View source for Chemistry:Pharmacodynamics of spironolactone

{{short description|Mechanisms of action}}
[[File:7α-Thiomethylspironolactone.svg|thumb|[[Chemistry:7α-Thiomethylspironolactone|7α-Thiomethylspironolactone]], the major active form of spironolactone. It accounts for about 80% of the potassium-sparing effect of spironolactone.<ref name="Sica2005">{{cite journal|last1=Sica|first1=Domenic A.|title=Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis|journal=Heart Failure Reviews|volume=10|issue=1|year=2005|pages=23–29|issn=1382-4147|doi=10.1007/s10741-005-2345-1|pmid=15947888|s2cid=21437788}}</ref><ref name="AgustiBourgeois2013">{{cite journal|last1=Agusti|first1=Géraldine|last2=Bourgeois|first2=Sandrine|last3=Cartiser|first3=Nathalie|last4=Fessi|first4=Hatem|last5=Le Borgne|first5=Marc|last6=Lomberget|first6=Thierry|title=A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone|journal=Steroids|volume=78|issue=1|year=2013|pages=102–107|issn=0039-128X|doi=10.1016/j.steroids.2012.09.005|pmid=23063964|s2cid=8992318}}</ref><ref name="CancerOrganization2001">{{cite book|author1=International Agency for Research on Cancer|author2=World Health Organization|title=Some Thyrotropic Agents|url=https://books.google.com/books?id=l965aqw_LSkC&pg=PA325|year=2001|publisher=World Health Organization|isbn=978-92-832-1279-9|pages=325–}}</ref>]]

[[File:Canrenone.svg|thumb|[[Chemistry:Canrenone|Canrenone]], the second major active form of spironolactone. It accounts for around 10 to 25% of the potassium-sparing effect of spironolactone.<ref name="GinésArroyo2008">{{cite book|author1=Pere Ginés|author2=Vicente Arroyo|author3=Juan Rodés|author4=Robert W. Schrier|title=Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment|url=https://books.google.com/books?id=Z3PARx4oYDgC&pg=PA231|date=15 April 2008|publisher=John Wiley & Sons|isbn=978-1-4051-4370-7|pages=229, 231|quote=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).}}</ref>]]


The '''[[Chemistry:Pharmacodynamics|pharmacodynamics]] of [[Biology:Spironolactone|spironolactone]]''', an [[Chemistry:Antimineralocorticoid|antimineralocorticoid]] and [[Biology:Antiandrogen|antiandrogen]] medication, concern its [[Chemistry:Mechanism of action|mechanisms of action]], including its [[Biology:Biological target|biological target]]s and [[Biology:Ligand (biochemistry)|activities]], as well as its [[Biology:Biological activity|physiological effect]]s. The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition. In addition, spironolactone has sometimes been found to increase [[Chemistry:Estradiol|estradiol]] and [[Chemistry:Cortisol|cortisol]] levels and hence could have slight indirect [[Chemistry:Estrogen (medication)|estrogen]]ic and [[Chemistry:Glucocorticoid|glucocorticoid]] effects. The medication has also been found to interact very weakly with the [[Biology:Estrogen receptor|estrogen]] and [[Biology:Progesterone receptor|progesterone receptor]]s, and to act as an [[Biology:Agonist|agonist]] of the [[Biology:Pregnane X receptor|pregnane X receptor]]. Likely due to increased activation of the estrogen and/or progesterone receptors, spironolactone has very weak but significant antigonadotropic effects.<ref name="Becker2001" /><ref name="pmid27072668" />

Spironolactone has a very short [[Biology:Biological half-life|biological half-life]] and is considered to be a [[Chemistry:Prodrug|prodrug]]; hence, its [[Biology:Active metabolite|active metabolite]]s are responsible for most of its pharmacodynamics. The major active forms of spironolactone include 7α-thiomethylspironolactone (7α-TMS) and [[Chemistry:Canrenone|canrenone]] (7α-desthioacetyl-δ<sup>6</sup>-spironolactone), while more minor [[Biology:Metabolite|metabolite]]s of spironolactone include 7α-thiospironolactone (7α-TS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and a number of others.

Aside from its primary mechanisms of action of antimineralocorticoid and antiandrogenic action, spironolactone has been found in preclinical research to interact very weakly with the [[Biology:Progesterone receptor|progesterone]] and [[Biology:Estrogen receptor|estrogen receptor]]s and to have very weak mixed [[Biology:Progestogen|progestogen]]ic and [[Chemistry:Antiprogestogen|antiprogestogen]]ic activity as well as very weak mixed [[Chemistry:Estrogen (medication)|estrogen]]ic and [[Chemistry:Antiestrogen|antiestrogen]]ic activity.<ref name="pmid7391714" /><ref name="pmid27072668" /><ref name="pmid8144871" /> The clinical significance of these actions, if any, is uncertain.<ref name="pmid8144871" /> However, a small clinical study found that high doses of spironolactone had neither progestogenic nor [[Chemistry:Antiprogestogen|antiprogestogen]]ic effects in women.<ref name="pmid8144871" /><ref name="pmid2744183">{{cite journal | vauthors = Nakajima ST, Brumsted JR, Riddick DH, Gibson M | title = Absence of progestational activity of oral spironolactone | journal = Fertil. Steril. | volume = 52 | issue = 1 | pages = 155–8 | year = 1989 | pmid = 2744183 | doi = 10.1016/s0015-0282(16)60807-5}}</ref> In any case, if one or both of these actions are clinically relevant, they might contribute to the menstrual irregularities and breast [[Medicine:Side effect|side effect]]s of spironolactone.<ref name="pmid27072668">{{cite journal | vauthors = Sabbadin C, Andrisani A, Zermiani M, Donà G, Bordin L, Ragazzi E, Boscaro M, Ambrosini G, Armanini D | title = Spironolactone and intermenstrual bleeding in polycystic ovary syndrome with normal BMI | journal = J. Endocrinol. Invest. | volume = 39 | issue = 9 | pages = 1015–21 | year = 2016 | pmid = 27072668 | doi = 10.1007/s40618-016-0466-0 | s2cid = 34201900 }}</ref><ref name="Delyani2000">{{cite journal|last1=Delyani|first1=John A|title=Mineralocorticoid receptor antagonists: The evolution of utility and pharmacology|journal=Kidney International|volume=57|issue=4|year=2000|pages=1408–1411|issn=0085-2538|doi=10.1046/j.1523-1755.2000.00983.x|pmid=10760075|doi-access=free}}</ref> Spironolactone is also an agonist of the [[Biology:Pregnane X receptor|pregnane X receptor]],<ref name="pmid9890159">{{cite journal | vauthors = Pelkonen O, Mäenpää J, Taavitsainen P, Rautio A, Raunio H | title = Inhibition and induction of human cytochrome P450 (CYP) enzymes | journal = Xenobiotica | volume = 28 | issue = 12 | pages = 1203–53 | year = 1998 | pmid = 9890159 | doi = 10.1080/004982598238886 | url = https://www.researchgate.net/publication/13399265 | url-status = live | archive-url = https://web.archive.org/web/20150924131438/http://www.researchgate.net/profile/Hannu_Raunio/publication/13399265_Inhibition_and_induction_of_human_cytochrome_P450_(CYP)_enzymes/links/0deec521eff4a0e032000000.pdf | archive-date = 2015-09-24 }}</ref> and is able to induce the [[Biology:Gene expression|expression]] of [[Biology:CYP3A4|CYP3A4]] and [[Biology:P-glycoprotein|P-glycoprotein]] in the body via this action.<ref name="pmid21459122" /><ref name="pmid9727070">{{cite journal |vauthors=Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = J. Clin. Invest. | volume = 102 | issue = 5 | pages = 1016–23 |date=September 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 }}</ref><ref name="pmid16863430">{{cite journal |vauthors=Christians U, Schmitz V, Haschke M | title = Functional interactions between P-glycoprotein and CYP3A in drug metabolism | journal = Expert Opin Drug Metab Toxicol | volume = 1 | issue = 4 | pages = 641–54 |date=December 2005 | pmid = 16863430 | doi = 10.1517/17425255.1.4.641 | s2cid = 17742146 }}</ref> This effect may contribute to the [[Medicine:Drug interaction|drug interaction]]s of spironolactone.<ref name="pmid21459122" /><ref name="pmid9727070" /><ref name="pmid16863430" />

==Antimineralocorticoid activity==
Spironolactone inhibits the effects of [[Chemistry:Mineralocorticoid|mineralocorticoid]]s, namely, [[Chemistry:Aldosterone|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 [[Medicine:Onset of action|onset of action]], and so it takes several days for diuresis to occur. This is because the MR is a [[Biology:Nuclear receptor|nuclear receptor]] which works through regulating gene transcription and [[Biology:Gene expression|gene expression]], in this case, to decrease the production and expression of ENaC and [[Biology:ROMK|ROMK]] electrolyte channels in the distal nephrons. In addition to direct antagonism of the MRs, the [[Chemistry:Antimineralocorticoid|antimineralocorticoid]] effects of spironolactone may also in part be mediated by direct inactivation of 11β-hydroxylase and [[Biology:Aldosterone synthase|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.<ref name="pmid976190" /> The [[Medicine:Onset of action|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.<ref name="Sica2005" /><ref name="pmid18729003">{{cite journal | vauthors = Maron BA, Leopold JA | title = Mineralocorticoid receptor antagonists and endothelial function | journal = Curr Opin Investig Drugs | volume = 9 | issue = 9 | pages = 963–9 | year = 2008 | pmid = 18729003 | pmc = 2967484 }}</ref>

Canrenone is an antagonist of the MR similarly to spironolactone,<ref name="ClarkHarvey2011">{{cite book|author1=Michelle A. Clark|author2=Richard A. Harvey|author3=Richard Finkel |author4=Jose A. Rey |author5=Karen Whalen |title=Pharmacology|url=https://books.google.com/books?id=Y558dgp_PjoC&pg=PA337|date=15 December 2011|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-1314-3|pages=286, 337}}</ref> but is slightly more potent in comparison.<ref name="pmid18729003" /><ref name="pmid23904409">{{cite journal | vauthors = Juruena MF, Pariante CM, Papadopoulos AS, Poon L, Lightman S, Cleare AJ | title = The role of mineralocorticoid receptor function in treatment-resistant depression | journal = J. Psychopharmacol. (Oxford) | volume = 27 | issue = 12 | pages = 1169–79 | year = 2013 | pmid = 23904409 | doi = 10.1177/0269881113499205 | s2cid = 41678453 }}</ref> It has been determined that 7α-TMS accounts for around 80% of the potassium-sparing effect of spironolactone<ref name="Sica2005"/><ref name="AgustiBourgeois2013"/><ref name="CancerOrganization2001"/> while canrenone accounts for the remaining approximate 10 to 25%.<ref name="GinésArroyo2008" /> In accordance, 7α-TMS occurs at higher circulating concentrations than does canrenone in addition to having a higher relative affinity for the MR.<ref name="AgustiBourgeois2013" />

==Antiandrogenic activity==
[[File:Androgen receptor antagonistic potency of spironolactone, cyproterone acetate, and flutamide in male rats.png|thumb|right|400px|Androgen receptor antagonistic potency of spironolactone, cyproterone acetate, and flutamide in castrated male rats treated with exogenous testosterone (as measured by inhibition of androgen-dependent ventral prostate weight).<ref name="pmid14751673" />]]

Spironolactone is an antagonist of the AR, the [[Biology:Biological target|biological target]] of [[Biology:Androgen|androgen]]s like testosterone and DHT.<ref name="pmid166833">{{cite journal | vauthors = Corvol P, Michaud A, Menard J, Freifeld M, Mahoudeau J | title = Antiandrogenic effect of spirolactones: mechanism of action | journal = Endocrinology | volume = 97 | issue = 1 | pages = 52–8 | date = July 1975 | pmid = 166833 | doi = 10.1210/endo-97-1-52 | url = http://endo.endojournals.org/cgi/pmidlookup?view=long&pmid=166833 | access-date = 2018-08-13 | archive-date = 2020-04-15 | archive-url = https://web.archive.org/web/20200415065033/http://endo.endojournals.org/cgi/pmidlookup?view=long&pmid=166833 | url-status = dead }}</ref><ref name="SeldinGiebisch1997">{{cite book|author1=Donald W. Seldin|author2=Gerhard H. Giebisch|title=Diuretic Agents: Clinical Physiology and Pharmacology|url=https://books.google.com/books?id=VHcsrw6unuAC&pg=PA630|date=23 September 1997|publisher=Academic Press|isbn=978-0-08-053046-8|pages=630–632|quote=The incidence of spironolactone in men is dose related. It is estimated that 50% of men treated with ≥150 mg/day of spironolactone will develop gynecomastia. The degree of gynecomastia varies considerably from patient to patient but in most instances causes mild symptoms. Associated breast tenderness is common but an inconsistent feature.|url-status=live|archive-url=https://web.archive.org/web/20140704201956/http://books.google.com/books?id=VHcsrw6unuAC&pg=PA630|archive-date=4 July 2014}}</ref> Its affinity for the AR has been found to vary widely between different studies, with a range of 2.7 to 67%<!--2.70%, 3.0%, 4.13%, 4.68%, 8.70%, 12.5%, 14.6%, 30.8%, 33.3%, and 67.0%--> of that of DHT.<ref name="pmid984618">{{cite journal | title = Spironolactone and endocrine dysfunction | journal = Annals of Internal Medicine | volume = 85 | issue = 5 | pages = 630–6 |date=November 1976 | pmid = 984618 | doi = 10.7326/0003-4819-85-5-630| last1 = Loriaux | first1 = D. Lynn }}</ref><ref name="pmid263288">{{cite journal | vauthors = Cutler GB, Pita JC, Rifka SM, Menard RH, Sauer MA, Loriaux DL | title = SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate | journal = J. Clin. Endocrinol. Metab. | volume = 47 | issue = 1 | pages = 171–5 | year = 1978 | pmid = 263288 | doi = 10.1210/jcem-47-1-171 }}</ref><ref name="pmid14751673">{{cite journal | vauthors = Yamasaki K, Sawaki M, Noda S, Muroi T, Takakura S, Mitoma H, Sakamoto S, Nakai M, Yakabe Y | title = Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals | journal = Toxicology | volume = 195 | issue = 2–3 | pages = 177–86 | year = 2004 | pmid = 14751673 | doi = 10.1016/j.tox.2003.09.012}}</ref><ref name="pmid6725525">{{cite journal | vauthors = Eil C, Edelson SK | title = The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors | journal = J. Clin. Endocrinol. Metab. | volume = 59 | issue = 1 | pages = 51–5 | date = July 1984 | pmid = 6725525 | doi = 10.1210/jcem-59-1-51 }}</ref> One study found affinities for the AR of 3.0% for spironolactone, 4.2% for 7α-TMS, and 3.1% for 7α-TS.<ref name="pmid263288" /> Conversely, the affinity of canrenone for the AR was found to be 0.84% of that of DHT in another study, relative to 67% for spironolactone.<ref name="pmid6725525" /> However, another study found the affinity of canrenone for the AR to be 2.5 to 14%<!--2.5%, 5.26%, 6.79%, 14.3%-->, relative to 4.1 to 31%<!--4.13%, 8.70%, 14.6%, 30.8%--> in the case of spironolactone.<ref name="pmid173527">{{cite journal | vauthors = Pita JC, Lippman ME, Thompson EB, Loriaux DL | title = Interaction of spironolactone and digitalis with the 5 alpha-dihydrotestosterone (DHT) receptor of rat ventral prostate | journal = Endocrinology | volume = 97 | issue = 6 | pages = 1521–7 | date = December 1975 | pmid = 173527 | doi = 10.1210/endo-97-6-1521 }}</ref> Another study that directly compared the affinities of spironolactone and canrenone reported that spironolactone had 5-fold higher affinity for the AR than canrenone (5% and 1% of that of DHT, respectively).<ref name="pmid166833" /> A comparative study of binding inhibition to the AR in rat prostate cytosol AR found IC<sub>50</sub> values of 3&nbsp;nM for DHT, 24&nbsp;nM for [[Chemistry:Cyproterone acetate|cyproterone acetate]], and 67&nbsp;nM for spironolactone.<ref name="pmid6887871">{{cite journal | vauthors = Liang T, Rasmusson GH, Brooks JR | title = 12. Androgens: Pharmacodynamics and antagonists. Biochemical and biological studies with 4-aza-steroidal 5 alpha-reductase inhibitors | journal = J. Steroid Biochem. | volume = 19 | issue = 1A | pages = 385–90 | date = July 1983 | pmid = 6887871 | doi = 10.1016/s0022-4731(83)80051-x }}</ref> Spironolactone antagonizes the effects of exogenous testosterone administered to castrated animals.<ref name="pmid984618" /> It works by binding to the AR and displacing androgens like testosterone and DHT from the receptor, thereby reducing its activation by these hormones.<ref name="pmid166833" /> A study found that oral spironolactone had "about 10 to 20% of the [[Medicine:Feminization|feminizing]] effect of [[Chemistry:Cyproterone acetate|cyproterone acetate]]" on [[Biology:Sexual differentiation|sexual differentiation]] in male rat [[Biology:Fetus|fetus]]es, with 40&nbsp;mg/day spironolactone having an equal effect to 1 to 3&nbsp;mg/day cyproterone acetate.<ref name="Hammerstein1990" /><ref name="pmid7456979">{{cite journal | vauthors = Hecker A, Hasan SH, Neumann F | title = Disturbances in sexual differentiation of rat foetuses following spironolactone treatment | journal = Acta Endocrinol. | volume = 95 | issue = 4 | pages = 540–5 | date = December 1980 | pmid = 7456979 | doi = 10.1530/acta.0.0950540 }}</ref>

The AR antagonism of spironolactone mostly underlies its antiandrogenic activity and is the major mechanism responsible for its therapeutic benefits in the treatment of [[Chemistry:Androgen-dependent condition|androgen-dependent condition]]s like acne, hirsutism, and pattern hair loss and its usefulness in hormone therapy for transgender women.<ref name="pmid166833" /><ref name="pmid8144871">{{cite journal | vauthors = McMullen GR, Van Herle AJ | title = Hirsutism and the effectiveness of spironolactone in its management | journal = J. Endocrinol. Invest. | volume = 16 | issue = 11 | pages = 925–32 | date = December 1993 | pmid = 8144871 | doi = 10.1007/BF03348960 | s2cid = 42231952 }}</ref> In addition, the AR antagonism of spironolactone is involved in its feminizing side effects in men like gynecomastia.<ref name="pmid166833" /> Spironolactone has been found to produce gynecomastia without changes in testosterone or estradiol levels, implicating AR antagonism in this side effect.<ref name="pmid984618" /> Gynecomastia is a major known side effect of AR antagonists.<ref name="pmid16321765">{{cite journal | vauthors = Di Lorenzo G, Autorino R, Perdonà S, De Placido S | title = Management of gynaecomastia in patients with prostate cancer: a systematic review | journal = Lancet Oncol. | volume = 6 | issue = 12 | pages = 972–9 | date = December 2005 | pmid = 16321765 | doi = 10.1016/S1470-2045(05)70464-2 }}</ref>

Spironolactone, similarly to other [[Biology:Steroidal antiandrogen|steroidal antiandrogen]]s such as [[Chemistry:Cyproterone acetate|cyproterone acetate]], is actually not a pure, or ''silent'', antagonist of the AR, but rather is a weak [[Chemistry:Partial agonist|partial agonist]] with the capacity for both antagonistic and agonistic effects.<ref name="pmid8252497">{{cite journal | vauthors = Labrie F | title = Mechanism of action and pure antiandrogenic properties of flutamide | journal = Cancer | volume = 72 | issue = 12 Suppl | pages = 3816–27 | date = December 1993 | pmid = 8252497 | doi = 10.1002/1097-0142(19931215)72:12+<3816::AID-CNCR2820721711>3.0.CO;2-3 | s2cid = 2195250 | doi-access = free }}</ref><ref name="pmid2462135">{{cite journal |vauthors=Luthy IA, Begin DJ, Labrie F | title = Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture | journal = Journal of Steroid Biochemistry | volume = 31 | issue = 5 | pages = 845–52 |date=November 1988 | pmid = 2462135 | doi = 10.1016/0022-4731(88)90295-6}}</ref><ref name="pmid10715537">{{cite journal  |vauthors=Térouanne B, Tahiri B, Georget V, etal | title = A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects | journal = Molecular and Cellular Endocrinology | volume = 160 | issue = 1–2 | pages = 39–49 |date=February 2000 | pmid = 10715537 | doi = 10.1016/S0303-7207(99)00251-8| s2cid = 13737435 }}</ref><ref name="FritzSperoff2010">{{cite book | author1 = Marc A. Fritz | author2 = Leon Speroff | title = Clinical Gynecologic Endocrinology and Infertility | url = https://books.google.com/books?id=Ll73ZsBKLkwC&pg=PA80 | access-date = 27 May 2012 | date = 20 December 2010 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-7968-5 | page = 80 | url-status = live | archive-url = https://web.archive.org/web/20140704202013/http://books.google.com/books?id=Ll73ZsBKLkwC&pg=PA80 | archive-date = 4 July 2014 }}</ref> However, in the presence of sufficiently high levels of potent full agonists like testosterone and DHT (the cases in which spironolactone is usually used even with regards to the "lower" relative levels present in females),<ref name="FritzSperoff2010" /> spironolactone will behave more similarly to a pure antagonist. Nonetheless, there may still be a potential for spironolactone to produce androgenic effects in the body at sufficiently high dosages and/or in those with very low endogenous androgen concentrations. As an example, one condition in which spironolactone is contraindicated is [[Medicine:Prostate cancer|prostate cancer]] in men being treated with [[Chemistry:Androgen deprivation therapy|androgen deprivation therapy]],<ref name="pmid19509232">{{cite journal |vauthors=Attard G, Reid AH, Olmos D, de Bono JS | title = Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven | journal = Cancer Research | volume = 69 | issue = 12 | pages = 4937–40 |date=June 2009 | pmid = 19509232 | doi = 10.1158/0008-5472.CAN-08-4531 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19509232| doi-access = free }}</ref> as spironolactone has been shown ''[[In vitro|in vitro]]'' to significantly accelerate [[Medicine:Carcinoma|carcinoma]] growth in the absence of any other androgens.<ref name="pmid2462135" /> In accordance, three [[Medicine:Case report|case report]]s have described significant worsening of prostate cancer with spironolactone treatment in patients with the disease, leading the authors to conclude that spironolactone has the potential for androgenic effects in some contexts and that it should perhaps be considered to be a [[Chemistry:Selective androgen receptor modulator|selective androgen receptor modulator]] (SARM), albeit with mostly antagonistic effects.<ref name="pmid22665559">{{cite journal | vauthors = Sundar S, Dickinson PD | title = Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate | journal = BMJ Case Rep | volume = 2012 | pages = bcr1120115238| year = 2012 | pmid = 22665559 | pmc = 3291010 | doi = 10.1136/bcr.11.2011.5238 }}</ref><ref name="pmid27641657">{{cite journal | vauthors = Flynn T, Guancial EA, Kilari M, Kilari D | title = Case Report: Spironolactone Withdrawal Associated With a Dramatic Response in a Patient With Metastatic Castrate-Resistant Prostate Cancer | journal = Clin Genitourin Cancer | volume = 15| issue = 1| pages = e95–e97| year = 2016 | pmid = 27641657 | doi = 10.1016/j.clgc.2016.08.006 | s2cid = 38441469 }}</ref><ref>{{cite journal |last1=Dhondt |first1=Bert |last2=Buelens |first2=Sarah |last3=Van Besien |first3=Jeroen |last4=Beysens |first4=Matthias |last5=De Bleser |first5=Elise |last6=Ost |first6=Piet |last7=Lumen |first7=Nicolaas |title=Abiraterone and spironolactone in prostate cancer: a combination to avoid |journal=Acta Clinica Belgica |volume=74 |issue=6 |date=26 November 2018 |pages=439–444 |doi=10.1080/17843286.2018.1543827|pmid=30477405 |hdl=1854/LU-8582726 |s2cid=53738534 }}</ref> However, in another case report, spironolactone was effective in normalizing [[Biology:Prostate-specific antigen|prostate-specific antigen]] in a man with prostate cancer.<ref name="pmid20142058">{{cite journal | vauthors = Rybikowski S, Maurin C, Deturmeny J, Delaporte V, Lechevallier E, Coulange C | title = PSA et spironolactone | trans-title = PSA and spironolactone | language = fr | journal = Prog. Urol. | volume = 20 | issue = 2 | pages = 154–7 | date = February 2010 | pmid = 20142058 | doi = 10.1016/j.purol.2009.04.002 }}</ref> In addition, spironolactone has been studied limitedly in the treatment of prostate cancer.<ref name="pmid29603164">{{cite journal | vauthors = Scott WW, Menon M, Walsh PC | title = Hormonal Therapy of Prostatic Cancer | journal = Cancer | volume = 45 | pages = 1929–1936 | date = April 1980 | issue = Suppl 7 | pmid = 29603164 | doi = 10.1002/cncr.1980.45.s7.1929 | s2cid = 4492779 | doi-access = free }}</ref><ref name="pmid3540320">{{cite journal | vauthors = Smith JA | title = New methods of endocrine management of prostatic cancer | journal = J. Urol. | volume = 137 | issue = 1 | pages = 1–10 | date = January 1987 | pmid = 3540320 | doi = 10.1016/S0022-5347(17)43855-9 }}</ref>

Canrenone binds to and blocks the AR ''in vitro''.<ref name="SeldinGiebisch1997" /> However, relative to spironolactone, canrenone is described as having very weak affinity for the AR.<ref name="BenniVemer1990">{{cite book|author1=H.J.T. Coelingh Benni|author2=H.M. Vemer|title=Chronic Hyperandrogenic Anovulation|url=https://books.google.com/books?id=q6zqFrCLUoIC&pg=PA152|date=15 December 1990|publisher=CRC Press|isbn=978-1-85070-322-8|pages=152–}}</ref> 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.<ref name="SeldinGiebisch1997" /> As such, based on the above, the antiandrogenic effects of spironolactone are considered to be largely due to other metabolites rather than due to canrenone.<ref name="SeldinGiebisch1997" /><ref name="pmid4064345">{{cite journal | vauthors = Armanini D, Karbowiak I, Goi A, Mantero F, Funder JW | title = In-vivo metabolites of spironolactone and potassium canrenoate: determination of potential anti-androgenic activity by a mouse kidney cytosol receptor assay | journal = Clin. Endocrinol. | volume = 23 | issue = 4 | pages = 341–7 | year = 1985 | pmid = 4064345 | doi = 10.1111/j.1365-2265.1985.tb01090.x| s2cid = 20161982 }}</ref><ref name="pmid2697627">{{cite journal | vauthors = Andriulli A, Arrigoni A, Gindro T, Karbowiak I, Buzzetti G, Armanini D | title = Canrenone and androgen receptor-active materials in plasma of cirrhotic patients during long-term K-canrenoate or spironolactone therapy | journal = Digestion | volume = 44 | issue = 3 | pages = 155–62 | year = 1989 | pmid = 2697627 | doi = 10.1159/000199905}}</ref> 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.<ref name="pmid263288" />

Spironolactone is described as having relatively weak antiandrogenic activity.<ref name="Wu2012">{{cite book|author=Jashin J. Wu|title=Comprehensive Dermatologic Drug Therapy E-Book|url=https://books.google.com/books?id=Tqpsm5WKKlcC&pg=PA364|date=18 October 2012|publisher=Elsevier Health Sciences|isbn=978-1-4557-3801-4|pages=364–|quote=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}}</ref><ref name="BenniVemer1990" /><ref name="pmid11322868" /><ref name="pmid8915726">{{cite journal | vauthors = Shaw JC | title = Antiandrogen therapy in dermatology | journal = Int. J. Dermatol. | volume = 35 | issue = 11 | pages = 770–8 | date = November 1996 | pmid = 8915726 | doi = 10.1111/j.1365-4362.1996.tb02970.x | s2cid = 39334280 }}</ref> Nonetheless, it is useful as an antiandrogen in women, who have low androgen levels compared to men.<ref name="pmid2941190">{{cite journal | vauthors = Tremblay RR | title = Treatment of hirsutism with spironolactone | journal = Clin Endocrinol Metab | volume = 15 | issue = 2 | pages = 363–71 | date = May 1986 | pmid = 2941190 | doi = 10.1016/S0300-595X(86)80030-5 }}</ref><ref name="GregoryTravis2015">{{cite book|author1=Haff , G. Gregory|author2=Triplett , N. Travis|title=Essentials of Strength Training and Conditioning 4th Edition|url=https://books.google.com/books?id=bfuXCgAAQBAJ&pg=PA76|date=23 September 2015|publisher=Human Kinetics|isbn=978-1-4925-0162-6|pages=76–}}</ref> In addition, considerable incidences{{verify spelling|date=September 2022|reason=''incidence'' is normally used only in the singular form, perhaps ''incidence'', ''incidents'',  or ''instances'' was intended}} of gynecomastia, decreased libido, and erectile dysfunction have been reported in men taking very high doses of spironolactone (200 to 400&nbsp;mg/day).<ref name="pmid2941190" />

{| class="wikitable sortable floatright" style="text-align:left; margin-left:auto; margin-right:auto; border:none;"
|+ class="nowrap" | Affinities of selected ligands at the androgen receptor
|-
! Compound !! {{abbrlink|AR|Androgen receptor}} {{abbrlink|RBA|Relative binding affinity}} (%) || {{abbrlink|AR|Androgen receptor}} K<sub>i</sub> (nM)
|-
| {{No selflink|Metribolone}} || 100 || 1.18
|-
| {{No selflink|Androstanolone|Dihydrotestosterone}} || 136 || 0.87
|-
| {{No selflink|Testosterone (medication)|Testosterone}} || 117 || 1.01
|-
| {{No selflink|Spironolactone}} || 67.0 || 1.76
|-
<!--| {{No selflink|Danazol}} || 41.4 || 2.85
|--->
| {{No selflink|Trimethyltrienolone}} || 14.8 || 8.0
|-
| {{No selflink|Megestrol acetate}} || 13.6 || 8.7
|-
| {{No selflink|Cyproterone acetate}} || 12.5 || 9.5
|-
<!--| {{No selflink|Medroxyprogesterone acetate}} || 11.6 || 10
|--->
| {{No selflink|Progesterone (medication)|Progesterone}} || 6.6 || 18
|-
| {{No selflink|Estradiol (medication)|Estradiol}} || 4.9 || 24
|-
| {{No selflink|Androstenedione}} || 2.0 || 58
|-
| {{No selflink|Canrenone}} || 0.84 || 140
|-
<!--| {{No selflink|Formestane}} || 0.79 || 150
|-
| {{No selflink|17α-Hydroxyprogesterone}} || 0.42 || 280
|--->
| {{No selflink|Flutamide}} || 0.079 || 1200
|-
<!--| {{No selflink|Testolactone}} || 0.0029 || 41000
|--->
| {{No selflink|Cimetidine}} || 0.00084 || 140,000
|- class="sortbottom"
| colspan="3" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' (1) Human skin fibroblasts used for assays. (2) Situation ''in vivo'' is different for flutamide and spironolactone due [[Biology:Biotransformation|biotransformation]]. (3) Conflicting findings for spironolactone. '''Sources:''' ''Main:'' <ref name="Hammerstein1990">{{cite book|last1=Hammerstein|first1=J.|title=Hair and Hair Diseases|chapter=Antiandrogens: Clinical Aspects|year=1990|pages=827–886|doi=10.1007/978-3-642-74612-3_35|isbn=978-3-642-74614-7}}</ref><ref name="pmid6725525"/> ''Related:'' <ref name="pmid6457421">{{cite journal | vauthors = Brown TR, Rothwell SW, Sultan C, Migeon CJ | title = Inhibition of androgen binding in human foreskin fibroblasts by antiandrogens | journal = Steroids | volume = 37 | issue = 6 | pages = 635–48 | date = June 1981 | pmid = 6457421 | doi = 10.1016/S0039-128X(81)90173-2 | s2cid = 88959 }}</ref><ref name="pmid3762019">{{cite journal | vauthors = Breiner M, Romalo G, Schweikert HU | title = Inhibition of androgen receptor binding by natural and synthetic steroids in cultured human genital skin fibroblasts | journal = Klinische Wochenschrift | volume = 64 | issue = 16 | pages = 732–7 | date = August 1986 | pmid = 3762019 | doi = 10.1007/BF01734339 | s2cid = 34846760 }}</ref><ref name="BreinerRomalo1986">{{cite journal| vauthors = Breiner M, Romalo G, Schweikert HU |title=Inhibition of androgen receptor binding by drugs in cultured human genital skin fibroblasts|journal=Acta Endocrinologica|volume=113|issue=1_Suppl|year=1986|pages=S152|issn=0804-4643|doi=10.1530/acta.0.111S152}}</ref>
|}

Spironolactone has been found to have effectiveness in the treatment of hirsutism in women at a dosage of as low as 50&nbsp;mg/day.<ref name="pmid9420861">{{cite journal | vauthors = Diamanti-Kandarakis E, Tolis G, Duleba AJ | title = Androgens and therapeutic aspects of antiandrogens in women | journal = J. Soc. Gynecol. Investig. | volume = 2 | issue = 4 | pages = 577–92 | date = 1995 | pmid = 9420861 | doi = 10.1177/107155769500200401 | s2cid = 32242838 }}</ref> The effectiveness of spironolactone in the treatment of hirsutism in women has been found to be near-significantly greater at a dosage of 100&nbsp;mg/day relative to a dosage of 200&nbsp;mg/day (19% ± 8% and 30% ± 3% reduction in hair shaft diameter, respectively; ''p'' = 0.07).<ref name="pmid3967781">{{cite journal | vauthors = Lobo RA, Shoupe D, Serafini P, Brinton D, Horton R | title = The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women | journal = Fertil. Steril. | volume = 43 | issue = 2 | pages = 200–5 | date = February 1985 | pmid = 3967781 | doi = 10.1016/S0015-0282(16)48373-1 | doi-access = free }}</ref><ref name="BrownFarquhar2009">{{cite journal|last1=Brown|first1=Julie|last2=Farquhar|first2=Cindy|last3=Lee|first3=Olivia|last4=Toomath|first4=Robyn|last5=Jepson|first5=Ruth G|title=Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne|journal=Cochrane Database of Systematic Reviews|issue=2|pages=CD000194|year=2009|issn=1465-1858|doi=10.1002/14651858.CD000194.pub2|pmid=19370553}}</ref><ref name="Hammerstein1990"/> Levels of free testosterone were unchanged, suggesting that the antiandrogenic efficacy of spironolactone was due exclusively to direct AR blockade.<ref name="pmid3967781" /><ref name="BrownFarquhar2009" /> In addition, other studies have found that 100&nbsp;mg/day spironolactone is significantly or near-significantly inferior to 500&nbsp;mg/day flutamide in improving symptoms of acne and hirsutism.<ref name="pmid9238337" /><ref name="pmid8150100">{{cite journal | vauthors = Erenus M, Gürbüz O, Durmuşoğlu F, Demirçay Z, Pekin S | title = Comparison of the efficacy of spironolactone versus flutamide in the treatment of hirsutism | journal = Fertil. Steril. | volume = 61 | issue = 4 | pages = 613–6 | date = April 1994 | pmid = 8150100 | doi = 10.1016/S0015-0282(16)56634-5 }}</ref><ref name="pmid8299783">{{cite journal | vauthors = Cusan L, Dupont A, Gomez JL, Tremblay RR, Labrie F | title = Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial | journal = Fertil. Steril. | volume = 61 | issue = 2 | pages = 281–7 | date = February 1994 | pmid = 8299783 | doi = 10.1016/S0015-0282(16)56518-2 }}</ref> One study compared placebo and dosages of spironolactone of 50, 100, 150, and 200&nbsp;mg/day in the treatment of acne in women and observed progressive increases in response rates up to the 200&nbsp;mg/day dosage.<ref name="Hammerstein1990" /><ref name="GoodfellowAlaghband-Zadeh1984" /> These findings suggest that the antiandrogenic effectiveness of spironolactone is not maximal below a dosage of 200&nbsp;mg/day, and are in accordance with the typical dosage range of spironolactone of 50 to 200&nbsp;mg/day in women.<ref name="pmid9238337">{{cite journal | vauthors = Shaw JC | title = Antiandrogen and hormonal treatment of acne | journal = Dermatol Clin | volume = 14 | issue = 4 | pages = 803–11 | date = October 1996 | pmid = 9238337 | doi = 10.1016/S0733-8635(05)70405-8 }}</ref><ref name="Wu2012" /><ref name="pmid28155090">{{cite journal | vauthors = Layton AM, Eady EA, Whitehouse H, Del Rosso JQ, Fedorowicz Z, van Zuuren EJ | title = Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review | journal = Am J Clin Dermatol | volume = 18 | issue = 2 | pages = 169–191 | date = April 2017 | pmid = 28155090 | pmc = 5360829 | doi = 10.1007/s40257-016-0245-x }}</ref><ref name="GoodfellowAlaghband-Zadeh1984" />

Studies have found that spironolactone is associated with a significantly lower risk of [[Medicine:Prostate cancer|prostate cancer]] in men ({{abbrlink|HR|hazard ratio}} = 0.69).<ref name="pmid27735065">{{cite journal | vauthors = Mackenzie IS, Morant SV, Wei L, Thompson AM, MacDonald TM | title = Spironolactone use and risk of incident cancers: a retrospective, matched cohort study | journal = Br J Clin Pharmacol | volume = 83 | issue = 3 | pages = 653–663 | date = March 2017 | pmid = 27735065 | pmc = 5306481 | doi = 10.1111/bcp.13152 }}</ref><ref name="pmid32123316">{{cite journal | vauthors = Beckmann K, Garmo H, Lindahl B, Holmberg L, Stattin P, Adolfsson J, Cruickshank JK, Van Hemelrijck M | title = Spironolactone use is associated with lower prostate cancer risk: a population-wide case-control study | journal = Prostate Cancer Prostatic Dis. | volume = 23| issue = 3| pages = 527–533| date = March 2020 | pmid = 32123316 | doi = 10.1038/s41391-020-0220-8 | s2cid = 211729232 }}</ref> This was apparent for high-dose spironolactone, using doses of 75&nbsp;mg/day and above ({{abbr|HR|hazard ratio}} = 0.74).<ref name="pmid27735065" /> Conversely, lower doses of spironolactone (<75&nbsp;mg/day) were not associated with a decreased risk of prostate cancer ({{abbr|HR|hazard ratio}} = 0.99).<ref name="pmid27735065" /> Levels of [[Biology:Prostate-specific antigen|prostate-specific antigen]] (PSA) were assessed and were found to be significantly lower in spironolactone-treated men.<ref name="pmid27735065" /> The decreased incidence of prostate cancer with spironolactone was hypothesized to be due to its known antiandrogenic activity.<ref name="pmid27735065" />

==Steroidogenesis inhibition==
Spironolactone is sometimes 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 [[Biology:Biosynthesis|biosynthesis]] of testosterone.<ref name="pmid984618" /><ref name="MelmedPolonsky2015">{{cite book| vauthors = Melmed S, Polonsky KS, Larsen PR, Kronenberg HM |title=Williams Textbook of Endocrinology|url=https://books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA743|date=30 November 2015|publisher=Elsevier Health Sciences|isbn=978-0-323-29738-7|pages=743–}}</ref><ref name="Sengupta2007">{{cite book|author=Sengupta|title=Gynaecology For Postgraduate And Practitioners|url=https://books.google.com/books?id=ELkWa34eBz4C&pg=PA172|date=1 January 2007|publisher=Elsevier India|isbn=978-81-312-0436-8|pages=172–}}</ref><ref name="CarrBlackwell1998">{{cite book|author1=Bruce R. Carr|author2=Richard E. Blackwell|title=Textbook of Reproductive Medicine|url=https://books.google.com/books?id=-8hsAAAAMAAJ|year=1998|publisher=McGraw-Hill Professional Publishing|isbn=978-0-8385-8893-2|page=261}}</ref> Although spironolactone is said to be a relatively weak inhibitor of 17α-hydroxylase and 17,20-lyase,<ref name="DesaiP.2001"/><ref name="pmid984618" /> at least compared to more potent steroidogenesis inhibitors like [[Biology:Ketoconazole|ketoconazole]] and [[Biology:Abiraterone acetate|abiraterone acetate]] (which can reduce testosterone concentrations to castrate levels), this action may contribute to a significant portion of the antiandrogenic activity of spironolactone, for instance lowering testosterone levels in women with hyperandrogenism and in transgender women.<ref name="pmid3950464">{{cite journal  |vauthors=Masahashi T, Wu MC, Ohsawa M, etal | title = Spironolactone therapy for hyperandrogenic anovulatory women--clinical and endocrinological study | journal = Nihon Sanka Fujinka Gakkai Zasshi | volume = 38 | issue = 1 | pages = 95–101 |date=January 1986 | pmid = 3950464 }}</ref><ref name="pmid907238">{{cite journal |vauthors=Rose LI, Underwood RH, Newmark SR, Kisch ES, Williams GH | title = Pathophysiology of spironolactone-induced gynecomastia | journal = Annals of Internal Medicine | volume = 87 | issue = 4 | pages = 398–403 |date=October 1977 | pmid = 907238 | doi = 10.7326/0003-4819-87-4-398}}</ref><ref name="pmid19648382">{{cite journal | vauthors = Haynes BA, Mookadam F | title = Male gynecomastia | journal = Mayo Clinic Proceedings | volume = 84 | issue = 8 | page = 672 | date = August 2009 | pmid = 19648382 | pmc = 2719518 | doi = 10.4065/84.8.672 }}</ref> Canrenone inhibits steroidogenic enzymes such as 17α-hydroxylase, 17,20-lyase, 11β-hydroxylase, [[Biology:Cholesterol side-chain cleavage enzyme|cholesterol side-chain cleavage enzyme]], and 21-hydroxylase similarly to spironolactone, but is more potent in doing so in comparison.<ref name="pmid6786868">{{cite journal | vauthors = Colby HD | title = Chemical suppression of steroidogenesis | journal = Environ. Health Perspect. | volume = 38 | pages = 119–27 | year = 1981 | pmid = 6786868 | pmc = 1568425 | doi = 10.1289/ehp.8138119}}</ref> In spite of the findings of spironolactone and canrenone on these [[Biology:Steroidogenic enzyme|steroidogenic enzyme]]s however, spironolactone has shown mixed and highly inconsistent effects on [[Biology:Steroid hormone|steroid hormone]] levels in clinical studies.<ref name="pmid984618" /><ref name="pmid8144871" /> In some studies, it significantly lowers testosterone levels, whereas in other studies, testosterone and estradiol levels remain unchanged, even at high dosages.<ref name="pmid984618" /><ref name="pmid1826112">{{cite journal | vauthors = Shaw JC | title = Spironolactone in dermatologic therapy | journal = J. Am. Acad. Dermatol. | volume = 24 | issue = 2 Pt 1 | pages = 236–43 | date = February 1991 | pmid = 1826112 | doi = 10.1016/0190-9622(91)70034-Y }}</ref><ref name="pmid29756046">{{cite journal | vauthors = Leinung MC, Feustel PJ, Joseph J | title = Hormonal Treatment of Transgender Women with Oral Estradiol | journal = Transgend Health | volume = 3 | issue = 1 | pages = 74–81 | date = 2018 | pmid = 29756046 | pmc = 5944393 | doi = 10.1089/trgh.2017.0035 }}</ref> It has been suggested that spironolactone may weakly and partially inhibit 17α-hydroxylase, which in turn results in upregulation of the HPG axis such that steroid hormone levels remain normal.<ref name="pmid984618" /> Conversely however, inhibition of 17α-hydroxylase in the ovary may disrupt the [[Medicine:Menstrual cycle|menstrual cycle]] and thereby result in menstrual irregularities.<ref name="pmid984618" />

Animal studies have found that spironolactone inhibits testicular CYP450-mediated steroidogenesis by 5 to 75% across a dosage range of 1 to 100&nbsp;mg/kg, with 50% inhibition occurring at a dose of 40&nbsp;mg/kg.<ref name="pmid984618" /> A decrease in the production of testosterone and 17α-hydroxyprogesterone due to inhibition of steroidogenic enzymes like 17α-hydroxylase has been found to occur at dosages of 40 to 200&nbsp;mg/kg.<ref name="pmid984618" /> For comparison, the clinical dosage range of spironolactone in humans is usually about 4 to 8&nbsp;mg/kg.<ref name="pmid984618" />

There is also mixed/conflicting evidence that spironolactone may inhibit [[Chemistry:5α-reductase|5α-reductase]], and thus the synthesis of the potent androgen DHT from testosterone, to some extent.<ref name="pmid166833" /><ref name="pmid4033118">{{cite journal |vauthors=Serafini PC, Catalino J, Lobo RA | title = The effect of spironolactone on genital skin 5 alpha-reductase activity | journal = Journal of Steroid Biochemistry | volume = 23 | issue = 2 | pages = 191–4 |date=August 1985 | pmid = 4033118 | doi = 10.1016/0022-4731(85)90236-5}}</ref><ref name="pmid7829618">{{cite journal | vauthors = Wong IL, Morris RS, Chang L, Spahn MA, Stanczyk FZ, Lobo RA | title = A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 80 | issue = 1 | pages = 233–8 | date = January 1995 | pmid = 7829618 | doi = 10.1210/jcem.80.1.7829618 | url = http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=7829618 }}{{Dead link|date=October 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="pmid1426314">{{cite journal |vauthors=Miles RA, Cassidenti DL, Carmina E, Gentzschein E, Stanczyk FZ, Lobo RA | title = Cutaneous application of an androstenedione gel as an in vivo test of 5 alpha-reductase activity in women | journal = Fertility and Sterility | volume = 58 | issue = 4 | pages = 708–12 |date=October 1992 | pmid = 1426314 | doi = 10.1016/S0015-0282(16)55316-3| doi-access = free }}</ref><ref name="pmid15012621">{{cite journal |vauthors=Keleştimur F, Everest H, Unlühizarci K, Bayram F, Sahin Y | title = A comparison between spironolactone and spironolactone plus finasteride in the treatment of hirsutism | journal = European Journal of Endocrinology| volume = 150 | issue = 3 | pages = 351–4 |date=March 2004 | pmid = 15012621 | doi = 10.1530/eje.0.1500351| s2cid = 32780296 | url = http://eje-online.org/cgi/pmidlookup?view=long&pmid=15012621| doi-access = free }}</ref> However, the combination of spironolactone and the potent 5α-reductase inhibitor [[Chemistry:Finasteride|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.<ref name="pmid15012621" /> Spironolactone has been found not to have activity as an [[Chemistry:Aromatase inhibitor|aromatase inhibitor]].<ref name="pmid12477487"/><ref name="pmid10428369"/>

==Estrogenic activity==
Spironolactone has been found to directly interact with the ER.<ref name="pmid7391714">{{cite journal | vauthors = Levy J, Burshell A, Marbach M, Afllalo L, Glick SM | title = Interaction of spironolactone with oestradiol receptors in cytosol | journal = J. Endocrinol. | volume = 84 | issue = 3 | pages = 371–9 | date = March 1980 | pmid = 7391714 | doi = 10.1677/joe.0.0840371 }}</ref> A study using human uterine tissue found that a 1,000-fold excess of spironolactone (0.3–2&nbsp;μM) resulted in no displacement of [[Chemistry:Estradiol (medication)|estradiol]] from the ER.<ref name="pmid86546">{{cite journal | vauthors = Rifka SM, Pita JC, Vigersky RA, Wilson YA, Loriaux DL | title = Interaction of digitalis and spironolactone with human sex steroid receptors | journal = J. Clin. Endocrinol. Metab. | volume = 46 | issue = 2 | pages = 338–44 | year = 1978 | pmid = 86546 | doi = 10.1210/jcem-46-2-338 }}</ref> However, a subsequent study found that the medication did interact with the human ER at higher concentrations, albeit with very low affinity (K<sub>i</sub> = 20&nbsp;μM).<ref name="pmid7391714" /> In the same study, spironolactone was administered to rats and found to produce mixed [[Chemistry:Estrogen (medication)|estrogen]]ic and [[Chemistry:Antiestrogen|antiestrogen]]ic or [[Chemistry:Selective estrogen receptor modulator|selective estrogen receptor modulator]] (SERM)-like effects that were described as very similar to those of [[Chemistry:Tamoxifen|tamoxifen]].<ref name="pmid7391714" /> In spite of the fact that tamoxifen had two orders of magnitude higher affinity for the ER than spironolactone however, the two medications showed similar potency ''in vivo''.<ref name="pmid7391714" /> The likelihood of spironolactone interacting with the ER itself is remote in consideration of its very low affinity for the receptor ''in vitro''.<ref name="pmid27072668" /> However, it has been hypothesized that metabolism of spironolactone might result in active metabolites with greater ER affinity, which might potentially account for the activity.<ref name="pmid7391714" /><ref name="pmid27072668" /> One of the major active metabolites of spironolactone, canrenone, likewise did not interact with the human uterine ER at up to a more than 5,000-fold excess (25&nbsp;μM).<ref name="pmid6849751">{{cite journal | vauthors = Fernandez MD, Carter GD, Palmer TN | title = The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol | journal = Br J Clin Pharmacol | volume = 15 | issue = 1 | pages = 95–101 | date = January 1983 | pmid = 6849751 | pmc = 1427833 | doi = 10.1111/j.1365-2125.1983.tb01470.x }}</ref> In other research, spironolactone has been found to have no estrogenic or antiestrogenic effects in the [[Biology:Uterus|uterus]] when administered by [[Medicine:Subcutaneous injection|subcutaneous injection]] in rodents even at very high doses.<ref name="Dorfman2016">{{cite book|author=Ralph I. Dorfman|title=Steroidal Activity in Experimental Animals and Man|url=https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA371|date=5 December 2016|publisher=Elsevier Science|isbn=978-1-4832-7299-3|pages=371–}}</ref>

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.<ref name="pmid7391714" /> Subsequently, it has also been suggested that, as a SERM-like medication, ER agonistic activity of spironolactone in the [[Medicine:Pituitary gland|pituitary gland]] could be responsible for its antigonadotropic effects while ER antagonistic activity of spironolactone in the endometrium could be responsible for the menstrual disturbances that are associated with it.<ref name="pmid27072668" /> 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.<ref name="pmid8144871"/><ref name="pmid2744183"/><ref name="pmid27072668"/>

In accordance, a study found that in women treated with a GnRH analogue, spironolactone therapy almost completely prevented the [[Medicine:Osteoporosis|bone loss]] that is associated with these medications, whereas treatment with the selective AR antagonist flutamide had no such effect.<ref name="pmid10199763">{{cite journal | vauthors = Moghetti P, Castello R, Zamberlan N, Rossini M, Gatti D, Negri C, Tosi F, Muggeo M, Adami S | title = Spironolactone, but not flutamide, administration prevents bone loss in hyperandrogenic women treated with gonadotropin-releasing hormone agonist | journal = J. Clin. Endocrinol. Metab. | volume = 84 | issue = 4 | pages = 1250–4 | year = 1999 | pmid = 10199763 | doi = 10.1210/jcem.84.4.5606 | s2cid = 36382302 | doi-access = free }}</ref><ref name="pmid11322868">{{cite journal | vauthors = Doggrell SA, Brown L | title = The spironolactone renaissance | journal = Expert Opin Investig Drugs | volume = 10 | issue = 5 | pages = 943–54 | year = 2001 | pmid = 11322868 | doi = 10.1517/13543784.10.5.943 | s2cid = 39820875 }}</ref> Other studies have also found an inverse relationship between spironolactone and decreased bone mineral density and [[Medicine:Bone fracture|bone fracture]]s in men.<ref name="pmid18598893">{{cite journal | vauthors = 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 | title = Fracture risk in men with congestive heart failure risk reduction with spironolactone | journal = J. Am. Coll. Cardiol. | volume = 52 | issue = 2 | pages = 135–8 | year = 2008 | pmid = 18598893 | doi = 10.1016/j.jacc.2008.03.039 | s2cid = 28002410 | doi-access = free }}</ref><ref name="pmid24504763">{{cite journal | vauthors = Ghosh M, Majumdar SR | title = Antihypertensive medications, bone mineral density, and fractures: a review of old cardiac drugs that provides new insights into osteoporosis | journal = Endocrine | volume = 46 | issue = 3 | pages = 397–405 | year = 2014 | pmid = 24504763 | doi = 10.1007/s12020-014-0167-4 | s2cid = 19284432 }}</ref> 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.<ref name="pmid10199763" /><ref name="pmid11322868" /><ref name="MoghettiCastello1999">{{cite journal|last1=Moghetti|first1=Paolo|last2=Castello|first2=Roberto|last3=Zamberlan|first3=Nicoletta|last4=Rossini|first4=Maurizio|last5=Gatti|first5=Davide|last6=Negri|first6=Carlo|last7=Tosi|first7=Flavia|last8=Muggeo|first8=Michele|last9=Adami|first9=Silvano|title=Authors' Response: Spironolactone But Not Flutamide Administration Prevents Bone Loss in Hyperandrogenic Women Treated with Gonadotropin-Releasing Hormone Agonist|journal=The Journal of Clinical Endocrinology & Metabolism|volume=84|issue=12|year=1999|pages=4747–b–4747|issn=0021-972X|doi=10.1210/jcem.84.12.4747b|doi-access=free}}</ref> 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.<ref name="pmid24504763" />

In addition to potential 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).<ref name="SeldinGiebisch1997" /><ref name="pmid10973921">{{cite journal |vauthors=Zhou J, Ng S, Adesanya-Famuiya O, Anderson K, Bondy CA | title = Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression | journal = FASEB Journal | volume = 14 | issue = 12 | pages = 1725–30 |date=September 2000 | pmid = 10973921 | doi = 10.1096/fj.99-0863com| s2cid = 17172449 }}<!-- https://zenodo.org/record/1236080--></ref>
* Inhibition of the conversion of estradiol to estrone, resulting in an increase in the ratio of circulating estradiol to estrone.<ref name="pmid12477487">{{cite journal |vauthors=Satoh T, Itoh S, Seki T, Itoh S, Nomura N, Yoshizawa I | title = On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 82 | issue = 2–3 | pages = 209–16 |date=October 2002 | pmid = 12477487 | doi = 10.1016/S0960-0760(02)00154-1| s2cid = 9972497 }}</ref> Estradiol is far more potent than estrone as an estrogen, which is comparatively almost inactive.<ref name="pmid12071379">{{cite journal |vauthors=Ruggiero RJ, Likis FE | title = Estrogen: physiology, pharmacology, and formulations for replacement therapy | journal = Journal of Midwifery & Women's Health | volume = 47 | issue = 3 | pages = 130–8 | year = 2002 | pmid = 12071379 | doi = 10.1016/s1526-9523(02)00233-7}}</ref><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | pages = 3–63 | year = 2005 | issue = Suppl 1 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf | url-status = live | archive-url = https://web.archive.org/web/20160822055012/http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf | archive-date = 2016-08-22 }}</ref>
* Enhancement of the rate of peripheral conversion of testosterone into estradiol, thus decreasing the ratio of circulating testosterone to estradiol.<ref name="pmid907238" />

Spironolactone has been found to act as a reversible inhibitor of human 17β-hydroxysteroid dehydrogenase 2 (17β-HSD2), albeit with weak potency (K<sub>i</sub> = 0.25–2.4&nbsp;μM; IC<sub>50</sub> = 0.27–1.1&nbsp;μM).<ref name="pmid12570693">{{cite journal | vauthors = Poirier D | title = Inhibitors of 17 beta-hydroxysteroid dehydrogenases | journal = Curr. Med. Chem. | volume = 10 | issue = 6 | pages = 453–77 | year = 2003 | pmid = 12570693 | doi = 10.2174/0929867033368222}}</ref><ref name="pmid19601747">{{cite journal | vauthors = Poirier D | title = Advances in development of inhibitors of 17beta hydroxysteroid dehydrogenases | journal = Anticancer Agents Med Chem | volume = 9 | issue = 6 | pages = 642–60 | year = 2009 | pmid = 19601747 | doi = 10.2174/187152009788680000}}</ref><ref name="pmid7473580">{{cite journal | vauthors = Sam KM, Auger S, Luu-The V, Poirier D | title = Steroidal spiro-gamma-lactones that inhibit 17 beta-hydroxysteroid dehydrogenase activity in human placental microsomes | journal = J. Med. Chem. | volume = 38 | issue = 22 | pages = 4518–28 | year = 1995 | pmid = 7473580 | doi = 10.1021/jm00022a018}}</ref><ref name="pmid10428369">{{cite journal | vauthors = Tremblay MR, Luu-The V, Leblanc G, Noël P, Breton E, Labrie F, Poirier D | title = Spironolactone-related inhibitors of type II 17beta-hydroxysteroid dehydrogenase: chemical synthesis, receptor binding affinities, and proliferative/antiproliferative activities | journal = Bioorg. Med. Chem. | volume = 7 | issue = 6 | pages = 1013–23 | year = 1999 | pmid = 10428369 | doi = 10.1016/s0968-0896(98)00260-0}}</ref> 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.<ref name="pmid12570693" /><ref name="pmid10428369" /> 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.<ref name="pmid12477487" /><ref name="pmid24189467" /> 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.<ref name="pmid21193039">{{cite journal | vauthors = 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 | title = 17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development | journal = J. Steroid Biochem. Mol. Biol. | volume = 125 | issue = 1–2 | pages = 66–82 | year = 2011 | pmid = 21193039 | doi = 10.1016/j.jsbmb.2010.12.013 | s2cid = 23767100 }}</ref><ref name="pmid26230882">{{cite journal | vauthors = Soubhye J, Alard IC, van Antwerpen P, Dufrasne F | title = Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis | journal = Future Med Chem | volume = 7 | issue = 11 | pages = 1431–56 | year = 2015 | pmid = 26230882 | doi = 10.4155/fmc.15.74 }}</ref> In contrast to 17β-HSD2, spironolactone does not appear to inhibit 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1) ''[[In vitro|in vitro]]''.<ref name="pmid984618" />

In contrast to estrogens and SERMs,<ref name="pmid16112947" /><ref name="pmid15755972">{{cite journal | vauthors = Fabian CJ, Kimler BF | title = Selective estrogen-receptor modulators for primary prevention of breast cancer | journal = J. Clin. Oncol. | volume = 23 | issue = 8 | pages = 1644–55 | date = March 2005 | pmid = 15755972 | doi = 10.1200/JCO.2005.11.005 | doi-access = free }}</ref> spironolactone does not increase sex hormone-binding globulin (SHBG) levels<ref name="Hammerstein1990" /><ref name="GoodfellowAlaghband-Zadeh1984">{{cite journal|last1=Goodfellow|first1=A.|last2=Alaghband-Zadeh|first2=J.|last3=Carter|first3=G.|last4=Cream|first4=J.J.|last5=Holland|first5=S.|last6=Scully|first6=J.|last7=Wise|first7=P.|title=Oral spironolactone improves acne vulgaris and reduces sebum excretion|journal=British Journal of Dermatology|volume=111|issue=2|year=1984|pages=209–214|issn=0007-0963|doi=10.1111/j.1365-2133.1984.tb04045.x|pmid=6235834|s2cid=24518527}}</ref><ref name="pmid17077951">{{cite journal | vauthors = Sato K, Matsumoto D, Iizuka F, Aiba-Kojima E, Watanabe-Ono A, Suga H, Inoue K, Gonda K, Yoshimura K | title = Anti-androgenic therapy using oral spironolactone for acne vulgaris in Asians | journal = Aesthetic Plast Surg | volume = 30 | issue = 6 | pages = 689–94 | date = 2006 | pmid = 17077951 | doi = 10.1007/s00266-006-0081-0 | s2cid = 13332616 }}</ref> or risk of venous thromboembolism.<ref name="ElbersSjouke2016">{{cite journal|last1=Elbers|first1=Laura P.B.|last2=Sjouke|first2=Barbara|last3=Zannad|first3=Faïez|last4=Cicoira|first4=Mariantonietta|last5=Vizzardi|first5=Enrico|last6=Václavík|first6=Jan|last7=Gerdes|first7=Victor E.A.|last8=Squizzato|first8=Alessandro|title=Effects of mineralocorticoid receptor antagonists on the risk of thrombosis, bleeding and mortality: A systematic review and meta-analysis of randomized controlled trials|journal=Thrombosis Research|volume=144|year=2016|pages=32–39|issn=0049-3848|doi=10.1016/j.thromres.2016.04.027|pmid=27270220}}</ref> Nor is there an increase in the risk of [[Medicine:Breast cancer|breast cancer]] or [[Medicine:Endometrial cancer|endometrial cancer]] with spironolactone.<ref name="pmid28979664">{{cite journal | vauthors = Endly DC, Miller RA | title = Oily Skin: A review of Treatment Options | journal = J Clin Aesthet Dermatol | volume = 10 | issue = 8 | pages = 49–55 | date = August 2017 | pmid = 28979664 | pmc = 5605215 }}</ref><ref name="pmid22797844">{{cite journal | vauthors = Mackenzie IS, Macdonald TM, Thompson A, Morant S, Wei L | title = Spironolactone and risk of incident breast cancer in women older than 55 years: retrospective, matched cohort study | journal = BMJ | volume = 345 | pages = e4447 | date = July 2012 | pmid = 22797844 | pmc = 3396460 | doi = 10.1136/bmj.e4447 }}</ref><ref name="pmid24189467">{{cite journal | vauthors = Biggar RJ, Andersen EW, Wohlfahrt J, Melbye M | title = Spironolactone use and the risk of breast and gynecologic cancers | journal = Cancer Epidemiol | volume = 37 | issue = 6 | pages = 870–5 | date = December 2013 | pmid = 24189467 | doi = 10.1016/j.canep.2013.10.004 }}</ref><ref name="pmid27735065"/><ref name="pmid31418056">{{cite journal | vauthors = Sabatier P, Amar J, Montastruc F, Rousseau V, Chebane L, Bouhanick B, Montastruc JL | title = Breast cancer and spironolactone: an observational postmarketing study | journal = Eur. J. Clin. Pharmacol. | volume = 75 | issue = 11 | pages = 1593–1598 | date = November 2019 | pmid = 31418056 | doi = 10.1007/s00228-019-02740-y | s2cid = 199668277 }}</ref><ref name="pmid32446820">{{cite journal | vauthors = Wei C, Bovonratwet P, Gu A, Moawad G, Silverberg JI, Friedman AJ | title = Spironolactone use does not increase the risk of female breast cancer recurrence: A retrospective analysis | journal = J. Am. Acad. Dermatol. | date = May 2020 | volume = 83 | issue = 4 | pages = 1021–1027 | pmid = 32446820 | doi = 10.1016/j.jaad.2020.05.081 | s2cid = 218873257 }}</ref><ref name="pmid32738426">{{cite journal | vauthors = Heymann WR | title = Spironolactone and breast cancer: Fear not! | journal = J. Am. Acad. Dermatol. | date = July 2020 | volume = 83 | issue = 4 | pages = 1008–1009 | pmid = 32738426 | doi = 10.1016/j.jaad.2020.07.104 | s2cid = 220924754 }}</ref>

Spironolactone is known to produce a high rate of menstrual irregularities in women at around the middle of the [[Medicine:Menstrual cycle|menstrual cycle]], when ovulation occurs.<ref name="pmid27072668" /><ref name="FioreZermiani2011" /> A study investigated the effects of 100&nbsp;mg/day spironolactone on the endometrium and hormone levels and the mechanism for the menstrual abnormalities associated with it in a group of women with [[Medicine:Polycystic ovary syndrome|polycystic ovary syndrome]].<ref name="pmid27072668" /><ref name="FioreZermiani2011">{{cite journal | vauthors = Fiore C, Zermiani M, Sabbadin C, Anddrisani A, Ambrosini G, Bordin L, Dona G, Clari G, Ragazzi E, Armanini D | title = Effect of Spironolactone on Endometrium in Patients with Polycystic Ovary Syndrome | journal = Endocrine Reviews | date = June 2011 | volume = 32 | issue = 3 Suppl | issn = 0163-769X | url = https://www.endocrine.org/-/media/endocrine/files/endo-annual-meetings/endo_abstracts_2011_02.pdf}}</ref> They found that spironolactone, likely due to inhibition of steroidogenesis, blunted the surge in estradiol levels around ovulation, with estradiol levels of about 41 to 66% of normal at this time.<ref name="FioreZermiani2011" /><ref name="pmid27072668" /> Conversely, periovulatory levels of the [[Biology:Gonadotropin|gonadotropin]]s, [[Biology:Luteinizing hormone|luteinizing hormone]] and [[Biology:Follicle-stimulating hormone|follicle-stimulating hormone]], were unchanged.<ref name="FioreZermiani2011" /><ref name="pmid27072668" /> Spironolactone significantly decreased endometrial thickness in the women (by 22 to 33%), and as estrogens stimulate endometrial growth, this effect of spironolactone may have been due to the decreased levels of estradiol.<ref name="FioreZermiani2011" /><ref name="pmid27072668" /> As such, spironolactone may have a functional antiestrogenic effect around ovulation in women, and this may be involved in its side effect of menstrual irregularities at high doses.<ref name="FioreZermiani2011" /><ref name="pmid27072668" />

==Progestogenic activity==
Spironolactone has weak [[Biology:Progestogen|progestogen]]ic activity in [[Earth:Bioassay|bioassay]]s.<ref name="DesaiP.2001">{{cite book | author1 = Desai | author2 = Meena P. | author3 = Vijayalakshmi Bhatia & P.S.N. Menon | title = Pediatric Endocrine Disorders | url = https://books.google.com/books?id=63naXWOc4NwC&pg=PA167 | access-date = 28 May 2012 | date = 1 January 2001 | publisher = Orient Blackswan | isbn = 978-81-250-2025-7 | page = 167 | url-status = live | archive-url = https://web.archive.org/web/20130620234745/http://books.google.com/books?id=63naXWOc4NwC&pg=PA167 | archive-date = 20 June 2013 }}</ref><ref name="SchanePotts1978">{{cite journal | last1 = Schane | first1 = H. P. | last2 = Potts | first2 = G. O. | title = Oral Progestational Activity of Spironolactone | journal = Journal of Clinical Endocrinology & Metabolism | volume = 47 | issue = 3 | pages = 691–4 | year = 1978 | issn = 0021-972X | doi = 10.1210/jcem-47-3-691 | pmid=95623}}</ref> Its actions in this regard are a result of direct agonist activity at the PR, though with a very low [[Chemistry:EC50|half-maximal]] potency.<ref name="pmid20650892">{{cite journal  |vauthors=Fagart J, Hillisch A, Huyet J, etal | title = A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule | journal = The Journal of Biological Chemistry | volume = 285 | issue = 39 | pages = 29932–40 |date=September 2010 | pmid = 20650892 | pmc = 2943305 | doi = 10.1074/jbc.M110.131342 | doi-access = free }}</ref> Spironolactone's progestogenic activity has been suggested to be involved in some of its side effects,<ref name="Delyani2000" /> including the menstrual irregularities seen in women and the undesirable [[Biology:Serum (blood)|serum]] [[Chemistry:Lipid|lipid]] profile changes that are seen at higher doses.<ref name="Carrell2010">{{cite book | author = Douglas T. Carrell | title = Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice | url = https://books.google.com/books?id=lcBEheiufVcC&pg=PA163 | access-date = 28 May 2012 | date = 12 April 2010 | publisher = Springer | isbn = 978-1-4419-1435-4 | pages = 162–163 | url-status = live | archive-url = https://web.archive.org/web/20140704201613/http://books.google.com/books?id=lcBEheiufVcC&pg=PA163 | archive-date = 4 July 2014 }}</ref><ref name="MelmedPolonsky2011">{{cite book | vauthors = Melmed S, Polonsky KS, Larsen PR, Kronenberg HM | title = Williams Textbook of Endocrinology E-Book: Expert Consult | url = https://books.google.com/books?id=nbg1QOAObicC&pg=PT2057 | access-date = 27 May 2012 | date = 31 May 2011 | publisher = Elsevier Health Sciences | isbn = 978-1-4377-3600-7 | page = 2057 | url-status = live | archive-url = https://web.archive.org/web/20130621122700/http://books.google.com/books?id=nbg1QOAObicC&pg=PT2057 | archive-date = 21 June 2013 }}</ref><ref name="pmid19843067">{{cite journal |vauthors=Nakhjavani M, Hamidi S, Esteghamati A, Abbasi M, Nosratian-Jahromi S, Pasalar P | title = Short term effects of spironolactone on blood lipid profile: a 3-month study on a cohort of young women with hirsutism | journal = British Journal of Clinical Pharmacology | volume = 68 | issue = 4 | pages = 634–7 |date=October 2009 | pmid = 19843067 | pmc = 2780289 | doi = 10.1111/j.1365-2125.2009.03483.x }}</ref> It has also been suggested to augment the [[Medicine:Gynecomastia|gynecomastia]] caused by the estrogenic effects of spironolactone,<ref name="OttowWeinmann2008">{{cite book | author1 = Eckhard Ottow | author2 = Hilmar Weinmann | title = Nuclear Receptors As Drug Targets | url = https://books.google.com/books?id=iATfLbPgRugC&pg=PA410 | access-date = 28 May 2012 | date = 9 July 2008 | publisher = John Wiley & Sons | isbn = 978-3-527-62330-3 | page = 410 | url-status = live | archive-url = https://web.archive.org/web/20130621121614/http://books.google.com/books?id=iATfLbPgRugC&pg=PA410 | archive-date = 21 June 2013 }}</ref> as progesterone is known to be involved in [[Medicine:Breast development|mammary gland development]].<ref name="pmid12223124">{{cite journal | author = Anderson E | title = The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis | journal = Breast Cancer Research | volume = 4 | issue = 5 | pages = 197–201 | year = 2002 | pmid = 12223124 | pmc = 138744 | doi =  10.1186/bcr452 | doi-access = free }}</ref> A major active metabolite of spironolactone, canrenone, has been found to interact with the human uterine PR with a K<sub>i</sub> of 300&nbsp;nM.<ref name="pmid6849751" /> This is relatively weak at approximately 100-fold less than that of progesterone.<ref name="pmid6849751" /> In any case, levels of canrenone of up to 1,200&nbsp;nM have been observed in some studies with 100 to 200&nbsp;mg doses of spironolactone.<ref name="pmid6849751" />

It has been widely stated that the menstrual irregularities associated with spironolactone are due to its progestogenic activity, and animal studies, both in rabbits and rhesus monkeys, have shown clear progestogenic effects of spironolactone.<ref name="pmid95623">{{cite journal | vauthors = Schane HP, Potts GO | title = Oral progestational activity of spironolactone | journal = J. Clin. Endocrinol. Metab. | volume = 47 | issue = 3 | pages = 691–4 | year = 1978 | pmid = 95623 | doi = 10.1210/jcem-47-3-691 }}</ref> However, the dosages of spironolactone used in animals to produce progestogenic effects were very high (50–200&nbsp;mg/kg/day in rabbits, 400&nbsp;mg/day in rhesus monkeys).<ref name="pmid95623" /> In one study, the threshold dose by [[Medicine:Subcutaneous injection|subcutaneous injection]] for endometrial transformation in rabbits was 0.003–0.01&nbsp;mg for [[Chemistry:Cyproterone acetate|cyproterone acetate]], 0.1–0.3&nbsp;mg for [[Biology:Drospirenone|drospirenone]], 0.5&nbsp;mg for [[Chemistry:Progesterone (medication)|progesterone]], and 10–20&nbsp;mg for spironolactone.<ref name="pmid7625729">{{cite journal | vauthors = Muhn P, Fuhrmann U, Fritzemeier KH, Krattenmacher R, Schillinger E | title = Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity | journal = Ann. N. Y. Acad. Sci. | volume = 761 | issue = 3| pages = 311–35 | date = June 1995 | pmid = 7625729 | doi = 10.1111/j.1749-6632.1995.tb31386.x | bibcode = 1995NYASA.761..311M | s2cid = 36861309 }}</ref> Spironolactone orally at 40&nbsp;mg/kg/day failed to show an antigonadotropic effect or decrease [[Chemistry:Testosterone|testosterone]] levels in male cynomolgus monkeys, whereas oral drospirenone at 4&nbsp;mg/day was effective and strongly suppressed testosterone levels.<ref name="pmid7625729" /> In addition, no evidence of progestogenic nor antiprogestogenic effects (as assessed by endometrial changes) have been observed in women even with high doses of spironolactone.<ref name="pmid8144871" /><ref name="pmid2744183" /> As such, the progestogenic potency of spironolactone appears to be below the level of clinical significance in humans.<ref name="pmid8144871" /><ref name="pmid2744183" /> Moreover, the menstrual abnormalities associated with spironolactone must have a different cause.<ref name="pmid8144871" /><ref name="pmid2744183" /> Suggestions for other possible mechanisms for the menstrual disturbances of spironolactone include interference with the hypothalamic–pituitary–gonadal axis, inhibition of enzymatic steroidogenesis,<ref name="SeldinGiebisch1997" /> and mixed estrogenic and antiestrogenic activity.<ref name="pmid27072668"/><ref name="pmid8144871" /><ref name="pmid2744183" />

==Antigonadotropic effects==
Pure AR antagonists like [[Biology:Flutamide|flutamide]] and [[Chemistry:Bicalutamide|bicalutamide]] are potent [[Medicine:Progonadotropin|progonadotropin]]s with indirect estrogenic activity in males.<ref name="pmid11121992">{{cite journal | vauthors = Iversen P, Melezinek I, Schmidt A | title = Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function | journal = BJU International | volume = 87 | issue = 1 | pages = 47–56 | date = January 2001 | pmid = 11121992 | doi = 10.1046/j.1464-410x.2001.00988.x | s2cid = 28215804 | doi-access = free }}</ref> This is because they block the AR in the [[Medicine:Pituitary gland|pituitary gland]] and [[Biology:Hypothalamus|hypothalamus]] and thereby inhibit the [[Negative feedback|negative feedback]] of androgens on the hypothalamic–pituitary–gonadal axis (HPG axis).<ref name="pmid11121992" /> This, in turn, results in increased [[Biology:Gonadotropin|gonadotropin]] secretion, activation of gonadal steroidogenesis, and an up to 2-fold increase in testosterone levels and 2.5-fold increase in estradiol levels.<ref name="pmid9592622">{{cite journal | vauthors = Mahler C, Verhelst J, Denis L | title = Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer | journal = Clinical Pharmacokinetics | volume = 34 | issue = 5 | pages = 405–17 | date = May 1998 | pmid = 9592622 | doi = 10.2165/00003088-199834050-00005 | s2cid = 25200595 }}</ref> Conversely, AR antagonists that are also progestogens, like cyproterone acetate, are not progonadotropic, as activation of the PR is antigonadotropic and preserves negative feedback on the HPG axis, and these medications are indeed potently antigonadotropic in clinical practice.<ref name="pmid11121992" />

Although spironolactone is an AR antagonist with no significant progestogenic effects in women even at high dosages and hence is a pure-like AR antagonist, many studies have not found it to be progonadotropic in men, nor to increase testosterone or estradiol levels.<ref name="pmid984618"/><ref name="Melmed2016">{{cite book|author=Shlomo Melmed|title=Williams Textbook of Endocrinology|url=https://books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA626|year=2016|publisher=Elsevier Health Sciences|isbn=978-0-323-29738-7|pages=626–}}</ref><ref name="pmid1176584">{{cite journal | vauthors = Stripp B, Taylor AA, Bartter FC, Gillette JR, Loriaux DL, Easley R, Menard RH | title = Effect of spironolactone on sex hormones in man | journal = J. Clin. Endocrinol. Metab. | volume = 41 | issue = 4 | pages = 777–81 | year = 1975 | pmid = 1176584 | doi = 10.1210/jcem-41-4-777 }}</ref> 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,<ref name="Becker2001">{{cite book|author=Kenneth L. Becker|title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1196|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=708, 777, 1087, 1196|quote=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}}</ref><ref name="Drapier-FaureFaure2006">{{cite book|last1=Drapier-Faure|first1=Evelyne|last2=Faure|first2=Michel|title=Hidradenitis Suppurativa |chapter=Antiandrogens |year=2006|pages=124–127|doi=10.1007/978-3-540-33101-8_16|isbn=978-3-540-33100-1}}</ref> although some conflicting reports exist.<ref name="CarrellPeterson2010">{{cite book|author1=Douglas T. Carrell|author2=C. Matthew Peterson|title=Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice|url=https://books.google.com/books?id=lcBEheiufVcC&pg=PA162|date=23 March 2010|publisher=Springer Science & Business Media|isbn=978-1-4419-1436-1|pages=162–|quote=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.}}</ref><ref>{{cite book|title=Israel Journal of Medical Sciences|url=https://books.google.com/books?id=sMNYAAAAYAAJ|date=July 1984|publisher=Israel Medical Association, National Council for Research and Development.}}</ref><ref name="Shapiro2012">{{cite book|author=Jerry Shapiro|title=Hair Disorders: Current Concepts in Pathophysiology, Diagnosis and Management, An Issue of Dermatologic Clinics|url=https://books.google.com/books?id=9rLeICotHEoC&pg=PT186|date=12 November 2012|publisher=Elsevier Health Sciences|isbn=978-1-4557-7169-1|pages=186–}}</ref> Nonetheless, since spironolactone does not generally increase gonadotropin levels in spite of inhibition of androgen signaling, it must have some degree of antigonadotropic activity sufficient to at least keep the HPG axis from being upregulated.<ref name="pmid11121992" /> 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.<ref name="pmid27072668" />

==Glucocorticoid activity==
Spironolactone weakly binds to and acts as an antagonist of the GR, showing [[Chemistry:Antiglucocorticoid|antiglucocorticoid]] properties, but to a significant degree only at very high concentrations that are probably not clinically relevant.<ref name="pmid20650892"/><ref name="pmid6128090">{{cite journal | vauthors = Campen TJ, Fanestil DD | title = Spironolactone: a glucocorticoid agonist or antagonist? | journal =  Clinical and Experimental Hypertension, Part A | volume = 4 | issue = 9–10 | pages = 1627–36 | year = 1982 | pmid = 6128090 | doi = 10.3109/10641968209061629}}</ref><ref name="pmid1309341">{{cite journal | vauthors = Couette B, Marsaud V, Baulieu EE, Richard-Foy H, Rafestin-Oblin ME | title = Spironolactone, an aldosterone antagonist, acts as an antiglucocorticosteroid on the mouse mammary tumor virus promoter | journal = Endocrinology | volume = 130 | issue = 1 | pages = 430–6 | year = 1992 | pmid = 1309341 | doi = 10.1210/endo.130.1.1309341 }}</ref>

Most studies have found that spironolactone has no effect on [[Chemistry:Cortisol|cortisol]] levels.<ref name="pmid8144871" /> However, some studies have observed increased cortisol levels with spironolactone treatment.<ref name="pmid9745451">{{cite journal | vauthors = Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H | title = The role of mineralocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation in humans | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 83 | issue = 9 | pages = 3339–45 | date = September 1998 | pmid = 9745451 | doi = 10.1210/jcem.83.9.5077 | url = http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=9745451 | doi-access = free }}{{Dead link|date=October 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="pmid17035932">{{cite journal | vauthors = Otte C, Moritz S, Yassouridis A, etal | title = Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition | journal = Neuropsychopharmacology | volume = 32 | issue = 1 | pages = 232–8 | date = January 2007 | pmid = 17035932 | doi = 10.1038/sj.npp.1301217 | s2cid = 10624783 | doi-access = free }}</ref> It is thought that this is due to the antimineralocorticoid activity of spironolactone, which prevents [[Negative feedback|negative feedback]] of [[Chemistry:Mineralocorticoid|mineralocorticoid]]s like [[Chemistry:Aldosterone|aldosterone]] on the [[Medicine:Hypothalamic–pituitary–adrenal axis|hypothalamic–pituitary–adrenal axis]] (HPA axis), and thereby upregulates [[Biology:Adrenocorticotropic hormone|adrenocorticotropic hormone]] (ACTH) and adrenal gland [[Biology:Biosynthesis|synthesis]] of [[Biology:Corticosteroid|corticosteroid]]s such as cortisol and aldosterone.<ref name="pmid9745451" /><ref name="pmid17035932" /> Although spironolactone usually doesn't affect cortisol levels, it does significantly increase concentrations of aldosterone.<ref name="pmid10495361">{{cite journal | vauthors = Diamanti-Kandarakis E | title = Current aspects of antiandrogen therapy in women | journal = Curr. Pharm. Des. | volume = 5 | issue = 9 | pages = 707–23 | date = September 1999 | doi = 10.2174/1381612805666230111201150 | pmid = 10495361 | url = https://books.google.com/books?id=9rfNZL6oEO0C&pg=PA707}}</ref>

Spironolactone has been shown to weakly inhibit 11β-hydroxylase ''[[In vitro|in vitro]]''.<ref name="pmid976190">{{cite journal | vauthors = Cheng SC, Suzuki K, Sadee W, Harding BW | title = Effects of spironolactone, canrenone and canrenoate-K on cytochrome P450, and 11beta- and 18-hydroxylation in bovine and human adrenal cortical mitochondria | journal = Endocrinology | volume = 99 | issue = 4 | pages = 1097–106 | date = October 1976 | pmid = 976190 | doi = 10.1210/endo-99-4-1097 }}</ref><ref name="pmid311283">{{cite journal | vauthors = Greiner JW, Rumbaugh RC, Kramer RE, Colby HD | title = Relation of canrenone to the actions of spironolactone on adrenal cytochrome P-450 dependent enzymes | journal = Endocrinology | volume = 103 | issue = 4 | pages = 1313–20 | date = October 1978 | pmid = 311283 | doi = 10.1210/endo-103-4-1313 | doi-access = free }}</ref> This enzyme is responsible for the transformation of 11-deoxycorticosterone into [[Chemistry:Corticosterone|corticosterone]] and of 11-deoxycortisol into [[Chemistry:Cortisol|cortisol]].<ref name="Becker2001" /> The clinical significance of this action, if any, is unclear.<ref name="pmid976190" /><ref name="pmid311283" /><ref name="Becker2001" /> Spironolactone notably does not decrease cortisol or aldosterone levels.<ref name="pmid8144871" /><ref name="pmid10495361" />

==Other activities==
Spironolactone is an [[Biology:Agonist|agonist]] of the [[Biology:Pregnane X receptor|pregnane X receptor]] (PXR), a [[Biology:Xenobiotic-sensing receptor|xenobiotic-sensing receptor]].<ref name="pmid9727070" /><ref name="pmid9855641">{{cite journal | vauthors = Schuetz EG, Brimer C, Schuetz JD | title = Environmental xenobiotics and the antihormones cyproterone acetate and spironolactone use the nuclear hormone pregnenolone X receptor to activate the CYP3A23 hormone response element | journal = Mol. Pharmacol. | volume = 54 | issue = 6 | pages = 1113–7 | date = December 1998 | pmid = 9855641 | pmc = 3662300 | doi = 10.1124/mol.54.6.1113}}</ref><ref name="pmid21459122">{{cite journal | vauthors = Rigalli JP, Ruiz ML, Perdomo VG, Villanueva SS, Mottino AD, Catania VA | title = Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells | journal = Toxicology | volume = 285 | issue = 1–2 | pages = 18–24 | date = July 2011 | pmid = 21459122 | doi = 10.1016/j.tox.2011.03.015 }}</ref> By activating the PXR, spironolactone [[Biology:Enzyme inducer|induce]]s the [[Biology:Gene expression|expression]] of [[Biology:Cytochrome P450|cytochrome P450]] [[Biology:CYP3A|CYP3A]] [[Biology:Enzyme|enzyme]]s and of the [[Biology:ATP-binding cassette transporter|ATP-binding cassette transporter]] (ABC transporters) [[Biology:P-glycoprotein|P-glycoprotein]] (multidrug resistance protein 1; MRP1; ABCB1) and multidrug resistance protein 2 (MRP2; ABCC2).<ref name="pmid9727070" /><ref name="pmid9855641" /><ref name="pmid21459122" /><ref name="pmid7628309">{{cite journal | vauthors = Kocarek TA, Schuetz EG, Strom SC, Fisher RA, Guzelian PS | title = Comparative analysis of cytochrome P4503A induction in primary cultures of rat, rabbit, and human hepatocytes | journal = Drug Metab. Dispos. | volume = 23 | issue = 3 | pages = 415–21 | date = March 1995 | pmid = 7628309 }}</ref><ref name="pmid9890159" /><ref name="pmid16740618">{{cite journal | vauthors = Ghanem CI, Gómez PC, Arana MC, Perassolo M, Delli Carpini G, Luquita MG, Veggi LM, Catania VA, Bengochea LA, Mottino AD | title = Induction of rat intestinal P-glycoprotein by spironolactone and its effect on absorption of orally administered digoxin | journal = J. Pharmacol. Exp. Ther. | volume = 318 | issue = 3 | pages = 1146–52 | date = September 2006 | pmid = 16740618 | doi = 10.1124/jpet.106.105668 | s2cid = 8680890 }}</ref><ref name="pmid15652244">{{cite journal | vauthors = Ruiz ML, Villanueva SS, Luquita MG, Sánchez-Pozzi EJ, Crocenzi FA, Pellegrino JM, Ochoa JE, Vore M, Mottino AD, Catania VA | title = Mechanisms involved in spironolactone-induced choleresis in the rat. Role of multidrug resistance-associated protein 2 | journal = Biochem. Pharmacol. | volume = 69 | issue = 3 | pages = 531–9 | date = February 2005 | pmid = 15652244 | doi = 10.1016/j.bcp.2004.10.017 }}</ref><ref name="pmid19766108">{{cite journal | vauthors = Ruiz ML, Villanueva SS, Luquita MG, Pellegrino JM, Rigalli JP, Arias A, Sánchez Pozzi EJ, Mottino AD, Catania VA | title = Induction of intestinal multidrug resistance-associated protein 2 (Mrp2) by spironolactone in rats | journal = Eur. J. Pharmacol. | volume = 623 | issue = 1–3 | pages = 103–6 | date = November 2009 | pmid = 19766108 | doi = 10.1016/j.ejphar.2009.09.014 }}</ref><ref name="pmid16863430" /> These [[Biology:Protein|protein]]s are involved in the [[Biology:Metabolism|metabolism]] and [[Biology:Elimination (pharmacology)|elimination]] of [[Biology:Xenobiotic|xenobiotic]]s, and as a result, their induction by spironolactone may contribute to [[Medicine:Drug interaction|drug interaction]]s of spironolactone.<ref name="pmid9727070" /><ref name="pmid9855641" /><ref name="pmid21459122" /> Examples of such interactions include [[Medicine:Oral administration|oral]] [[Chemistry:Digoxin|digoxin]] and [[Chemistry:Estradiol (medication)|estradiol]].<ref name="pmid16740618" /><ref name="pmid29756046" />

There is evidence that spironolactone may block voltage-dependent Ca<sup>2+</sup> channels.<ref name="pmid10942165">{{cite journal | vauthors = Sorrentino R, Autore G, Cirino G, d'Emmanuele de Villa Bianca R, Calignano A, Vanasia M, etal | title = Effect of spironolactone and its metabolites on contractile property of isolated rat aorta rings. | journal = J Cardiovasc Pharmacol | year = 2000 | volume = 36 | issue = 2 | pages = 230–235 | doi = 10.1097/00005344-200008000-00013 | pmid = 10942165 | doi-access = free }}</ref><ref name="BendtzenHansen2003">{{cite journal | last1 = Bendtzen | first1 = K. | last2 = Hansen | first2 = P. R. | last3 = Rieneck | first3 = K. | title = Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis | journal = Clinical and Experimental Immunology | volume = 134 | issue = 1 | pages = 151–158 | year = 2003 | issn = 0009-9104 | doi = 10.1046/j.1365-2249.2003.02249.x| pmid = 12974768 | pmc = 1808828 }}</ref> It has also been found to block [[Biology:Voltage-gated potassium channel|voltage-gated potassium (K<sup>+</sup>) channel]]s.<ref name="GómezNúñez2005">{{cite journal|last1=Gómez|first1=Ricardo|last2=Núñez|first2=Lucía|last3=Caballero|first3=Ricardo|last4=Vaquero|first4=Miguel|last5=Tamargo|first5=Juan|last6=Delpón|first6=Eva|title=Spironolactone and its main metabolite canrenoic acid block hKv1.5, Kv4.3 and Kv7.1+minK channels|journal=British Journal of Pharmacology|volume=146|issue=1|year=2005|pages=146–161|issn=0007-1188|doi=10.1038/sj.bjp.0706302|pmid=15980874|pmc=1576250}}</ref>

Spironolactone has been identified as an inhibitor of NRG1‐ERBB4 signaling.<ref name="pmid28743784">{{cite journal | vauthors = Wehr MC, Hinrichs W, Brzózka MM, Unterbarnscheidt T, Herholt A, Wintgens JP, Papiol S, Soto-Bernardini MC, Kravchenko M, Zhang M, Nave KA, Wichert SP, Falkai P, Zhang W, Schwab MH, Rossner MJ | title = Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice | journal = EMBO Mol Med | volume = 9 | issue = 10 | pages = 1448–1462 | date = October 2017 | pmid = 28743784 | pmc = 5653977 | doi = 10.15252/emmm.201707691 }}</ref>

Spironolactone has been found to act as a potent inhibitor of the pannexin 1 channel, and this action appears to be involved in its antihypertensive effects independently of MR antagonism.<ref name="GoodChiu2018">{{cite journal|last1=Good|first1=Miranda E.|last2=Chiu|first2=Yu-Hsin|last3=Poon|first3=Ivan K.H.|last4=Medina|first4=Christopher B.|last5=Butcher|first5=Joshua T.|last6=Mendu|first6=Suresh K.|last7=DeLalio|first7=Leon J.|last8=Lohman|first8=Alexander W.|last9=Leitinger|first9=Norbert|last10=Barrett|first10=Eugene|last11=Lorenz|first11=Ulrike M.|last12=Desai|first12=Bimal N.|last13=Jaffe|first13=Iris Z.|last14=Bayliss|first14=Douglas A.|last15=Isakson|first15=Brant E.|last16=Ravichandran|first16=Kodi S.|title=Pannexin 1 Channels as an Unexpected New Target of the Anti-Hypertensive Drug Spironolactone|journal=Circulation Research|volume=122|issue=4|year=2018|pages=606–615|issn=0009-7330|doi=10.1161/CIRCRESAHA.117.312380|pmid=29237722|pmc=5815904}}</ref>

Spironolactone has been found to block [[Biology:HERG|hERG]] channels.<ref name="CaballeroMoreno2003">{{cite journal|last1=Caballero|first1=Ricardo|last2=Moreno|first2=Ignacio|last3=González|first3=Teresa|last4=Arias|first4=Cristina|last5=Valenzuela|first5=Carmen|last6=Delpón|first6=Eva|last7=Tamargo|first7=Juan|title=Spironolactone and Its Main Metabolite, Canrenoic Acid, Block Human Ether-a-Go-Go–Related Gene Channels|journal=Circulation|volume=107|issue=6|year=2003|pages=889–895|issn=0009-7322|doi=10.1161/01.CIR.0000048189.58449.F7|pmid=12591761|s2cid=24556181|hdl=10261/24675|hdl-access=free}}</ref>

==Hormone levels==
A 2 sysreview of 18&nbsp;studies found that spironolactone shows no significant effects on levels of [[Biology:Estrogen|estrogen]], [[Chemistry:Estradiol|estradiol]], [[Chemistry:Testosterone|testosterone]], androstened, dehydroep sulfate, [[Biology:Luteinizing hormone|luteinizing hormone]], or [[Biology:Follicle-stimulating hormone|follicle-stimulating hormone]] in women.<ref name="pmid30467659">{{cite journal | vauthors = Rozner RN, Freites-Martinez A, Shapiro J, Geer EB, Goldfarb S, Lacouture ME | title = Safety of 5α-reductase inhibitors and spironolactone in breast cancer patients receiving endocrine therapies | journal = Breast Cancer Res. Treat. | volume = 174| issue = 1| pages = 15–26| date = November 2018 | pmid = 30467659 | pmc = 6773272 | doi = 10.1007/s10549-018-4996-3 }}</ref> A 2017 hybrid systematic review reported that data from 50&nbsp;studies on androgen levels with spironolactone in women were equivocal.<ref name="pmid28155090" /> A 1993 review reported that changes in hormone levels with spironolactone were very heterogeneous, with most changes not achieving significance.<ref name="pmid8144871" /> Levels of cortisol were unchanged in all studies (four total) and levels of dehydroepiandrosterone sulfate were unchanged in all but one of seven studies.<ref name="pmid8144871" /> However, it was reported that testosterone levels were decreased in 81% of the studies (13 of 16).<ref name="pmid8144871" /> However, neither of the two placebo-controlled trials in the review found a significant difference in testosterone levels between the placebo and treatment groups.<ref name="pmid8144871" /> A 1991 review reported that the influences of spironolactone on androgen levels in women were variable and inconsistent.<ref name="pmid1826112" />

Spironolactone has shown no significant effect on levels of testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone in men.<ref name="pmid8094898">{{cite journal | vauthors = Thompson DF, Carter JR | title = Drug-induced gynecomastia | journal = Pharmacotherapy | volume = 13 | issue = 1 | pages = 37–45 | date = 1993 | pmid = 8094898 | doi = 10.1002/j.1875-9114.1993.tb02688.x | s2cid = 30322620 }}</ref><ref name="pmid1826112" />

No or only small changes in cortisol levels have been observed in clinical studies with spironolactone.<ref name="pmid30477405">{{cite journal | vauthors = Dhondt B, Buelens S, Van Besien J, Beysens M, De Bleser E, Ost P, Lumen N | title = Abiraterone and spironolactone in prostate cancer: a combination to avoid | journal = Acta Clin Belg | volume = 74| issue = 6| pages = 439–444 | date = November 2018 | pmid = 30477405 | doi = 10.1080/17843286.2018.1543827 | hdl = 1854/LU-8582726 | s2cid = 53738534 }}</ref><ref name="pmid628197">{{cite journal | vauthors = Abshagen U, Spörl S, L'age M | title = Non-interaction of spironolactone medication and cortisol metabolism in man | journal = Klin. Wochenschr. | volume = 56 | issue = 3 | pages = 135–8 | date = February 1978 | pmid = 628197 | doi = 10.1007/BF01478568 | s2cid = 30885047 }}</ref><ref name="pmid642407">{{cite journal | vauthors = Abshagen U, Spörl S, Schöneshöfer M, L'age M, Oelkers W | title = Interference of spironolactone therapy with adrenal steroid metabolism in secondary hyperaldosteronism | journal = Klin. Wochenschr. | volume = 56 | issue = 7 | pages = 341–9 | date = April 1978 | pmid = 642407 | doi = 10.1007/BF01477394 | s2cid = 40979545 }}</ref><ref name="pmid6386025">{{cite journal | vauthors = Millar JA, Fraser R, Mason P, Leckie B, Cumming AM, Robertson JI | title = Metabolic effects of high dose amiloride and spironolactone: a comparative study in normal subjects | journal = Br J Clin Pharmacol | volume = 18 | issue = 3 | pages = 369–75 | date = September 1984 | pmid = 6386025 | pmc = 1463638 | doi = 10.1111/j.1365-2125.1984.tb02478.x }}</ref><ref name="pmid423483">{{cite journal | vauthors = Abshagen U, Spörl S, Oelkers W | title = Influence of spironolactone on serum corticosteroids in primary hyperaldosteronism | journal = Klin. Wochenschr. | volume = 57 | issue = 4 | pages = 173–80 | date = February 1979 | pmid = 423483 | doi = 10.1007/BF01477405 | s2cid = 39169638 }}</ref><ref name="pmid21095280">{{cite journal | vauthors = Yamaji M, Tsutamoto T, Kawahara C, Nishiyama K, Yamamoto T, Fujii M, Horie M | title = Effect of eplerenone versus spironolactone on cortisol and hemoglobin A₁(c) levels in patients with chronic heart failure | journal = Am. Heart J. | volume = 160 | issue = 5 | pages = 915–21 | date = November 2010 | pmid = 21095280 | doi = 10.1016/j.ahj.2010.04.024 }}</ref>

The influence of canrenoate potassium on cortisol levels has been studied.<ref name="pmid12364444">{{cite journal | vauthors = Grottoli S, Giordano R, Maccagno B, Pellegrino M, Ghigo E, Arvat E | title = The stimulatory effect of canrenoate, a mineralocorticoid antagonist, on the activity of the hypothalamus-pituitary-adrenal axis is abolished by alprazolam, a benzodiazepine, in humans | journal = J. Clin. Endocrinol. Metab. | volume = 87 | issue = 10 | pages = 4616–20 | date = October 2002 | pmid = 12364444 | doi = 10.1210/jc.2002-020331 | doi-access = free }}</ref><ref name="pmid11443185">{{cite journal | vauthors = Arvat E, Maccagno B, Giordano R, Pellegrino M, Broglio F, Gianotti L, Maccario M, Camanni F, Ghigo E | title = Mineralocorticoid receptor blockade by canrenoate increases both spontaneous and stimulated adrenal function in humans | journal = J. Clin. Endocrinol. Metab. | volume = 86 | issue = 7 | pages = 3176–81 | date = July 2001 | pmid = 11443185 | doi = 10.1210/jcem.86.7.7663 | s2cid = 18906508 | doi-access = free }}</ref><ref name="pmid15472204">{{cite journal | vauthors = Wellhoener P, Born J, Fehm HL, Dodt C | title = Elevated resting and exercise-induced cortisol levels after mineralocorticoid receptor blockade with canrenoate in healthy humans | journal = J. Clin. Endocrinol. Metab. | volume = 89 | issue = 10 | pages = 5048–52 | date = October 2004 | pmid = 15472204 | doi = 10.1210/jc.2004-0086 | s2cid = 9856650 | doi-access = free }}</ref><ref name="pmid8115025">{{cite journal | vauthors = Dodt C, Kern W, Fehm HL, Born J | title = Antimineralocorticoid canrenoate enhances secretory activity of the hypothalamus-pituitary-adrenocortical (HPA) axis in humans | journal = Neuroendocrinology | volume = 58 | issue = 5 | pages = 570–4 | date = November 1993 | pmid = 8115025 | doi = 10.1159/000126592 }}</ref><ref name="pmid24423282">{{cite journal | vauthors = Iqbal J, Andrew R, Cruden NL, Kenyon CJ, Hughes KA, Newby DE, Hadoke PW, Walker BR | title = Displacement of cortisol from human heart by acute administration of a mineralocorticoid receptor antagonist | journal = J. Clin. Endocrinol. Metab. | volume = 99 | issue = 3 | pages = 915–22 | date = March 2014 | pmid = 24423282 | pmc = 4392799 | doi = 10.1210/jc.2013-2049 }}</ref><ref name="pmid9100581">{{cite journal | vauthors = Born J, Steinbach D, Dodt C, Fehm HL | title = Blocking of central nervous mineralocorticoid receptors counteracts inhibition of pituitary-adrenal activity in human sleep | journal = J. Clin. Endocrinol. Metab. | volume = 82 | issue = 4 | pages = 1106–10 | date = April 1997 | pmid = 9100581 | doi = 10.1210/jcem.82.4.3856 | doi-access = free }}</ref>

Spironolactone has no influence on sex hormone-binding globulin levels in women or men.<ref name="YoungGoldzieher1987">{{cite journal|last1=Young|first1=Ronald L.|last2=Goldzieher|first2=Joseph W.|last3=Elkind-Hirsch|first3=Karen|title=The endocrine effects of spironolactone used as an antiandrogen|journal=Fertility and Sterility|volume=48|issue=2|year=1987|pages=223–228|issn=0015-0282|doi=10.1016/S0015-0282(16)59346-7|pmid=2956130}}</ref><ref name="GoodfellowAlaghband-Zadeh1984"/>

==References==
{{Reflist}}

{{Spironolactone}}
{{Androgens and antiandrogens}}
{{Mineralocorticoids and antimineralocorticoids}}
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[[Category:Spironolactone]]

{{Sourceattribution|Pharmacodynamics of spironolactone}}