|Systematic (IUPAC) name|
17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone acetate
|Biological half-life||1.3-2 hours|
|CAS Registry Number|
|Molecular mass||416.574 g/mol|
|(what is this?)|
Spironolactone (pronounced //, and commonly shortened simply to "spiro") (INN, BAN, USAN), marketed mainly under the brand name Aldactone in most countries, is a synthetic, steroidal antimineralocorticoid, antiandrogen, and, to a lesser extent, progestin. It belongs to a class of pharmaceutical drugs known as potassium-sparing diuretics, and is used primarily as a diuretic and antihypertensive in the treatment of heart failure and hypertension. As a secondary use, spironolactone is also frequently employed off-label for the purpose of reducing elevated or unwanted androgen levels and activity in the body, such as in the treatment of hyperandrogenism in women and, especially, as a component of hormone replacement therapy for trans women.
Spironolactone is a relatively old drug, having been introduced clinically in 1959. Futterman and Lemberg predicted that spironolactone will be less commonly used in cardiovascular conditions as newer agents such as eplerenone are more selective and produce fewer side effects – namely, antiandrogenic side effects. However, spironolactone remains widely used for indications in which its antiandrogen effects are the intention of treatment.
Spironolactone is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
- 1 Medical uses
- 2 Adverse reactions
- 3 Pharmacology
- 4 Pharmacokinetics
- 5 Spironolactone bodies
- 6 Synthesis 1
- 7 Synthesis 2
- 8 See also
- 9 References
- 10 External links
Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in patients with liver disease, essential hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis), and Conn's syndrome (primary hyperaldosteronism). On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy. About one person in one hundred with hypertension has elevated levels of aldosterone; in these persons, 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.
While loop diuretics remain first-line for most patients 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%.
In a randomized evaluation which studied people with severe congestive heart failure, patients treated with spironolactone were found to have a relative risk of death of 0.70 or an overall 30% relative risk reduction compared to the placebo group, indicating a significant Death and morbidity benefit of the drug. Patients in the study's intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently. Likewise, it has shown benefit for and is recommended in patients who recently suffered a heart attack and have an ejection fraction <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. 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.
It is recommended that alternatives to spironolactone be considered if serum creatinine is >2.5 mg/dL (221µmol/L) in males or >2 mg/dL (176.8 µmol/L) in females, if glomerular filtration rate is below 30mL/min or with a serum potassium of >5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of renal function as well.
According to systematic review, in patients with 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.
Because spironolactone reduces the body's production of testosterone, it can be quite effective in clearing severe acne conditions, such as cystic acne, caused by slightly elevated or elevated levels of testosterone in women. In reducing the levels of testosterone, excess oil that is naturally produced in the skin is also reduced. Though not the primary intended purpose of the medication, its ability to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful. Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill. A significant amount of patients have reported that they have seen positive results in the pairing of these two medications, although these results may not be seen for up to three months.
Because spironolactone reduces the body's production of testosterone and blocks the androgen receptor, it can cause effects associated with low testosterone 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. The newer drug, eplerenone has been approved by the U.S. Food and Drug Administration for treatment of heart failure, but lacks the rather potent antiandrogen effects and thus is far more suitable for men for whom long term medication is being chosen. 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 cardiac arrythmias.
Spironolactone is a potent antagonist of the androgen receptor as well 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, acne, and seborrhea in women. Spironolactone is the most commonly used drug in the treatment of hirsutism in the United States. 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.
Spironolactone is frequently used as a component of hormone replacement therapy in trans women, especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen. It is generally recommended to be prescribed at a dose of 100–200 mg per day for this purpose, though it is frequently used at doses up to 300–400 mg in cases of treatment-resistant individuals, and doses as high as 600 mg have been used in some clinical studies with additional benefits seen. Spironolactone significantly depresses plasma testosterone levels, reducing them to female/castrate levels at sufficient doses and in combination with estrogen. The clinical response consists of, among other effects, decreased male pattern body hair, the induction of breast development, feminization in general, and lack of spontaneous erections.
There are few available options for antiandrogen therapy. Spironolactone, cyproterone acetate, and flutamide are some of the most well-known and widely-used drugs. Compared to cyproterone acetate, spironolactone is considerably less potent as an antiandrogen by weight and binding affinity to the androgen receptor. However, despite this, at the doses of which they are typically used, spironolactone and cyproterone acetate have been found to be generally about equivalent in terms of effectiveness for a variety of androgen-related conditions, though, cyproterone acetate has shown a slight though non-statistically-significant advantage in some studies. 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.
Flutamide, another frequently used antiandrogen which is non-steroidal and a pure androgen receptor antagonist, though much less potent by weight and binding affinity than either spironolactone or cyproterone acetate, has been found to be more effective than either of them as an antiandrogen when it is used at the typical treatment doses. Unfortunately, the uses of both cyproterone acetate and flutamide have been associated with hepatotoxicity, which can be severe with flutamide and has resulted in the withdrawal of cyproterone acetate from the United States drug market for this indication. 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. As such, spironolactone may be the only practical, safe, available, and well-supported antiandrogen option in some cases.
The most common side effect of spironolactone is urinary frequency. Other general side effects include ataxia, drowsiness, dry skin, and rashes. Because it reduces androgen levels and blocks androgen receptors, spironolactone can, in males, cause breast tenderness, gynecomastia, and physical feminization in general, as well as testicular atrophy, reversible infertility, and sexual dysfunction, including loss of libido and erectile dysfunction. In females, spironolactone can cause menstrual irregularities and breast tenderness and enlargement, likely due to a combination of its progestogenic and indirect estrogenic actions.
The most important potential side effect of spironolactone is hyperkalemia, which can be life-threatening. Spironolactone may put patients at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis. In addition, there has been some evidence suggesting an association between use of the drug and bleeding from the stomach and duodenum, though a causal relationship between the two has not been established. Also, it has been shown to be immunosuppressive in the treatment of sarcoidosis.
Spironolactone may rarely cause more severe side effects such as anaphylaxis, renal failure, hepatotoxicity, agranulocytosis, DRESS syndrome, Stevens-Johnson Syndrome or toxic epidermal necrolysis.
Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this drug avoid potassium supplements and salt substitutes containing potassium. 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.
Research has suggested that spironolactone may be able to interfere with the effectiveness of antidepressant treatment. As the drug acts as an antagonist of the mineralocorticoid receptor, 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. However, other research contradicts this hypothesis and has suggested that spironolactone may actually produce antidepressant-like effects.
Spironolactone is considered Pregnancy Category C by the FDA and should not be taken by pregnant women due to the high risk of birth defects and feminization of male fetuses. 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 breast-feeding infants, it is generally recommended that women also not take the drug while nursing.
- Mineralocorticoid receptor (MR) antagonist (IC50 = 24 nM)
- Androgen receptor (AR) antagonist/very weak partial agonist (IC50 = 77 nM)
- Progesterone receptor agonist (EC50 = 740 nM)
- Glucocorticoid receptor antagonist (IC50 = 2,410 nM)
- Steroid 11β-hydroxylase, aldosterone synthase (18-hydroxylase), 17α-hydroxylase, and 17,20-lyase inhibitor
- Pregnane X receptor (PXR) agonist (and thus CYP3A4 and P-glycoprotein inducer)
Spironolactone does not have significant affinity for either of the estrogen receptors (ERα or ERβ), nor is its low affinity for the GR thought to be of significance at clinically-relevant concentrations.
Spironolactone inhibits the effects of mineralocorticoids, namely, aldosterone, by displacing them from mineralocorticoid receptors (MR) in the cortical collecting duct of renal nephrons. This decreases the reabsorption of sodium and water, while limiting the excretion of potassium (A K+ sparing diuretic). The drug has a slightly delayed onset of action, and so it takes several days for diuresis to occur. This is because the MR is a nuclear receptor which works through regulating gene transcription and gene expression, in this case to decrease the production and expression of ENaC and ROMK electrolyte channels in the distal nephrons. In addition to direct antagonism of the MRs, the antimineralocorticoid effects of spironolactone may also in part be mediated by direct inactivation of steroid 11β-hydroxylase and aldosterone synthase (18-hydroxylase), enzymes involved in the biosynthesis of mineralocorticoids. If levels of mineralocorticoids are decreased then there are lower circulating levels to compete with spironolactone to influence gene expression as mentioned above.
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 would in theory be lowered alongside the lower levels of mineralocorticoids (i.e. spironolactone should also produce some degree of antiglucocorticoid effect). In clinical practice however, this has not been found to be the case, as spironolactone has actually been shown 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 glucocorticoids as well. Therefore, by disinhibiting the regulation on ACTH, its levels rise and spironolactone essentially causes an indirect rise in cortisol production. Thus, 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 secondary to ACTH.
Spironolactone mediates its antiandrogenic effects via multiple actions, including the following:
- Direct blockade of androgens from interacting with the androgen receptor. It should be noted however that spironolactone, similarly to other steroidal antiandrogens such as cyproterone acetate, is not a pure, or silent, antagonist of the androgen receptor, but rather a weak partial agonist with the capacity for both agonist and antagonist effects. However, in the presence of significant enough levels of potent full agonists like testosterone and DHT, the cases in which it is usually used even with regards to the "lower" relative levels present in females, spironolactone will behave similar to a pure antagonist. Nonetheless, there may still be a potential for spironolactone to produce androgenic effects (i.e. act as a receptor agonist) in the body at sufficiently high doses and/or in those with low enough endogenous androgen concentrations. As an example, one condition in which spironolactone is contraindicated is prostate cancer, as the drug has been shown in vitro to significantly accelerate carcinoma growth in the absence of any other androgens, and was found to do so at the relatively high rate of approximately 32%, which was about 35% that of DHT (thus also indicating that its potential intrinsic activity at the androgen receptor may be somewhere around one-third that of endogenous full agonists).
- Inhibition of 17α-hydroxylase and 17,20-desmolase, enzymes in the androgen biosynthesis pathway, which in turn results in decreased testosterone and dihydrotestosterone (DHT) levels. Though, its inhibition of these enzymes is said to be relatively weak.
- Activation of the progesterone receptor, as, in sufficient amounts, this results in an antigonadotropic effect due to negative feedback on the hypothalamic-pituitary-gonadal axis, which in turn reduces sex steroid production and by extension androgen levels.
- Inhibition of 5α-reductase, the enzyme responsible for converting testosterone into the 3- to 10-fold more potent androgen dihydrotestosterone (DHT). However, there is conflicting data on the ability of spironolactone to affect this enzyme. An in vitro study of the effect of spironolactone on prostate tissue 5α-reductase activity found no change even with very high concentrations of the drug. In contrast, another study, after one month of treatment of spironolactone at a dose of 100 mg per day via the oral route, found a significant in vivo inhibitory effect of spironolactone on genital skin 5α-reductase activity in hirsute women as well as an inhibitory effect of the drug on 5α-reductase activity in normal genital skin in vitro, and concluded that spironolactone directly inhibits the 5α-reductase enzyme and that the property could play a role of the beneficial effects of the drug on hirsutism. However, another study of spironolactone in hirsute women, after 6 months of treatment at the same dose (100 mg/d orally), found no significant effects of the drug on the serum ratios of testosterone to DHT and its metabolites—a reliable marker of 5α-reductase activity—whereas significant changes were found with 5 mg per day oral finasteride, a well-established 5α-reductase inhibitor. Finally, yet another study of spironolactone in hirsute women, after 3 months of treatment at a higher dose of 200 mg per day orally, did report significant changes, in the same metabolic markers of 5α-reductase activity. In summation then, whether spironolactone actually inhibits 5α-reductase to some clinical end-point or not and how it may do so remain unclear. It can be deduced from comparison studies, however, that if it does have an effect at reducing hirsutism, it is not as effective as more potent and selective 5α-reductase inhibitors like finasteride. Supporting this conclusion is another trial in which the combination of 100 mg/d spironolactone and 5 mg/d finasteride was found to be significantly more effective than spironolactone alone in the treatment of hirsutism in women.
- Acceleration of the rate of metabolism/clearance of testosterone by enhancing the rate of peripheral conversion of testosterone to estradiol.
Spironolactone has weak progestogenic properties. Its actions in this regard are a result of direct agonist activity at the progesterone receptor, but with a half-maximal potency approximately one-tenth that of its activity at the androgen receptor. Spironolactone's progestogenic actions are thought to be responsible for some of its side effects, including the menstrual irregularities seen in women and the undesirable serum lipid profile changes that are seen at higher doses. They may also serve to augment the gynecomastia caused by the estrogenic effects of spironolactone, as progesterone is known to play a role in breast development.
Spironolactone has some indirect estrogenic effects which it mediates via several actions, including the following:
- By acting as an antiandrogen, as androgens suppress both estrogen production and action.
- Displacement of estrogens from sex hormone-binding globulin (SHBG). This occurs because spironolactone binds to SHBG at a relatively high rate, as do endogenous estrogens and androgens, but estrogens like estradiol and estrone are more easily displaced than are androgens like testosterone. As a result, spironolactone blocks relatively more estrogens from interacting with SHBG than androgens, resulting in a higher ratio of free estrogens to free androgens.
- Inhibition of the conversion of estradiol to estrone, resulting in an increase in the ratio of estradiol to estrone. This is important because estradiol is approximately 10 times as potent as estrone as an estrogen.
- Enhancement of the rate of peripheral conversion of testosterone to estradiol, thus further lowering testosterone levels and increasing estradiol levels.
Spironolactone has an onset of action of about 2–3 hours after taking the first dose, with a half-life of about 1–2 hours. Due to its relatively short half-life, it is thought that spironolactone may behave mainly as a prodrug to an array of active metabolites with much longer half-lives (e.g., 12–20 hours in the case of canrenone). Some of its metabolites include canrenone, canrenoic acid, 7α-methylthiospironolactone, and 6β-hydroxy-7α-methylthiospironolactone, among many others. The drug is highly plasma protein bound. It is metabolized by the liver, from which it is partially eliminated with the majority being handled by the kidneys. Minimal amounts are handled by biliary excretion.
Of note, the clinical benefits of the drug when used a diuretic are typically not seen until 2–3 days after dosing begins, perhaps accounted for by the need for 4-5 doses before reaching a steady state concentration. Likewise, the maximal antihypertensive effective may not be seen for 2–3 weeks.
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.
Spironolactone can be synthesized from 3-hydroxyandrost-5-en-17-one (DHEA).
Spironolactone is the 7-acetate of the γ-lactone of 17-hydroxy-7-mercapto-3-oxo-17-α-pregn-4-ene-21-carboxylic acid (21.5.8). Spironolactone is synthesized industrially in two different ways from androstenolone—3β-hydroxy-5-androsten-17-one.
According to the first method, androstenolone undergoes ethynylation by acetylene in a Normant reaction condition using sodium amide in liquid ammonia, which forms 17α-ethynyl-3β-,17β-dihydroxy-5-androstene. Subsequent reaction of this with methylmagnesiumbromide and then with carbon dioxide gives the corresponding propenal acid. Reduction of the triple bond in this product with hydrogen using a palladium on calcium carbonate catalyst forms the corresponding acrylic acid derivative, which is treated with acid without being isolated, which leads to cyclization into an unsaturated lactone derivative. The double bond is reduced by hydrogen, in this case using a palladium on carbon catalyst. The resulting lactone undergoes oxidation in an Oppenauer reaction, giving an unsaturated keto-derivative—4-androsten-3,17-dione. Further oxidation of the product using chloroanyl gives dienone, which when reacted with thioacetic acid gives the desired spionolactone.
- J.A. Cella, R.C. Tweit, U.S. Patent 3,013,012 (1961).
- W.F. Johns, Ger. Pat. DE 1121610 (1959).
- J.A. Cella, R.C. Tweit,U.S. Patent 3,137,690 (1964).
- Cella, J. A.; Tweit, R. C. (1959). "Steroidal Aldosterone Blockers. II1". The Journal of Organic Chemistry 24 (8): 1109. doi:10.1021/jo01090a019.
- Dodson, R. M.; Tweit, R. C. (1959). "Addition of Alkanethiolic Acids to Δ1,4-3-Oxo- and Δ4,6-3-Oxosteroids1". Journal of the American Chemical Society 81 (5): 1224. doi:10.1021/ja01514a052.
The second way is from 4-androsten-3,17-dione, which undergoes ethynylation by propargyl alcohol in the presence of potassium tert-butylate, forming 17β-hydroxy-17α-(3-hydroxypropinyl)-4-androsten-3-one, the triple bond of which is completely reduced by hydrogen using as a catalyst a complex of triphenylphospine and rhodium chloride, which forms 17β-hydroxy-17α-(3-hydroxypropyl)-4-androsten-3-one. Oxidation of this product with chromium (VI) oxide in pyridine gives lactone, which is oxidized in the manner described above by chloranyl to and reacted further with thioacetic acid to the desired spironolactone.
- R. Philippson, Ger. Pat. DE 2327448 (1973).
- Harry G. Brittain (26 November 2002). Analytical Profiles of Drug Substances and Excipients. Academic Press. p. 309. ISBN 978-0-12-260829-2. Retrieved 27 May 2012.
- "Spironolactone: MedlinePlus Drug Information". Retrieved 2012-06-20.
- Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 1614. ISBN 978-3-88763-075-1. Retrieved 13 June 2012.
- F.. Macdonald (1997). Dictionary of Pharmacological Agents. CRC Press. pp. 1832–1833. ISBN 978-0-412-46630-4. Retrieved 12 May 2012.
- Camille Georges Wermuth (24 July 2008). The Practice of Medicinal Chemistry. Academic Press. p. 34. ISBN 978-0-12-374194-3. Retrieved 27 May 2012.
- Marshall Sittig (1988). Pharmaceutical Manufacturing Encyclopedia. William Andrew. p. 1385. ISBN 978-0-8155-1144-1. Retrieved 27 May 2012.
- Futterman LG, Lemberg L (March 2004). "The resurrection of spironolactone on its golden anniversary". American Journal of Critical Care : an Official Publication, American Association of Critical-Care Nurses 13 (2): 162–5. PMID 15043244.
- "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- Yancy, CW; Jessup, M; Bozkurt, B; Butler, J; Casey DE, Jr; Drazner, MH; Fonarow, GC; Geraci, SA; Horwich, T; Januzzi, JL; Johnson, MR; Kasper, EK; Levy, WC; Masoudi, FA; McBride, PE; McMurray, JJ; Mitchell, JE; Peterson, PN; Riegel, B; Sam, F; Stevenson, LW; Tang, WH; Tsai, EJ; Wilkoff, BL; American College of Cardiology, Foundation; American Heart Association Task Force on Practice, Guidelines (Oct 15, 2013). "2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.". Journal of the American College of Cardiology 62 (16): e147–239. doi:10.1016/j.jacc.2013.05.019. PMID 23747642.
- Pitt B, Zannad F, Remme W, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (1999). "The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators". N Engl J Med 341 (10): 709–17. doi:10.1056/NEJM199909023411001. PMID 10471456.
- Yancy CW, Jessup M, Bozkurt B et al. (October 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". J. Am. Coll. Cardiol. 62 (16): e147–239. doi:10.1016/j.jacc.2013.05.019. PMID 23747642.
- 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; TOPCAT, Investigators (Apr 10, 2014). "Spironolactone for heart failure with preserved ejection fraction.". The New England Journal of Medicine 370 (15): 1383–92. doi:10.1056/nejmoa1313731. PMID 24716680.
- Pitt B. et. al. (2014). "Spironolactone for Heart Failure with Preserved Ejection Fraction". N Engl J Med 370 (15): 1383–1392. doi:10.1056/NEJMoa1313731. PMID 24716680.
- Hughes BR, Cunliffe WJ (May 1988). "Tolerance of spironolactone". The British Journal of Dermatology 118 (5): 687–91. doi:10.1111/j.1365-2133.1988.tb02571.x. PMID 2969259.
- Victor R. Preedy (1 January 2012). Handbook of Hair in Health and Disease. Springer Science & Business Media. pp. 132–. ISBN 978-90-8686-728-8.
- Loy R, Seibel MM (December 1988). "Evaluation and therapy of polycystic ovarian syndrome". Endocrinology and Metabolism Clinics of North America 17 (4): 785–813. PMID 3143568.
- The World Professional Association for Transgender Health (WPATH) (2011). "Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People" (PDF). Retrieved 2012-05-27.
- 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.
- Prior JC, Vigna YM, Watson D (February 1989). "Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism". Archives of Sexual Behavior 18 (1): 49–57. doi:10.1007/bf01579291. PMID 2540730.
- Reismann P, Likó I, Igaz P, Patócs A, Rácz K (August 2009). "Pharmacological options for treatment of hyperandrogenic disorders". Mini Reviews in Medicinal Chemistry 9 (9): 1113–26. doi:10.2174/138955709788922692. PMID 19689407.
- Robert S. Haber; Dowling Bluford Stough (2006). Hair Transplantation. Elsevier Health Sciences. p. 6. ISBN 978-1-4160-3104-8. Retrieved 28 May 2012.
- 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. Retrieved 28 May 2012.
- 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. Retrieved 28 May 2012.
- Gökmen O, Senöz S, Gülekli B, Işik AZ (August 1996). "Comparison of four different treatment regimes in hirsutism related to polycystic ovary syndrome". Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology 10 (4): 249–55. doi:10.3109/09513599609012316. PMID 8908525.
- O'Brien RC, Cooper ME, Murray RM, Seeman E, Thomas AK, Jerums G (May 1991). "Comparison of sequential cyproterone acetate/estrogen versus spironolactone/oral contraceptive in the treatment of hirsutism". The Journal of Clinical Endocrinology and Metabolism 72 (5): 1008–13. doi:10.1210/jcem-72-5-1008. PMID 1827125.
- Douglas T. Carrell (12 April 2010). Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice. Springer. p. 163. ISBN 978-1-4419-1435-4. Retrieved 28 May 2012.
- 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. Retrieved 28 May 2012.
- 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. Retrieved 28 May 2012.
- 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 : the Official Journal of the International Society of Gynecological Endocrinology 10 (2): 119–23. doi:10.3109/09513599609097901. PMID 8701785.
- "Spironolactone and endocrine dysfunction". Annals of Internal Medicine 85 (5): 630–6. November 1976. doi:10.7326/0003-4819-85-5-630. PMID 984618.
- Verhamme KMC, Mosis G, Dieleman JP et al. (2006). "Spironolactone and risk of upper gastrointestinal events: population based case-control study". Brit Med J 333 (7563): 330–3. doi:10.1136/bmj.38883.479549.2F. PMC 1539051. PMID 16840442.
- Wandelt-Freerksen E. (1977). "Aldactone in the treatment of sarcoidosis of the lungs". JZ Erkr Atmungsorgane. 149 (1): 156–9. PMID 607621.
- "Advisory Statement" (PDF). Klinge Chemicals / LoSalt. Archived from the original (pdf) on 2006-11-15. Retrieved 2007-03-15.
- Plovanich M, Weng QY, Mostaghimi A (2015). "Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne". JAMA Dermatology. doi:10.1001/jamadermatol.2015.34. PMID 25796182.
- Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).
- Otte C, Hinkelmann K, Moritz S et al. (April 2010). "Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study". J Psychiatr Res 44 (6): 339–46. doi:10.1016/j.jpsychires.2009.10.006. PMID 19909979.
- Mostalac-Preciado CR, de Gortari P, López-Rubalcava C (September 2011). "Antidepressant-like effects of mineralocorticoid but not glucocorticoid antagonists in the lateral septum: interactions with the serotonergic system". Behav. Brain Res. 223 (1): 88–98. doi:10.1016/j.bbr.2011.04.008. PMID 21515309.
- Fagart J, Hillisch A, Huyet J et al. (September 2010). "A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule". The Journal of Biological Chemistry 285 (39): 29932–40. doi:10.1074/jbc.M110.131342. PMC 2943305. PMID 20650892.
- 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.
- Rigalli JP, Ruiz ML, Perdomo VG, Villanueva SS, Mottino AD, Catania VA (July 2011). "Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells". Toxicology 285 (1-2): 18–24. doi:10.1016/j.tox.2011.03.015. PMID 21459122.
- Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (September 1998). "The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions". J. Clin. Invest. 102 (5): 1016–23. doi:10.1172/JCI3703. PMC 508967. PMID 9727070.
- Christians U, Schmitz V, Haschke M (December 2005). "Functional interactions between P-glycoprotein and CYP3A in drug metabolism". Expert Opin Drug Metab Toxicol 1 (4): 641–54. doi:10.1517/17425255.1.4.641. PMID 16863430.
- Sorrentino R, Autore G, Cirino G, d'Emmanuele de Villa Bianca R, Calignano A, Vanasia M et al. (2000). "Effect of spironolactone and its metabolites on contractile property of isolated rat aorta rings.". J Cardiovasc Pharmacol 36 (2): 230–235. doi:10.1097/00005344-200008000-00013. PMID 10942165.
- 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.
- 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.
- Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H (September 1998). "The role of mineralocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation in humans". The Journal of Clinical Endocrinology and Metabolism 83 (9): 3339–45. doi:10.1210/jcem.83.9.5077. PMID 9745451.
- Otte C, Moritz S, Yassouridis A et al. (January 2007). "Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition". Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology 32 (1): 232–8. doi:10.1038/sj.npp.1301217. PMID 17035932.
- 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.
- Donald W. Seldin; Gerhard H. Giebisch (4 September 1997). Diuretic agents: clinical physiology and pharmacology. Academic Press. p. 630. ISBN 978-0-12-635690-8. Retrieved 17 November 2011.
- Luthy IA, Begin DJ, Labrie F (November 1988). "Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture". Journal of Steroid Biochemistry 31 (5): 845–52. doi:10.1016/0022-4731(88)90295-6. PMID 2462135.
- Térouanne B, Tahiri B, Georget V et al. (February 2000). "A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects". Molecular and Cellular Endocrinology 160 (1-2): 39–49. doi:10.1016/S0303-7207(99)00251-8. PMID 10715537.
- Marc A. Fritz; Leon Speroff (20 December 2010). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. p. 80. ISBN 978-0-7817-7968-5. Retrieved 27 May 2012.
- 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.
- Haynes BA, Mookadam F (August 2009). "Male gynecomastia". Mayo Clinic Proceedings. Mayo Clinic 84 (8): 672. doi:10.4065/84.8.672. PMC 2719518. PMID 19648382.
- 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.
- 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.
- Serafini PC, Catalino J, Lobo RA (August 1985). "The effect of spironolactone on genital skin 5 alpha-reductase activity". Journal of Steroid Biochemistry 23 (2): 191–4. doi:10.1016/0022-4731(85)90236-5. PMID 4033118.
- Wong IL, Morris RS, Chang L, Spahn MA, Stanczyk FZ, Lobo RA (January 1995). "A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women". The Journal of Clinical Endocrinology and Metabolism 80 (1): 233–8. doi:10.1210/jcem.80.1.7829618. PMID 7829618.
- Miles RA, Cassidenti DL, Carmina E, Gentzschein E, Stanczyk FZ, Lobo RA (October 1992). "Cutaneous application of an androstenedione gel as an in vivo test of 5 alpha-reductase activity in women". Fertility and Sterility 58 (4): 708–12. PMID 1426314.
- 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.
- 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.
- Delyani, John A (2000). "Mineralocorticoid receptor antagonists: The evolution of utility and pharmacology". Kidney International 57 (4): 14081411. doi:10.1046/j.1523-1755.2000.00983.x. ISSN 0085-2538.
- Shlomo Melmed; Kenneth S. Polonsky; P. Reed MD Larsen; Henry M. Kronenberg (31 May 2011). Williams Textbook of Endocrinology E-Book: Expert Consult. Elsevier Health Sciences. p. 2057. ISBN 978-1-4377-3600-7. Retrieved 27 May 2012.
- Nakhjavani M, Hamidi S, Esteghamati A, Abbasi M, Nosratian-Jahromi S, Pasalar P (October 2009). "Short term effects of spironolactone on blood lipid profile: a 3-month study on a cohort of young women with hirsutism". British Journal of Clinical Pharmacology 68 (4): 634–7. doi:10.1111/j.1365-2125.2009.03483.x. PMC 2780289. PMID 19843067.
- Eckhard Ottow; Hilmar Weinmann (9 July 2008). Nuclear Receptors As Drug Targets. John Wiley & Sons. p. 410. ISBN 978-3-527-62330-3. Retrieved 28 May 2012.
- Anderson E (2002). "The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis". Breast Cancer Research : BCR 4 (5): 197–201. PMC 138744. PMID 12223124.
- 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.
- Braunstein GD (September 2007). "Clinical practice. Gynecomastia". The New England Journal of Medicine 357 (12): 1229–37. doi:10.1056/NEJMcp070677. PMID 17881754.
- Satoh T, Itoh S, Seki T, Itoh S, Nomura N, Yoshizawa I (October 2002). "On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production". The Journal of Steroid Biochemistry and Molecular Biology 82 (2-3): 209–16. doi:10.1016/S0960-0760(02)00154-1. PMID 12477487.
- Ruggiero RJ, Likis FE (2002). "Estrogen: physiology, pharmacology, and formulations for replacement therapy". Journal of Midwifery & Women's Health 47 (3): 130–8. doi:10.1016/s1526-9523(02)00233-7. PMID 12071379.
- Overdiek HW, Merkus FW (November 1986). "Influence of food on the bioavailability of spironolactone". Clinical Pharmacology and Therapeutics 40 (5): 531–6. doi:10.1038/clpt.1986.219. PMID 3769384.
- Melander A, Danielson K, Scherstén B, Thulin T, Wåhlin E (July 1977). "Enhancement by food of canrenone bioavailability from spironolactone". Clinical Pharmacology and Therapeutics 22 (1): 100–3. PMID 872489.
- Mellar P. Davis (28 May 2009). Opioids in Cancer Pain. OUP Oxford. pp. 222–. ISBN 978-0-19-923664-0.
- 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.
- Aiba M, Suzuki H, Kageyama K et al. (June 1981). "Spironolactone bodies in aldosteronomas and in the attached adrenals. Enzyme histochemical study of 19 cases of primary aldosteronism and a case of aldosteronism due to bilateral diffuse hyperplasia of the zona glomerulosa". Am. J. Pathol. 103 (3): 404–10. PMC 1903848. PMID 7195152.