{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:18:07Z","timestamp":1791494287590,"version":"4.3.4"},"reference-count":48,"publisher":"PAGEPress Publications","issue":"4","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arch Ital Urol Androl"],"abstract":"<jats:p>Objective: To review the evidence concerning treatment-related gynecomastia in patients taking spironolactone, antiandrogens, 5 alpha-reductase inhibitors, lipid-lowering and psychotropic drugs. Material and methods: A search of Medline and EMBASE was performed up to 30 June 2021. We included randomized controlled trials comparing the effects of a drug belonging to these classes versus placebo or versus a drug of the same class. Results: A total of 32 randomized controlled trials were included in the final review. There was an increased odds of gynecomastia in men receiving antiandrogens (OR = 17.38, 95% CI: 11.26 to 26.82; 6 trials, 9599 participants) and 5 alpha-reductase inhibitors compared to controls (OR = 1.77, 95% CI: 1.53 to 2.06; 7 series out of 6 trials, 34860 participants). The use of spironolactone in mixed gender populations was characterized by significantly higher odds of having gynecomastia compared to controls (OR = 8.39, 95% CI: 5.03 to 13.99; 14 trials, 3745 participants). No placebo-controlled trials focusing on the risk of gynecomastia in patients taking antipsychotic drugs was available, although there was a significant difference in the odds of having gynecomastia in a comparison between risperidone and quetiapine (OR = 4.32, 95% CI: 1.31 to 14.27; 3 trials, 343 participants). Limited evidence about the effects of statins on mammary glands was found. Conclusions: Antiandrogens and to a lesser extent 5 alphareductase inhibitors and spironolactone are associated with an increased risk of developing gynecomastia. Such effect can be explained by a modification of the testosterone to estradiol ratio. Gynecomastia (and galactorrhea) associated to the use of conventional and certain atypical antipsychotics can be related to high prolactin levels.<\/jats:p>","DOI":"10.4081\/aiua.2021.4.489","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T15:39:54Z","timestamp":1640101194000},"page":"489-496","source":"Crossref","is-referenced-by-count":23,"title":["Drug-induced gynecomastia: A systematic review and meta-analysis of randomized clinical trials"],"prefix":"10.4081","volume":"93","author":[{"given":"Alberto","family":"Trinchieri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianpaolo","family":"Perletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittorio","family":"Magri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Stamatiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Trinchieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Montanari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2549","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"key":"46740","doi-asserted-by":"crossref","unstructured":"Bowman JD, Hyunah Kim H, Bustamante JJ. Drug-induced gynecomastia. Pharmacotherapy. 2012; 32:1123-1140","DOI":"10.1002\/phar.1138"},{"key":"46741","doi-asserted-by":"crossref","unstructured":"Higgins JP, Altman DG, G\u00f8tzsche P, Cet al.Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928.","DOI":"10.1136\/bmj.d5928"},{"key":"46742","doi-asserted-by":"crossref","unstructured":"Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6: e1000097.","DOI":"10.1371\/journal.pmed.1000097"},{"key":"46743","doi-asserted-by":"crossref","unstructured":"Iversen P, McLeod DG, See WA, et al. Casodex Early Prostate Cancer Trialists' Group. Antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide Early Prostate Cancer programme at a median followup of 9.7 years. BJU Int. 2010; 105:1074-81.","DOI":"10.1111\/j.1464-410X.2010.09319.x"},{"key":"46744","doi-asserted-by":"crossref","unstructured":"Shipley WU, Seiferheld W, Lukka HR, et al. NRG Oncology RTOG. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 2017; 376:417-428.","DOI":"10.1056\/NEJMoa1607529"},{"key":"46745","doi-asserted-by":"crossref","unstructured":"Zanardi S, Puntoni M, Maffezzini M, et al. Phase I-II trial of weekly bicalutamide in men with elevated prostate-specific antigen and negative prostate biopsies. Cancer Prev Res (Phila). 2009;2:377-84.","DOI":"10.1158\/1940-6207.CAPR-08-0205"},{"key":"46746","doi-asserted-by":"crossref","unstructured":"Alberts SR, Novotny PJ, Sloan JA, et al. Flutamide in men with prostatic intraepithelial neoplasia: A randomized, placebo-controlled chemoprevention trial American Journal of Therapeutics. 2006; 13:4(291-297).","DOI":"10.1097\/00045391-200607000-00002"},{"key":"46747","doi-asserted-by":"crossref","unstructured":"Narayan P, Trachtenberg J, Lepor H, et al. A dose-response study of the effect of flutamide on benign prostatic hyperplasia: results of a multicenter study. Urology. 1996; 47:497-504.","DOI":"10.1016\/S0090-4295(99)80484-1"},{"key":"46748","doi-asserted-by":"crossref","unstructured":"Berger BM, Naadimuthu A, Boddy A, et al. The effect of zanoterone, a steroidal androgen receptor antagonist, in men with benign prostatic hyperplasia. The Zanoterone Study Group. J Urol. 1995;154:1060-4","DOI":"10.1016\/S0022-5347(01)66976-3"},{"key":"46749","doi-asserted-by":"crossref","unstructured":"Andriole GL, Bostwick DG, Brawley OW, et al. REDUCE Study Group Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010; 362:1192-202","DOI":"10.1056\/NEJMoa0908127"},{"key":"46750","doi-asserted-by":"crossref","unstructured":"Na Y, Ye Z, Zhang S. Efficacy and Safety of Dutasteride in Chinese Adults with Symptomatic Benign Prostatic Hyperplasia : A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with an Open-Label Extension. Clin Drug Investig. 2012; 32:29-39.","DOI":"10.2165\/11593750-000000000-00000"},{"key":"46751","doi-asserted-by":"crossref","unstructured":"Roehrborn CG, Boyle P, Nickel J, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia Urology. 2002; 60:3(434-441).","DOI":"10.1016\/S0090-4295(02)01905-2"},{"key":"46752","doi-asserted-by":"crossref","unstructured":"McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med. 1998;338:557-63.","DOI":"10.1056\/NEJM199802263380901"},{"key":"46753","doi-asserted-by":"crossref","unstructured":"Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer.N Engl J Med.2003; 349:215-24.","DOI":"10.1056\/NEJMoa030660"},{"key":"46754","doi-asserted-by":"crossref","unstructured":"Amory JK, Wang C, Swerdloff RS, et al. The effect of 5a-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men Journal of Clinical Endocrinology and Metabolism. 2007; 92:5(1659-1665).","DOI":"10.1210\/jc.2006-2203"},{"key":"46755","doi-asserted-by":"crossref","unstructured":"Nickel JC, Gilling P, Tammela TL, et al. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int. 2011; 108:388-94.","DOI":"10.1111\/j.1464-410X.2011.10195.x"},{"key":"46756","doi-asserted-by":"crossref","unstructured":"Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease Kidney International 2006; 70:2116-2123.","DOI":"10.1038\/sj.ki.5001854"},{"key":"46757","doi-asserted-by":"crossref","unstructured":"Charytan DM, Himmelfarb J, Ikizler TA, et al. Hemodialysis Novel Therapies Consortium. Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebocontrolled, multiple dosage trial. Kidney Int. 2019; 95:973-982.","DOI":"10.1016\/j.kint.2018.08.034"},{"key":"46758","doi-asserted-by":"crossref","unstructured":"Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: The Aldo-DHF randomized controlled trial JAMA - Journal of the American Medical Association 2013; 309:781-791.","DOI":"10.1001\/jama.2013.905"},{"key":"46759","doi-asserted-by":"crossref","unstructured":"Gao X, Peng L, Adhikari CM, et al. Spironolactone Reduced Arrhythmia and Maintained Magnesium Homeostasis in Patients With Congestive Heart Failure Journal of Cardiac Failure 2007; 13:170-177.","DOI":"10.1016\/j.cardfail.2006.11.015"},{"key":"46760","doi-asserted-by":"crossref","unstructured":"Ito Y, Mizuno M, Suzuki Y, et al. Long-term effects of spironolactone in peritoneal dialysis patients Journal of the American Society of Nephrology. 2014; 25:1094-1102.","DOI":"10.1681\/ASN.2013030273"},{"key":"46761","doi-asserted-by":"crossref","unstructured":"Kayrak M, Bacaksiz A, Vatankulu MA, et al. The effects of spironolactone on atrial remodeling in patients with preserved left ventricular function after an acute myocardial infarction: A randomized follow-up study Coronary Artery Disease. 2010; 21:477-485.","DOI":"10.1097\/MCA.0b013e32833fd243"},{"key":"46762","doi-asserted-by":"crossref","unstructured":"Matsumoto Y, Mori Y, Kageyama S, et al. Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol. 2014; 63:528-36.","DOI":"10.1016\/j.jacc.2013.09.056"},{"key":"46763","doi-asserted-by":"crossref","unstructured":"Ni X, Zhang J, Zhang P, et al. Effects of spironolactone on dialysis patients with refractory hypertension: A randomized controlled study Journal of Clinical Hypertension. 2014; 16:658-663.","DOI":"10.1111\/jch.12374"},{"key":"46764","doi-asserted-by":"crossref","unstructured":"Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341:709-17.","DOI":"10.1056\/NEJM199909023411001"},{"key":"46765","unstructured":"Skvortsov AA, Mareev VY, Chelmakina SM, et al. Efficacy and safety of long-term application of spironolactone in patients with moderate and severe chronic heart failure receiving optimal therapy. Kardiologiia. 2007; 47:12-23."},{"key":"46766","doi-asserted-by":"crossref","unstructured":"Tofte N, Lindhardt M, Adamova K, et al. PRIORITY investigators. Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): a prospective observational study and embedded randomised placebo-controlled trial. Lancet Diabetes Endocrinol. 2020;8:301-312.","DOI":"10.1016\/S2213-8587(20)30026-7"},{"key":"46767","doi-asserted-by":"crossref","unstructured":"Vatankulu MA, Bacaksiz A, Sonmez O, et al. Does spironolactone have a dose-dependent effect on left ventricular remodeling in patients with preserved left ventricular function after an acute myocardial infarction? Cardiovascular Therapeutics. 2013; 31:224-229.","DOI":"10.1111\/1755-5922.12006"},{"key":"46768","doi-asserted-by":"crossref","unstructured":"Vizzardi E, Pina PD, Caretta G, et al. The effect of aldosteroneantagonist therapy on aortic elastic properties in patients with nonischemic dilated cardiomyopathy Journal of Cardiovascular Medicine. 2015; 16:597-602.","DOI":"10.2459\/JCM.0000000000000102"},{"key":"46769","doi-asserted-by":"crossref","unstructured":"Zarraga IGE, Dougherty CM, MacMurdy KS, Raitt MH. Tachyarrhythmias the effect of spironolactone on ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillators Circulation: Arrhythmia and Electrophysiology. 2012; 5:739-747.","DOI":"10.1161\/CIRCEP.112.970566"},{"key":"46770","doi-asserted-by":"crossref","unstructured":"Kelly DL., Conley RR. A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia Psychoneuroendocrinology. 2006; 31:340-346.","DOI":"10.1016\/j.psyneuen.2005.08.010"},{"key":"46771","doi-asserted-by":"crossref","unstructured":"McEvoy JP, Lieberman JA, Stroup TS, et al. CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600-10.","DOI":"10.1176\/ajp.2006.163.4.600"},{"key":"46772","doi-asserted-by":"crossref","unstructured":"McEvoy JP, Lieberman JA, Perkins DO, et al. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: A randomized, double-blind 52-week comparison American Journal of Psychiatry. 2007; 164:1050-1060.","DOI":"10.1176\/ajp.2007.164.7.1050"},{"key":"46773","doi-asserted-by":"crossref","unstructured":"McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA. 2014;311:1978-87.","DOI":"10.1001\/jama.2014.4310"},{"key":"46774","doi-asserted-by":"crossref","unstructured":"Schr\u00f6der FH, Whelan P, de Reijke TM, et al. Members of the EORTC Genito-Urinary Group. Metastatic prostate cancer treated by flutamide versus cyproterone acetate. Final analysis of the \"European Organization for Research and Treatment of Cancer\" (EORTC) Protocol 30892. Eur Urol. 2004; 45:457-64.","DOI":"10.1016\/S1569-9056(03)80743-1"},{"key":"46775","doi-asserted-by":"crossref","unstructured":"Narula HS, Carlson HE. Gynaecomastia-pathophysiology, diagnosis and treatment. Nat Rev Endocrinol. 2014; 10:684-698.","DOI":"10.1038\/nrendo.2014.139"},{"key":"46776","doi-asserted-by":"crossref","unstructured":"Kanakis GA, Nordkap L, Bang AK, et al. EAA clinical practice guidelines-gynecomastia evaluation and management. Andrology. 2019; 7:778-793.","DOI":"10.1111\/andr.12636"},{"key":"46777","doi-asserted-by":"crossref","unstructured":"Wirth M, Tyrrell C, Wallace M, et al. Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression Urology. 2001; 58:146-150.","DOI":"10.1016\/S0090-4295(01)01213-4"},{"key":"46778","doi-asserted-by":"crossref","unstructured":"Wirth M, Tyrrell C, Delaere K, et al. Bicalutamide ('Casodex') 150mg in addition to standard care in patients with nonmetastatic prostate cancer: Updated results from a randomised double-blind phase III study (median follow-up 5.1y) in the early prostate cancer programme Prostate Cancer and Prostatic Diseases 2005; 8:194-200.","DOI":"10.1038\/sj.pcan.4500799"},{"key":"46779","doi-asserted-by":"crossref","unstructured":"Iversen P, McLeod DG, See WA, et al. Casodex Early Prostate Cancer Trialists' Group. Antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide Early Prostate Cancer programme at a median followup of 9.7 years.BJU Int. 2010; 105:1074-81.","DOI":"10.1111\/j.1464-410X.2010.09319.x"},{"key":"46780","doi-asserted-by":"crossref","unstructured":"Skeldon SC, Carleton B, Brophy JM, et al. Statin medications and the risk of gynecomastia. Clin Endocrinol (Oxf). 2018; 89:470-473.","DOI":"10.1111\/cen.13794"},{"key":"46781","doi-asserted-by":"crossref","unstructured":"Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med. 2013;11:57.","DOI":"10.1186\/1741-7015-11-57"},{"key":"46782","doi-asserted-by":"crossref","unstructured":"Roberto G, Biagi C, Montanaro N, et al. Statin-associated gynecomastia: evidence coming from the Italian spontaneous ADR reporting database and literature. Eur J Clin Pharmacol. 2012; 68:1007-11.","DOI":"10.1007\/s00228-012-1218-5"},{"key":"46783","doi-asserted-by":"crossref","unstructured":"Batteux B, Llopis B, Muller C, et al. French National Network of Pharmacovigilance Centres. The drugs that mostly frequently induce gynecomastia: A national case - noncase study. Therapie. 2020;75:225-238.","DOI":"10.1016\/j.therap.2019.06.001"},{"key":"46784","doi-asserted-by":"crossref","unstructured":"Grigg J, Worsley R, Thew C, et al. Antipsychotic-induced hyperprolactinemia: synthesis of world-wide guidelines and integrated recommendations for assessment, management and future research. Psychopharmacology. 2017; 234:3279-3297.","DOI":"10.1007\/s00213-017-4730-6"},{"key":"46785","doi-asserted-by":"crossref","unstructured":"Ferreira M, Mesquita M, Quaresma M & Andr\u00e9 S. Prolactin receptor expression in gynaecomastia and male breast carcinoma. Histopathology. 2008; 53:56-61.","DOI":"10.1111\/j.1365-2559.2008.03059.x"},{"key":"46786","doi-asserted-by":"crossref","unstructured":"Layton AM, Eady EA, Whitehouse H, et al. Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review. Am J Clin Dermatol. 2017; 18:169-191.","DOI":"10.1007\/s40257-016-0245-x"},{"key":"46787","doi-asserted-by":"crossref","unstructured":"Muhlemann MF, Carter GD, Cream JJ, Wise P. Oral spironolactone: an effective treatment for acne vulgaris in women. Br J Dermatol. 1986; 115:227-32.","DOI":"10.1111\/j.1365-2133.1986.tb05722.x"}],"container-title":["Archivio Italiano di Urologia e Andrologia"],"original-title":[],"link":[{"URL":"https:\/\/www.pagepressjournals.org\/index.php\/aiua\/article\/download\/aiua.2021.4.489\/9810","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.pagepressjournals.org\/index.php\/aiua\/article\/download\/aiua.2021.4.489\/9809","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T15:45:42Z","timestamp":1640101542000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.pagepressjournals.org\/index.php\/aiua\/article\/view\/aiua.2021.4.489"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,21]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,12,20]]}},"URL":"https:\/\/doi.org\/10.4081\/aiua.2021.4.489","relation":{},"ISSN":["2282-4197","1124-3562"],"issn-type":[{"value":"2282-4197","type":"electronic"},{"value":"1124-3562","type":"print"}],"subject":[],"published":{"date-parts":[[2021,12,21]]}}}