Spironolactone

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Spironolactone
Systematic (IUPAC) name
7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone
or
17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone acetate
Clinical data
Trade namesAldactone
AHFS/Drugs.commonograph
MedlinePlusa682627
Pregnancy cat.B3 (AU) C (US)
Legal statusPOM (UK) -only (US)
RoutesOral
Pharmacokinetic data
Protein binding90%+[1]
MetabolismHepatic CYP450
Half-life1.3-2 hours
ExcretionUrine, bile
Identifiers
CAS number52-01-7 YesY
ATC codeC03DA01
PubChemCID 5833
IUPHAR ligand2875
DrugBankDB00421
ChemSpider5628 YesY
UNII27O7W4T232 YesY
KEGGD00443 YesY
ChEBICHEBI:9241 YesY
ChEMBLCHEMBL1393 YesY
Chemical data
FormulaC24H32O4S 
Mol. mass416.574 g/mol
 YesY (what is this?)  (verify)
 
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Spironolactone
Systematic (IUPAC) name
7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone
or
17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone acetate
Clinical data
Trade namesAldactone
AHFS/Drugs.commonograph
MedlinePlusa682627
Pregnancy cat.B3 (AU) C (US)
Legal statusPOM (UK) -only (US)
RoutesOral
Pharmacokinetic data
Protein binding90%+[1]
MetabolismHepatic CYP450
Half-life1.3-2 hours
ExcretionUrine, bile
Identifiers
CAS number52-01-7 YesY
ATC codeC03DA01
PubChemCID 5833
IUPHAR ligand2875
DrugBankDB00421
ChemSpider5628 YesY
UNII27O7W4T232 YesY
KEGGD00443 YesY
ChEBICHEBI:9241 YesY
ChEMBLCHEMBL1393 YesY
Chemical data
FormulaC24H32O4S 
Mol. mass416.574 g/mol
 YesY (what is this?)  (verify)

Spironolactone (INN, BAN, USAN) (pronounced /ˌsprɵnɵˈlæktn/),[2] commonly referred to simply as "spiro",[3][4] and marketed primarily under the brand name Aldactone in most countries, is a synthetic, steroidal antimineralocorticoid agent with additional antiandrogen and weak progestogen properties, as well as some indirect estrogen and glucocorticoid effects, which is used primarily as a diuretic and antihypertensive, but also for the purpose of reducing elevated or unwanted androgen activity in the body.[5] It acts predominantly as a competitive antagonist of the aldosterone (or mineralocorticoid) receptor, and belongs to a class of pharmaceutical drugs known as potassium-sparing diuretics.

Spironolactone is a relatively old drug, having been introduced clinically in 1959.[6][7] It has been predicted that spironolactone will be superseded in cardiovascular conditions (e.g., heart failure and hypertension) by the newer agents such as the structurally related compound eplerenone, which is also an aldosterone antagonist but is selective and lacks many of the actions and side effects of spironolactone, and as such is much more tolerable in comparison.[8] However, spironolactone is still far more widely used than eplerenone. Spironolactone nonetheless still finds frequent use as an antiandrogen.

Uses[edit]

As a diuretic/antihypertensive[edit]

Spironolactone is used primarily to treat heart failure, ascites in patients with liver disease, low-renin 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 its effects target the distal nephron (collecting tubule), where 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.

Because spironolactone reduces the body's production of testosterone and blocks the androgen receptors, in men it can cause effects associated with low testosterone levels and hypogonadism in males. For this reason, men are not typically prescribed spironolactone for any longer than a short period of time as for acute heart failure. A newer drug, eplerenone has been approved by the U.S. Food and Drug Administration for treatment of heart failure, has no similar antiandrogen effects and thus is far more suitable for men for whom long term medication is contemplated. Potassium supplementation should not be administered while taking spironolactone as this may cause hyperkalemia, a potentially deadly condition. Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone, especially during the first twelve months of use and whenever dosage is increased.

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 30% relative risk reduction compared to the placebo group, indicating a significant mortality and morbidity benefit of the drug. Patients in the study arm also had fewer symptoms of heart failure and were hospitalized less frequently.[9]

As an antiandrogen[edit]

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 to treat a variety of cosmetic conditions in which androgen hormones such as testosterone and dihydrotestosterone (DHT) play a role, including hirsutism, androgenic alopecia, acne, and seborrhea in females,[10] and male pattern baldness in either low doses or as a topical formulation in males; higher doses are not recommended for males due to the high risk of feminization and other side effects. In addition, it is also commonly used to treat symptoms of hyperandrogenism in polycystic ovary syndrome.[11]

Spironolactone is frequently used as a component of hormone replacement therapy in trans women undergoing sex reassignment therapy, 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 by the major transgender healthcare guideline bodies,[12][13] 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 clinical studies with additional benefit.[14] 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 hair, the induction of breast development, feminization in general, and lack of spontaneous erections.[14]

There are very few available options for androgen receptor antagonist drug therapy. Spironolactone, cyproterone acetate, and flutamide are the most well-known and widely used agents.[15] Compared to cyproterone acetate, spironolactone is considerably less potent as an antiandrogen by weight and binding affinity to the androgen receptor.[16][17] However, despite this, at the doses in which they are typically used, spironolactone and cyproterone acetate have been found to be generally equivalent in terms of effectiveness for a variety of androgen-related conditions;[18] though, cyproterone acetate has frequently shown a slight but non-statistically significant advantage in many studies.[19][20] 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.[18] Flutamide, another frequently employed antiandrogen which is a pure, selective androgen receptor antagonist, is much less potent by weight and binding affinity than either spironolactone or cyproterone acetate,[21][22] but at the doses used, has usually been found to be more effective than either of them as an antiandrogen.[16][23][24] Unfortunately, both cyproterone acetate and flutamide have been associated with hepatotoxicity, severely so in the case of the latter, and cyproterone acetate is not available in certain countries such as the United States. Gonadotropin-releasing hormone (GnRH) analogues are another option for antiandrogen therapy, and are the most effective of any other by far, but on account of their limited use and peptide nature, despite the fact that many are now available as generics, they tend to be very expensive, and are not always covered by insurance.[13] Thus, spironolactone may be the only practical, available, and safe option in many cases.

Pharmacology[edit]

Activity profile[edit]

Spironolactone acts as an antagonist (IC50) and/or agonist (EC50) at the following sites:[25]

It does not significantly bind to either of the two estrogen receptors (ERα, ERβ), nor is its very weak activity at the glucocorticoid receptor listed above considered to be significant at clinically relevant concentrations.

Antimineralocorticoid[edit]

Spironolactone inhibits the effects of mineralocorticoids including aldosterone and corticosterone by competing for intracellular mineralocorticoid receptors in the cortical collecting duct. This decreases the reabsorption of sodium and water, while decreasing the secretion of potassium. The drug has a fairly slow onset of action, and so, it takes several days to develop. This is because steroid receptors are nuclear receptors which work via regulating gene transcription (in this case the ENaC and ROMK channels will be decreased), and it takes time for gene expression to change. In addition to direct antagonism of the mineralocorticoid receptors, 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 the mineralocorticoids.[26]

Antiglucocorticoids[edit]

Spironolactone inhibits steroid 11β-hydroxylase, and notably, this enzyme is essential for the production of the glucocorticoid hormone cortisol. Thus, in theory, glucocorticoids would be lowered in addition to mineralocorticoids (indicating that spironolactone should also produce some degree of antiglucocorticoid effects). However, in practice this has been found not to be the case, and spironolactone has actually been shown to increase cortisol levels, both with acute and chronic administration. This has been elucidated to be due to its antagonism of the mineralocorticoid receptor, 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, and so by disinhibiting it, spironolactone raises their circulating levels.[27][28] Thus, any antiglucocorticoid activity of spironolactone via suppression of glucocorticoid synthesis appears to be more than fully offset by its concurrent stimulatory effects on glucocorticoid production.

Antiandrogenic[edit]

Spironolactone mediates its antiandrogenic effects via a variety of actions, which include the following:

Progestogenic[edit]

Spironolactone has weak progestogenic properties.[42][22] These are due to it acting as a direct agonist of the progesterone receptor, at which it has a half-maximal potency of approximately one tenth of that of at the androgen receptor.[25] Spironolactone's progestogenic actions are thought to be responsible for some of its side effects,[43] including the menstrual irregularities seen in women and the undesirable serum lipid profile changes (which are both seen with other progestins as well) that are seen at higher doses.[21][44][45] They may also play a role in augmenting the gynecomastia and breast tenderness caused by the antiandrogenic/estrogenic effects of spironolactone,[46] as progesterone is known to play a role in breast development.[47]

Estrogenic[edit]

Spironolactone has some estrogenic effects which it mediates via several indirect actions, including the following:

Miscellaneous[edit]

There is evidence that spironolactone may block voltage-dependent Ca2+ channels.[52][53]

Pharmacokinetics[edit]

Spironolactone has 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) including canrenone, 7α-methylthiospironolactone, and 6β-hydroxy-7α-methylthiospironolactone, among many others. The drug is highly plasma protein bound. It is metabolized by the liver, and is eliminated mostly renally, with only minimal biliary excretion.[1]

The bioavailability of spironolactone improves significantly when it is taken with food.[54][55]

Adverse reactions[edit]

Side effects[edit]

The most common side effect of spironolactone is urinary frequency. Other general side effects include ataxia, drowsiness, dry skin, and rashes. Because it also affects the androgen receptors, spironolactone can cause gynecomastia and feminization in general, testicular atrophy, and sexual dysfunction consisting of loss of libido and erectile dysfunction,[56] and in females it can cause menstrual irregularities and breast tenderness and enlargement.[10]

Spironolactone may put patients at a heightened risk for bleeding from the stomach and duodenum, though a causal relationship between the two has not been established.[57] Also, it has been shown to be immunosuppressive in the treatment of sarcoidosis.[58]

Interactions[edit]

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.[59] Doctors usually recommend periodic screening of serum potassium levels and some patients may be advised to limit dietary consumption of potassium.

Research has also shown spironolactone can interfere with the effectiveness of antidepressant treatment. The drug is actually (among its other receptor interactions) a mineralocorticoid (MR) antagonist, and has been found to reduce the effectiveness of antidepressant drugs in the treatment of major depression, it is presumed, by interfering with normalization of the hypothalamic-pituitary-adrenal axis in patients receiving antidepressant therapy.[60]

Contraindications[edit]

Spironolactone should not be taken under any circumstance by pregnant women due to the high risk of feminization of male fetuses.[10]

It is also not taken under anuria, acute renal insufficiency, significant impairment of renal excretory function,or hyperkalemia.

Spironolactone bodies[edit]

Micrograph of an adrenal gland spironolactone bodies. H&E stain.

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.[61]

Chemical synthesis[edit]

Spironolactone can be synthesized from 3-hydroxyandrost-5-en-17-one.[62]

Spironolactone synth.png

See also[edit]


References[edit]

  1. ^ a b 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. 
  2. ^ "Spironolactone: MedlinePlus Drug Information". Retrieved 2012-06-20. 
  3. ^ Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 1614. ISBN 978-3-88763-075-1. Retrieved 13 June 2012. 
  4. ^ Lannie Rose (30 October 2004). How to Change Your Sex: A Lighthearted Look at the Hardest Thing You'll Ever Do. Lulu.com. p. 98. ISBN 978-1-4116-3956-0. Retrieved 13 June 2012. 
  5. ^ F.. Macdonald (1997). Dictionary of Pharmacological Agents. CRC Press. pp. 1832–1833. ISBN 978-0-412-46630-4. Retrieved 12 May 2012. 
  6. ^ 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. 
  7. ^ Marshall Sittig (1988). Pharmaceutical Manufacturing Encyclopedia. William Andrew. p. 1385. ISBN 978-0-8155-1144-1. Retrieved 27 May 2012. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ a b c Hughes BR, Cunliffe WJ (May 1988). "Tolerance of spironolactone". The British Journal of Dermatology 118 (5): 687–91. PMID 2969259. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ a b 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. 
  14. ^ a b 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. PMID 2540730. 
  15. ^ 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. PMID 19689407. 
  16. ^ a b Robert S. Haber; Dowling Bluford Stough (2006). Hair Transplantation. Elsevier Health Sciences. p. 6. ISBN 978-1-4160-3104-8. Retrieved 28 May 2012. 
  17. ^ 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. 
  18. ^ 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. Retrieved 28 May 2012. 
  19. ^ 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. PMID 8908525. 
  20. ^ 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. 
  21. ^ a b 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. 
  22. ^ 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. Retrieved 28 May 2012. 
  23. ^ 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. 
  24. ^ 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. PMID 8701785. 
  25. ^ a b 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. 
  26. ^ 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. 
  27. ^ 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. PMID 9745451. 
  28. ^ 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. 
  29. ^ a b 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. 
  30. ^ a b c 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. 
  31. ^ 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. PMID 2462135. 
  32. ^ 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. 
  33. ^ 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. Retrieved 27 May 2012. 
  34. ^ 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. 
  35. ^ a b 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. 
  36. ^ a b c 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. PMID 907238. 
  37. ^ 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. 
  38. ^ 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. PMID 4033118. 
  39. ^ 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. PMID 7829618. 
  40. ^ 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. 
  41. ^ 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. PMID 15012621. 
  42. ^ 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. 
  43. ^ 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. 
  44. ^ 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. 
  45. ^ 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. 
  46. ^ 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. 
  47. ^ 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. 
  48. ^ 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. PMID 10973921. 
  49. ^ Braunstein GD (September 2007). "Clinical practice. Gynecomastia". The New England Journal of Medicine 357 (12): 1229–37. doi:10.1056/NEJMcp070677. PMID 17881754. 
  50. ^ 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. 
  51. ^ Ruggiero RJ, Likis FE (2002). "Estrogen: physiology, pharmacology, and formulations for replacement therapy". Journal of Midwifery & Women's Health 47 (3): 130–8. PMID 12071379. 
  52. ^ 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. PMID 10942165. 
  53. ^ 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. 
  54. ^ Overdiek HW, Merkus FW (November 1986). "Influence of food on the bioavailability of spironolactone". Clinical Pharmacology and Therapeutics 40 (5): 531–6. PMID 3769384. 
  55. ^ 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. 
  56. ^ "Spironolactone and endocrine dysfunction". Annals of Internal Medicine 85 (5): 630–6. November 1976. PMID 984618. 
  57. ^ 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. 
  58. ^ Wandelt-Freerksen E. (1977). "Aldactone in the treatment of sarcoidosis of the lungs". JZ Erkr Atmungsorgane. 149 (1): 156–9. PMID 607621. 
  59. ^ "Advisory Statement" (pdf). Klinge Chemicals / LoSalt. Archived from the original on 2006-11-15. Retrieved 2007-03-15. 
  60. ^ Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).
  61. ^ 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. 
  62. ^ . doi:10.1021/jo01090a019.  Missing or empty |title= (help)

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