View source for Spironolactone

{{Short description|Steroidal antiandrogen and antimineralocorticoid}}
{{Distinguish|Spirolactone}}
{{Use dmy dates|date=October 2025}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 470470172
| image = Spironolacton.svg
| image_class = skin-invert-image
| alt = Skeletal formula of spironolactone
| width = 235
| image2 = Spironolactone 3D ball.png
| image_class2 = bg-transparent
| alt2 = Ball-and-stick model of the spironolactone molecule
| width2 = 225

<!-- Clinical data -->
| pronounce = {{IPAc-en|ˌ|s|p|aɪ|r|oʊ|n|oʊ|ˈ|l|æ|k|t|oʊ|n}} {{respell|SPY|roh|noh|LAK|tone}},<ref name="LoughlinGenerali2006">{{cite book|vauthors=Loughlin KR, Generali JA|title=The Guide to Off-label Prescription Drugs: New Uses for FDA-approved Prescription Drugs|url=https://books.google.com/books?id=fhEFkBxEtH8C&pg=PA131|year=2006|publisher=Simon and Schuster|isbn=978-0-7432-8667-1|pages=131–|access-date=6 November 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007092256/https://books.google.com/books?id=fhEFkBxEtH8C&pg=PA131|url-status=live}}</ref> {{IPAc-en|ˌ|s|p|ɪər|oʊ|n|oʊ|ˈ|l|æ|k|t|oʊ|n|audio=LL-Q1860 (eng)-NaomiAmethyst-spironolactone.wav}} {{respell|SPEER|oh|noh|LAK|tone}}<ref name="ClarkHarvey2011">{{cite book|vauthors=Clark MA, Harvey RA, Finkel R, Rey JA, Whalen K|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|access-date=6 November 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007092256/https://books.google.com/books?id=Y558dgp_PjoC&pg=PA337|url-status=live}}</ref>
| tradename = Aldactone, others
| Drugs.com = {{drugs.com|monograph|spironolactone}}
| MedlinePlus = a682627
| DailyMedID = Spironolactone
| pregnancy_AU = B3
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web|title=Spironolactone Pregnancy and Breastfeeding Warnings|url=https://www.drugs.com/pregnancy/spironolactone.html|publisher=The American Society of Health-System Pharmacists|access-date=29 November 2015|url-status=live|archive-url=https://web.archive.org/web/20151202081203/http://www.drugs.com/pregnancy/spironolactone.html|archive-date=2 December 2015}}</ref>
| pregnancy_category =
| routes_of_administration = [[Oral administration|By mouth]],<ref name=AHFS2015 /> [[Topical administration|topical]]<ref name="FARIDDiamanti-Kandarakis2009" />
| class = [[Antimineralocorticoid]]; [[Steroidal antiandrogen]]
| ATC_prefix = C03
| ATC_suffix = DA01
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Aldactone 25 mg Film-Coated TabletsSummary of Product Characteristics (SmPC) | website=(emc) | date=3 February 2022 | url=https://www.medicines.org.uk/emc/product/1619/smpc | access-date=2 August 2023 | archive-date=6 October 2022 | archive-url=https://web.archive.org/web/20221006131733/https://www.medicines.org.uk/emc/product/1619/smpc | url-status=live }}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref name="Aldactone label" />
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Qaialdo EPAR">{{cite web | title=Qaialdo EPAR | website=[[European Medicines Agency]] (EMA) | date=25 July 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/qaialdo | access-date=2 August 2023 | archive-date=27 July 2023 | archive-url=https://web.archive.org/web/20230727164314/https://www.ema.europa.eu/en/medicines/human/EPAR/qaialdo | url-status=live }}</ref><ref>{{cite web | title=Qaialdo | website=Union Register of medicinal products | date=31 May 2023 | url=https://ec.europa.eu/health/documents/community-register/html/h1731.htm | access-date=6 June 2023 | archive-date=6 June 2023 | archive-url=https://web.archive.org/web/20230606224550/https://ec.europa.eu/health/documents/community-register/html/h1731.htm | url-status=live }}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability = 60–90%<ref name="pmid15947888"/><ref name="pmid18729003">{{cite journal | vauthors = Maron BA, Leopold JA | title = Mineralocorticoid receptor antagonists and endothelial function | journal = Current Opinion in Investigational Drugs | volume = 9 | issue = 9 | pages = 963–9 | date = September 2008 | pmid = 18729003 | pmc = 2967484 }}</ref><ref name="CaroneOxberry2017">{{cite journal | vauthors = Carone L, Oxberry SG, Twycross R, Charlesworth S, Mihalyo M, Wilcock A | title = Spironolactone | journal = Journal of Pain and Symptom Management | volume = 53 | issue = 2 | pages = 288–292 | date = February 2017 | pmid = 28024992 | doi = 10.1016/j.jpainsymman.2016.12.320 | doi-access = free | title-link = doi }}</ref>
| protein_bound = Spironolactone: 88% (to [[human serum albumin|albumin]] and {{abbrlink|AGP|alpha-1-acid glycoprotein}})<ref name="TakamuraMaruyama1997"/><br />Canrenone: 99.2% (to albumin)<ref name="TakamuraMaruyama1997" />
| metabolism = [[Liver]], others:<br />• [[Deacetylation]] via {{abbrlink|CES|carboxylesterase}}<br />• ''S''-[[Oxidation|Oxygenation]] via {{abbrlink|FOM|flavin-containing monooxygenase}}<br />• ''S''-[[Methylation]] via {{abbrlink|TMT|thiol S-methyltransferase}}<br />• [[Dethioacetylation]]<br />• [[Hydroxylation]] via [[CYP3A4]]<br />• [[Lactone]] [[hydrolysis]] via [[PON3]]<ref name="pmid15947888"/><ref name="pmid18729003" /><ref name="Parkinson2001" /><ref name="Klaassen2007" /><ref name="pmid7895608" /><ref name="BlackElliott2006" /><ref name="pmid14579013" />
| metabolites = {{abbrlink|7α-TS|7α-Thiospironolactone}}, {{abbrlink|7α-TMS|7α-thiomethylspironolactone}}, {{abbrlink|6β-OH-7α-TMS|6β-hydroxy-7α-thiomethylspironolactone}}, [[canrenone]], others<ref name="pmid15947888"/><ref name="pmid18729003" /><ref name="SzaszBudvari-Barany1990" /><br />(All three active)<ref name="McDonaghGardner2011">{{cite book| vauthors = McDonagh TA, Gardner RS, Clark AL, Dargie H |title=Oxford Textbook of Heart Failure|url=https://books.google.com/books?id=KDDCiTQyGLsC&pg=PA403|date=14 July 2011|publisher=OUP Oxford|isbn=978-0-19-957772-9|pages=403–|url-status=live|archive-url=https://web.archive.org/web/20170327090209/https://books.google.com/books?id=KDDCiTQyGLsC&pg=PA403|archive-date=27 March 2017}}</ref>
| onset =
| elimination_half-life = Spironolactone: 1.4 hrs<ref name="pmid15947888"/><br />{{abbrlink|7α-TMS|7α-thiomethylspironolactone}}: 13.8 hours<ref name="pmid15947888"/><br />{{abbrlink|6β-OH-7α-TMS|6β-hydroxy-7α-thiomethylspironolactone}}: 15.0 hrs<ref name="pmid15947888"/><br />[[Canrenone]]: 16.5 hours<ref name="pmid15947888"/>
| duration_of_action =
| excretion = [[Urine]], [[bile]]<ref name="pmid18729003" />

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 52-01-7
| CAS_supplemental =
| PubChem = 5833
| IUPHAR_ligand = 2875
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00421
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5628
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 27O7W4T232
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00443
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9241
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1393
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = SC-9420; NSC-150339; 7α-Acetylthiospirolactone; 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone

<!-- Chemical and physical data -->
| IUPAC_name = ''S''-[(7''R'',8''R'',9''S'',10''R'',13''S'',14''S'',17''R'')-10,13-Dimethyl-3,5'-dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1''H''-cyclopenta[''a'']phenanthrene-17,2'-oxolane]-7-yl] ethanethioate
| C=24 | H=32 | O=4 | S=1
| SMILES = O=C5O[C@@]4([C@@]3([C@H]([C@@H]2[C@H](SC(=O)C)C/C1=C/C(=O)CC[C@]1(C)[C@H]2CC3)CC4)C)CC5
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C24H32O4S/c1-14(25)29-19-13-15-12-16(26)4-8-22(15,2)17-5-9-23(3)18(21(17)19)6-10-24(23)11-7-20(27)28-24/h12,17-19,21H,4-11,13H2,1-3H3/t17-,18-,19+,21+,22-,23-,24+/m0/s1
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = LXMSZDCAJNLERA-ZHYRCANASA-N
| density =
| density_notes =
| melting_point = 134
| melting_high = 135
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}

[[File:Spironolacton - 25 mg überzogene Tabletten - Verpackung für Deutschland - Tabletten mit Verpackung.jpg|thumb|Spironolactone 25 mg]]
<!-- Definition and medical uses -->
'''Spironolactone''', sold under the brand name '''Aldactone''' among others, is classed as a [[diuretic]] [[medication]].<ref>{{Cite web |title=Australian Medicines Handbook |url=https://amhonline.amh.net.au/auth |access-date=12 May 2025 |website=amhonline.amh.net.au}}</ref> It can be used to treat [[edema|fluid build-up]] due to  [[hepatic cirrhosis|liver disease]] or [[kidney disease]].<ref name=AHFS2015>{{cite web|title=Spironolactone|url=https://www.drugs.com/monograph/spironolactone.html|publisher=The American Society of Health-System Pharmacists|access-date=24 October 2015|url-status=live|archive-url=https://web.archive.org/web/20151116054857/http://www.drugs.com/monograph/spironolactone.html|archive-date=16 November 2015}}</ref> It is also used to reduce risk of disease progression, hospitalization, and death due to some types of heart failure.<ref name=":0"/><ref>{{cite journal | vauthors = Li S, Zhang X, Dong M, Gong S, Shang Z, Jia X, Chen W, Yang J, Li J | title = Effects of spironolactone in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials | language = en-US | journal = Medicine | volume = 97 | issue = 35 | article-number = e11942 | date = August 2018 | pmid = 30170387 | pmc = 6392615 | doi = 10.1097/MD.0000000000011942 }}</ref> Other uses include acne and excessive hair growth in women, [[hypokalemia|low blood potassium]] that does not improve with [[Potassium#Supplementation|supplementation]], high blood pressure that is difficult to treat, and early puberty in boys.<ref name=AHFS2015/><ref>{{cite journal | vauthors = Friedman AJ | title = Spironolactone for Adult Female Acne | journal = Cutis | volume = 96 | issue = 4 | pages = 216–217 | date = October 2015 | pmid = 27141564 }}</ref><ref>{{cite book| vauthors = Maizes V |title=Integrative Women's Health|date=2015|isbn=978-0-19-021480-7|page=746|publisher=Oxford University Press |edition=2|url=https://books.google.com/books?id=uveJCgAAQBAJ&pg=PA746}}</ref><ref>{{cite journal | vauthors = Sinnott SJ, Tomlinson LA, Root AA, Mathur R, Mansfield KE, Smeeth L, Douglas IJ | title = Comparative effectiveness of fourth-line antihypertensive agents in resistant hypertension: A systematic review and meta-analysis | journal = European Journal of Preventive Cardiology | volume = 24 | issue = 3 | pages = 228–238 | date = February 2017 | pmid = 27856806 | doi = 10.1177/2047487316675194 | url = https://researchonline.lshtm.ac.uk/id/eprint/3157879/1/Comparative%20effectiveness%20of%204th%20line%20anti-hypertensive%20agents%20in%20resistant%20hypertension%3B%20A%20systematic%20review%20and%20meta-analysis%20.pdf }}</ref> It can also be used to block the effects of [[testosterone]] as a part of [[feminizing hormone therapy]].<ref name="WPATH2011" /> Spironolactone is usually available in tablets, taken [[oral administration|by mouth]], though topical forms are also available.<ref name=AHFS2015/>

<!-- Side effects and mechanism -->
Common [[side effect]]s include [[electrolyte abnormalities]], particularly [[hyperkalemia|high blood potassium]], nausea, vomiting, headache, rashes, and a decreased desire for sex.<ref name=AHFS2015/> In those with liver or kidney problems, extra care should be taken.<ref name=AHFS2015/>

If taken during pregnancy, some animal studies suggest that spironolactone may affect the development of sex organs in babies.<ref name="pmid30352280" /> While this has not occurred in the few human studies available,<ref name="pmid30352280" /><ref name="pmid27156905" /><ref>{{cite journal | vauthors = Deng N, Zhong J, Deng Z, Chen M, Yan L, Li H, Han J, Tao E | title = Case report: A pregnant woman accidental treated with spironolactone in mid-gestation | journal = Frontiers in Pharmacology | volume = 15 | article-number = 1404251 | date = 25 July 2024 | pmid = 39119600 | pmc = 11306061 | doi = 10.3389/fphar.2024.1404251 | doi-access = free }}</ref> women who are pregnant or considering pregnancy should discuss spironolactone use with their doctor due to the theoretical risk.<ref name="pmid27156905" />

Spironolactone is a [[steroid]] that [[receptor antagonist|block]]s the effects of the [[hormone]]s [[aldosterone]], and to a lesser degree, testosterone, causing some [[estrogen (medication)|estrogen]]-like effects.<ref name="Burinkul_2021">{{cite journal | vauthors = Burinkul S, Panyakhamlerd K, Suwan A, Tuntiviriyapun P, Wainipitapong S | title = Anti-Androgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial | journal = The Journal of Sexual Medicine | volume = 18 | issue = 7 | pages = 1299–1307 | date = July 2021 | pmid = 34274044 | doi = 10.1016/j.jsxm.2021.05.003 }}</ref>{{Unreliable source?|reason=primary|date=July 2024}}<ref name="Sehgal_2023">{{cite journal | vauthors = Sehgal I | title = Review of adult gender transition medications: mechanisms, efficacy measures, and pharmacogenomic considerations | journal = Frontiers in Endocrinology | volume = 14 | issue = | article-number = 1184024 | date = 2023 | pmid = 37476490 | pmc = 10355117 | doi = 10.3389/fendo.2023.1184024 | doi-access = free }}</ref><ref name="ineffectiveness in HRT">{{cite web | vauthors = Cosgrove B |title=The Case Against Spironolactone |url=https://moderntranshormones.com/2018/01/01/whats-wrong-with-spironolactone/ |website=Modern Trans Hormones |date=January 2018 |access-date=8 July 2024}}</ref>{{Unreliable medical source|date=July 2024}}<ref name="AHFS2015" /><ref name="Deedwania2014">{{cite book|vauthors=Deedwania PC|title=Drug & Device Selection in Heart Failure|url=https://books.google.com/books?id=k8bUAgAAQBAJ&pg=PA47|date=30 January 2014|publisher=JP Medical Ltd|isbn=978-93-5090-723-8|pages=47–|access-date=5 July 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007092257/https://books.google.com/books?id=k8bUAgAAQBAJ&pg=PA47|url-status=live}}</ref> Spironolactone belongs to a class of medications known as [[potassium-sparing diuretic]]s.<ref name="AHFS2015" />

<!-- History, society, and culture -->
Spironolactone was discovered in 1957, and was introduced in 1959.<ref name="OttowWeinmann2008">{{cite book | vauthors = Ottow E, Weinmann H | 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><ref name="Wermuth2008">{{cite book | vauthors = Wermuth CG | title = The Practice of Medicinal Chemistry | url = https://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34 | access-date = 27 May 2012 | date = 24 July 2008 | publisher = Academic Press | isbn = 978-0-12-374194-3 | page = 34 | url-status = live | archive-url = https://web.archive.org/web/20130621115634/http://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34 | archive-date = 21 June 2013 | author-link = Camille Georges Wermuth }}</ref><ref name="Sittig1988">{{cite book | vauthors = Sittig M | title = Pharmaceutical Manufacturing Encyclopedia | url = https://books.google.com/books?id=XCsJgUnclbcC&pg=PA1385 | access-date = 27 May 2012 | year = 1988 | publisher = William Andrew | isbn = 978-0-8155-1144-1 | page = 1385 | url-status = live | archive-url = https://web.archive.org/web/20130620225714/http://books.google.com/books?id=XCsJgUnclbcC&pg=PA1385 | archive-date = 20 June 2013 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO24th">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines, 2025: WHO Model List of Essential Medicines, 24th list | year = 2025 | hdl = 10665/382243 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | hdl-access = free | doi = 10.2471/B09474 | doi-access = free | id = License: CC BY-NC-SA 3.0 IGO }}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/> In 2023, it was the 52nd most commonly prescribed medication in the United States, with more than 12{{nbsp}}million prescriptions.<ref>{{cite web | title=Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Spironolactone Drug Usage Statistics, United States, 2013 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Spironolactone | access-date = 18 August 2025 }}</ref> Spironolactone has a history of use in the trans community.<ref>{{cite journal | vauthors = Prior JC, Vigna YM, Watson D | title = Spironolactone with Physiological Female Steroids for Presurgical Therapy of Male-To-Female Transsexualism | journal = Archives of Sexual Behavior | volume = 18 | issue = 1 | pages = 49–57 | date = 1989| doi = 10.1007/BF01579291 | pmid = 2540730 }}</ref> Its use continues despite the rise of various accessible alternatives such as [[bicalutamide]] and [[cyproterone acetate]] with more precise action and fewer side effects.<ref name="Burinkul_2021" /><ref name="Sehgal_2023" />
{{TOC limit|3}}

==Medical uses==
Spironolactone is primarily used in the treatment of [[heart failure with reduced ejection fraction]] (HFrEF), where it has demonstrated significant benefits in reducing mortality and hospitalizations when added to standard therapy.<ref>{{cite journal | vauthors = Zannad F, Gattis Stough W, Rossignol P, Bauersachs J, McMurray JJ, Swedberg K, Struthers AD, Voors AA, Ruilope LM, Bakris GL, O'Connor CM, Gheorghiade M, Mentz RJ, Cohen-Solal A, Maggioni AP, Beygui F, Filippatos GS, Massy ZA, Pathak A, Piña IL, Sabbah HN, Sica DA, Tavazzi L, Pitt B | title = Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice | journal = European Heart Journal | volume = 33 | issue = 22 | pages = 2782–2795 | date = November 2012 | pmid = 22942339 | doi = 10.1093/eurheartj/ehs257 }}</ref><ref>{{cite journal | vauthors = Berbenetz NM, Mrkobrada M | title = Mineralocorticoid receptor antagonists for heart failure: systematic review and meta-analysis | journal = BMC Cardiovascular Disorders | volume = 16 | issue = 1 | article-number = 246 | date = December 2016 | pmid = 27905877 | pmc = 5134129 | doi = 10.1186/s12872-016-0425-x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bayoumi E, Lam PH, Dooley DJ, Singh S, Faselis C, Morgan CJ, Patel S, Sheriff HM, Mohammed SF, Palant CE, Pitt B, Fonarow GC, Ahmed A | title = Spironolactone and Outcomes in Older Patients with Heart Failure and Reduced Ejection Fraction | journal = The American Journal of Medicine | volume = 132 | issue = 1 | pages = 71–80.e1 | date = January 2019 | pmid = 30240686 | pmc = 6511886 | doi = 10.1016/j.amjmed.2018.09.011 }}</ref>

Multiple studies show that spironolactone improves left ventricular diastolic function and reduces heart failure hospitalisations in patients with heart failure with preserved ejection fraction (HFpEF), though without benefits in all-cause death or overall hospitalisation rates.<ref>{{cite journal | vauthors = Li S, Zhang X, Dong M, Gong S, Shang Z, Jia X, Chen W, Yang J, Li J | title = Effects of spironolactone in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials | journal = Medicine | volume = 97 | issue = 35 | article-number = e11942 | date = August 2018 | pmid = 30170387 | doi = 10.1097/md.0000000000011942 | pmc = 6392615 }}</ref> Also, some evidence suggests spironolactone may be effective in HFpEF with resistant hypertension (defined as blood pressure >130/80 mmHg) refractory to an ACE inhibitor/ARB, calcium channel blocker, and diuretic.<ref>{{cite journal | vauthors = Tsujimoto T, Kajio H | title = Spironolactone Use and Improved Outcomes in Patients With Heart Failure With Preserved Ejection Fraction With Resistant Hypertension | journal = Journal of the American Heart Association | volume = 9 | issue = 23 | article-number = e018827 | date = December 2020 | pmid = 33222584 | pmc = 7763779 | doi = 10.1161/JAHA.120.018827 }}</ref>

It is also used to treat [[edema]]tous conditions such as [[nephrotic syndrome]] or [[ascites]] in people with [[liver disease]], essential [[hypertension]], [[hypokalemia|low blood levels of potassium]], [[secondary hyperaldosteronism]] (such as occurs with [[liver cirrhosis]]), and [[Conn's syndrome]] (primary hyperaldosteronism).{{medical citation needed|date=July 2024}} The most common use of spironolactone is in the treatment of heart failure.<ref name="RoncoBellomo2017" /> On its own, spironolactone is only a weak [[diuretic]] because it primarily targets the [[distal nephron]] ([[collecting duct system|collecting tubule]]), where only small amounts of [[sodium]] are reabsorbed, but it can be combined with other diuretics to increase efficacy.{{medical citation needed|date=July 2024}} The classification of spironolactone as a "potassium-sparing diuretic" has been described as obsolete.<ref name="pmid10760075">{{cite journal | vauthors = Delyani JA | title = Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology | journal = Kidney International | volume = 57 | issue = 4 | pages = 1408–1411 | date = April 2000 | pmid = 10760075 | doi = 10.1046/j.1523-1755.2000.00983.x | title-link = doi | doi-access = free }}</ref> Spironolactone is also used to treat [[Bartter's syndrome]] due to its ability to raise potassium levels.<ref name="EndouHosoyamada1995">{{cite book| vauthors = Endou H, Hosoyamada M |title= Diuretics|chapter=Potassium-Retaining Diuretics: Aldosterone Antagonists|volume=117|year=1995|pages=335–361|issn=0171-2004|doi=10.1007/978-3-642-79565-7_9|series=Handbook of Experimental Pharmacology|publisher= Springer|isbn=978-3-642-79567-1}}</ref>

Spironolactone, which has antiandrogenic effects, may help improve acne in adult women, with modest benefits demonstrated in recent clinical trials. Its use is limited by short-term outcome data and minimal reporting of side effects. It is considered a possible alternative to antibiotics for hormonal acne.<ref>{{cite journal | vauthors = Santer M, Lawrence M, Renz S, Eminton Z, Stuart B, Sach TH, Pyne S, Ridd MJ, Francis N, Soulsby I, Thomas K, Permyakova N, Little P, Muller I, Nuttall J, Griffiths G, Thomas KS, Layton AM | title = Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial | journal = BMJ | volume = 381 | article-number = e074349 | date = May 2023 | pmid = 37192767 | pmc = 10543374 | doi = 10.1136/bmj-2022-074349 }}</ref><ref>{{cite journal | vauthors = Kow CS, Ramachandram DS, Hasan SS, Thiruchelvam K | title = Spironolactone for the Treatment of Moderate to Severe Acne in Adult Women: A Systematic Review and Meta-Analysis of Randomised Controlled Trials | journal = The Australasian Journal of Dermatology | volume = 66 | issue = 3 | pages = 165–168 | date = May 2025 | pmid = 39912292 | doi = 10.1111/ajd.14428 }}</ref> It is also used to manage other androgen-related conditions such as hirsutism, seborrhoea, and female pattern hair loss <ref name="pmid2969259">{{cite journal | vauthors = Hughes BR, Cunliffe WJ | title = Tolerance of spironolactone | journal = The British Journal of Dermatology | volume = 118 | issue = 5 | pages = 687–691 | date = May 1988 | pmid = 2969259 | doi = 10.1111/j.1365-2133.1988.tb02571.x | s2cid = 208286107 }}</ref> Spironolactone is used for the treatment of hirsutism in the United States.<ref name="Preedy2012">{{cite book|vauthors=Preedy VR|title=Handbook of Hair in Health and Disease|url=https://books.google.com/books?id=7N3nEX6eL_MC&pg=PA132|date=1 January 2012|publisher=Springer Science & Business Media|isbn=978-90-8686-728-8|pages=132–|access-date=6 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007092258/https://books.google.com/books?id=7N3nEX6eL_MC&pg=PA132|url-status=live}}</ref> High doses of spironolactone, which are needed for considerable antiandrogenic effects, are not recommended for men due to the high risk of [[feminization (biology)|feminization]] and other side effects. Spironolactone can be used to treat [[symptom]]s of [[hyperandrogenism]], such as due to [[polycystic ovary syndrome]].<ref name="pmid3143568">{{cite journal | vauthors = Loy R, Seibel MM | title = Evaluation and therapy of polycystic ovarian syndrome | journal = Endocrinology and Metabolism Clinics of North America | volume = 17 | issue = 4 | pages = 785–813 | date = December 1988 | pmid = 3143568 | doi = 10.1016/S0889-8529(18)30410-9 }}</ref>

===Heart failure===
Although [[loop diuretics]] help to treat acute symptoms of heart failure,<ref>{{cite journal | vauthors = Matsue Y, Damman K, Voors AA, Kagiyama N, Yamaguchi T, Kuroda S, Okumura T, Kida K, Mizuno A, Oishi S, Inuzuka Y, Akiyama E, Matsukawa R, Kato K, Suzuki S, Naruke T, Yoshioka K, Miyoshi T, Baba Y, Yamamoto M, Murai K, Mizutani K, Yoshida K, Kitai T | title = Time-to-Furosemide Treatment and Mortality in Patients Hospitalized With Acute Heart Failure | journal = Journal of the American College of Cardiology | volume = 69 | issue = 25 | pages = 3042–3051 | date = June 2017 | pmid = 28641794 | doi = 10.1016/j.jacc.2017.04.042 }}</ref> mineralocorticoid receptor antagonist diuretics (such as spironolactone) can be used long-term to reduce mortality and morbidity associated with certain types of chronic heart failure.<ref name=":0">{{cite journal | vauthors = Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J | title = The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators | journal = The New England Journal of Medicine | volume = 341 | issue = 10 | pages = 709–717 | date = September 1999 | pmid = 10471456 | doi = 10.1056/NEJM199909023411001 }}</ref><ref>{{cite journal | vauthors = Burnett H, Earley A, Voors AA, Senni M, McMurray JJ, Deschaseaux C, Cope S | title = Thirty Years of Evidence on the Efficacy of Drug Treatments for Chronic Heart Failure With Reduced Ejection Fraction: A Network Meta-Analysis | journal = Circulation: Heart Failure | volume = 10 | issue = 1 | article-number = e003529 | date = January 2017 | pmid = 28087688 | pmc = 5265698 | doi = 10.1161/CIRCHEARTFAILURE.116.003529 }}</ref> One randomized control trial in 1999 found that the addition of spironolactone to standard therapy reduced all-cause mortality in patients with HF by 30%.<ref name=":0" />  Current recommendations from the [[American Heart Association]] are to use spironolactone in patients with NYHA Class II-IV heart failure who have a left ventricular [[ejection fraction]] of less than 35%.<ref name="Yancy e147-239">{{cite journal | vauthors = Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL | title = 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines | journal = Journal of the American College of Cardiology | volume = 62 | issue = 16 | pages = e147–e239 | date = October 2013 | pmid = 23747642 | doi = 10.1016/j.jacc.2013.05.019 | title-link = doi | doi-access = free }}</ref>

Spironolactone improves left ventricular [[diastolic function]] in patients with [[heart failure with preserved ejection fraction]], but it has no effect on mortality and hospitalization.<ref name="Li_2018">{{cite journal | vauthors = Li S, Zhang X, Dong M, Gong S, Shang Z, Jia X, Chen W, Yang J, Li J | title = Effects of spironolactone in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials | journal = Medicine | volume = 97 | issue = 35 | article-number = e11942 | date = August 2018 | pmid = 30170387 | pmc = 6392615 | doi = 10.1097/MD.0000000000011942 }}</ref><ref name="Kosmas_2018">{{cite journal | vauthors = Kosmas CE, Silverio D, Sourlas A, Montan PD, Guzman E | title = Role of spironolactone in the treatment of heart failure with preserved ejection fraction | journal = Annals of Translational Medicine | volume = 6 | issue = 23 | page = 461 | date = December 2018 | pmid = 30603649 | pmc = 6312809 | doi = 10.21037/atm.2018.11.16 | doi-access = free | title-link = doi }}</ref>

Due to its antiandrogenic properties, spironolactone can cause effects associated with low androgen levels and [[hypogonadism]] in males. For this reason, men are typically not prescribed spironolactone for any longer than a short period of time, e.g., for an acute exacerbation of heart failure. A newer medication, [[eplerenone]], has been approved by the US [[Food and Drug Administration]] (FDA) for the treatment of heart failure, and lacks the antiandrogenic effects of spironolactone. As such, it is far more suitable for men for whom long-term medication is being chosen. While mineralocorticoid receptor antagonist (MRA) as a class (including spironolactone, eplerenone, and canrenone) is likely to be beneficial in heart-failure patients, the precise comparative magnitude of effect on mortality between spironolactone and eplerenone remains subject to some clinical uncertainty, with limited comparative data available for canrenone.<ref name="pmid22840667">{{cite journal | vauthors = Chatterjee S, Moeller C, Shah N, Bolorunduro O, Lichstein E, Moskovits N, Mukherjee D | title = Eplerenone is not superior to older and less expensive aldosterone antagonists | journal = The American Journal of Medicine | volume = 125 | issue = 8 | pages = 817–25 | date = August 2012 | pmid = 22840667 | doi = 10.1016/j.amjmed.2011.12.018 }}</ref><ref>{{cite journal | vauthors = Elshahat A, Mansour A, Ellabban M, Diaa A, Hassan A, Fawzy A, Saad OA, Abouelmagd M, Eid M, Elaraby A, Elkasaby MH, Abdelaziz A | title = Comparative effectiveness and safety of eplerenone and spironolactone in patients with heart failure: a systematic review and meta-analysis | journal = BMC Cardiovascular Disorders | volume = 24 | issue = 1 | article-number = 489 | date = September 2024 | pmid = 39271992 | pmc = 11395778 | doi = 10.1186/s12872-024-04103-7 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Frankenstein L, Seide S, Täger T, Jensen K, Fröhlich H, Clark AL, Seiz M, Katus HA, Nee P, Uhlmann L, Naci H, Atar D | title = Relative Efficacy of Spironolactone, Eplerenone, and cAnRenone in patients with Chronic Heart failure (RESEARCH): a systematic review and network meta-analysis of randomized controlled trials | journal = Heart Failure Reviews | volume = 25 | issue = 2 | pages = 161–171 | date = March 2020 | pmid = 31364027 | doi = 10.1007/s10741-019-09832-y }}</ref>

===High blood pressure===
About one in 100 people with hypertension have elevated levels of aldosterone; in these people, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives since it targets the primary cause of the elevated blood pressure. However, a [[Cochrane review]] found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure.<ref name=Bat2010>{{cite journal | vauthors = Batterink J, Stabler SN, Tejani AM, Fowkes CT | title = Spironolactone for hypertension | journal = The Cochrane Database of Systematic Reviews | issue = 8 | article-number = CD008169 | date = August 2010 | pmid = 20687095 | doi = 10.1002/14651858.CD008169.pub2 }}</ref> There is no evidence of person-oriented outcome at any dose in this group.<ref name=Bat2010/>

===High aldosterone levels===
Spironolactone is used in the treatment of [[hyperaldosteronism]] (high aldosterone levels or mineralocorticoid excess), for instance [[primary aldosteronism]] (Conn's syndrome).<ref name="pmid30854950">{{cite journal | vauthors = Stavropoulos K, Papadopoulos C, Koutsampasopoulos K, Lales G, Mitas C, Doumas M | title = Mineralocorticoid Receptor Antagonists in Primary Aldosteronism | journal = Curr Pharm Des | volume = 24 | issue = 46 | pages = 5508–5516 | date = 2018 | pmid = 30854950 | doi = 10.2174/1381612825666190311130138 | s2cid = 73727928 }}</ref> Antimineralocorticoids including spironolactone and eplerenone are [[first-line treatment]]s for hyperaldosteronism.<ref name="pmid30854950" /> They improve blood pressure and potassium levels, as well as [[left ventricular hypertrophy]], [[albuminuria]], and [[carotid intima-media thickness]], in people with primary aldosteronism.<ref name="pmid30854950" /> In people with hyperaldosteronism due to unilateral aldosterone-producing [[adrenocortical adenoma]], [[adrenalectomy]] should be preferred instead of antimineralocorticoids.<ref name="pmid30854950" /> Spironolactone should not be used to treat primary aldosteronism in pregnancy due to its antiandrogen-related risk of [[teratogen]]icity in male fetuses.<ref name="pmid35536535">{{cite journal | vauthors = Forestiero V, Sconfienza E, Mulatero P, Monticone S | title = Primary aldosteronism in pregnancy | journal = Rev Endocr Metab Disord | volume = 24| issue = 1| pages = 39–48| date = May 2022 | pmid = 35536535 | doi = 10.1007/s11154-022-09729-6 | pmc = 9884655 | s2cid = 248574316 }}</ref><ref name="pmid27156905">{{cite journal | vauthors = Landau E, Amar L | title = Primary aldosteronism and pregnancy | journal = Ann Endocrinol (Paris) | volume = 77 | issue = 2 | pages = 148–60 | date = June 2016 | pmid = 27156905 | doi = 10.1016/j.ando.2016.04.009 }}</ref><ref name="pmid25163723">{{cite journal | vauthors = Riester A, Reincke M | title = Progress in primary aldosteronism: mineralocorticoid receptor antagonists and management of primary aldosteronism in pregnancy | journal = Eur J Endocrinol | volume = 172 | issue = 1 | pages = R23–30 | date = January 2015 | pmid = 25163723 | doi = 10.1530/EJE-14-0444 | s2cid = 43338556 | doi-access = free | title-link = doi }}</ref><ref name="pmid32586668">{{cite journal | vauthors = Araujo-Castro M | title = Treatment of primary hyperaldosteronism | journal = Med Clin (Barc) | volume = 155 | issue = 7 | pages = 302–308 | date = October 2020 | pmid = 32586668 | doi = 10.1016/j.medcli.2020.04.029 | s2cid = 225657804 }}</ref>

===Skin and hair conditions===
Androgens such as testosterone and DHT play a critical role in the [[pathogenesis]] of a number of [[cutaneous condition|dermatological conditions]] including [[oily skin]], [[acne]], [[seborrhea]], [[hirsutism]] (excessive facial/body hair growth in women), and [[male pattern hair loss]] (androgenic alopecia).<ref name="pmid15507105">{{cite journal | vauthors = Zouboulis CC, Degitz K | title = Androgen action on human skin -- from basic research to clinical significance | journal = Experimental Dermatology | volume = 13 | issue = Suppl 4 | pages = 5–10 | year = 2004 | pmid = 15507105 | doi = 10.1111/j.1600-0625.2004.00255.x | s2cid = 34863608 }}</ref><ref name="pmid28979664">{{cite journal | vauthors = Endly DC, Miller RA | title = Oily Skin: A review of Treatment Options | journal = The Journal of Clinical and Aesthetic Dermatology | volume = 10 | issue = 8 | pages = 49–55 | date = August 2017 | pmid = 28979664 | pmc = 5605215 }}</ref> In demonstration of this, women with [[complete androgen insensitivity syndrome]] <!-- (CAIS) --> do not produce [[sebum]] or develop acne and have little to no [[body hair|body]], [[pubic hair|pubic]], or [[axillary hair]].<ref name="ShalitaRosso2011">{{cite book| vauthors = Shalita AR, Del Rosso JQ, Webster G |title=Acne Vulgaris|url=https://books.google.com/books?id=CIPOBQAAQBAJ&pg=PA33|date=21 March 2011|publisher=CRC Press|isbn=978-1-61631-009-7|pages=33–|url-status=live|archive-url=https://web.archive.org/web/20161209210819/https://books.google.com/books?id=CIPOBQAAQBAJ&pg=PA33|archive-date=9 December 2016}}</ref><ref name="ZouboulisKatsambas2014">{{cite book| vauthors = Zouboulis CC, Katsambas AD, Kligman AM |title=Pathogenesis and Treatment of Acne and Rosacea|url=https://books.google.com/books?id=vnQqBAAAQBAJ&pg=PA121|date=28 July 2014|publisher=Springer|isbn=978-3-540-69375-8|pages=121–|url-status=live|archive-url=https://web.archive.org/web/20161210040108/https://books.google.com/books?id=vnQqBAAAQBAJ&pg=PA121|archive-date=10 December 2016}}</ref> Moreover, men with [[congenital disorder|congenital]] [[5α-reductase deficiency|5α-reductase type II deficiency]], [[5α-reductase]] being an [[enzyme]] that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty [[facial hair]], reduced body hair, and reportedly no incidence of male-pattern hair loss.<ref name="pmid16985920">{{cite journal | vauthors = Marks LS | title = 5alpha-reductase: history and clinical importance | journal = Reviews in Urology | volume = 6 | pages = S11-21 | year = 2004 | issue = Suppl 9 | pmid = 16985920 | pmc = 1472916 }}</ref><ref name="Sloane2002">{{cite book|vauthors=Sloane E|title=Biology of Women|url=https://books.google.com/books?id=kqcYyk7zlHYC&pg=PA160|year=2002|publisher=Cengage Learning|isbn=978-0-7668-1142-3|pages=160–|access-date=5 July 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007092759/https://books.google.com/books?id=kqcYyk7zlHYC&pg=PA160|url-status=live}}</ref><ref name="HannoGuzzo2014">{{cite book|vauthors=Hanno PM, Guzzo TJ, Malkowicz SB, Wein AJ|title=Penn Clinical Manual of Urology E-Book: Expert Consult - Online|url=https://books.google.com/books?id=OQTbAgAAQBAJ&pg=PA782|date=26 January 2014|publisher=Elsevier Health Sciences|isbn=978-0-323-24466-4|pages=782–|access-date=5 July 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007092759/https://books.google.com/books?id=OQTbAgAAQBAJ&pg=PA782|url-status=live}}</ref><ref name="Harper2007">{{cite book|vauthors=Harper C|title=Intersex|url=https://books.google.com/books?id=fM6vAwAAQBAJ&pg=PA123|date=1 August 2007|publisher=Berg|isbn=978-1-84788-339-1|pages=123–|access-date=5 July 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007092759/https://books.google.com/books?id=fM6vAwAAQBAJ&pg=PA123|url-status=live}}</ref><ref name="Blume-PeytaviWhiting2008">{{cite book|vauthors=Blume-Peytavi U, Whiting DA, Trüeb RM|title=Hair Growth and Disorders|url=https://books.google.com/books?id=pHrX2-huQCoC&pg=PA161|date=26 June 2008|publisher=Springer Science & Business Media|isbn=978-3-540-46911-7|pages=161–162|access-date=16 July 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007092814/https://books.google.com/books?id=pHrX2-huQCoC&pg=PA161|url-status=live}}</ref> Conversely, [[hyperandrogenism]] in women, for instance due to [[polycystic ovary syndrome]] <!-- (PCOS) --> or [[congenital adrenal hyperplasia]]<!-- (CAH) -->, is commonly associated with acne and hirsutism, as well as [[virilization]] (masculinization) in general.<ref name="pmid15507105" /> In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned [[androgen-dependent condition|androgen-dependent]] skin and hair conditions.<ref name="pmid9420861" /><ref name="pmid20082945" />

Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women.<ref name="pmid22468178">{{cite journal | vauthors = Kim GK, Del Rosso JQ | title = Oral Spironolactone in Post-teenage Female Patients with Acne Vulgaris: Practical Considerations for the Clinician Based on Current Data and Clinical Experience | journal = The Journal of Clinical and Aesthetic Dermatology | volume = 5 | issue = 3 | pages = 37–50 | date = March 2012 | pmid = 22468178 | pmc = 3315877 }}</ref><ref name="pmid28155090" /><ref>{{cite journal | vauthors = Santer M, Lawrence M, Renz S, Eminton Z, Stuart B, Sach TH, Pyne S, Ridd MJ, Francis N, Soulsby I, Thomas K, Permyakova N, Little P, Muller I, Nuttall J, Griffiths G, Thomas KS, Layton AM | title = Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial | journal = BMJ | volume = 381 | article-number = e074349 | date = May 2023 | pmid = 37192767 | doi = 10.1136/bmj-2022-074349 | pmc = 10543374 | s2cid = 258717921 }}</ref> In addition, spironolactone reduces oil that is naturally produced in the skin, so can be used to treat oily skin.<ref name="pmid28155090" /><ref name="pmid26897386" /><ref name="pmid28979664" /> Though not the primary intended purpose of the medication, the ability of spironolactone to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful.<ref name="pmid28155090" /><ref name="pmid26897386" /> Oftentimes, for women treating acne, spironolactone is prescribed and paired with a [[combined oral contraceptive pill|birth control pill]].<ref name="pmid28155090" /><ref name="pmid26897386" /> Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months.<ref name="pmid28155090" /><ref name="pmid26897386" /> Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses.<ref name="pmid9238337" /> Response to treatment generally requires 1 to 3&nbsp;months in the case of acne and up to 6&nbsp;months in the case of hirsutism.<ref name="pmid9238337" /> Ongoing therapy is generally required to avoid relapse of symptoms.<ref name="pmid9238337" /> Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication.<ref name="pmid24889738" /> Spironolactone can be used in the treatment of [[female-pattern hair loss]] (pattern scalp hair loss in women).<ref name="pmid21413648">{{cite journal | vauthors = Rathnayake D, Sinclair R | title = Use of spironolactone in dermatology | journal = Skinmed | volume = 8 | issue = 6 | pages = 328–32; quiz 333 | year = 2010 | pmid = 21413648 }}</ref> There is tentative low quality evidence supporting its use for this indication.<ref>{{cite journal | vauthors = Harfmann KL, Bechtel MA | title = Hair loss in women | journal = Clinical Obstetrics and Gynecology | volume = 58 | issue = 1 | pages = 185–99 | date = March 2015 | pmid = 25517757 | doi = 10.1097/GRF.0000000000000081 | s2cid = 20364810 }}</ref>

Antiandrogens such as spironolactone are male-specific [[teratogen]]s, which can feminize male [[fetus]]es due to their antiandrogenic effects.<ref name="pmid9420861" /><ref name="IswaranImai1997">{{cite journal | vauthors = Iswaran TJ, Imai M, Betton GR, Siddall RA | title = An overview of animal toxicology studies with bicalutamide (ICI 176,334) | journal = The Journal of Toxicological Sciences | volume = 22 | issue = 2 | pages = 75–88 | date = May 1997 | pmid = 9198005 | doi = 10.2131/jts.22.2_75 | doi-access = free | title-link = doi }}</ref><ref name="Smith2013">{{cite book | vauthors = Smith RE |title=Medicinal Chemistry – Fusion of Traditional and Western Medicine |url=https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306 |date=4 April 2013 |publisher=Bentham Science Publishers |isbn=978-1-60805-149-6 |pages=306– |url-status=live |archive-url=https://web.archive.org/web/20160529034219/https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306 |archive-date=29 May 2016 }}</ref> For this reason, antiandrogens are recommended only to be used to treat women who are of reproductive age in conjunction with adequate contraception.<ref name="pmid9420861" /><ref name="IswaranImai1997" /><ref name="Smith2013" /> Oral contraceptives, which contain an [[estrogen (medication)|estrogen]] and a [[progestin]], are typically used for this purpose.<ref name="pmid9420861" /> Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.<ref name="pmid9420861" /><ref name="Ostrzenski2002">{{cite book|vauthors=Ostrzenski A|title=Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy|url=https://books.google.com/books?id=TYlZsGdwqrQC&pg=PA86|year=2002|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-2761-7|pages=86–|access-date=5 July 2017|archive-date=6 October 2022|archive-url=https://web.archive.org/web/20221006095556/https://books.google.com/books?id=TYlZsGdwqrQC&pg=PA86|url-status=live}}</ref>

Spironolactone is not generally used in men for the treatment of androgen-dependent dermatological conditions because of its feminizing side effects, but it is effective for such indications in men similarly.<ref name="pmid21413648" /> As an example, spironolactone has been reported to reduce symptoms of acne in males.<ref name="pmid9557251">{{cite journal | vauthors = Schmidt JB | title = Other antiandrogens | journal = Dermatology | volume = 196 | issue = 1 | pages = 153–7 | date = 1998 | pmid = 9557251 | doi = 10.1159/000017850 | s2cid = 22119267 }}</ref> An additional example is the usefulness of spironolactone as an antiandrogen in transgender women and nonbinary individuals.<ref name="WPATH2011">{{cite web | url = http://www.wpath.org/documents/Standards%20of%20Care_FullBook_1g-1.pdf | title = Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People | author = The World Professional Association for Transgender Health (WPATH) | year = 2011 | access-date = 27 May 2012 | archive-url = https://web.archive.org/web/20120523064935/http://www.wpath.org/documents/Standards%20of%20Care_FullBook_1g-1.pdf | archive-date = 23 May 2012 }}</ref><ref name="pmid19509099">{{cite journal | vauthors = Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, Gooren LJ, Meyer WJ, Spack NP, Tangpricha V, Montori VM | title = Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 94 | issue = 9 | pages = 3132–54 | date = September 2009 | pmid = 19509099 | doi = 10.1210/jc.2009-0345 | doi-access = free | title-link = doi }}</ref><ref name="pmid2540730">{{cite journal | vauthors = Prior JC, Vigna YM, Watson D | title = Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism | journal = Archives of Sexual Behavior | volume = 18 | issue = 1 | pages = 49–57 | date = February 1989 | pmid = 2540730 | doi = 10.1007/bf01579291 | s2cid = 22802329 }}</ref>

[[Topical medication|Topical]] spironolactone is effective in the treatment of acne, as well.<ref name="pmid1387779">{{cite journal | vauthors = Cunliffe WJ, Bottomley WW | title = Antiandrogens and acne. A topical approach? | journal = Archives of Dermatology | volume = 128 | issue = 9 | pages = 1261–4 | date = September 1992 | pmid = 1387779 | doi = 10.1001/archderm.1992.01680190117017 }}</ref> As a result, topical pharmaceutical formulations containing 2 or 5% spironolactone cream became available in Italy for the treatment of acne and hirsutism in the early 1990s.<ref name="pmid8112074">{{cite journal | vauthors = Vincenzi C, Trevisi P, Farina P, Stinchi C, Tosti A | title = Facial contact dermatitis due to spironolactone in an anti-acne cream | journal = Contact Dermatitis | volume = 29 | issue = 5 | pages = 277–8 | date = November 1993 | pmid = 8112074 | doi = 10.1111/j.1600-0536.1993.tb03569.x | s2cid = 19134415 }}</ref><ref name="Benvenga2009">{{cite book| vauthors = Benvenga S | title= Diagnosis and Management of Polycystic Ovary Syndrome|chapter=Therapy of Hirsutism|year=2009|pages=233–242| publisher= Springer|doi=10.1007/978-0-387-09718-3_19|isbn=978-0-387-09717-6}}</ref> The products were discontinued in 2006 when the creams were added to the list of doping substances with a decree of the [[Ministry of Health (Italy)|Ministry of Health]] that year.<ref name="Benvenga2009" />

====Comparison====
Spironolactone, the [[5α-reductase inhibitor]] [[finasteride]], and the [[nonsteroidal antiandrogen]] [[flutamide]] all appear to have similar effectiveness in the treatment of hirsutism.<ref name="pmid24889738">{{cite journal | vauthors = Somani N, Turvy D | title = Hirsutism: an evidence-based treatment update | journal = American Journal of Clinical Dermatology | volume = 15 | issue = 3 | pages = 247–66 | date = July 2014 | pmid = 24889738 | doi = 10.1007/s40257-014-0078-4 | s2cid = 45234892 }}</ref><ref name="pmid25918921">{{cite journal | vauthors = van Zuuren EJ, Fedorowicz Z, Carter B, Pandis N | title = Interventions for hirsutism (excluding laser and photoepilation therapy alone) | journal = The Cochrane Database of Systematic Reviews | issue = 4 | article-number = CD010334 | date = April 2015 | volume = 2015 | pmid = 25918921 | pmc = 6481758 | doi = 10.1002/14651858.CD010334.pub2 }}</ref><ref name="pmid29522176">{{cite journal | vauthors = Barrionuevo P, Nabhan M, Altayar O, Wang Z, Erwin PJ, Asi N, Martin KA, Murad MH | title = Treatment Options for Hirsutism: A Systematic Review and Network Meta-Analysis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 4 | pages = 1258–1264 | date = April 2018 | pmid = 29522176 | doi = 10.1210/jc.2017-02052 | s2cid = 3783739 | doi-access = free | title-link = doi }}</ref> Some clinical research, though, has found that the effectiveness of spironolactone for hirsutism is greater than that of finasteride, but is less than that of flutamide.<ref name="pmid24889738" /> The combination of spironolactone with finasteride is more effective than either alone for hirsutism and the combination of spironolactone with a birth-control pill is more effective than a birth-control pill alone.<ref name="pmid24889738" /> One study showed that spironolactone or the [[steroidal antiandrogen]] [[cyproterone acetate]] both in combination with a birth-control pill had equivalent effectiveness for hirsutism.<ref name="pmid24889738" /> Spironolactone is considered to be a first-line treatment for hirsutism, finasteride and the steroidal antiandrogen cyproterone acetate are considered to be second-line treatments, and flutamide is no longer recommended for hirsutism due to [[liver toxicity]] concerns.<ref name="pmid24889738" /> The nonsteroidal antiandrogen [[bicalutamide]] is an alternative option to flutamide with improved [[drug safety|safety]].<ref name="pmid24455796">{{cite journal | vauthors = Erem C | title = Update on idiopathic hirsutism: diagnosis and treatment | journal = Acta Clinica Belgica | volume = 68 | issue = 4 | pages = 268–74 | date = 2013 | pmid = 24455796 | doi = 10.2143/ACB.3267 | s2cid = 39120534 }}</ref><ref name="pmid29211888">{{cite journal | vauthors = Moretti C, Guccione L, Di Giacinto P, Simonelli I, Exacoustos C, Toscano V, Motta C, De Leo V, Petraglia F, Lenzi A | title = Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism: A Double-Blind Randomized Controlled Trial | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 3 | pages = 824–838 | date = March 2018 | pmid = 29211888 | doi = 10.1210/jc.2017-01186 | s2cid = 3784055 | doi-access = free | title-link = doi }}</ref>

The combination of spironolactone with a birth-control pill in the treatment of acne appears to have similar effectiveness to a birth-control pill alone and the combination of a birth-control pill with cyproterone acetate, flutamide, or finasteride.<ref name="pmid28155090" /> However, this was based on low- to very low-quality evidence.<ref name="pmid28155090" /> Spironolactone may be more effective than birth-control pills in the treatment of acne, and the combination of spironolactone with a birth-control pill may have greater effectiveness for acne than either alone.<ref name="pmid22994662" /> In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne.<ref name="pmid28155090" /> In one study, flutamide decreased acne scores by 80% within 3&nbsp;months, whereas spironolactone decreased symptoms by only 40% in the same period.<ref name="pmid10495361" /><ref name="ShelleyShelley2001">{{cite book|vauthors=Shelley WB, Shelley ED|title=Advanced Dermatologic Therapy II|url=https://books.google.com/books?id=vuJsAAAAMAAJ|year=2001|publisher=W. B. Saunders|isbn=978-0-7216-8258-7|access-date=2 January 2019|archive-date=6 October 2022|archive-url=https://web.archive.org/web/20221006095557/https://books.google.com/books?id=vuJsAAAAMAAJ|url-status=live}}</ref><ref name="BalenFranks2010">{{cite book|vauthors=Balen A, Franks S, Homburg R, Kehoe S|title=Current Management of Polycystic Ovary Syndrome|url=https://books.google.com/books?id=0rtUBAAAQBAJ&pg=PA132|date=October 2010|publisher=Cambridge University Press|isbn=978-1-906985-41-7|pages=132–|access-date=2 January 2019|archive-date=6 October 2022|archive-url=https://web.archive.org/web/20221006095557/https://books.google.com/books?id=0rtUBAAAQBAJ&pg=PA132|url-status=live}}</ref> However, the use of flutamide for acne is limited by its liver toxicity.<ref name="pmid28379593">{{cite journal | vauthors = Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A | title = Flutamide-induced hepatotoxicity: ethical and scientific issues | journal = European Review for Medical and Pharmacological Sciences | volume = 21 | issue = 1 Suppl | pages = 69–77 | date = March 2017 | pmid = 28379593 }}</ref><ref name="pmid28492054">{{cite journal | vauthors = Trivedi MK, Shinkai K, Murase JE | title = A Review of hormone-based therapies to treat adult acne vulgaris in women | journal = International Journal of Women's Dermatology | volume = 3 | issue = 1 | pages = 44–52 | date = March 2017 | pmid = 28492054 | pmc = 5419026 | doi = 10.1016/j.ijwd.2017.02.018 }}</ref><ref name="YasaDural2016">{{cite journal| vauthors = Yasa C, Dural Ö, Bastu E, Uğurlucan FG |title=Hirsutism, Acne, and Hair Loss: Management of Hyperandrogenic Cutaneous Manifestations of Polycystic Ovary Syndrome|journal=Gynecology Obstetrics & Reproductive Medicine|year=2016|volume=23|issue=2|pages=110–119|issn=1300-4751|doi=10.21613/GORM.2016.613| doi-access = free | title-link = doi }}</ref><ref name="pmid28274354">{{cite journal | vauthors = Barros B, Thiboutot D | title = Hormonal therapies for acne | journal = Clinics in Dermatology | volume = 35 | issue = 2 | pages = 168–172 | date = 2017 | pmid = 28274354 | doi = 10.1016/j.clindermatol.2016.10.009 }}</ref> Bicalutamide is a potential alternative to flutamide for acne as well.<ref name="pmid27416311">{{cite journal | vauthors = Hassoun LA, Chahal DS, Sivamani RK, Larsen LN | title = The use of hormonal agents in the treatment of acne | journal = Seminars in Cutaneous Medicine and Surgery | volume = 35 | issue = 2 | pages = 68–73 | date = June 2016 | pmid = 27416311 | doi = 10.12788/j.sder.2016.027 | doi-broken-date = 12 July 2025 }}</ref><ref name="pmid30312645">{{cite journal | vauthors = Azarchi S, Bienenfeld A, Lo Sicco K, Marchbein S, Shapiro J, Nagler AR | title = Androgens in women: Hormone-modulating therapies for skin disease | journal = Journal of the American Academy of Dermatology | volume = 80 | issue = 6 | pages = 1509–1521 | date = June 2019 | pmid = 30312645 | doi = 10.1016/j.jaad.2018.08.061 | s2cid = 52973096 }}</ref> Spironolactone can be considered as a first-line treatment for acne in those who have failed other standard treatments such as topical therapies and under certain other circumstances, although this is controversial due to the side effects of spironolactone and its [[teratogenicity]].<ref name="pmid22994662" /><ref name="pmid20082945">{{cite journal | vauthors = Katsambas AD, Dessinioti C | title = Hormonal therapy for acne: why not as first line therapy? facts and controversies | journal = Clinics in Dermatology | volume = 28 | issue = 1 | pages = 17–23 | date = 2010 | pmid = 20082945 | doi = 10.1016/j.clindermatol.2009.03.006 }}</ref>

Insufficient clinical evidence exists to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss.<ref name="pmid27225981">{{cite journal | vauthors = van Zuuren EJ, Fedorowicz Z, Schoones J | title = Interventions for female pattern hair loss | journal = The Cochrane Database of Systematic Reviews | issue = 5 | article-number = CD007628 | date = May 2016 | volume = 2016 | pmid = 27225981 | pmc = 6457957 | doi = 10.1002/14651858.CD007628.pub4 }}</ref> The effectiveness of spironolactone in the treatment of both acne and hirsutism appears to be dose-dependent, with higher doses being more effective than lower doses.<ref name="pmid22994662">{{cite journal | vauthors = Kamangar F, Shinkai K | title = Acne in the adult female patient: a practical approach | journal = International Journal of Dermatology | volume = 51 | issue = 10 | pages = 1162–74 | date = October 2012 | pmid = 22994662 | doi = 10.1111/j.1365-4632.2012.05519.x | s2cid = 5777817 | doi-access = free | title-link = doi }}</ref><ref name="pmid19370553">{{cite journal | vauthors = Brown J, Farquhar C, Lee O, Toomath R, Jepson RG | title = Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne | journal = The Cochrane Database of Systematic Reviews | issue = 2 | article-number = CD000194 | date = April 2009 | pmid = 19370553 | doi = 10.1002/14651858.CD000194.pub2 | hdl = 2292/9640 | hdl-access = free }}</ref><ref name="Hammerstein1990">{{cite book| vauthors = Hammerstein J |title=Hair and Hair Diseases|chapter=Antiandrogens: Clinical Aspects|year=1990|pages=827–886|publisher=Springer |doi=10.1007/978-3-642-74612-3_35|isbn=978-3-642-74614-7}}</ref> Higher doses also have greater side effects, such as [[menstrual irregularities]].<ref name="pmid28155090" />

===Transgender hormone therapy===
{{See also|Feminizing hormone therapy#Steroidal antiandrogens}}
Despite [[paradoxical reaction]]s, spironolactone is used [[off-label use|off-label]] as a component of [[feminizing hormone therapy]] in [[transgender women]], especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen.<ref name="Paradoxical reactions">{{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 Reports | volume = 2012 | issue = | date = February 2012 | pages = bcr1120115238 | pmid = 22665559 | pmc = 3291010 | doi = 10.1136/bcr.11.2011.5238 }}</ref>{{Unreliable source?|reason=primary|date=July 2024}}<ref name="WPATH2011" /><ref name="pmid19509099" /><ref name="pmid2540730" /> Alternatives like [[bicalutamide]] do not have a similar level of popularity.<ref>{{cite journal | vauthors = Randolph JF | title = Gender-Affirming Hormone Therapy for Transgender Females | journal = Clinical Obstetrics and Gynecology | volume = 61 | issue = 4 | pages = 705–721 | date = December 2018 | pmid = 30256230 | doi = 10.1097/GRF.0000000000000396 }}</ref> As spironolactone's antiandrogenic effect appears only in high doses, it can have a wide array of side effects not found in antiandrogens working more exclusively on the androgen receptor.<ref name="Burinkul_2021" /><ref name="Sehgal_2023" /><ref name="ineffectiveness in HRT" />{{Unreliable medical source|date=July 2024}} When coupled with estradiol, effects in transgender women include decreased [[hirsutism|male pattern body hair]], induction of [[breast development]] and of [[feminization (biology)|feminization]] in general, and reduced [[spontaneous erection]]s.<ref name="pmid2540730" />

===Forms===
Spironolactone is available in the form of [[tablet (pharmacy)|tablet]]s (25, 50, and 100&nbsp;mg; brand name Aldactone, others) and [[suspension (chemistry)|suspension]]s (25&nbsp;mg/5&nbsp;mL; brand name Carospir) for oral administration.<ref name="Muller1998">{{cite book| vauthors = Muller NF, Dessing RP |title=European Drug Index: European Drug Registrations | edition = Fourth |url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA44|date=19 June 1998|publisher=CRC Press|isbn=978-3-7692-2114-5|pages=44–|access-date=29 November 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093304/https://books.google.com/books?id=2HBPHmclMWIC&pg=PA44|url-status=live}}</ref><ref name="LeeDesai2007">{{cite book|vauthors=Lee M, Desai A|title=Gibaldi's Drug Delivery Systems in Pharmaceutical Care|url=https://books.google.com/books?id=v0rLyVSc8EYC&pg=PA312|year=2007|publisher=ASHP|isbn=978-1-58528-136-7|pages=312–|access-date=1 December 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093304/https://books.google.com/books?id=v0rLyVSc8EYC&pg=PA312|url-status=live}}</ref><ref name="Niazi2016">{{cite book|vauthors=Niazi SK|title=Handbook of Pharmaceutical Manufacturing Formulations, Second Edition: Volume One, Compressed Solid Products|url=https://books.google.com/books?id=XprMBQAAQBAJ&pg=PA470|date=19 April 2016|publisher=CRC Press|isbn=978-1-4200-8117-6|pages=470–|access-date=1 December 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093305/https://books.google.com/books?id=XprMBQAAQBAJ&pg=PA470|url-status=live}}</ref><ref name="WakelinMaibach2002">{{cite book|vauthors=Wakelin SH, Maibach HI, Archer CB|title=Systemic Drug Treatment in Dermatology: A Handbook|url=https://books.google.com/books?id=F1ZiAgAAQBAJ&pg=PA35|date=1 June 2002|publisher=CRC Press|isbn=978-1-84076-013-2|pages=32, 35|access-date=1 December 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093305/https://books.google.com/books?id=F1ZiAgAAQBAJ&pg=PA35|url-status=live}}</ref><ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = U.S. [[Food and Drug Administration]] (FDA) | access-date = 14 August 2018 | url = https://www.accessdata.fda.gov/scripts/cder/daf/ | archive-date = 16 November 2016 | archive-url = https://web.archive.org/web/20161116164727/http://www.accessdata.fda.gov/scripts/cder/daf/ | url-status = live }}</ref>{{failed verification|date=July 2024}} It had also been marketed in the form of 2 or 5% [[topical]] cream in Italy for the treatment of acne and hirsutism under the brand name Spiroderm, but this product is no longer available.<ref name="FARIDDiamanti-Kandarakis2009">{{cite book|vauthors=Farid NR, Diamanti-Kandarakis E|title=Diagnosis and Management of Polycystic Ovary Syndrome|url=https://books.google.com/books?id=fgMYVxmPDnMC&pg=PA235|date=27 February 2009|publisher=Springer Science & Business Media|isbn=978-0-387-09718-3|pages=235–|access-date=6 November 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093305/https://books.google.com/books?id=fgMYVxmPDnMC&pg=PA235|url-status=live}}</ref><ref name="IndexNominum2000" /> The medication is also available in combination with other medications, such as [[hydrochlorothiazide]] (brand name Aldactazide, others).<ref name="Drugs@FDA" />{{failed verification|date=July 2024}}<ref name="Drugs.com" /> Spironolactone has poor [[water solubility]], so only oral and topical formulations have been developed; other [[routes of administration]] such as [[intravenous administration|intravenous injection]] are not used.<ref name="pmid15947888">{{cite journal | vauthors = Sica DA | title = Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis | journal = Heart Failure Reviews | volume = 10 | issue = 1 | pages = 23–9 | date = January 2005 | pmid = 15947888 | doi = 10.1007/s10741-005-2345-1 | s2cid = 21437788 }}</ref> The only antimineralocorticoid that is available as a [[Solution (chemistry)|solution]] for [[parenteral]] use is the related medication [[potassium canrenoate]].<ref name="pmid28634268" />

==Contraindications==
[[Contraindication]]s of spironolactone include [[hyperkalemia]] (high potassium levels), [[end-stage kidney disease|severe and end-stage kidney disease]] (due to high hyperkalemia risk, except possibly in those on [[Kidney dialysis|dialysis]]), [[Addison's disease]] (adrenal insufficiency and low aldosterone levels), and concomitant use of eplerenone.<ref name="Aldactone label" /><ref name="GoldsmithCovic2014">{{cite book|vauthors=Goldsmith D, Covic A, Spaak J|title=Cardio-Renal Clinical Challenges|url=https://books.google.com/books?id=GvZWBQAAQBAJ&pg=PA167|date=12 November 2014|publisher=Springer|isbn=978-3-319-09162-4|pages=167–|access-date=17 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093305/https://books.google.com/books?id=GvZWBQAAQBAJ&pg=PA167|url-status=live}}</ref> It should also be used with caution in people with certain [[neurological disorder]]s, as well as those who experience or have experienced [[anuria]] (lack of urine production), [[acute kidney injury]], or [[kidney failure|significant impairment of kidney excretory function]] with risk of hyperkalemia.<ref name="Aldactone label" />

==Side effects==
One of the most common side effects of spironolactone is [[frequent urination]]. Other general side effects include [[dehydration]], [[hyponatremia]] (low [[sodium]] levels), mild [[hypotension]],<ref name="pmid10495361" /> [[ataxia]] (muscle incoordination), [[drowsiness]], [[dizziness]],<ref name="pmid10495361" /> [[dry skin]], and [[rash]]es. Because of its antiandrogenic activity, spironolactone can cause [[breast tenderness]], [[gynecomastia]] (breast development), [[feminization (biology)|feminization]] in general, and [[demasculinization]], as well as [[sexual dysfunction]] including [[loss of libido]] and [[erectile dysfunction]], although these side effects are usually confined to high doses.<ref name="pmid984618" /> At very high doses (400&nbsp;mg/day), spironolactone has also been associated with [[testicular atrophy]] and reversibly [[infertility|reduced fertility]], including [[semen abnormalities]], such as decreased [[sperm count]] and [[sperm motility|motility]] in men,<ref name="SeldinGiebisch1997" /><ref name="Aronson2009" /> but such doses of spironolactone are rarely used clinically.<ref name="Aronson2009" /> In women, spironolactone can cause [[menstrual irregularities]], breast tenderness, and breast enlargement.<ref name="pmid2969259"/><ref name="pmid28155090" /><ref name="CarrellPeterson2010">{{cite book|vauthors=Carrell DT, Peterson CM|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–|access-date=6 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093304/https://books.google.com/books?id=lcBEheiufVcC&pg=PA162|url-status=live}}</ref> Aside from these adverse effects, the side effects of spironolactone in women taking high doses are minimal, and it is well tolerated.<ref name="pmid28155090" /><ref name="pmid10495361" /><ref name="PescovitzEugster2004">{{cite book| vauthors = Pescovitz OH, Eugster EA |title=Pediatric Endocrinology: Mechanisms, Manifestations, and Management|url=https://books.google.com/books?id=9gvBlktAT6YC&pg=PA368|year=2004|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-4059-3|pages=368–}}</ref>

A potential side effect of spironolactone is hyperkalemia (high potassium levels), which in severe cases, can be life-threatening.<ref name="Aldactone label" /> Hyperkalemia can present as a normal anion-gap metabolic acidosis.<ref name="Aldactone label" /> The addition of spironolactone to loop diuretics in people with heart failure reportedly was associated with a higher risk of hyperkalemia and [[acute kidney injury]].<ref>{{cite journal | vauthors = Secora AM, Shin JI, Qiao Y, Alexander GC, Chang AR, Inker LA, Coresh J, Grams ME | title = Hyperkalemia and Acute Kidney Injury with Spironolactone Use Among Patients with Heart Failure | journal = Mayo Clinic Proceedings | volume = 95 | issue = 11 | pages = 2408–2419 | date = November 2020 | pmid = 33153631 | doi = 10.1016/j.mayocp.2020.03.035 | pmc = 8005315 }}</ref> Spironolactone may put people at a heightened risk for gastrointestinal issues such as nausea, vomiting, diarrhea, cramping, and [[gastritis]].<ref name="Aldactone label" /><ref>{{Cite web |url= https://medlineplus.gov/druginfo/meds/a682627.html |title=Spironolactone | publisher = U.S. National Library of Medicine|date=2019| work = MedlinePlus |access-date=31 October 2019 |archive-date=5 July 2016 |archive-url= https://web.archive.org/web/20160705111532/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682627.html |url-status=live }}</ref> In addition, some evidence suggests an association between use of the medication and [[hemorrhage|bleeding]] from the [[stomach]] and [[duodenum]],<ref name="Aldactone label" /> though a causal relationship between the two has not been established.<ref>{{cite journal | vauthors = Verhamme K, Mosis G, Dieleman J, Stricker B, Sturkenboom M | title = Spironolactone and risk of upper gastrointestinal events: population based case-control study | journal = BMJ | volume = 333 | issue = 7563 | page = 330 | date = August 2006 | pmid = 16840442 | pmc = 1539051 | doi = 10.1136/bmj.38883.479549.2F }}</ref><ref name="pmid18507655">{{cite journal | vauthors = Gulmez SE, Lassen AT, Aalykke C, Dall M, Andries A, Andersen BS, Hansen JM, Andersen M, Hallas J | title = Spironolactone use and the risk of upper gastrointestinal bleeding: a population-based case-control study | journal = Br J Clin Pharmacol | volume = 66 | issue = 2 | pages = 294–9 | date = August 2008 | pmid = 18507655 | pmc = 2492928 | doi = 10.1111/j.1365-2125.2008.03205.x }}</ref> Also, spironolactone is [[immunosuppression|immunosuppressive]] in the treatment of [[sarcoidosis]].<ref>{{cite journal | vauthors = Wandelt-Freerksen E | title = [Aldactone in the treatment of sarcoidosis of the lungs (author's transl)] | journal = Zeitschrift für Erkrankungen der Atmungsorgane | volume = 149 | issue = 1 | pages = 156–9 | date = July 1977 | pmid = 607621 }}</ref>

Most of the side effects of spironolactone are dose-dependent.<ref name="pmid22468178" /> Low-dose spironolactone is generally very well tolerated.<ref name="pmid22468178" /> Even higher doses of spironolactone, such as 100&nbsp;mg/day, are well tolerated in most individuals.<ref name="pmid22468178" /> Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness, and enlargement, [[orthostatic hypotension]], and hyperkalemia.<ref name="pmid22468178" /> Its side effects are usually mild and rarely result in discontinuation.<ref name="pmid22468178" />

{{Side effects of spironolactone in women in clinical studies for acne}}

===High potassium levels===
Spironolactone can cause high blood potassium levels.<ref name="Aronson2009">{{cite book|vauthors=Aronson JK|title=Meyler's Side Effects of Cardiovascular Drugs|url=https://books.google.com/books?id=oeBgU3UwgZkC&pg=PA255|date=2 March 2009|publisher=Elsevier|isbn=978-0-08-093289-7|pages=253–258|access-date=16 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093806/https://books.google.com/books?id=oeBgU3UwgZkC&pg=PA255|url-status=live}}</ref> Rarely, this can be fatal.<ref name="Aronson2009" /> Of people with heart disease prescribed typical dosages of spironolactone, 10 to 15% develop some degree of hyperkalemia, and 6% develop severe hyperkalemia.<ref name="Aronson2009" /> At a higher dosage,<!--75 mg/day--> a rate of hyperkalemia of 24% has been observed.<ref name="pmid26404748">{{cite journal | vauthors = Lainscak M, Pelliccia F, Rosano G, Vitale C, Schiariti M, Greco C, Speziale G, Gaudio C | title = Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone | journal = International Journal of Cardiology | volume = 200 | pages = 25–9 | date = December 2015 | pmid = 26404748 | doi = 10.1016/j.ijcard.2015.05.127 }}</ref> An abrupt and major increase in the rate of hospitalization due to hyperkalemia from 0.2 to 11% and in the rate of death due to hyperkalemia from 0.3 to 2.0 per 1,000 between early 1994 and late 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone upon the publication of the Randomized Aldactone Evaluation Study (RALES) in July 1999.<ref name="Aronson2009" /><ref name="pmid26404748" /><ref name="pmid15295047">{{cite journal | vauthors = Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA | title = Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study | journal = The New England Journal of Medicine | volume = 351 | issue = 6 | pages = 543–51 | date = August 2004 | pmid = 15295047 | doi = 10.1056/NEJMoa040135 | doi-access = free | title-link = doi }}</ref><ref name="RoncoBellomo2017">{{cite book|vauthors=Ronco C, Bellomo R, Kellum JA, Ricci Z|title=Critical Care Nephrology E-Book|url=https://books.google.com/books?id=HTdDDwAAQBAJ&pg=PA371|date=14 December 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-51199-5|pages=371–|access-date=17 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093807/https://books.google.com/books?id=HTdDDwAAQBAJ&pg=PA371|url-status=live}}</ref> However, another population-based study in Scotland failed to replicate these findings.<ref name="pmid22942339">{{cite journal | vauthors = Zannad F, Gattis Stough W, Rossignol P, Bauersachs J, McMurray JJ, Swedberg K, Struthers AD, Voors AA, Ruilope LM, Bakris GL, O'Connor CM, Gheorghiade M, Mentz RJ, Cohen-Solal A, Maggioni AP, Beygui F, Filippatos GS, Massy ZA, Pathak A, Piña IL, Sabbah HN, Sica DA, Tavazzi L, Pitt B | title = Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice | journal = European Heart Journal | volume = 33 | issue = 22 | pages = 2782–95 | date = November 2012 | pmid = 22942339 | doi = 10.1093/eurheartj/ehs257 | doi-access = free | title-link = doi }}</ref><ref name="pmid20483947">{{cite journal | vauthors = Wei L, Struthers AD, Fahey T, Watson AD, Macdonald TM | title = Spironolactone use and renal toxicity: population based longitudinal analysis | journal = BMJ | volume = 340 | article-number = c1768 | date = May 2010 | pmid = 20483947 | doi = 10.1136/bmj.c1768 | s2cid = 14815504 | doi-access = free | title-link = doi }}</ref> The risk of hyperkalemia with spironolactone is greatest in the elderly, in people with [[renal impairment]] (e.g., due to [[chronic kidney disease]] or [[diabetic nephropathy]]), in people taking certain other medications (including [[ACE inhibitor|{{abbr|ACE|angiotensin-converting-enzyme}} inhibitor]]s, [[angiotensin II receptor blocker]]s, [[nonsteroidal anti-inflammatory drug]]s, the [[antibiotic]] [[trimethoprim]], and potassium [[dietary supplement|supplement]]s), and at higher dosages of spironolactone.<ref name="Aronson2009" /><ref name="RoncoBellomo2017" /><ref name="pmid21911446">{{cite journal | vauthors = Antoniou T, Gomes T, Mamdani MM, Yao Z, Hellings C, Garg AX, Weir MA, Juurlink DN | title = Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study | journal = BMJ | volume = 343 | issue = | article-number = d5228 | date = September 2011 | pmid = 21911446 | pmc = 3171211 | doi = 10.1136/bmj.d5228 }}</ref><ref name="pmid25646289">{{cite journal | vauthors = Antoniou T, Hollands S, Macdonald EM, Gomes T, Mamdani MM, Juurlink DN | title = Trimethoprim-sulfamethoxazole and risk of sudden death among patients taking spironolactone | journal = CMAJ | volume = 187 | issue = 4 | pages = E138–E143 | date = March 2015 | pmid = 25646289 | pmc = 4347789 | doi = 10.1503/cmaj.140816 }}</ref>

Although spironolactone poses an important risk of hyperkalemia in the elderly, in those with kidney or cardiovascular disease, and/or in those taking medications or supplements, which increase circulating potassium levels, a large retrospective study found that the rate of hyperkalemia in young women without such characteristics who had been treated with high doses of spironolactone for dermatological conditions did not differ from those of controls.<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 = American Journal of Clinical Dermatology | volume = 18 | issue = 2 | pages = 169–191 | date = April 2017 | pmid = 28155090 | pmc = 5360829 | doi = 10.1007/s40257-016-0245-x }}</ref><ref name="pmid26897386">{{cite journal | vauthors = Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, Bowe WP, Graber EM, Harper JC, Kang S, Keri JE, Leyden JJ, Reynolds RV, Silverberg NB, Stein Gold LF, Tollefson MM, Weiss JS, Dolan NC, Sagan AA, Stern M, Boyer KM, Bhushan R | title = Guidelines of care for the management of acne vulgaris | journal = Journal of the American Academy of Dermatology | volume = 74 | issue = 5 | pages = 945–73.e33 | date = May 2016 | pmid = 26897386 | doi = 10.1016/j.jaad.2015.12.037 | doi-access = free | title-link = doi }}</ref><ref name="pmid25796182">{{cite journal | vauthors = Plovanich M, Weng QY, Mostaghimi A | title = Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne | journal = JAMA Dermatology | volume = 151 | issue = 9 | pages = 941–4 | date = September 2015 | pmid = 25796182 | doi = 10.1001/jamadermatol.2015.34 | doi-access = free | title-link = doi }}</ref> This was the conclusion of a 2017 hybrid systematic review of studies of spironolactone for acne in women, as well, which found that hyperkalemia was rare and was invariably mild and clinically insignificant.<ref name="pmid28155090" /> These findings suggest that hyperkalemia may not be a significant risk in such individuals, and that routine monitoring of circulating potassium levels may be unnecessary in this population.<ref name="pmid28155090" /><ref name="pmid26897386" /><ref name="pmid25796182" /> Other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors.<ref name="RoncoBellomo2017" /> Occasional testing on a case-by-case basis in those with known risk factors may be justified.<ref name="pmid28155090" /> Side effects of spironolactone that may be indicative of hyperkalemia and if persistent could justify serum potassium testing include nausea, fatigue, and particularly muscle weakness.<ref name="pmid28155090" /> Notably, reduced or no routine potassium monitoring with spironolactone in young women would reduce costs associated with its use.<ref name="pmid28155090" />

Among young, gender-diverse individuals taking spironolactone, hyperkalemia is rare and (if present) transient and asymptomatic. Larger doses do not appear to increase risks in this population.<ref name="pmid31065620">{{cite journal | vauthors = Millington K, Liu E, Chan YM | title = The Utility of Potassium Monitoring in Gender-Diverse Adolescents Taking Spironolactone | journal = Journal of the Endocrine Society | volume = 3 | issue = 5 | pages = 1031–1038 | date = May 2019 | pmid = 31065620 | doi = 10.1210/js.2019-00030 | doi-access = free | title-link = doi | pmc = 6497918 }}</ref> A broader retrospective study found that the rate of hyperkalemia in gender-diverse individuals is correlated with age, with those above 45 years old being more at risk. The finding suggests that patients below or at 45 years old without other conditions that affect potassium handling can be spared from routine monitoring.<ref name="pmid36267595">{{cite journal | vauthors = Hayes H, Russell R, Haugen A, Nagavally S, Sarvaideo J | title = The Utility of Monitoring Potassium in Transgender, Gender Diverse, and Nonbinary Individuals on Spironolactone | journal = Journal of the Endocrine Society | volume = 6 | issue = 11 | article-number = bvac133 | date = October 2022 | pmid = 36267595 | doi = 10.1210/jendso/bvac133 | doi-access = free | title-link = doi | pmc = 9562816 }}</ref>

===Breast changes===
Spironolactone can cause [[mastodynia|breast pain]] and enlargement in women.<ref name="Becker2001">{{cite book|vauthors=Becker KL|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|access-date=6 May 2018|archive-date=6 October 2022|archive-url=https://web.archive.org/web/20221006095556/https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1196|url-status=live}}</ref><ref name="TsioufisSchmieder2016" /> This is "probably because of estrogenic effects on target tissue."<ref name="Aronson2009" /> At low doses, breast tenderness has been reported in only 5% of women, but at high doses, it has been reported in up to 40% of women.<ref name="ConnJacobs1998">{{cite journal | vauthors = Conn JJ, Jacobs HS | title = Managing hirsutism in gynaecological practice | journal = British Journal of Obstetrics and Gynaecology | volume = 105 | issue = 7 | pages = 687–96 | date = July 1998 | pmid = 9692407 | doi = 10.1111/j.1471-0528.1998.tb10197.x | s2cid = 34751086 }}</ref><ref name="pmid22468178" /> Breast enlargement and tenderness may occur in 26% of women at high doses.<ref name="pmid10495361">{{cite journal | vauthors = Diamanti-Kandarakis E | title = Current aspects of antiandrogen therapy in women | journal = Current Pharmaceutical Design | volume = 5 | issue = 9 | pages = 707–23 | date = September 1999 | doi = 10.2174/1381612805666230111201150 | pmid = 10495361 }}</ref> Some women regard spironolactone-induced breast enlargement as a positive effect.<ref name="pmid28155090" />

Spironolactone also commonly and dose-dependently produces [[gynecomastia]] (breast development) as a side effect in men.<ref name="SeldinGiebisch1997">{{cite book| vauthors = Seldin DW, Giebisch GH |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 |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><ref name="TsioufisSchmieder2016">{{cite book|vauthors=Tsioufis C, Schmieder R, Mancia G|title=Interventional Therapies for Secondary and Essential Hypertension|url=https://books.google.com/books?id=MFfYDAAAQBAJ&pg=PA44|date=15 August 2016|publisher=Springer|isbn=978-3-319-34141-5|page=44 |access-date=16 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093807/https://books.google.com/books?id=MFfYDAAAQBAJ&pg=PA44|url-status=live}}</ref><ref name="Elsevier2014">{{cite book|title=Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions|url=https://books.google.com/books?id=NfqxAwAAQBAJ&pg=PA293|date=1 December 2014|publisher=Elsevier Science|isbn=978-0-444-63391-0|page=293 }}</ref><ref name="McInnes2008">{{cite book|vauthors=McInnes GT|title=Clinical Pharmacology and Therapeutics of Hypertension|url=https://books.google.com/books?id=9nqP9iz7NNAC&pg=PA125|year=2008|publisher=Elsevier|isbn=978-0-444-51757-9|page=125|access-date=6 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093807/https://books.google.com/books?id=9nqP9iz7NNAC&pg=PA125|url-status=live}}</ref> At low doses, the rate is only 5 to 10%,<ref name="McInnes2008" /> but at high doses, up to or exceeding 50% of men may develop gynecomastia.<ref name="SeldinGiebisch1997"/><ref name="TsioufisSchmieder2016"/><ref name="Elsevier2014"/> In the RALES, 9.1% of men taking 25&nbsp;mg/day spironolactone developed gynecomastia, compared to 1.3% of controls.<ref name="pmid15134800" /> Conversely, in studies of healthy men given high-dose spironolactone, gynecomastia occurred in 3 of 10 (30%) at 100&nbsp;mg/day, in 5 of 8 (62.5%) at 200&nbsp;mg/day, and in 6 of 9 (66.7%) at 400&nbsp;mg/day, relative to none of 12 controls.<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="Wilcox2008">{{cite book|vauthors=Wilcox CS|title=Therapy in Nephrology and Hypertension E-Book: A Companion to Brenner & Rector's The Kidney|url=https://books.google.com/books?id=XcnpBdq84MEC&pg=PA607|date=22 August 2008|publisher=Elsevier Health Sciences|isbn=978-1-4377-1124-0|pages=607–|access-date=17 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093807/https://books.google.com/books?id=XcnpBdq84MEC&pg=PA607|url-status=live}}</ref> The severity of gynecomastia with spironolactone varies considerably, but is usually mild.<ref name="SeldinGiebisch1997" /> As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often, although inconsistently, accompanied by breast tenderness.<ref name="SeldinGiebisch1997" /> In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls.<ref name="pmid15134800" />

The time to onset of spironolactone-induced gynecomastia has been found to be 27 ± 20 months at low doses and 9 ± 12 months at high doses.<ref name="pmid15134800" /> Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication.<ref name="SeldinGiebisch1997" /> However, after a sufficient duration of gynecomastia being present (e.g., one year), [[hyalinization]] and [[fibrosis]] of the tissue occurs and drug-induced gynecomastia may become irreversible.<ref name="pmid18983216">{{cite journal | vauthors = Eckman A, Dobs A | title = Drug-induced gynecomastia | journal = Expert Opinion on Drug Safety | volume = 7 | issue = 6 | pages = 691–702 | date = November 2008 | pmid = 18983216 | doi = 10.1517/14740330802442382 | s2cid = 72716346 }}</ref><ref name="pmid11546925">{{cite journal | vauthors = Mathur R, Braunstein GD | title = Gynecomastia: pathomechanisms and treatment strategies | journal = Hormone Research | volume = 48 | issue = 3 | pages = 95–102 | date = 1997 | pmid = 11546925 | doi = 10.1159/000185497 }}</ref>

===Menstrual disturbances===
Spironolactone at higher doses can cause menstrual irregularities as a side effect in women,<ref name="pmid22468178" /> including [[metrorrhagia]] (intermenstrual bleeding), [[amenorrhea]] (absence of menstruation), and [[breakthrough bleeding]].<ref name="pmid22468178" /> They are common during spironolactone therapy, with 10 to 50% of women experiencing them at moderate doses and almost all experiencing them at a high doses.<ref name="pmid10495361" /><ref name="Aronson2009" /> For example, about 20% of women experienced menstrual irregularities with 50 to 100&nbsp;mg/day spironolactone, whereas about 70% experienced menstrual irregularities at 200&nbsp;mg/day.<ref name="pmid22468178" /> Most women taking moderate doses of spironolactone develop amenorrhea, and normal [[menstruation]] usually returns within two months of discontinuation.<ref name="Aronson2009" /> Spironolactone produces an [[irregular menstruation|irregular]] and [[anovulation|anovulatory]] pattern of [[menstrual cycle]]s.<ref name="pmid10495361" /> It is also associated with metrorrhagia and [[menorrhagia]] (heavy menstrual bleeding) in large percentages of women,<ref name="Becker2001" /> as well as with [[polymenorrhea]] (short menstrual cycles).<ref name="pmid16076921">{{cite journal | vauthors = Christy NA, Franks AS, Cross LB | title = Spironolactone for hirsutism in polycystic ovary syndrome | journal = The Annals of Pharmacotherapy | volume = 39 | issue = 9 | pages = 1517–21 | date = September 2005 | pmid = 16076921 | doi = 10.1345/aph.1G025 | s2cid = 45708497 }}</ref><ref name="pmid10792338">{{cite journal | vauthors = Spritzer PM, Lisboa KO, Mattiello S, Lhullier F | title = Spironolactone as a single agent for long-term therapy of hirsute patients | journal = Clinical Endocrinology | volume = 52 | issue = 5 | pages = 587–94 | date = May 2000 | pmid = 10792338 | doi = 10.1046/j.1365-2265.2000.00982.x | s2cid = 40606594 }}</ref> The medication reportedly has no [[contraceptive|birth control]] effect.<ref name="RabeGrunwald2009">{{cite journal| vauthors = Rabe T, Grunwald K, Feldmann K, Runnebaum B |title=Treatment of hyperandrogenism in women|journal=Gynecological Endocrinology|volume=10|issue=sup3|year=2009|pages=1–44|issn=0951-3590|doi=10.3109/09513599609045658}}</ref>

The weak progestogenic activity of spironolactone has been suggested to be responsible for these effects, although not established, and spironolactone has been shown to possess insignificant progestogenic and antiprogestogenic activity even at high dosages in women.<ref name="pmid10495361" /><ref name="pmid8144871">{{cite journal | vauthors = McMullen GR, Van Herle AJ | title = Hirsutism and the effectiveness of spironolactone in its management | journal = Journal of Endocrinological Investigation | volume = 16 | issue = 11 | pages = 925–32 | date = December 1993 | pmid = 8144871 | doi = 10.1007/BF03348960 | s2cid = 42231952 }}</ref><ref name="pmid2744183">{{cite journal | vauthors = Nakajima ST, Brumsted JR, Riddick DH, Gibson M | title = Absence of progestational activity of oral spironolactone | journal = Fertility and Sterility | volume = 52 | issue = 1 | pages = 155–8 | date = July 1989 | pmid = 2744183 | doi = 10.1016/s0015-0282(16)60807-5 }}</ref> An alternative proposed cause is inhibition of 17α-hydroxylase and hence [[sex steroid]] [[metabolism]] by spironolactone and consequent changes in sex hormone levels.<ref name="SeldinGiebisch1997" /> Indeed, ''[[CYP17A1]]'' [[genotype]] is associated with polymenorrhea.<ref name="pmid32038990">{{cite journal | vauthors = Olsson HL, Olsson ML | title = The Menstrual Cycle and Risk of Breast Cancer: A Review | journal = Frontiers in Oncology | volume = 10 | article-number = 21 | date = 2020 | pmid = 32038990 | pmc = 6993118 | doi = 10.3389/fonc.2020.00021 | doi-access = free | title-link = doi }}</ref> Regardless of their mechanism, the menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with a birth-control pill, due to the progestin component.<ref name="pmid10495361" /><ref name="JemecRevuz2006">{{cite book|vauthors=Jemec G, Revuz J, Leyden JJ|title=Hidradenitis Suppurativa|url=https://books.google.com/books?id=hpKFsXwcKlgC&pg=PA125|date=24 November 2006|publisher=Springer Science & Business Media|isbn=978-3-540-33101-8|pages=125–|access-date=15 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093808/https://books.google.com/books?id=hpKFsXwcKlgC&pg=PA125|url-status=live}}</ref>

===Mood changes===
Research is mixed on whether antimineralocorticoids such as spironolactone have positive or negative effects on [[mood (psychology)|mood]].<ref name="pmid25459896">{{cite journal | vauthors = ter Heegde F, De Rijk RH, Vinkers CH | title = The brain mineralocorticoid receptor and stress resilience | journal = Psychoneuroendocrinology | volume = 52 | pages = 92–110 | date = February 2015 | pmid = 25459896 | doi = 10.1016/j.psyneuen.2014.10.022 | hdl-access = free | s2cid = 14297156 | hdl = 1874/331554 }}</ref><ref name="Schultebraucks2016">{{cite thesis | vauthors = Schultebraucks K | title = The Role of the Mineralocorticoid Receptor for Cognitive Function, Mood and Social Cognition |type=Dissertation| date = 2016 | url = https://refubium.fu-berlin.de/handle/fub188/2739 | format = PDF | doi = 10.17169/refubium-6940 | access-date = 27 December 2018 | archive-date = 28 December 2018 | archive-url = https://web.archive.org/web/20181228082908/https://refubium.fu-berlin.de/handle/fub188/2739 | url-status = live }}</ref><ref name="pmid10367986">{{cite journal | vauthors = Holsboer F | title = The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety | journal = Journal of Psychiatric Research | volume = 33 | issue = 3 | pages = 181–214 | date = 1999 | pmid = 10367986 | doi = 10.1016/S0022-3956(98)90056-5 }}</ref> In any case, spironolactone might have the capacity to increase the risk of [[depression (mood)|depressive]] symptoms.<ref name="pmid25459896" /><ref name="Schultebraucks2016" /><ref name="pmid10367986" /> However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%.<ref name="pmid28155090" /> Likewise, a 10-year observational study found that the incidence of depression in 196&nbsp;transgender women taking high-dose<!--300 mg/day--> spironolactone in combination with an estrogen was less than 1%.<ref name="BassonPrior1997">{{cite book | vauthors = Basson R, Prior JC | chapter = Hormonal Therapy of Gender Dysphoria: The Male-to-Female Transsexual | pages = 277–296 | doi = 10.4324/9780203775134 | title = Current Concepts in Transgender Identity | veditors = Denny D | year = 1998 | publisher = Taylor & Francis | isbn = 978-1-134-82110-5 | chapter-url = https://books.google.com/books?id=zJBvR-Zy7LgC&pg=PA286 | access-date = 2 January 2019 | archive-date = 7 October 2022 | archive-url = https://web.archive.org/web/20221007093807/https://books.google.com/books?id=zJBvR-Zy7LgC&pg=PA286 | url-status = live }}</ref>

===Lipid changes===
Spironolactone has been found to increase [[LDL cholesterol|LDL ("bad") cholesterol]] and decrease [[HDL cholesterol|HDL ("good") cholesterol]] levels at the relatively high doses used in women with [[polycystic ovary syndrome]]<!-- (PCOS) -->.<ref name="pmid28944709">{{cite journal | vauthors = Baldani DP, Skrgatic L, Ougouag R, Kasum M | title = The cardiometabolic effect of current management of polycystic ovary syndrome: strategies of prevention and treatment | journal = Gynecol Endocrinol | volume = 34 | issue = 2 | pages = 87–91 | date = February 2018 | pmid = 28944709 | doi = 10.1080/09513590.2017.1381681 | s2cid = 205631980 }}</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 = Br J Clin Pharmacol | volume = 68 | issue = 4 | pages = 634–7 | date = October 2009 | pmid = 19843067 | pmc = 2780289 | doi = 10.1111/j.1365-2125.2009.03483.x }}</ref> As such, it may have unfavorable effects on the [[blood lipids|blood]] [[lipid profile]] in this context.<ref name="pmid28944709" /><ref name="pmid19843067" /> Heightened LDL cholesterol levels are a potential [[risk factor]] for [[cardiovascular disease]], such as [[atherosclerosis]] or [[coronary heart disease]].<ref name="pmid30586774">{{cite journal | vauthors = Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L, Virani SS, Yeboah J | title = 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines | journal = Circulation | volume = 139 | issue = 25 | pages = e1082–e1143 | date = June 2019 | pmid = 30586774 | pmc = 7403606 | doi = 10.1161/CIR.0000000000000625 }}</ref> Consequently, spironolactone probably should not be given to women with [[dyslipidemia]] (e.g., [[hypercholesterolemia|high cholesterol]]).<ref name="pmid28944709" /><ref name="pmid19843067" /> Unfavorable lipid changes have also been seen with other antiandrogens, such as cyproterone acetate<ref name="WPATH-SOC8">{{cite journal | vauthors = Coleman E, Radix AE, Bouman WP, Brown GR, de Vries AL, Deutsch MB, Ettner R, Fraser L, Goodman M, Green J, Hancock AB, Johnson TW, Karasic DH, Knudson GA, Leibowitz SF, Meyer-Bahlburg HF, Monstrey SJ, Motmans J, Nahata L, Nieder TO, Reisner SL, Richards C, Schechter LS, Tangpricha V, Tishelman AC, Van Trotsenburg MA, Winter S, Ducheny K, Adams NJ, Adrián TM, Allen LR, Azul D, Bagga H, Başar K, Bathory DS, Belinky JJ, Berg DR, Berli JU, Bluebond-Langner RO, Bouman M, Bowers ML, Brassard PJ, Byrne J, Capitán L, Cargill CJ, Carswell JM, Chang SC, Chelvakumar G, Corneil T, Dalke KB, De Cuypere G, de Vries E, Den Heijer M, Devor AH, Dhejne C, D'Marco A, Edmiston EK, Edwards-Leeper L, Ehrbar R, Ehrensaft D, Eisfeld J, Elaut E, Erickson-Schroth L, Feldman JL, Fisher AD, Garcia MM, Gijs L, Green SE, Hall BP, Hardy TL, Irwig MS, Jacobs LA, Janssen AC, Johnson K, Klink DT, Kreukels BP, Kuper LE, Kvach EJ, Malouf MA, Massey R, Mazur T, McLachlan C, Morrison SD, Mosser SW, Neira PM, Nygren U, Oates JM, Obedin-Maliver J, Pagkalos G, Patton J, Phanuphak N, Rachlin K, Reed T, Rider GN, Ristori J, Robbins-Cherry S, Roberts SA, Rodriguez-Wallberg KA, Rosenthal SM, Sabir K, Safer JD, Scheim AI, Seal LJ, Sehoole TJ, Spencer K, St Amand C, Steensma TD, Strang JF, Taylor GB, Tilleman K, T'Sjoen GG, Vala LN, Van Mello NM, Veale JF, Vencill JA, Vincent B, Wesp LM, West MA, Arcelus J| title = Standards of Care for the Health of Transgender and Gender Diverse People, Version 8 | journal = [[International Journal of Transgender Health]] | date = August 2022 | volume = 23 | issue = Suppl 1 | pages = S1–S259 | issn = 2689-5269 | doi = 10.1080/26895269.2022.2100644 | doi-access = free | title-link = doi | pmid = 36238954 | pmc = 9553112 }}</ref><ref name="pmid3318361">{{cite journal | vauthors = Godsland IF, Wynn V, Crook D, Miller NE | title = Sex, plasma lipoproteins, and atherosclerosis: prevailing assumptions and outstanding questions | journal = American Heart Journal | volume = 114 | issue = 6 | pages = 1467–1503 | date = December 1987 | pmid = 3318361 | doi = 10.1016/0002-8703(87)90552-7 }}</ref> and [[bicalutamide]].<ref name="pmid33334002">{{cite journal | vauthors = Cignarella A, Mioni R, Sabbadin C, Dassie F, Parolin M, Vettor R, Barbot M, Scaroni C | title = Pharmacological Approaches to Controlling Cardiometabolic Risk in Women with PCOS | journal = Int J Mol Sci | volume = 21 | issue = 24 | date = December 2020 | page = 9554 | pmid = 33334002 | pmc = 7765466 | doi = 10.3390/ijms21249554 | doi-access = free | title-link = doi }}</ref><ref name="pmid29211888"/>

===Rare reactions===
Aside from hyperkalemia, spironolactone may rarely cause adverse reactions such as [[anaphylaxis]], [[kidney failure]],<ref name="pmid19006114">{{cite journal | vauthors = Lopes RJ, Lourenço AP, Mascarenhas J, Azevedo A, Bettencourt P | title = Safety of spironolactone use in ambulatory heart failure patients | journal = Clinical Cardiology | volume = 31 | issue = 11 | pages = 509–13 | date = November 2008 | pmid = 19006114 | pmc = 6652974 | doi = 10.1002/clc.20284 }}</ref> [[hepatitis]] (two reported cases, neither serious),<ref name="ThaiSinclair2001">{{cite journal | vauthors = Thai KE, Sinclair RD | title = Spironolactone-induced hepatitis | journal = The Australasian Journal of Dermatology | volume = 42 | issue = 3 | pages = 180–2 | date = August 2001 | pmid = 11488711 | doi = 10.1046/j.1440-0960.2001.00510.x | s2cid = 12160891 }}</ref> [[agranulocytosis]], [[DRESS syndrome]], [[Stevens–Johnson syndrome]], or [[toxic epidermal necrolysis]].<ref>{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258786.htm |title=Aldactazide (spironolactone/hydrochlorothiazide) Tablets |website=U.S. [[Food and Drug Administration]] (FDA) |access-date=3 March 2014 |archive-url=https://web.archive.org/web/20150310163603/https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm258786.htm |archive-date=10 March 2015 }}</ref><ref>online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7699#f_adverse-reactions</ref> Five cases of [[breast cancer]] in patients who took spironolactone for prolonged periods of time have been reported.<ref name="Aronson2009"/><ref name="McInnes2008" />

===Spironolactone bodies===
[[File:Spironolactone bodies.png|thumb|175px|[[Micrograph]] ([[H&E stain]]) of an [[adrenal gland]] showing spironolactone bodies]]

Long-term administration of spironolactone gives the [[histologic]] characteristic of "spironolactone bodies" in the [[adrenal cortex]], which are [[eosinophilic]], round, concentrically laminated [[cytoplasm]]ic inclusions surrounded by clear halos in preparations stained with [[hematoxylin]] and [[eosin]].<ref name="pmid7195152">{{cite journal | vauthors = Aiba M, Suzuki H, Kageyama K, Murai M, Tazaki H, Abe O, Saruta T | title = Spironolactone bodies in aldosteronomas and in the attached adrenals. Enzyme histochemical study of 19 cases of primary aldosteronism and a case of aldosteronism due to bilateral diffuse hyperplasia of the zona glomerulosa | journal = The American Journal of Pathology | volume = 103 | issue = 3 | pages = 404–10 | date = June 1981 | pmid = 7195152 | pmc = 1903848 }}</ref>

===Pregnancy and breastfeeding===
Spironolactone can cross the [[placenta]].<ref name="Becker2001" /> It has been found in the breast milk of lactating mothers,<ref name="Aldactone label" /> but only very small amounts of spironolactone and its metabolite canrenone enter [[breast milk]], and the amount received by an infant during breastfeeding (<0.5% of the mother's dose) is considered to be insignificant.<ref name="Ainsworth2014" />

A study found that spironolactone was not associated with [[teratogen]]icity in the offspring of rats.<ref name="Little2006">{{cite book| vauthors = Little B |title=Drugs and Pregnancy: A Handbook|url=https://books.google.com/books?id=lnySHcBjXsEC&pg=PA63|date=29 September 2006|publisher=CRC Press|isbn=978-0-340-80917-4|pages=63–|url-status=live|archive-url=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=lnySHcBjXsEC&pg=PA63|archive-date=8 September 2017}}</ref><ref name="RubinRamsey2008">{{cite book| vauthors = Rubin PC, Ramsey M |title=Prescribing in Pregnancy|url=https://books.google.com/books?id=2zHGHec53oMC&pg=PA83|date=30 April 2008|publisher=John Wiley & Sons|isbn=978-0-470-69555-5|pages=83–|url-status=live|archive-url=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=2zHGHec53oMC&pg=PA83|archive-date=8 September 2017}}</ref><ref name="BriggsFreeman2011">{{cite book| vauthors = Briggs GG, Freeman RK, Yaffe SJ |title=Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk|url=https://books.google.com/books?id=OIgTE4aynrMC&pg=PA1349|year=2011|publisher=Lippincott Williams & Wilkins|isbn=978-1-60831-708-0|pages=1349–|url-status=live|archive-url=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=OIgTE4aynrMC&pg=PA1349|archive-date=8 September 2017}}</ref> Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses.<ref name="Little2006" /><ref name="RubinRamsey2008" /> In accordance, a subsequent study found that partial feminization of the genitalia occurred in the male offspring of rats that received doses of spironolactone that were five times higher than those normally used in humans (200&nbsp;mg/kg per day).<ref name="Little2006" /><ref name="BriggsFreeman2011" /> Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100&nbsp;mg/kg per day).<ref name="BriggsFreeman2011" />

In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans.<ref name="Little2006" /><ref name="RubinRamsey2008" /><ref name="ElkayamGleicher1998">{{cite book| vauthors = Gleicher N, Elkayam U, Gleicher N |title=Cardiac Problems in Pregnancy: Diagnosis and Management of Maternal and Fetal Heart Disease|url=https://books.google.com/books?id=z6E-Hgeu1nYC&pg=PA353|date=23 June 1998|publisher=John Wiley & Sons|isbn=978-0-471-16358-9|pages=353–|url-status=live|archive-url=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=z6E-Hgeu1nYC&pg=PA353|archive-date=8 September 2017}}</ref><ref name="Schaefer2001">{{cite book| vauthors = Schaefer C |title=Drugs During Pregnancy and Lactation: Handbook of Prescription Drugs and Comparative Risk Assessment|url=https://books.google.com/books?id=CE569saGK70C&pg=PA115|year=2001|publisher=Gulf Professional Publishing|isbn=978-0-444-50763-1|pages=115, 143|url-status=live|archive-url=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=CE569saGK70C&pg=PA115|archive-date=8 September 2017}}</ref> Among 31 human newborns exposed to spironolactone in the first trimester, no signs of any specific [[birth defect]]s were seen.<ref name="Schaefer2001" /> A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy; no observable  feminization occurred in the boy.<ref name="Schaefer2001" /> In addition, spironolactone has been used at high doses to treat pregnant women with [[Bartter's syndrome]], and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants.<ref name="Ainsworth2014">{{cite book| vauthors = Ainsworth SB |title=Neonatal Formulary: Drug Use in Pregnancy and the First Year of Life|url=https://books.google.com/books?id=VOLhBQAAQBAJ&pg=PA486|date=10 November 2014|publisher=John Wiley & Sons|isbn=978-1-118-81959-3|pages=486–|url-status=live|archive-url=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=VOLhBQAAQBAJ&pg=PA486|archive-date=8 September 2017}}</ref><ref name="Little2006"/> Similar findings, albeit also limited, exist for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human abnormalities (including feminization of male fetuses) at both a low dose of 2&nbsp;mg/day or high doses of 50 to 100&nbsp;mg/day).<ref name="Schaefer2001" /> In any case, spironolactone is nonetheless not recommended during pregnancy due to theoretical concerns relating to feminization of males and also to potential alteration of fetal potassium levels.<ref name="Little2006" /><ref name="Upfal2006">{{cite book| vauthors = Upfal J |title=Australian Drug Guide|url=https://books.google.com/books?id=7O9kiqN2q2YC&pg=PA671|year=2006|publisher=Black Inc.|isbn=978-1-86395-174-6|pages=671–|url-status=live|archive-url=https://web.archive.org/web/20170908165041/https://books.google.com/books?id=7O9kiqN2q2YC&pg=PA671|archive-date=8 September 2017}}</ref>

A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans.<ref name="pmid30352280">{{cite journal | vauthors = Liszewski W, Boull C | title = Lack of evidence for feminization of males exposed to spironolactone in utero: A systematic review | journal = Journal of the American Academy of Dermatology | volume = 80 | issue = 4 | pages = 1147–1148 | date = April 2019 | pmid = 30352280 | doi = 10.1016/j.jaad.2018.10.023 | s2cid = 53022388 | doi-access = free | title-link = doi }}</ref> Evidence was insufficient to be certain that it does not.<ref name="pmid30352280" />

==Overdose==
Spironolactone is relatively safe in acute [[overdose]].<ref name="Aldactone label" /> [[Symptom]]s following an acute overdose of spironolactone may include [[drowsiness]], [[mental confusion|confusion]], [[maculopapular rash|maculopapular]] or [[erythematous rash]], [[nausea]], [[vomiting]], [[dizziness]], and [[diarrhea]].<ref name="Aldactone label" /> In rare cases, [[hyponatremia]], [[hyperkalemia]], or [[hepatic coma]] may occur in individuals with [[severe liver disease]].<ref name="Aldactone label" /> These [[adverse reaction]]s are unlikely, though, in the event of an acute overdose.<ref name="Aldactone label" /> Hyperkalemia can occur following an overdose of spironolactone, and this is especially so in people with decreased kidney function.<ref name="Aldactone label" /> Spironolactone has been studied at extremely high oral doses of up to 2,400&nbsp;mg per day in [[clinical trial]]s.<ref name="pmid28634268" /><ref name="pmid15134797">{{cite journal | vauthors = Garthwaite SM, McMahon EG | title = The evolution of aldosterone antagonists | journal = Molecular and Cellular Endocrinology | volume = 217 | issue = 1–2 | pages = 27–31 | date = March 2004 | pmid = 15134797 | doi = 10.1016/j.mce.2003.10.005 | s2cid = 8499861 }}</ref> Its oral [[median lethal dose]] (LD<sub>50</sub>) is more than 1,000&nbsp;mg/kg in mice, rats, and rabbits.<ref name="Aldactone label" />

No specific [[antidote]] for overdose of spironolactone is known.<ref name="Aldactone label" /> Treatment may consist of induction of vomiting or stomach evacuation by [[gastric lavage]].<ref name="Aldactone label" /> The treatment of spironolactone overdose is supportive, with the purpose of maintaining [[tissue hydration|hydration]], [[electrolyte balance]], and [[vital function]]s.<ref name="Aldactone label" /> Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia.<ref name="Aldactone label" />

== Interactions ==

Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, people using this medication should avoid potassium supplements and salt substitutes containing potassium.<ref>{{cite web | title = Advisory Statement | publisher = Klinge Chemicals / LoSalt | url = http://www.losalt.com/docs/lo_salt_web_advice.pdf | access-date = 15 March 2007 | archive-url = https://web.archive.org/web/20061115185827/http://www.losalt.com/docs/lo_salt_web_advice.pdf | archive-date = 15 November 2006 }}</ref> Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first 12 months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. Recent data suggest<!-- data is the plural of datum --> that both potassium monitoring and dietary restriction of potassium intake are unnecessary in healthy young women taking spironolactone for acne<ref name="pmid25796182"/> and in healthy, young, gender-diverse individuals taking spironolactone for hormone therapy.<ref name="pmid36267595"/> Spironolactone together with [[trimethoprim/sulfamethoxazole]] increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.<ref>{{cite journal | vauthors = Juvet T, Gourineni VC, Ravi S, Zarich SW | title = Life-threatening hyperkalemia: a potentially lethal drug combination | journal = Connecticut Medicine | volume = 77 | issue = 8 | pages = 491–3 | date = September 2013 | pmid = 24156179 }}</ref>

Spironolactone has been reported to induce the [[enzyme]]s [[CYP3A4]] and certain [[UDP-glucuronosyltransferase]]s <!-- (UGTs) -->, which can result in [[drug interaction|interaction]]s with various medications.<ref name="Parkinson2001" /><ref name="Davis2009">{{cite book|vauthors=Davis MP|title=Opioids in Cancer Pain|url=https://books.google.com/books?id=aEzg6i2nPMQC&pg=PA222|date=28 May 2009|publisher=OUP Oxford|isbn=978-0-19-923664-0|pages=222–|access-date=6 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094310/https://books.google.com/books?id=aEzg6i2nPMQC&pg=PA222|url-status=live}}</ref><ref name="pmid1826112">{{cite journal | vauthors = Shaw JC | title = Spironolactone in dermatologic therapy | journal = Journal of the American Academy of Dermatology | volume = 24 | issue = 2 Pt 1 | pages = 236–43 | date = February 1991 | pmid = 1826112 | doi = 10.1016/0190-9622(91)70034-Y }}</ref> However,  metabolites of spironolactone reortedly [[irreversible inhibition|irreversibly inhibit]] CYP3A4.<ref name="Wolverton2007">{{cite book|vauthors=Wolverton SE|title=Comprehensive Dermatologic Drug Therapy|url=https://books.google.com/books?id=AaJwq_X6U6MC&pg=PT2677|date=8 March 2007|publisher=Elsevier Health Sciences|isbn=978-1-4377-2070-9|pages=2677–|access-date=7 May 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094310/https://books.google.com/books?id=AaJwq_X6U6MC&pg=PT2677|url-status=live}}</ref> In any case, spironolactone has been found to reduce the [[bioavailability]] of oral [[estradiol (medication)|estradiol]], which could be due to induction of estradiol metabolism via CYP3A4.<ref name="pmid29756046">{{cite journal | vauthors = Leinung MC, Feustel PJ, Joseph J | title = Hormonal Treatment of Transgender Women with Oral Estradiol | journal = Transgender Health | volume = 3 | issue = 1 | pages = 74–81 | date = 2018 | pmid = 29756046 | pmc = 5944393 | doi = 10.1089/trgh.2017.0035 }}</ref> Spironolactone has also been found to [[enzyme inhibitor|inhibit]] [[UGT2B7]].<ref name="JhajraRamesh Varkhede2012">{{cite book | vauthors = Jhajra S, Ramesh Varkhede N, Suresh Ahire D, Vidyasagar Naik B, Prasad B, Paliwal J, Singh S | chapter = Extrahepatic Drug-Metabolizing Enzymes and Their Significance | title=Encyclopedia of Drug Metabolism and Interactions |year=2012| pages = 1–99 | publisher = Wiley |doi=10.1002/9780470921920.edm028|isbn=978-0-470-92192-0}}</ref> Spironolactone can also have numerous other interactions, most commonly with other [[cardiac]] and blood-pressure medications, for instance [[digoxin]].<ref name="Aldactone label">{{cite web | title=Aldactone- spironolactone tablet, film coated | website=DailyMed | date=29 November 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0fed2822-3a03-4b64-9857-c682fcd462bc | access-date=1 January 2020 | archive-date=10 September 2015 | archive-url=https://web.archive.org/web/20150910033318/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0fed2822-3a03-4b64-9857-c682fcd462bc | url-status=live }}</ref>

[[Licorice]], which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone.<ref name="pmid27450358" /><ref name="pmid17113210">{{cite journal | vauthors = Armanini D, Castello R, Scaroni C, Bonanni G, Faccini G, Pellati D, Bertoldo A, Fiore C, Moghetti P | title = Treatment of polycystic ovary syndrome with spironolactone plus licorice | journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology | volume = 131 | issue = 1 | pages = 61–67 | date = March 2007 | pmid = 17113210 | doi = 10.1016/j.ejogrb.2006.10.013 }}</ref><ref name="pmid13991036">{{cite journal | vauthors = Salassa RM, Mattox VR, Rosevear JW | title = Inhibition of the "mineralocorticoid" activity of licorice by spironolactone | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 22 | issue = 11 | pages = 1156–9 | date = November 1962 | pmid = 13991036 | doi = 10.1210/jcem-22-11-1156 }}</ref> Moreover, the addition of licorice to spironolactone has been found to reduce the antimineralocorticoid side effects of spironolactone in women treated with it for hyperandrogenism, and licorice hence may be used to reduce these side effects in women treated with spironolactone as an antiandrogen who are bothered by them.<ref name="pmid27450358" /><ref name="pmid17113210" /> Conversely, spironolactone is useful in reversing licorice-induced hypokalemia.<ref name="pmid23185686">{{cite journal | vauthors = Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, Yerramadha MR, Ali Y, Helal E, Camporesi EM | title = Licorice abuse: time to send a warning message | journal = Therapeutic Advances in Endocrinology and Metabolism | volume = 3 | issue = 4 | pages = 125–38 | date = August 2012 | pmid = 23185686 | pmc = 3498851 | doi = 10.1177/2042018812454322 }}</ref><ref name="pmid12640291">{{cite journal | vauthors = Lin SH, Yang SS, Chau T, Halperin ML | title = An unusual cause of hypokalemic paralysis: chronic licorice ingestion | journal = The American Journal of the Medical Sciences | volume = 325 | issue = 3 | pages = 153–6 | date = March 2003 | pmid = 12640291 | doi = 10.1097/00000441-200303000-00008 }}</ref> [[Aspirin]] and other [[nonsteroidal anti-inflammatory drug|NSAIDs]] have been found to attenuate the [[diuresis]] and [[natriuresis]] induced by spironolactone, but not to affect its antihypertensive effect.<ref name="EndouHosoyamada1995" /><ref name="pmid17362671">{{cite journal | vauthors = Parthasarathy HK, MacDonald TM | title = Mineralocorticoid receptor antagonists | journal = Current Hypertension Reports | volume = 9 | issue = 1 | pages = 45–52 | date = March 2007 | pmid = 17362671 | doi = 10.1007/s11906-007-0009-3 | s2cid = 2090391 }}</ref>

Some research has suggested that spironolactone might be able to interfere with the effectiveness of antidepressant treatment. As the medication acts as an antimineralocorticoid, it might be able to reduce the effectiveness of certain antidepressants by interfering with normalization of the [[hypothalamic–pituitary–adrenal axis]] and by increasing levels of glucocorticoids such as [[cortisol]].<ref>Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).</ref><ref name="pmid19909979">{{cite journal | vauthors = Otte C, Hinkelmann K, Moritz S, Yassouridis A, Jahn H, Wiedemann K, Kellner M | title = Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study | journal = Journal of Psychiatric Research | volume = 44 | issue = 6 | pages = 339–46 | date = April 2010 | pmid = 19909979 | doi = 10.1016/j.jpsychires.2009.10.006 }}</ref> Other research contradicts this hypothesis and has suggested that spironolactone might produce antidepressant effect, for instance, in studies showing antidepressant-like effects of spironolactone in animals.<ref name="pmid21515309">{{cite journal | vauthors = Mostalac-Preciado CR, de Gortari P, López-Rubalcava C | title = Antidepressant-like effects of mineralocorticoid but not glucocorticoid antagonists in the lateral septum: interactions with the serotonergic system | journal = Behavioural Brain Research | volume = 223 | issue = 1 | pages = 88–98 | date = September 2011 | pmid = 21515309 | doi = 10.1016/j.bbr.2011.04.008 | s2cid = 26986501 }}</ref>

==Pharmacology==

===Pharmacodynamics===
{{Main|Pharmacodynamics of spironolactone}}
[[File:7α-Thiomethylspironolactone.svg|class=skin-invert-image|thumb|[[7α-Thiomethylspironolactone]], the major [[active metabolite|active form]] of spironolactone. It accounts for about 80% of the potassium-sparing effect of spironolactone.<ref name="pmid15947888"/><ref name="AgustiBourgeois2013"/><ref name="CancerOrganization2001"/>]]
[[File:Canrenone.svg|class=skin-invert-image|thumb|[[Canrenone]], the second major [[active metabolite|active form]] of spironolactone. It accounts for around 10 to 25% of the potassium-sparing effect of spironolactone.<ref name="GinésArroyo2008">{{cite book|vauthors=Ginés P, Arroyo V, Rodés J, Schrier RW|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|access-date=6 May 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007092802/https://books.google.com/books?id=Z3PARx4oYDgC&pg=PA231|url-status=live}}</ref>]]

The [[pharmacodynamics]] of spironolactone are characterized by high [[antimineralocorticoid]] activity, moderate [[antiandrogen]]ic activity, and weak [[steroidogenesis inhibitor|steroidogenesis inhibition]], among other more minor activities.<ref name="pmid28634268" /><ref name="pmid984618" /><ref name="pmid8094898" /> Spironolactone is a [[prodrug]], so most of its actions are actually mediated by its various [[active metabolite]]s.<ref name="pmid28634268" /> The major active forms of spironolactone are [[7α-thiomethylspironolactone]] (7α-TMS) and [[canrenone]] (7α-desthioacetyl-δ<sup>6</sup>-spironolactone).<ref name="pmid15947888"/><ref name="pmid28634268" />

Spironolactone is a [[potency (pharmacology)|potent]] antimineralocorticoid.<ref name="pmid15947888"/> That is, it is an [[receptor antagonist|antagonist]] of the [[mineralocorticoid receptor]] (MR), the [[biological target]] of [[mineralocorticoid]]s like [[aldosterone]] and [[11-deoxycorticosterone]].<ref name="pmid15947888"/> By blocking the MR, spironolactone inhibits the effects of mineralocorticoids in the body.<ref name="pmid15947888"/> The antimineralocorticoid activity of spironolactone is responsible for its therapeutic efficacy in the treatment of [[edema]], [[high blood pressure]], [[heart failure]], [[hyperaldosteronism]], and [[ascites]] due to [[cirrhosis]].<ref name="Feldman2008">{{cite book|vauthors=Feldman AM|title=Heart Failure: Pharmacologic Management|url=https://books.google.com/books?id=6IfumyQQ35wC&pg=PA89|date=15 April 2008|publisher=John Wiley & Sons|isbn=978-1-4051-7253-0|pages=89–103|access-date=13 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094310/https://books.google.com/books?id=6IfumyQQ35wC&pg=PA89|url-status=live}}</ref><ref name="Health2015">{{cite book | publisher = Wolter Kluwer Health | title = Pharmacology | edition = 6th | vauthors = Walar K | url = https://books.google.com/books?id=AK1fDwAAQBAJ&pg=PA248 | date = 15 June 2015 | pages = 248–249 | id = GGKEY:N57K51AQ0UA }}{{Dead link|date=January 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> It is also responsible for many of the side effects of spironolactone, such as [[urinary frequency]], [[dehydration]], [[hyponatremia]], [[low blood pressure]], [[fatigue (medical)|fatigue]], [[dizziness]], [[metabolic acidosis]], decreased [[kidney function]], and its risk of [[hyperkalemia]].<ref name="pmid24456327">{{cite journal | vauthors = Tamargo J, Segura J, Ruilope LM | title = Diuretics in the treatment of hypertension. Part 2: loop diuretics and potassium-sparing agents | journal = Expert Opinion on Pharmacotherapy | volume = 15 | issue = 5 | pages = 605–21 | date = April 2014 | pmid = 24456327 | doi = 10.1517/14656566.2014.879117 | s2cid = 2338377 }}</ref> Due to the antimineralocorticoid activity of spironolactone, levels of [[aldosterone]] are significantly increased by the medication, probably reflecting an attempt of the body to maintain [[homeostasis]].<ref name="pmid9420861">{{cite journal | vauthors = Diamanti-Kandarakis E, Tolis G, Duleba AJ | title = Androgens and therapeutic aspects of antiandrogens in women | journal = Journal of the Society for Gynecologic Investigation | volume = 2 | issue = 4 | pages = 577–92 | date = 1995 | pmid = 9420861 | doi = 10.1177/107155769500200401 | s2cid = 32242838 }}</ref><ref name="pmid10495361" />

Spironolactone is a moderate antiandrogen.<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 | vauthors = Loriaux DL }}</ref><ref name="pmid8144871" /><ref name="pmid1826112" /> That is, it is an [[receptor antagonist|antagonist]] of the [[androgen receptor]] (AR), the biological target of [[androgen]]s like [[testosterone]] and [[dihydrotestosterone]] (DHT).<ref name="pmid984618" /><ref name="pmid8144871" /><ref name="pmid1826112" /> By blocking the AR, spironolactone inhibits the effects of androgens in the body.<ref name="pmid984618" /><ref name="pmid8144871" /><ref name="pmid1826112" /> The antiandrogenic activity of spironolactone is mainly responsible for its therapeutic efficacy in the treatment of [[androgen-dependent condition|androgen-dependent]] [[cutaneous condition|skin and hair condition]]s like [[acne]], [[seborrhea]], [[hirsutism]], and [[pattern hair loss]] and [[hyperandrogenism]] in women, [[precocious puberty]] in boys with [[testotoxicosis]], and as a component of [[feminizing hormone therapy]] for [[transgender women]].<ref name="pmid8144871" /><ref name="pmid29756046" /><ref name="pmid11322868">{{cite journal | vauthors = Doggrell SA, Brown L | title = The spironolactone renaissance | journal = Expert Opinion on Investigational Drugs | volume = 10 | issue = 5 | pages = 943–54 | date = May 2001 | pmid = 11322868 | doi = 10.1517/13543784.10.5.943 | s2cid = 39820875 }}</ref> It is also primarily responsible for some of its side effects, like [[breast tenderness]], [[gynecomastia]], [[feminization (biology)|feminization]], and [[demasculinization]] in men.<ref name="SeldinGiebisch1997" /><ref name="pmid11322868" /> Blockade of androgen signaling in the [[breast]] disinhibits the actions of [[estrogen]]s in this tissue.<ref name="StraussIII2013">{{cite book|vauthors=Strauss III JF, Barbieri RL|title=Yen and Jaffe's Reproductive Endocrinology|url=https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA237|date=13 September 2013|publisher=Elsevier Health Sciences|isbn=978-1-4557-2758-2|pages=237–|access-date=13 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094311/https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA237|url-status=live}}</ref> Although useful as an antiandrogen in women, who have low testosterone levels compared to men,<ref name="pmid2941190">{{cite journal | vauthors = Tremblay RR | title = Treatment of hirsutism with spironolactone | journal = Clinics in Endocrinology and Metabolism | 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|vauthors=Haff GG, Triplett NT|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–|access-date=14 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094311/https://books.google.com/books?id=bfuXCgAAQBAJ&pg=PA76|url-status=live}}</ref> spironolactone is described as having relatively weak antiandrogenic activity.<ref name="Wu2012">{{cite book|vauthors=Wu JJ|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–|access-date=6 May 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007093304/https://books.google.com/books?id=Tqpsm5WKKlcC&pg=PA364|url-status=live}}</ref><ref name="pmid11322868" /><ref name="BenniVemer1990">{{cite book|vauthors=Coelingh Benni HJ, Vemer HM|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–|access-date=6 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094812/https://books.google.com/books?id=q6zqFrCLUoIC&pg=PA152|url-status=live}}</ref><ref name="pmid8915726">{{cite journal | vauthors = Shaw JC | title = Antiandrogen therapy in dermatology | journal = International Journal of Dermatology | volume = 35 | issue = 11 | pages = 770–8 | date = November 1996 | pmid = 8915726 | doi = 10.1111/j.1365-4362.1996.tb02970.x | s2cid = 39334280 }}</ref>

Spironolactone is a weak steroidogenesis inhibitor.<ref name="pmid984618" /><ref name="pmid8094898"/><ref name="pmid8144871" /><ref name="pmid6786868">{{cite journal | vauthors = Colby HD | title = Chemical suppression of steroidogenesis | journal = Environmental Health Perspectives | volume = 38 | pages = 119–27 | date = April 1981 | pmid = 6786868 | pmc = 1568425 | doi = 10.1289/ehp.8138119 | bibcode = 1981EnvHP..38..119C }}</ref> That is, it inhibits [[steroidogenic enzyme]]s, or [[enzyme]]s involved in the [[steroidogenesis|production of steroid hormone]]s.<ref name="pmid984618" /><ref name="pmid8094898" /><ref name="pmid8144871" /><ref name="pmid6786868" /> Spironolactone and/or its metabolites have been found ''[[in vitro]]'' to weakly [[enzyme inhibitor|inhibit]] a broad array of steroidogenic enzymes including [[cholesterol side-chain cleavage enzyme]], [[17α-hydroxylase]], [[17,20-lyase]], [[5α-reductase]], [[3β-hydroxysteroid dehydrogenase]], [[11β-hydroxylase]], [[21-hydroxylase]], and [[aldosterone synthase]] (18-hydroxylase).<ref name="pmid8144871" /><ref name="pmid6786868" /><ref name="pmid26001184">{{cite journal | vauthors = Rocca ML, Venturella R, Mocciaro R, Di Cello A, Sacchinelli A, Russo V, Trapasso S, Zullo F, Morelli M | title = Polycystic ovary syndrome: chemical pharmacotherapy | journal = Expert Opinion on Pharmacotherapy | volume = 16 | issue = 9 | pages = 1369–93 | date = June 2015 | pmid = 26001184 | doi = 10.1517/14656566.2015.1047344 | s2cid = 43770017 }}</ref><ref name="pmid18819053">{{cite journal | vauthors = Ye P, Yamashita T, Pollock DM, Sasano H, Rainey WE | title = Contrasting effects of eplerenone and spironolactone on adrenal cell steroidogenesis | journal = Hormone and Metabolic Research | volume = 41 | issue = 1 | pages = 35–9 | date = January 2009 | pmid = 18819053 | pmc = 4277847 | doi = 10.1055/s-0028-1087188 }}</ref> However, although very high doses of spironolactone can considerably decrease steroid hormone levels in animals, spironolactone has shown mixed and inconsistent effects on steroid hormone levels in clinical studies, even at high clinical doses.<ref name="pmid28155090" /><ref name="pmid984618" /><ref name="pmid8094898" /><ref name="pmid8144871" /><ref name="pmid1826112" /> In any case, the levels of most steroid hormones, including testosterone and [[cortisol]], are usually unchanged by spironolactone in humans, which may in part be related to compensatory upregulation of their synthesis.<ref name="pmid984618" /><ref name="pmid8094898" /><ref name="WattsFaingold2009">{{cite book| vauthors = Watts S, Faingold C, Dunaway G, Crespo L |title=Brody's Human Pharmacology - E-Book|url=https://books.google.com/books?id=kfsrz_-OrMQC&pg=PA472|date=1 April 2009|publisher=Elsevier Health Sciences|isbn=978-0-323-07575-6|pages=472–}}</ref> The weak steroidogenesis inhibition of spironolactone might contribute to its antiandrogenic efficacy to some degree and may explain its side effect of menstrual irregularities in women.<ref name="pmid984618" /><ref name="SeldinGiebisch1997" /> However, its androgen synthesis inhibition is probably clinically insignificant.<ref name="pmid9238337">{{cite journal | vauthors = Shaw JC | title = Antiandrogen and hormonal treatment of acne | journal = Dermatologic Clinics | volume = 14 | issue = 4 | pages = 803–11 | date = October 1996 | pmid = 9238337 | doi = 10.1016/S0733-8635(05)70405-8 }}</ref>

Spironolactone has been found in some studies to increase levels of [[estradiol]], an [[estrogen]], although many other studies have found no changes in estradiol levels.<ref name="pmid984618" /><ref name="pmid8094898" /> The mechanism of how spironolactone increases estradiol levels is unclear, but it may involve inhibition of the inactivation of estradiol into [[estrone]] and enhancement of the peripheral conversion of testosterone into estradiol.<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><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> It is notable that spironolactone has been found ''in vitro'' to act as a weak inhibitor of [[17β-hydroxysteroid dehydrogenase 2]], an enzyme that is involved in the conversion of estradiol into estrone.<ref name="pmid12570693">{{cite journal | vauthors = Poirier D | title = Inhibitors of 17 beta-hydroxysteroid dehydrogenases | journal = Current Medicinal Chemistry | volume = 10 | issue = 6 | pages = 453–77 | date = March 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 = Anti-Cancer Agents in Medicinal Chemistry | volume = 9 | issue = 6 | pages = 642–60 | date = July 2009 | pmid = 19601747 | doi = 10.2174/187152009788680000 }}</ref> Increased levels of estradiol with spironolactone may be involved in its preservation of [[bone density]] and in its side effects such as breast tenderness, breast enlargement, and gynecomastia in women and men.<ref name="pmid12477487" /><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 Epidemiology | volume = 37 | issue = 6 | pages = 870–5 | date = December 2013 | pmid = 24189467 | doi = 10.1016/j.canep.2013.10.004 }}</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 Medicinal Chemistry | volume = 7 | issue = 11 | pages = 1431–56 | year = 2015 | pmid = 26230882 | doi = 10.4155/fmc.15.74 }}</ref>

In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain [[homeostasis]], the body increases aldosterone production in the [[adrenal cortex]].<ref name="Adams2014">{{cite book|vauthors=Adams KF|title=Pharmacologic Approaches to Heart Failure, An Issue of Heart Failure Clinics, E-Book|url=https://books.google.com/books?id=KNWlBAAAQBAJ&pg=PA562|date=28 October 2014|publisher=Elsevier Health Sciences|isbn=978-0-323-32612-4|pages=562–|access-date=13 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094813/https://books.google.com/books?id=KNWlBAAAQBAJ&pg=PA562|url-status=live}}</ref><ref name="pmid22836869" /><ref name="pmid17035932">{{cite journal | vauthors = Otte C, Moritz S, Yassouridis A, Koop M, Madrischewski AM, Wiedemann K, Kellner M | 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 | title-link = doi }}</ref> Some studies have found that levels of [[cortisol]], a [[glucocorticoid]] hormone that is also produced in the adrenal cortex, are increased as well.<ref name="pmid22836869">{{cite journal | vauthors = Berardelli R, Karamouzis I, D'Angelo V, Zichi C, Fussotto B, Giordano R, Ghigo E, Arvat E | title = Role of mineralocorticoid receptors on the hypothalamus-pituitary-adrenal axis in humans | journal = Endocrine | volume = 43 | issue = 1 | pages = 51–8 | date = February 2013 | pmid = 22836869 | doi = 10.1007/s12020-012-9750-8 | s2cid = 34916537 }}</ref><ref name="pmid17035932" /><ref name="pmid27519144">{{cite journal | vauthors = Hinkelmann K, Hellmann-Regen J, Wingenfeld K, Kuehl LK, Mews M, Fleischer J, Heuser I, Otte C | title = Mineralocorticoid receptor function in depressed patients and healthy individuals | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 71 | pages = 183–8 | date = November 2016 | pmid = 27519144 | doi = 10.1016/j.pnpbp.2016.08.003 | s2cid = 4775178 }}</ref> Spironolactone "acts at the basolateral side of the upper-distal tubule as well as in the collecting tubule," and does not have glucocorticoid-like effects at these specific sites; it can sometimes be prescribed as an alternative to glucocorticoids for patients with Glucocorticoid-Remediable Aldosteronism characterized by aldosterone excess,<ref name="pmid8144871" /><ref name="FalconeHurd2007">{{cite book|vauthors=Falcone T, Hurd WW|title=Clinical Reproductive Medicine and Surgery|url=https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA271|date=1 January 2007|publisher=Elsevier Health Sciences|isbn=978-0-323-03309-1|pages=271–|access-date=13 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094813/https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA271|url-status=live}}</ref><ref name="Hammerstein1990"/><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 = Klinische Wochenschrift | volume = 56 | issue = 3 | pages = 135–8 | date = February 1978 | pmid = 628197 | doi = 10.1007/BF01478568 | s2cid = 30885047 }}</ref> In patients "receiving spironolactone, there was a significant positive correlation between the change in cortisol and the change in HbA1c (r = 0.489, P = .003)."<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 A<sub>1</sub>(c) levels in patients with chronic heart failure | journal = American Heart Journal | volume = 160 | issue = 5 | pages = 915–21 | date = November 2010 | pmid = 21095280 | doi = 10.1016/j.ahj.2010.04.024 }}</ref> Patients taking spironolactone must be monitored for side effects including dizziness, headache, fatigue, diarrhea, hypertriglyceridemia and elevated liver enzymes.<ref name="KuntzKuntz2009">{{cite book|vauthors=Kuntz E, Kuntz HD|title=Hepatology: Textbook and Atlas|url=https://books.google.com/books?id=oL6d9KuVqLQC&pg=PA312|date=11 March 2009|publisher=Springer Science & Business Media|isbn=978-3-540-76839-5|pages=312–|access-date=13 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094813/https://books.google.com/books?id=oL6d9KuVqLQC&pg=PA312|url-status=live}}</ref><ref name="MelmedPolonsky2011">{{cite book| vauthors = Melmed S, Polonsky KS, Larsen PR, Kronenberg HM |title=Williams Textbook of Endocrinology E-Book|url=https://books.google.com/books?id=nbg1QOAObicC&pg=PA571|date=12 May 2011|publisher=Elsevier Health Sciences|isbn=978-1-4377-3600-7|pages=571–}}</ref>

Other activities of spironolactone may include very weak interactions with the [[estrogen receptor|estrogen]] and [[progesterone receptor]]s and [[agonist|agonism]] of the [[pregnane X receptor]].<ref name="Hammerstein1990" /><ref name="pmid12372848">{{cite journal | vauthors = Kliewer SA, Goodwin B, Willson TM | title = The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism | journal = Endocrine Reviews | volume = 23 | issue = 5 | pages = 687–702 | date = October 2002 | pmid = 12372848 | doi = 10.1210/er.2001-0038 | doi-access = free | title-link = doi }}</ref> These activities could contribute to the [[menstrual irregularity|menstrual irregularities]] and [[breast]] side effects of spironolactone and to its [[drug interaction]]s, respectively.<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 = Journal of Endocrinological Investigation | volume = 39 | issue = 9 | pages = 1015–21 | date = September 2016 | pmid = 27072668 | doi = 10.1007/s40618-016-0466-0 | s2cid = 34201900 }}</ref><ref name="Delyani2000">{{cite journal | vauthors = Delyani JA | title = Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology | journal = Kidney International | volume = 57 | issue = 4 | pages = 1408–11 | date = April 2000 | pmid = 10760075 | doi = 10.1046/j.1523-1755.2000.00983.x | doi-access = free | title-link = doi }}</ref><ref name="pmid9727070">{{cite journal | vauthors = Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = The Journal of Clinical Investigation | volume = 102 | issue = 5 | pages = 1016–23 | date = September 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 | bibcode = 1998JCliI.102.1016L }}</ref>

===Pharmacokinetics===
The [[pharmacokinetics]] of spironolactone have not been studied well, which is in part because it is an old medication that was developed in the 1950s.<ref name="Wilcox2008" /> Nonetheless, much has been elucidated about the pharmacokinetics of spironolactone over the decades.<ref name="pmid363379">{{cite journal | vauthors = Karim A | title = Spironolactone: disposition, metabolism, pharmacodynamics, and bioavailability | journal = Drug Metabolism Reviews | volume = 8 | issue = 1 | pages = 151–88 | date = 1978 | pmid = 363379 | doi = 10.3109/03602537808993782 }}</ref><ref name="pmid6369882">{{cite journal | vauthors = Beermann B | title = Aspects on pharmacokinetics of some diuretics | journal = Acta Pharmacologica et Toxicologica | volume = 54 | issue = Suppl 1 | pages = 17–29 | date = 1984 | pmid = 6369882 | doi = 10.1111/j.1600-0773.1984.tb03626.x }}</ref><ref name="pmid3333882">{{cite journal | vauthors = Overdiek HW, Merkus FW | title = The metabolism and biopharmaceutics of spironolactone in man | journal = Reviews on Drug Metabolism and Drug Interactions | volume = 5 | issue = 4 | pages = 273–302 | date = 1987 | pmid = 3333882 | doi = 10.1515/DMDI.1987.5.4.273 | s2cid = 29482256 }}</ref><ref name="pmid15947888"/><ref name="pmid22099505">{{cite journal | vauthors = Brater DC | title = Update in diuretic therapy: clinical pharmacology | journal = Seminars in Nephrology | volume = 31 | issue = 6 | pages = 483–94 | date = November 2011 | pmid = 22099505 | doi = 10.1016/j.semnephrol.2011.09.003 }}</ref><ref name="pmid21771637">{{cite journal | vauthors = Kolkhof P, Borden SA | title = Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics | journal = Molecular and Cellular Endocrinology | volume = 350 | issue = 2 | pages = 310–7 | date = March 2012 | pmid = 21771637 | doi = 10.1016/j.mce.2011.06.025 | s2cid = 36894459 }}</ref><ref name="pmid26939027">{{cite journal | vauthors = Yang J, Young MJ | title = Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences | journal = Current Opinion in Pharmacology | volume = 27 | pages = 78–85 | date = April 2016 | pmid = 26939027 | doi = 10.1016/j.coph.2016.02.005 }}</ref><ref name="pmid27830348">{{cite book | vauthors = Kolkhof P, Jaisser F, Kim SY, Filippatos G, Nowack C, Pitt B | title = Heart Failure | chapter = Steroidal and Novel Non-steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside | volume = 243 | pages = 271–305 | date = 2017 | pmid = 27830348 | doi = 10.1007/164_2016_76 | series = Handbook of Experimental Pharmacology | publisher = Springer | isbn = 978-3-319-59658-7 }}</ref>

====Absorption====
[[File:Spironolactone and metabolite levels after a single oral dose of 100 mg spironolactone.png|class=skin-invert-image|thumb|right|400px|Levels of spironolactone and its major active metabolites after a single oral dose of 100&nbsp;mg spironolactone in humans.<ref name="pmid8818057">{{cite journal | vauthors = Jankowski A, Skorek-Jankowska A, Lamparczyk H | title = Simultaneous determination of spironolactone and its metabolites in human plasma | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 14 | issue = 8–10 | pages = 1359–65 | date = June 1996 | pmid = 8818057 | doi = 10.1016/S0731-7085(96)01767-0 }}</ref>]]

The [[bioavailability]] of spironolactone when taken [[oral administration|by mouth]] is 60 to 90%.<ref name="pmid15947888"/><ref name="pmid18729003" /><ref name="CaroneOxberry2017" /> The bioavailability of spironolactone and its metabolites increases significantly (+22–95% increases in levels) when spironolactone is taken with food, although it is uncertain whether this further increases the therapeutic effects of the medication.<ref name="DeinumRiksen2015" /><ref name="pmid3769384">{{cite journal | vauthors = Overdiek HW, Merkus FW | title = Influence of food on the bioavailability of spironolactone | journal = Clinical Pharmacology and Therapeutics | volume = 40 | issue = 5 | pages = 531–6 | date = November 1986 | pmid = 3769384 | doi = 10.1038/clpt.1986.219 | s2cid = 32313529 }}</ref><ref name="pmid872489">{{cite journal | vauthors = Melander A, Danielson K, Scherstén B, Thulin T, Wåhlin E | title = Enhancement by food of canrenone bioavailability from spironolactone | journal = Clinical Pharmacology and Therapeutics | volume = 22 | issue = 1 | pages = 100–3 | date = July 1977 | pmid = 872489 | doi = 10.1002/cpt1977221100 | s2cid = 12827850 }}</ref> The increase in bioavailability is thought to be due to promotion of the gastric dissolution and [[absorption (pharmacokinetics)|absorption]] of spironolactone, as well as due to a decrease of the [[first-pass metabolism]].<ref name="DeinumRiksen2015">{{cite journal | vauthors = Deinum J, Riksen NP, Lenders JW | title = Pharmacological treatment of aldosterone excess | journal = Pharmacology & Therapeutics | volume = 154 | pages = 120–33 | date = October 2015 | pmid = 26213109 | doi = 10.1016/j.pharmthera.2015.07.006 }}</ref><ref name="Saini-ChohanHatch2009">{{cite journal | vauthors = Saini-Chohan HK, Hatch GM | title = Biological actions and metabolism of currently used pharmacological agents for the treatment of congestive heart failure | journal = Current Drug Metabolism | volume = 10 | issue = 3 | pages = 206–19 | date = March 2009 | pmid = 19442083 | doi = 10.2174/138920009787846314 }}</ref><ref name="Al-HadiyaBelal2002">{{cite journal | vauthors = Al-Hadiya BM, Belal F, Asiri YA, Gubara OA |title=Spironolactone|journal=Analytical Profiles of Drug Substances and Excipients|volume=29|year=2002|pages=261–320|issn=1075-6280|doi=10.1016/S1075-6280(02)29009-6 |isbn=978-0-12-260829-2}}</ref> The relationship between a single dose of spironolactone and plasma levels of [[canrenone]], a major [[active metabolite]] of spironolactone, has been found to be linear across a dose range of 25 to 200&nbsp;mg spironolactone.<ref name="Wu2012" /> [[Elimination (pharmacology)#Steady state|Steady-state concentration]]s of spironolactone are achieved within 8 to 10&nbsp;days of treatment initiation.<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–|access-date=6 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094813/https://books.google.com/books?id=l965aqw_LSkC&pg=PA325|url-status=live}}</ref><ref name="Elsevier2019">{{cite book|title=Aldosterone|url=https://books.google.com/books?id=5daEDwAAQBAJ&pg=PA11|date=23 January 2019|publisher=Elsevier Science|isbn=978-0-12-817783-9|pages=11, 46|access-date=20 September 2019|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094813/https://books.google.com/books?id=5daEDwAAQBAJ&pg=PA11|url-status=live}}</ref>

Little or no systemic [[absorption (pharmacokinetics)|absorption]] has been observed with topical spironolactone.<ref name="pmid3411088">{{cite journal | vauthors = Rey FO, Valterio C, Locatelli L, Ramelet AA, Felber JP | title = Lack of endocrine systemic side effects after topical application of spironolactone in man | journal = Journal of Endocrinological Investigation | volume = 11 | issue = 4 | pages = 273–8 | date = April 1988 | pmid = 3411088 | doi = 10.1007/BF03350151 | s2cid = 30535049 }}</ref>

====Distribution====
Spironolactone and its metabolite canrenone are highly [[plasma protein bound]], with percentages of 88.0% and 99.2%, respectively.<ref name="pmid15947888"/><ref name="TakamuraMaruyama1997" >{{cite journal | vauthors = Takamura N, Maruyama T, Ahmed S, Suenaga A, Otagiri M | title = Interactions of aldosterone antagonist diuretics with human serum proteins | journal = Pharmaceutical Research | volume = 14 | issue = 4 | pages = 522–6 | date = April 1997 | pmid = 9144743 | doi = 10.1023/A:1012168020545 | s2cid = 13227538 }}</ref> Spironolactone is bound equivalently to [[human serum albumin|albumin]] and [[orosomucoid|α<sub>1</sub>-acid glycoprotein]], while canrenone is bound only to albumin.<ref name="pmid15947888"/><ref name="TakamuraMaruyama1997" /> Spironolactone and its metabolite [[7α-thiospironolactone]] show very low or negligible affinity for [[sex hormone-binding globulin]] (SHBG).<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 = The Journal of Clinical Endocrinology and Metabolism | volume = 46 | issue = 2 | pages = 338–44 | date = February 1978 | pmid = 86546 | doi = 10.1210/jcem-46-2-338 }}</ref><ref name="pmid7195405">{{cite journal | vauthors = Pugeat MM, Dunn JF, Nisula BC | title = Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 53 | issue = 1 | pages = 69–75 | date = July 1981 | pmid = 7195405 | doi = 10.1210/jcem-53-1-69 }}</ref> In accordance, a study of high-dosage spironolactone treatment found no change in steroid binding capacity related to SHBG or to [[corticosteroid-binding globulin]] (CBG), suggesting that spironolactone does not displace [[steroid hormone]]s from their [[carrier protein]]s.<ref name="pmid7189544">{{cite journal | vauthors = Kaulhausen H, Rohner HG, Siedek M, Lafosse M, Breuer H | title = [Binding capacity of sex hormone binding globulin and corticosteroid-binding globulin in serum of male patients with liver cirrhosis (author's transl)] | language = de | journal = Journal of Clinical Chemistry and Clinical Biochemistry | volume = 18 | issue = 2 | pages = 137–43 | date = February 1980 | pmid = 7189544 }}</ref> This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG.<ref name="Hammerstein1990" /><ref name="BlandIII2009">{{cite book|vauthors=Bland KI, Copeland III EM|title=The Breast: Comprehensive Management of Benign and Malignant Diseases|url=https://books.google.com/books?id=1u4x_iGiHNEC&pg=PA161|date=9 September 2009|publisher=Elsevier Health Sciences|isbn=978-1-4377-1121-9|pages=161–|access-date=14 September 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094814/https://books.google.com/books?id=1u4x_iGiHNEC&pg=PA161|url-status=live}}</ref>

Spironolactone appears to cross the [[blood–brain barrier]].<ref name="pmid25376974">{{cite journal | vauthors = Murck H, Büttner M, Kircher T, Konrad C | title = Genetic, molecular and clinical determinants for the involvement of aldosterone and its receptors in major depression | journal = Nephron Physiology | volume = 128 | issue = 1–2 | pages = 17–25 | date = 2014 | pmid = 25376974 | doi = 10.1159/000368265 | s2cid = 19905165 | doi-access = free | title-link = doi }}</ref><ref name="pmid22351473">{{cite journal | vauthors = Künzel HE | title = Psychopathological symptoms in patients with primary hyperaldosteronism--possible pathways | journal = Hormone and Metabolic Research | volume = 44 | issue = 3 | pages = 202–7 | date = March 2012 | pmid = 22351473 | doi = 10.1055/s-0032-1301921 | s2cid = 23273751 }}</ref>

====Metabolism====
[[File:Spironolactone metabolism.png|class=skin-invert-image|thumb|right|400px|Spironolactone [[metabolism]] in humans.<ref name="pmid1629288">{{cite journal | vauthors = Varin F, Tu TM, Benoît F, Villeneuve JP, Théorêt Y | title = High-performance liquid chromatographic determination of spironolactone and its metabolites in human biological fluids after solid-phase extraction | journal = Journal of Chromatography | volume = 574 | issue = 1 | pages = 57–64 | date = February 1992 | pmid = 1629288 | doi = 10.1016/0378-4347(92)80097-A }}</ref> [[Canrenone]] may be further [[redox|reduced]] (into di-, tetra-, and hexahydrogenated metabolites), [[hydroxylation|hydroxylated]], and [[conjugation (biochemistry)|conjugated]] (e.g., [[glucuronidation|glucuronidated]]).<ref name="pmid1629288" />]]

Spironolactone is rapidly and extensively [[metabolism|metabolized]] in the [[liver]] upon [[oral administration]] and has a very short [[biological half-life|terminal half-life]] of 1.4 hours.<ref name="pmid15947888"/><ref name="pmid18729003" /> The major [[metabolite]]s of spironolactone are [[7α-thiomethylspironolactone]] (7α-TMS), [[6β-hydroxy-7α-thiomethylspironolactone]] (6β-OH-7α-TMS), and [[canrenone]] (7α-desthioacetyl-δ<sup>6</sup>-spironolactone).<ref name="pmid15947888"/><ref name="pmid18729003" /><ref name="AgustiBourgeois2013">{{cite journal | vauthors = Agusti G, Bourgeois S, Cartiser N, Fessi H, Le Borgne M, Lomberget T | title = A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone | journal = Steroids | volume = 78 | issue = 1 | pages = 102–7 | date = January 2013 | pmid = 23063964 | doi = 10.1016/j.steroids.2012.09.005 | s2cid = 8992318 }}</ref> These metabolites have much longer elimination half-lives than spironolactone of 13.8 hours, 15.0 hours, and 16.5 hours, respectively, and are responsible for the therapeutic effects of the medication.<ref name="pmid15947888"/><ref name="pmid18729003" /> As such, spironolactone is a [[prodrug]].<ref name="Oxford2003">{{cite book|title=Oxford Textbook of Medicine: Vol. 1|url=https://books.google.com/books?id=_s65U1n9Lf8C&pg=RA1-PA962|year=2003|publisher=Oxford University Press|isbn=978-0-19-262922-7|pages=1–|access-date=6 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007094814/https://books.google.com/books?id=_s65U1n9Lf8C&pg=RA1-PA962|url-status=live}}</ref> The 7α-thiomethylated metabolites of spironolactone were not known for many years and it was originally thought that canrenone was the major active metabolite of the medication, but subsequent research identified 7α-TMS as the major metabolite.<ref name="pmid15947888"/><ref name="AgustiBourgeois2013" /><ref name="CancerOrganization2001" /> Other known but more minor metabolites of spironolactone include [[7α-thiospironolactone]] (7α-TS), which is an important [[metabolic intermediate|intermediate]] to the major metabolites of spironolactone,<ref name="Parkinson2001" /> as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.<ref name="SzaszBudvari-Barany1990">{{cite book| vauthors = Szasz G, Budvari-Barany Z |title=Pharmaceutical Chemistry of Antihypertensive Agents|url=https://books.google.com/books?id=LMl4Sd38q4kC&pg=PA91|date=19 December 1990|publisher=CRC Press|isbn=978-0-8493-4724-5|pages=91–}}</ref>

Spironolactone is [[hydrolysis|hydrolyzed]] or [[acetylation|deacetylated]] at the [[thioester]] of the C7α position into 7α-TS by [[carboxylesterase]]s.<ref name="Parkinson2001">{{cite book|vauthors=Parkinson A|title=Biotransformation of Xenobiotics|url=https://books.google.com/books?id=pAovcgAACAAJ|year=2001|publisher=McGraw-Hill|pages=137–138, 169, 171, 180, 195, 208|access-date=12 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095315/https://books.google.com/books?id=pAovcgAACAAJ|url-status=live}}</ref><ref name="AnzenbacherZanger2012">{{cite book|vauthors=Anzenbacher P, Zanger UM|title=Metabolism of Drugs and Other Xenobiotics|url=https://books.google.com/books?id=f-XHh17NfwgC&pg=PA166|date=23 February 2012|publisher=John Wiley & Sons|isbn=978-3-527-64632-6|pages=166, 169|access-date=12 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095315/https://books.google.com/books?id=f-XHh17NfwgC&pg=PA166|url-status=live}}</ref> Following formation of 7α-TS, it is ''S''-[[oxidation|oxygenated]] by [[flavin-containing monooxygenase]]s to form an [[electrophilic]] [[sulfenic acid]] [[metabolite]].<ref name="Parkinson2001" /> This metabolite is involved in the CYP450 inhibition of spironolactone, and also binds [[covalent bond|covalently]] to other [[protein]]s.<ref name="Parkinson2001" /> 7α-TS is also ''S''-[[methylation|methylated]] into 7α-TMS, a transformation catalyzed by [[thiol S-methyltransferase|thiol ''S''-methyltransferase]].<ref name="Parkinson2001" /> Unlike the related medication [[eplerenone]], spironolactone is said to not be metabolized by [[CYP3A4]].<ref name="SmithPh.D.2014">{{cite book|vauthors=Smith BT, Seaward BL, Smith BT|title=Pharmacology for Nurses|url=https://books.google.com/books?id=7P-9BQAAQBAJ&pg=PA169|date=1 November 2014|publisher=Jones & Bartlett Publishers|isbn=978-1-4496-8940-7|pages=169–|access-date=6 October 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095315/https://books.google.com/books?id=7P-9BQAAQBAJ&pg=PA169|url-status=live}}</ref> However, hepatic CYP3A4 is likely responsible for the 6β-[[hydroxylation]] of 7α-TMS into 6β-OH-7α-TMS.<ref name="Klaassen2007">{{cite book|vauthors=Klaassen CD|title=Casarett & Doull's Toxicology: The Basic Science of Poisons, Seventh Edition|url=https://books.google.com/books?id=4yi7-j48uhIC|date=11 December 2007|publisher=McGraw Hill Professional|isbn=978-0-07-159351-9|page=173|access-date=12 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095316/https://books.google.com/books?id=4yi7-j48uhIC|url-status=live}}</ref><ref name="Montellano2015">{{cite book|vauthors=Ortiz de Montellano PR|title=Cytochrome P450: Structure, Mechanism, and Biochemistry|url=https://books.google.com/books?id=abZnBwAAQBAJ&pg=PA867|date=13 March 2015|publisher=Springer|isbn=978-3-319-12108-6|pages=867–|access-date=12 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095316/https://books.google.com/books?id=abZnBwAAQBAJ&pg=PA867|url-status=live}}</ref> 7α-TMS may also be [[hydroxyl]]ated at the C3α and C3β positions.<ref name="pmid7895608">{{cite journal | vauthors = Los LE, Pitzenberger SM, Ramjit HG, Coddington AB, Colby HD | title = Hepatic metabolism of spironolactone. Production of 3-hydroxy-thiomethyl metabolites | journal = Drug Metabolism and Disposition | volume = 22 | issue = 6 | pages = 903–8 | date = 1994 | doi = 10.1016/S0090-9556(25)08434-X | pmid = 7895608 }}</ref> Spironolactone is [[dethioacetylated]] into canrenone.<ref name="BlackElliott2006">{{cite book|vauthors=Black HR, Elliott W|title=Hypertension: A Companion to Braunwald's Heart Disease|url=https://books.google.com/books?id=42Fcmne6_w8C&pg=PA295|date=28 December 2006|publisher=Elsevier Health Sciences|isbn=978-1-4377-1078-6|pages=295–|access-date=12 August 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095317/https://books.google.com/books?id=42Fcmne6_w8C&pg=PA295|url-status=live}}</ref> Finally, the C17 γ-[[lactone]] [[ring (chemistry)|ring]] of spironolactone is hydrolyzed by the [[paraoxonase]] [[PON3]].<ref name="pmid14579013">{{cite journal | vauthors = Draganov DI, La Du BN | title = Pharmacogenetics of paraoxonases: a brief review | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 369 | issue = 1 | pages = 78–88 | date = January 2004 | pmid = 14579013 | doi = 10.1007/s00210-003-0833-1 | hdl-access = free | s2cid = 15825605 | hdl = 2027.42/46312 }}</ref><ref name="AcademicPress2012">{{cite book|title=Advances in Clinical Chemistry|url=https://books.google.com/books?id=sC8h4KM0nmYC&pg=PA69|date=31 December 2012|publisher=Academic Press|isbn=978-0-12-405852-1|pages=69–}}</ref> It was originally thought to be hydrolyzed by PON1, but this was due to contamination with PON3.<ref name="pmid14579013" />

{{Pharmacokinetics of 100 mg per day spironolactone and its metabolites}}

====Elimination====
The majority of spironolactone is eliminated by the [[kidney]]s, while minimal amounts are handled by [[bile|biliary]] excretion.<ref name="Brittain2002">{{cite book | vauthors = Brittain HG | title = Analytical Profiles of Drug Substances and Excipients | url = https://books.google.com/books?id=RMN5zMW64ZEC&pg=PA309 | access-date = 27 May 2012 | date = 26 November 2002 | publisher = Academic Press | isbn = 978-0-12-260829-2 | page = 309 | url-status = live | archive-url = https://web.archive.org/web/20130621104609/http://books.google.com/books?id=RMN5zMW64ZEC&pg=PA309 | archive-date = 21 June 2013 }}</ref>

==Chemistry==
{{See also|Spirolactone|List of steroidal antiandrogens#Spirolactone derivatives}}

Spironolactone, also known as ''7α-acetylthiospirolactone'', is a [[steroid]]al [[17α-spirolactone]], or more simply a spirolactone.<ref name="pmid28634268">{{cite journal | vauthors = Kolkhof P, Bärfacker L | title = 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development | journal = The Journal of Endocrinology | volume = 234 | issue = 1 | pages = T125–T140 | date = July 2017 | pmid = 28634268 | pmc = 5488394 | doi = 10.1530/JOE-16-0600 }}</ref> It can most appropriately be conceptualized as a [[chemical derivative|derivative]] of [[progesterone (medication)|progesterone]],<ref name="pmid15134800" /><ref name="JamesonGroot2010" /><ref name="Elsevier2019" /> itself also a potent antimineralocorticoid, in which a [[hydroxyl group]] has been [[substituent|substituted]] at the C17α position (as in [[17α-hydroxyprogesterone]]), the [[acetyl group]] at the C17β position has been [[cyclic compound|cyclized]] with the C17α hydroxyl group to form a [[spiro compound|spiro]] 21-[[carboxylic acid]] γ-[[lactone]] [[ring (chemistry)|ring]], and an acetyl[[thio-|thio]] group has been substituted in at the C7α position.<ref name="Elks2014" /><ref name="PubChem" /><ref name="ChemSpider" /> These [[structural modification]]s of progesterone confer increased [[oral administration|oral]] [[bioavailability]] and [[potency (pharmacology)|potency]],<ref name="pmid8616985">{{cite journal | vauthors = Simon JA | title = Micronized progesterone: vaginal and oral uses | journal = Clinical Obstetrics and Gynecology | volume = 38 | issue = 4 | pages = 902–14 | date = December 1995 | pmid = 8616985 | doi = 10.1097/00003081-199538040-00024 }}</ref> potent antiandrogenic activity, and strongly reduced progestogenic activity.<ref name="pmid16101407">{{cite journal | vauthors = Hu X, Li S, McMahon EG, Lala DS, Rudolph AE | title = Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone | journal = Mini Reviews in Medicinal Chemistry | volume = 5 | issue = 8 | pages = 709–18 | date = August 2005 | pmid = 16101407 | doi = 10.2174/1389557054553811 }}</ref> The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as [[7α-thioprogesterone]] (SC-8365), unlike progesterone,<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref> is an antiandrogen with similar affinity to the AR as that of spironolactone.<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 = The Journal of Clinical Endocrinology and Metabolism | volume = 47 | issue = 1 | pages = 171–5 | date = July 1978 | pmid = 263288 | doi = 10.1210/jcem-47-1-171 }}</ref> In addition, the C7α substitution appears to be responsible for the loss of progestogenic activity and good oral bioavailability of spironolactone, as [[SC-5233]], the analogue of spironolactone without a C7α substitution, has potent progestogenic activity but very poor oral bioavailability similarly to progesterone.<ref name="pmid16112947" /><ref name="pmid13601900">{{cite journal | vauthors = Hertz R, Tullner WW | title = Progestational activity of certain steroid-17-spirolactones | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 99 | issue = 2 | pages = 451–2 | date = November 1958 | pmid = 13601900 | doi = 10.3181/00379727-99-24380 | s2cid = 20150966 }}</ref><ref name="Butterworth1961">{{cite book|title=The British Encyclopaedia of Medical Practice: Medical progress|url=https://books.google.com/books?id=wvIfAQAAMAAJ|year=1961|page=302|publisher=Butterworth & Company|access-date=2 February 2018|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095317/https://books.google.com/books?id=wvIfAQAAMAAJ|url-status=live}}</ref>

===Names===
Spironolactone is also known by the following equivalent chemical names:<ref name="Elks2014" /><ref name="PubChem">{{cite web |url=https://pubchem.ncbi.nlm.nih.gov/compound/5833 |title=Spironolactone |access-date=4 July 2017 |url-status=live |archive-url=https://web.archive.org/web/20160630101052/http://pubchem.ncbi.nlm.nih.gov/compound/5833/ |archive-date=30 June 2016 }}</ref><ref name="ChemSpider">{{Cite web | url=http://www.chemspider.com/Chemical-Structure.5628.html?rid=b578a389-d64b-4ec2-ae20-309e5f3abd11 | title=Spironolactone {{pipe}} C24H32O4S | work = ChemSpider | publisher = Royal Society of Chemistry | access-date=4 July 2017 | archive-date=9 September 2017 | archive-url=https://web.archive.org/web/20170909005013/http://www.chemspider.com/Chemical-Structure.5628.html?rid=b578a389-d64b-4ec2-ae20-309e5f3abd11 | url-status=live }}</ref>
* 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
* 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone
* 3-(3-Oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17α-yl)propionic acid lactone
* 7α-Acetylthio-17α-(2-carboxyethyl)androst-4-en-17β-ol-3-one γ-lactone
* 7α-Acetylthio-17α-(2-carboxyethyl)testosterone γ-lactone

===Analogues===
{{Spirolactone structures|align=right|caption=[[Chemical structure]]s of [[progesterone (medication)|progesterone]] and [[spirolactone]]s (steroid-17α-spirolactones).}}

Spironolactone is closely related structurally to other clinically used spirolactones such as [[canrenone]], [[potassium canrenoate]], [[drospirenone]], and [[eplerenone]], as well as to the never-marketed spirolactones [[SC-5233]] (6,7-dihydrocanrenone; 7α-desthioacetylspironolactone), [[SC-8109]] (19-nor-6,7-dihydrocanrenone), [[spiroxasone]], [[prorenone]] (SC-23133), [[mexrenone]] (SC-25152, ZK-32055), [[dicirenone]] (SC-26304), [[spirorenone]] (ZK-35973), and [[mespirenone]] (ZK-94679).<ref name="pmid28634268" />

===Synthesis===
[[Chemical synthesis|Chemical syntheses]] of spironolactone and its [[structural analog|analogue]]s and [[chemical derivative|derivative]]s have been described and reviewed.<ref name="pmid28041953">{{cite journal | vauthors = Larik FA, Saeed A, Shahzad D, Faisal M, El-Seedi H, Mehfooz H, Channar PA | title = Synthetic approaches towards the multi target drug spironolactone and its potent analogues/derivatives | journal = Steroids | volume = 118 | pages = 76–92 | date = February 2017 | pmid = 28041953 | doi = 10.1016/j.steroids.2016.12.010 | s2cid = 7003499 }}</ref>

==History==
The [[natriuretic]] effects of [[progesterone (medication)|progesterone]] were demonstrated in 1955, and the development of spironolactone as a [[synthetic compound|synthetic]] antimineralocorticoid [[structural analog|analogue]] of progesterone shortly followed this.<ref name="pmid15134800">{{cite journal | vauthors = Ménard J | title = The 45-year story of the development of an anti-aldosterone more specific than spironolactone | journal = Molecular and Cellular Endocrinology | volume = 217 | issue = 1–2 | pages = 45–52 | date = March 2004 | pmid = 15134800 | doi = 10.1016/j.mce.2003.10.008 | s2cid = 19701784 }}</ref><ref name="JamesonGroot2010">{{cite book| vauthors = Jameson JL, De Groot LJ |title=Endocrinology - E-Book: Adult and Pediatric|url=https://books.google.com/books?id=W4dZ-URK8ZoC&pg=PA2401|date=18 May 2010|publisher=Elsevier Health Sciences|isbn=978-1-4557-1126-0|pages=2401–}}</ref><ref name="pmid13486053">{{cite journal| vauthors = Kagawa CM, Cella JA, Van Arman CG | title = Action of new steroids in blocking effects of aldosterone and desoxycorticosterone on salt | journal = Science | volume = 126 | issue = 3281 | pages = 1015–6 | date = November 1957 | pmid = 13486053 | doi = 10.1126/science.126.3281.1015 | bibcode = 1957Sci...126.1015K }}</ref><ref name="pmid13486054">{{cite journal | vauthors = Liddle GW | title = Sodium diuresis induced by steroidal antagonists of aldosterone | journal = Science | volume = 126 | issue = 3281 | pages = 1016–8 | date = November 1957 | pmid = 13486054 | doi = 10.1126/science.126.3281.1016 | bibcode = 1957Sci...126.1016L }}</ref> Spironolactone was first [[chemical synthesis|synthesized]] in 1957,<ref name="OttowWeinmann2008" /><ref name="pmid13486053" /><ref name="pmid13486054" /> was [[patent]]ed between 1958 and 1961,<ref name="EngelKleemann2014">{{cite book|vauthors=Engel J, Kleemann A, Kutscher B, Reichert D|title=Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs|url=https://books.google.com/books?id=4lCGAwAAQBAJ&pg=PA1279|date=14 May 2014|publisher=Thieme|isbn=978-3-13-179275-4|pages=1279–1280|access-date=27 December 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095317/https://books.google.com/books?id=4lCGAwAAQBAJ&pg=PA1279|url-status=live}}</ref><ref name="LandauAchilladelis1999">{{cite book|vauthors=Landau R, Achilladelis B, Scriabine A|title=Pharmaceutical Innovation: Revolutionizing Human Health|url=https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA198|year=1999|publisher=Chemical Heritage Foundation|isbn=978-0-941901-21-5|pages=198–|access-date=27 December 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095318/https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA198|url-status=live}}</ref> and was first marketed, as an antimineralocorticoid, in 1959.<ref name="Jugdutt2014">{{cite book|vauthors=Jugdutt BI|title=Aging and Heart Failure: Mechanisms and Management|url=https://books.google.com/books?id=0e23BAAAQBAJ&pg=PA175|date=19 February 2014|publisher=Springer Science & Business Media|isbn=978-1-4939-0268-2|pages=175–|access-date=27 December 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095841/https://books.google.com/books?id=0e23BAAAQBAJ&pg=PA175|url-status=live}}</ref><ref name="Wermuth2011">{{cite book| vauthors = Wermuth CG |title=The Practice of Medicinal Chemistry|url=https://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34|date=2 May 2011|publisher=Academic Press|isbn=978-0-08-056877-5|pages=34–|url-status=live|archive-url=https://web.archive.org/web/20130621115634/http://books.google.com/books?id=Qmt1_DQkCpEC&pg=PA34|archive-date=21 June 2013}}</ref> Gynecomastia was first reported with spironolactone in 1962,<ref name="pmid28634268" /><ref name="Smith1962">{{cite journal| vauthors = Smith WG |title=Spironolactone and gynaecomastia|journal=The Lancet|volume=280|issue=7261|year=1962|page=886|issn=0140-6736|doi=10.1016/S0140-6736(62)90668-2}}</ref> and the antiandrogenic activity of the medication was first described in 1969.<ref name="pmid5344274">{{cite journal | vauthors = Steelman SL, Brooks JR, Morgan ER, Patanelli DJ | title = Anti-androgenic activity of spironolactone | journal = Steroids | volume = 14 | issue = 4 | pages = 449–50 | date = October 1969 | pmid = 5344274 | doi = 10.1016/s0039-128x(69)80007-3 }}</ref> This shortly followed the discovery in 1967 that gynecomastia is an important and major side effect of AR antagonists.<ref name="pmid148431">{{cite journal | vauthors = Stewart ME, Pochi PE | title = Antiandrogens and the skin | journal = International Journal of Dermatology | volume = 17 | issue = 3 | pages = 167–79 | date = April 1978 | pmid = 148431 | doi = 10.1111/j.1365-4362.1978.tb06057.x | s2cid = 43649686 }}</ref><ref name="NeillJohansson1968">{{cite journal | vauthors = Neill JD, Johansson ED, Datta JK, Knobil, E | title = Endocrinology: Relationship Between the Plasma Levels of Luteinizing Hormone and Progesterone During the Normal Menstrual Cycle | journal = Obstetrical & Gynecological Survey | volume = 23 | issue = 3 | pages = 271–277 | year = 1968 | doi = 10.1097/00006254-196803000-00006 }}</ref> Spironolactone was first studied in the treatment of hirsutism in women in 1978.<ref name="pmid6205409">{{cite journal | vauthors = Tindall DJ, Chang CH, Lobl TJ, Cunningham GR | title = Androgen antagonists in androgen target tissues | journal = Pharmacology & Therapeutics | volume = 24 | issue = 3 | pages = 367–400 | date = 1984 | pmid = 6205409 | doi = 10.1016/0163-7258(84)90010-X }}</ref><ref name="pmid27450358">{{cite journal | vauthors = Armanini D, Andrisani A, Bordin L, Sabbadin C | title = Spironolactone in the treatment of polycystic ovary syndrome | journal = Expert Opinion on Pharmacotherapy | volume = 17 | issue = 13 | pages = 1713–5 | date = September 2016 | pmid = 27450358 | doi = 10.1080/14656566.2016.1215430 | s2cid = 19345088 | doi-access = free | title-link = doi }}</ref><ref name="pmid717935">{{cite journal | vauthors = Ober KP, Hennessy JF | title = Spironolactone therapy for hirsutism in a hyperandrogenic woman | journal = Annals of Internal Medicine | volume = 89 | issue = 5 Pt 1 | pages = 643–4 | date = November 1978 | pmid = 717935 | doi = 10.7326/0003-4819-89-5-643 }}</ref><ref name="pmid488407">{{cite journal | vauthors = Boisselle A, Tremblay RR | title = New therapeutic approach to the hirsute patient | journal = Fertility and Sterility | volume = 32 | issue = 3 | pages = 276–9 | date = September 1979 | pmid = 488407 | doi = 10.1016/s0015-0282(16)44232-9 }}</ref><ref name="pmid7410528">{{cite journal | vauthors = Shapiro G, Evron S | title = A novel use of spironolactone: treatment of hirsutism | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 51 | issue = 3 | pages = 429–32 | date = September 1980 | pmid = 7410528 | doi = 10.1210/jcem-51-3-429 }}</ref> It has since become the most widely used antiandrogen for dermatological indications in women in the United States.<ref name="WakelinMaibach2002" /><ref name="Curtis2014">{{cite book| vauthors = Curtis M |title=Glass' Office Gynecology|url=https://books.google.com/books?id=w2AGBAAAQBAJ&pg=PA47|year=2014|publisher=Lippincott Williams & Wilkins|isbn=978-1-60831-820-9|pages=47–}}</ref><ref name="ShahBhathena2004">{{cite book|vauthors=Shah D, Bhathena RK, Shroff S|title=The Polycystic Ovary Syndrome|url=https://books.google.com/books?id=Jxd03OBIn9wC&pg=PA78|year=2004|publisher=Orient Blackswan|isbn=978-81-250-2633-4|pages=78–|access-date=4 July 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095842/https://books.google.com/books?id=Jxd03OBIn9wC&pg=PA78|url-status=live}}</ref><ref name="Hillard2013">{{cite book|vauthors=Hillard PJ|title=Practical Pediatric and Adolescent Gynecology|url=https://books.google.com/books?id=vAA5Z5aqlUQC&pg=PT371|date=29 March 2013|publisher=John Wiley & Sons|isbn=978-1-118-53857-9|pages=371–|access-date=4 July 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095842/https://books.google.com/books?id=vAA5Z5aqlUQC&pg=PT371|url-status=live}}</ref> Spironolactone was first studied as an antiandrogen in transgender women in 1986, and has since become widely adopted for this purpose as well, particularly in the United States where cyproterone acetate is not available.<ref name="DahlFeldman2006">{{cite journal| vauthors = Dahl M, Feldman JL, Goldberg JM, Jaberi A |title=Physical Aspects of Transgender Endocrine Therapy|journal=International Journal of Transgenderism|volume=9|issue=3–4|year=2006|pages=111–134|issn=1553-2739|doi=10.1300/J485v09n03_06 |s2cid=146232471}}</ref><ref name="PriorVigna1986">{{cite journal | vauthors = Prior JC, Vigna YM, Watson D, Diewold P, Robinow O | title = Spironolactone in the presurgical therapy of male to female transsexuals: Philosophy and experience of the Vancouver Gender Dysphoria Clinic | journal = Journal of Sex Information & Education Council of Canada | issue = 1 | pages = 1–7 }}</ref><ref name="FisherMaggi2015">{{cite book| vauthors = Fisher AD, Maggi M | title=Management of Gender Dysphoria |chapter=Endocrine Treatment of Transsexual Male-to-Female Persons|year=2015|pages=83–91| publisher=Springer |doi=10.1007/978-88-470-5696-1_10|isbn=978-88-470-5695-4}}</ref>

Early oral spironolactone tablets showed poor absorption.<ref name="Dorfman2016">{{cite book| vauthors = Dorfman RI |title=Steroidal Activity in Experimental Animals and Man|url=https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA392|date=5 December 2016|publisher=Elsevier Science|isbn=978-1-4832-7299-3|pages=392–}}</ref> The formulation was eventually changed to a [[micronization|micronized]] formulation with [[particle size]]s of less than 50&nbsp;μg, which resulted in approximately 4-fold increased potency.<ref name="Dorfman2016" /><ref name="GlázVecsei2017">{{cite book|vauthors=Gláz E, Vecsei P|title=Aldosterone: International Series of Monographs in Pure and Applied Biology|url=https://books.google.com/books?id=ya3YBAAAQBAJ&pg=PA380|date=11 January 2017|publisher=Elsevier Science|isbn=978-1-4831-5997-3|page=379|access-date=31 December 2020|archive-date=10 October 2022|archive-url=https://web.archive.org/web/20221010052225/https://books.google.com/books?id=ya3YBAAAQBAJ&pg=PA380|url-status=live}}</ref>

==Society and culture==

===Generic names===
[[File:Spironolactone for veterinary use.jpg|thumb|Generic spironolactone for veterinary use]]
The English, French, and [[generic drug|generic name]] of the medication is spironolactone and this is its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA960|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=960ff}}</ref><ref name="Drugs.com">{{cite web |url=https://www.drugs.com/international/spironolactone.html |title=Spironolactone |access-date=1 December 2016 |url-status=live |archive-url=https://web.archive.org/web/20161202040938/https://www.drugs.com/international/spironolactone.html |archive-date=2 December 2016 }}</ref><ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1111|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|page=1111|url-status=live|archive-url=https://web.archive.org/web/20170215024945/https://books.google.com/books?id=0vXTBwAAQBAJ|archive-date=15 February 2017}}</ref><ref name="MortonHall1999">{{cite book|vauthors=Morton IK, Hall JM|title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA261|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=261ff|access-date=1 December 2016|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095843/https://books.google.com/books?id=mqaOMOtk61IC&pg=PA261|url-status=live}}</ref> Its name is {{lang|la|spironolactonum}} in Latin, {{lang|de|Spironolacton}} in German, {{lang|es|espironolactona}} in Spanish and Portuguese, and {{lang|it|spironolattone}} in Italian (which is also its {{abbrlink|DCIT|Denominazione Comune Italiana}}).<ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name="MortonHall1999" />

Spironolactone is also known by its developmental code names SC-9420 and NSC-150339.<ref name="IndexNominum2000"/><ref name="Drugs.com" /><ref name="Elks2014" />

===Brand names===
Spironolactone is marketed under various brand names throughout the world.<ref name="IndexNominum2000"/><ref name="Drugs.com" /> The original brand name of spironolactone is Aldactone.<ref name="IndexNominum2000"/><ref name="Drugs.com" /> Other brand names include Aldactone-A, Berlactone, CaroSpir, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone ([[veterinary medicine|veterinary]]), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued),<ref name="FARIDDiamanti-Kandarakis2009" /> Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis, Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (veterinary), Uractone, Uractonum, Verospiron, and Vivitar.<ref name="IndexNominum2000"/><ref name="Drugs.com" />

Spironolactone is also formulated in combination with a variety of other medications, including with [[hydrochlorothiazide]] as Aldactazide, with [[hydroflumethiazide]] as Aldactide, Lasilacton, Lasilactone, and Spiromide, with [[altizide]] as Aldactacine and Aldactazine, with [[furosemide]] as Fruselac, with [[benazepril]] as Cardalis (veterinary),<ref>{{cite web | title=Cardalis 5 mg/40 mg chewable tablets for Dogs (Canada) | website=Drugs.com | date=27 August 2025 | url=https://www.drugs.com/vet/cardalis-5-mg-40-mg-chewable-tablets-can.html | access-date=30 October 2025}}</ref> with [[metolazone]] as Metolactone, with [[bendroflumethiazide]] as Sali-Aldopur, and with [[torasemide]] as Dytor Plus, Torlactone, and Zator Plus.<ref name="Drugs.com" />

===Availability===
Spironolactone is marketed throughout the world.<ref name="IndexNominum2000"/><ref name="Drugs.com" />

==Research==

===Prostate conditions===
Spironolactone has been studied at a high dosage<!--100 mg/day--> in the treatment of [[benign prostatic hyperplasia]] (BPH; enlarged prostate).<ref name="Springer2012">{{cite book|title=Benign Prostatic Hypertrophy|url=https://books.google.com/books?id=Z5K-BwAAQBAJ&pg=PA266|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-5476-8|pages=266–|access-date=30 July 2017|archive-date=7 October 2022|archive-url=https://web.archive.org/web/20221007095843/https://books.google.com/books?id=Z5K-BwAAQBAJ&pg=PA266|url-status=live}}</ref><ref name="pmid1702565">{{cite journal | vauthors = Matzkin H, Braf Z | title = Endocrine treatment of benign prostatic hypertrophy: current concepts | journal = Urology | volume = 37 | issue = 1 | pages = 1–16 | date = January 1991 | pmid = 1702565 | doi = 10.1016/0090-4295(91)80069-j }}</ref><ref name="pmid4104441">{{cite journal | vauthors = Castro JE, Griffiths HJ, Edwards DE | title = A double-blind, controlled, clinical trial of spironolactone for benign prostatic hypertrophy | journal = The British Journal of Surgery | volume = 58 | issue = 7 | pages = 485–9 | date = July 1971 | pmid = 4104441 | doi = 10.1002/bjs.1800580703 | s2cid = 27601630 }}</ref> It was found to be better than placebo in terms of symptom relief following three months of treatment.<ref name="Springer2012" /><ref name="pmid1702565" /> However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared.<ref name="Springer2012" /><ref name="pmid1702565" /><ref name="pmid4104441" /> Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size.<ref name="Springer2012" /><ref name="pmid1702565" /> Gynecomastia was observed in about 5% of people.<ref name="pmid1702565" /> On the basis of these results, it has been said that spironolactone has no place in the treatment of BPH.<ref name="pmid1702565" />

Spironolactone has been studied and used 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 | issue = Suppl 7 | pages = 1929–1936 | date = April 1980 | pmid = 29603164 | doi = 10.1002/cncr.1980.45.s7.1929 | s2cid = 4492779 | doi-access = free | title-link = doi }}</ref><ref name="pmid3540320">{{cite journal | vauthors = Smith JA | title = New methods of endocrine management of prostatic cancer | journal = The Journal of Urology | volume = 137 | issue = 1 | pages = 1–10 | date = January 1987 | pmid = 3540320 | doi = 10.1016/S0022-5347(17)43855-9 }}</ref><ref name="EndouHosoyamada1995" />

===Epstein–Barr virus===
Spironolactone has been found to block [[Epstein–Barr virus]] (EBV) production and that of other [[human herpesviruses]] by inhibiting the function of an EBV protein SM, which is essential for infectious virus production.<ref name="Verma2016">{{cite journal | vauthors = Verma D, Thompson J, Swaminathan S | title = Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 13 | pages = 3609–14 | date = March 2016 | pmid = 26976570 | pmc = 4822607 | doi = 10.1073/pnas.1523686113 | bibcode = 2016PNAS..113.3609V | doi-access = free | title-link = doi }}</ref> This effect of spironolactone was determined to be independent of its antimineralocorticoid actions.<ref name="Verma2016" />

===Other conditions===
Spironolactone has been studied in the treatment of [[rosacea]] in both males and females.<ref name="pmid15389184">{{cite journal | vauthors = Pelle MT, Crawford GH, James WD | title = Rosacea: II. Therapy | journal = Journal of the American Academy of Dermatology | volume = 51 | issue = 4 | pages = 499–512; quiz 513–4 | date = October 2004 | pmid = 15389184 | doi = 10.1016/j.jaad.2004.03.033 }}</ref><ref name="GiurcăneanuMarinescu2016">{{cite journal| vauthors = Merticariu A, Marinescu L, Giurcăneanu C |title=Rosacea and its comorbidities|journal=Journal of Translational Medicine and Research|volume=21|issue=1|year=2016|page=17|issn=2393-4999|doi=10.21614/jtmr-21-1-68| doi-access = free | url=https://www.sgo-iasgo.com/articles/view.php?art_url=rosacea-and-its-comorbidities <!-- doi is spam now --> |doi-broken-date=12 July 2025 |url-access=subscription}}</ref><ref name="Wollina2014">{{cite book| vauthors = Wollina U |title=Pathogenesis and Treatment of Acne and Rosacea|chapter=Nonclassical Treatments|year=2014|pages=713–717|publisher=Springer |doi=10.1007/978-3-540-69375-8_95|isbn=978-3-540-69374-1}}</ref><ref name="pmid9557251" /><ref name="pmid23594595">{{cite journal | vauthors = Spoendlin J, Voegel JJ, Jick SS, Meier CR | title = Spironolactone may reduce the risk of incident rosacea | journal = The Journal of Investigative Dermatology | volume = 133 | issue = 10 | pages = 2480–2483 | date = October 2013 | pmid = 23594595 | doi = 10.1038/jid.2013.186 | doi-access = free | title-link = doi }}</ref>

Spironolactone has been studied in [[fibromyalgia]] in women.<ref name="WernzeHerdegen2014">{{cite journal | vauthors = Wernze H, Herdegen T | title = Long-term efficacy of spironolactone on pain, mood, and quality of life in women with fibromyalgia: An observational case series | journal = Scandinavian Journal of Pain | volume = 5 | issue = 2 | pages = 63–71 | date = April 2014 | pmid = 29913681 | doi = 10.1016/j.sjpain.2013.12.003 | s2cid = 49305801 }}</ref><ref name="Kalso2014">{{cite journal | vauthors = Kalso E | title = From patient observation to potential new therapies-Is old spironolactone a new analgesic? | journal = Scandinavian Journal of Pain | volume = 5 | issue = 2 | pages = 61–62 | date = April 2014 | pmid = 29913669 | doi = 10.1016/j.sjpain.2014.02.006 | s2cid = 49298333 }}</ref> It has also been studied in [[bulimia nervosa]] in women, but was not found to be effective.<ref name="pmid22946772">{{cite journal | vauthors = McElroy SL, Guerdjikova AI, Mori N, O'Melia AM | title = Current pharmacotherapy options for bulimia nervosa and binge eating disorder | journal = Expert Opinion on Pharmacotherapy | volume = 13 | issue = 14 | pages = 2015–26 | date = October 2012 | pmid = 22946772 | doi = 10.1517/14656566.2012.721781 | s2cid = 1747393 }}</ref>

== References ==
{{Reflist}}

{{Spironolactone}}
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