSalt. Archived from the original (pdf) on 2006-11-15. Retrieved 2007-03-15. 
  122. ^ 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. 
  123. ^ Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).
  124. ^ 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. 
  125. ^ 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. 
  126. ^ Juvet T, Gourineni V, Ravi S, Zarich S (September 2013). "Life-threatening hyperkalemia: a potentially lethal drug combination". Connecticut Medicine. 77 (8): 491–493. 
  127. ^ Mellar P. Davis (28 May 2009). Opioids in Cancer Pain. OUP Oxford. pp. 222–. ISBN 978-0-19-923664-0. 
  128. ^ Stephen E. Wolverton (8 March 2007). Comprehensive Dermatologic Drug Therapy. Elsevier Health Sciences. pp. 2677–. ISBN 1-4377-2070-6. 
  129. ^ 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. 
  130. ^ 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. 
  131. ^ 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. 
  132. ^ 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 3498851Freely accessible. PMID 23185686. 
  133. ^ 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. 
  134. ^ Parthasarathy HK, MacDonald TM (2007). "Mineralocorticoid receptor antagonists". Curr. Hypertens. Rep. 9 (1): 45–52. doi:10.1007/s11906-007-0009-3. PMID 17362671. 
  135. ^ Rainer F. Greger; H. Knauf; E. Mutschler (6 December 2012). Diuretics. Springer Science & Business Media. pp. 352–. ISBN 978-3-642-79565-7. 
  136. ^ "The Binding Database (Binding DB)". University of California, San Diego and ChemAxon. Retrieved 21 December 2017. 
  137. ^ Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017. 
  138. ^ a b c d e f Bell MG, Gernert DL, Grese TA, Belvo MD, Borromeo PS, Kelley SA, Kennedy JH, Kolis SP, Lander PA, Richey R, Sharp VS, Stephenson GA, Williams JD, Yu H, Zimmerman KM, Steinberg MI, Jadhav PK (2007). "(S)-N-{3-[1-cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mineralocorticoid receptor". J. Med. Chem. 50 (26): 6443–5. doi:10.1021/jm701186z. PMID 18038968. 
  139. ^ a b c d e Hasui T, Matsunaga N, Ora T, Ohyabu N, Nishigaki N, Imura Y, Igata Y, Matsui H, Motoyaji T, Tanaka T, Habuka N, Sogabe S, Ono M, Siedem CS, Tang TP, Gauthier C, De Meese LA, Boyd SA, Fukumoto S (2011). "Identification of benzoxazin-3-one derivatives as novel, potent, and selective nonsteroidal mineralocorticoid receptor antagonists". J. Med. Chem. 54 (24): 8616–31. doi:10.1021/jm2011645. PMID 22074142. 
  140. ^ a b c d e f g Hu X, Li S, McMahon EG, Lala DS, Rudolph AE (2005). "Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone". Mini Rev Med Chem. 5 (8): 709–18. doi:10.2174/1389557054553811. PMID 16101407. 
  141. ^ a b c d e f g h i Yang C, Shen HC, Wu Z, Chu HD, Cox JM, Balsells J, Crespo A, Brown P, Zamlynny B, Wiltsie J, Clemas J, Gibson J, Contino L, Lisnock J, Zhou G, Garcia-Calvo M, Bateman T, Xu L, Tong X, Crook M, Sinclair P (2013). "Discovery of novel oxazolidinedione derivatives as potent and selective mineralocorticoid receptor antagonists". Bioorg. Med. Chem. Lett. 23 (15): 4388–92. doi:10.1016/j.bmcl.2013.05.077. PMID 23777778. 
  142. ^ a b Meyers MJ, Arhancet GB, Hockerman SL, Chen X, Long SA, Mahoney MW, Rico JR, Garland DJ, Blinn JR, Collins JT, Yang S, Huang HC, McGee KF, Wendling JM, Dietz JD, Payne MA, Homer BL, Heron MI, Reitz DB, Hu X (2010). "Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy". J. Med. Chem. 53 (16): 5979–6002. doi:10.1021/jm100505n. PMID 20672822. 
  143. ^ 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 2943305Freely accessible. PMID 20650892. 
  144. ^ 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. 
  145. ^ 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. 
  146. ^ 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 (PDF) from the original on 2015-09-24. 
  147. ^ 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. 
  148. ^ 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 508967Freely accessible. PMID 9727070. 
  149. ^ 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. 
  150. ^ 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. 
  151. ^ 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. PMC 1808828Freely accessible. 
  152. ^ 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. 
  153. ^ 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. 
  154. ^ 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. 
  155. ^ 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. 
  156. ^ 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. 
  157. ^ 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. 
  158. ^ 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. 
  159. ^ 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. 
  160. ^ 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. 
  161. ^ 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. 
  162. ^ 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 3291010Freely accessible. PMID 22665559. 
  163. ^ 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. 
  164. ^ 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. 
  165. ^ 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. 
  166. ^ 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. 
  167. ^ 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. 
  168. ^ 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. 
  169. ^ 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. 
  170. ^ 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. 
  171. ^ 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. 
  172. ^ 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. 
  173. ^ 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. 
  174. ^ 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. 
  175. ^ a b c 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 (PDF) from the original on 2016-08-22. 
  176. ^ 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. 
  177. ^ a b Poirier D (2003). "Inhibitors of 17 beta-hydroxysteroid dehydrogenases". Curr. Med. Chem. 10 (6): 453–77. doi:10.2174/0929867033368222. PMID 12570693. 
  178. ^ 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. 
  179. ^ 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. 
  180. ^ 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. 
  181. ^ 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. 
  182. ^ 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. 
  183. ^ 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. 
  184. ^ 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. 
  185. ^ 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. 
  186. ^ 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. 
  187. ^ 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 2780289Freely accessible. PMID 19843067. 
  188. ^ 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 138744Freely accessible. PMID 12223124. Archived from the original on 2013-02-18. 
  189. ^ 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. 
  190. ^ 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. 
  191. ^ 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. 
  192. ^ Shlomo Melmed (2016). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 626–. ISBN 978-0-323-29738-7. 
  193. ^ 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. 
  194. ^ Drapier-Faure, Evelyne; Faure, Michel (2006). "Antiandrogens". Hidradenitis Suppurativa: 124–127. doi:10.1007/978-3-540-33101-8_16. 
  195. ^ Israel Journal of Medical Sciences. Israel Medical Association, National Council for Research and Development. July 1984. 
  196. ^ 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. 
  197. ^ 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. 
  198. ^ Sengupta (1 January 2007). Gynaecology For Postgraduate And Practitioners. Elsevier India. pp. 172–. ISBN 978-81-312-0436-8. 
  199. ^ Bruce R. Carr; Richard E. Blackwell (1998). Textbook of Reproductive Medicine. McGraw-Hill Professional Publishing. p. 261. ISBN 978-0-8385-8893-2. 
  200. ^ 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. 
  201. ^ Haynes BA, Mookadam F (August 2009). "Male gynecomastia". Mayo Clinic Proceedings. 84 (8): 672. doi:10.4065/84.8.672. PMC 2719518Freely accessible. PMID 19648382. 
  202. ^ Colby HD (1981). "Chemical suppression of steroidogenesis". Environ. Health Perspect. 38: 119–27. doi:10.1289/ehp.8138119. PMC 1568425Freely accessible. PMID 6786868. 
  203. ^ 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. 
  204. ^ 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. 
  205. ^ 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. 
  206. ^ 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. 
  207. ^ 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. 
  208. ^ 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. 
  209. ^ Campen TJ, Fanestil DD (1982). "Spironolactone: a glucocorticoid agonist or antagonist?". Clin Exp Hypertens A. 4 (9–10): 1627–36. PMID 6128090. 
  210. ^ 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. 
  211. ^ 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. 
  212. ^ 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. 
  213. ^ 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. doi:10.1002/cpt1977221100. PMID 872489. 
  214. ^ Rey FO, Valterio C, Locatelli L, Ramelet AA, Felber JP (April 1988). "Lack of endocrine systemic side effects after topical application of spironolactone in man". J. Endocrinol. Invest. 11 (4): 273–8. doi:10.1007/BF03350151. PMID 3411088. 
  215. ^ 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. 
  216. ^ 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. 
  217. ^ 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. 
  218. ^ 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. 
  219. ^ Oxford Textbook of Medicine: Vol. 1. Oxford University Press. 2003. pp. 1–. ISBN 978-0-19-262922-7. 
  220. ^ 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. 
  221. ^ 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 5488394Freely accessible. PMID 28634268. 
  222. ^ a b Ménard J (2004). "The 45-year story of the development of an anti-aldosterone more specific than spironolactone". Mol. Cell. Endocrinol. 217 (1-2): 45–52. doi:10.1016/j.mce.2003.10.008. PMID 15134800. [Spironolactone] was synthesized after the demonstration of the natriuretic effect of progesterone (Landau et al., 1955). 
  223. ^ a b J. Larry Jameson; Leslie J. De Groot (18 May 2010). Endocrinology - E-Book: Adult and Pediatric. Elsevier Health Sciences. pp. 2401–. ISBN 1-4557-1126-8. [Spironolactone] is a potent antimineralocorticoid which was developed as a progestational analog [...] 
  224. ^ 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. 
  225. ^ a b "Archived copy". Archived from the original on 2016-06-30. Retrieved 2017-07-04. 
  226. ^ a b http://www.chemspider.com/Chemical-Structure.5628.html?rid=b578a389-d64b-4ec2-ae20-309e5f3abd11
  227. ^ Simon JA (1995). "Micronized progesterone: vaginal and oral uses". Clin Obstet Gynecol. 38 (4): 902–14. doi:10.1097/00003081-199538040-00024. PMID 8616985. 
  228. ^ Hertz R, Tullner WW (1958). "Progestational activity of certain steroid-17-spirolactones". Proc. Soc. Exp. Biol. Med. 99 (2): 451–2. doi:10.3181/00379727-99-24380. PMID 13601900. 
  229. ^ The British Encyclopaedia of Medical Practice: Medical progress. Butterworth & Company. 1961. p. 302. Cena and Kagawa first synthesized 3-(3-oxo-17β-hydroxy-4-androsten-17α-yl)-propionic acid-gamma-lactone and later prepared its 19-nor analogue. These compounds were designated SC-5233 and SC-8109, respectively. Both have anti-aldosterone activity and most of the early work on aldosterone antagonism was done with their aid. SC-5233 is not appreciably absorbed when given by mouth and the parenteral dose is large. 
  230. ^ Larik FA, Saeed A, Shahzad D, Faisal M, El-Seedi H, Mehfooz H, Channar PA (February 2017). "Synthetic approaches towards the multi target drug spironolactone and its potent analogues/derivatives". Steroids. 118: 76–92. doi:10.1016/j.steroids.2016.12.010. PMID 28041953. 
  231. ^ a b Kagawa CM, Cella JA, Van Arman CG (1957). "Action of new steroids in blocking effects of aldosterone and desoxycorticosterone on salt". Science. 126 (3281): 1015–6. doi:10.1126/science.126.3281.1015. PMID 13486053. 
  232. ^ a b Liddle GW (1957). "Sodium diuresis induced by steroidal antagonists of aldosterone". Science. 126 (3281): 1016–8. doi:10.1126/science.126.3281.1016. PMID 13486054. 
  233. ^ 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. 
  234. ^ 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. 
  235. ^ 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. 
  236. ^ 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. 
  237. ^ 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. 
  238. ^ 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."
  239. ^ Ober KP, Hennessy JF (1978). "Spironolactone therapy for hirsutism in a hyperandrogenic woman". Ann. Intern. Med. 89 (5 Pt 1): 643–4. doi:10.7326/0003-4819-89-5-643. PMID 717935. 
  240. ^ 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. 
  241. ^ 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. 
  242. ^ Duru Shah; R. K. Bhathena; Safala Shroff (2004). The Polycystic Ovary Syndrome. Orient Blackswan. pp. 78–. ISBN 978-81-250-2633-4. 
  243. ^ Paula J. Adams Hillard (29 March 2013). Practical Pediatric and Adolescent Gynecology. John Wiley & Sons. pp. 371–. ISBN 978-1-118-53857-9. 
  244. ^ Michele Curtis (2014). Glass' Office Gynecology. Lippincott Williams & Wilkins. pp. 47–. ISBN 978-1-60831-820-9. 
  245. ^ a b c d e f g h "Archived copy". Archived from the original on 2016-12-02. Retrieved 2016-12-01. 
  246. ^ 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. 
  247. ^ a b c d Benign Prostatic Hypertrophy. Springer Science & Business Media. 6 December 2012. pp. 266–. ISBN 978-1-4612-5476-8. 
  248. ^ 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. 
  249. ^ 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. 
  250. ^ 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 4822607Freely accessible. PMID 26976570. Archived from the original on 2016-03-24. 
  251. ^ 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. 
  252. ^ 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. 
  253. ^ McElroy SL, Guerdjikova AI, Mori N, O'Melia AM (2012). "Current pharmacotherapy options for bulimia nervosa and binge eating disorder". Expert Opin Pharmacother. 13 (14): 2015–26. doi:10.1517/14656566.2012.721781. PMID 22946772. 

External links[edit]