{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T07:26:38Z","timestamp":1787037998405,"version":"build-2736575974"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100019864","name":"Universidade Nove De Julho","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019864","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Clin Pharmacol"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Male hypogonadism, including age-related and functional forms, is characterized by insufficient testosterone production often associated with obesity and metabolic comorbidities. Testosterone replacement therapy (TRT) increases serum testosterone but suppresses spermatogenesis and may cause adverse effects. Selective estrogen receptor modulators (SERMs), such as clomiphene citrate, have emerged as an alternative approach to restore endogenous testosterone while preserving fertility. This study aimed to compare the efficacy of clomiphene citrate versus testosterone replacement therapy (TRT) in increasing serum testosterone levels in men with hypogonadism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a systematic review of the literature in PubMed, Embase, Scopus, The Cochrane Library, and Google Scholar to identify studies comparing clomiphene citrate and testosterone replacement therapy (TRT) in men with male hypogonadism\u2019. The primary outcome was the change in serum testosterone levels before and after treatment. Secondary outcomes included variations in other hormonal parameters, and clinical symptom improvement assessed through standardized instruments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 11 studies with 1512 patients were included (764 on clomiphene citrate; 748 on testosterone replacement therapy, TRT). For serum testosterone, the overall pooled effect showed no significant difference between clomiphene and TRT (MD\u2009=\u20096.64 ng\/dL; 95% CI -35.35 to 48.63; I\u00b2 = 80.6%). Subgroup analyses indicated injectable testosterone achieved higher levels than clomiphene (1 study, 62 patients; MD = -290.50; 95% CI -518.78 to -62.22), whereas gel-based TRT showed no difference (8 studies, 1012 patients; MD\u2009=\u200924.29; 95% CI -18.91 to 67.48; I\u00b2 = 76.1%). For sexual function, three studies (199 patients; 85 on clomiphene; 114 on TRT) assessing post-treatment libido (ADAM 1\u20135) showed lower libido scores with clomiphene than TRT (MD = \u2212\u20090.54; 95% CI\u2009\u2212\u20090.87 to \u2212\u20090.21; P\u2009=\u20090.009; I\u00b2 = 18.8%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>No statistically significant difference in serum testosterone levels was observed between clomiphene citrate and testosterone gel, although the evidence is limited by high heterogeneity and some concerns to high risk of bias. TRT was associated with greater improvements in libido. These findings should be interpreted as preliminary, and large-scale randomized trials incorporating clinical and fertility endpoints are needed.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00228-026-04134-3","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T05:02:54Z","timestamp":1783746174000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clomiphene citrate versus testosterone replacement therapy in male hypogonadism: a systematic review of literature and meta-analysis"],"prefix":"10.1007","volume":"82","author":[{"given":"Beatriz T.","family":"Constantinou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca C.","family":"Benedicto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian","family":"Galligani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz N.","family":"Schiavon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caio M.O","family":"Mendes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Micaela G.","family":"Petri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Uzueli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronaldo Soares","family":"Maia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo Afonso Silva","family":"da Sardenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Fraietta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4203-3196","authenticated-orcid":false,"given":"Jose Arnaldo","family":"Shiomi da Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,11]]},"reference":[{"key":"4134_CR1","unstructured":"European Association of Urology Male Hypogonadism. In: EAU Guidelines on Sexual and Reproductive Health. https:\/\/uroweb.org\/guidelines\/sexual-and-reproductive-health\/chapter\/male-hypogonadism(uroweb.org)"},{"issue":"10","key":"4134_CR2","doi-asserted-by":"publisher","first-page":"3007","DOI":"10.1210\/jc.2011-1137","volume":"96","author":"AB Araujo","year":"2011","unstructured":"Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA (2011) Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab 96(10):3007\u20133019. https:\/\/doi.org\/10.1210\/jc.2011-1137 Epub 2011 Aug 3. PMID: 21816776; PMCID: PMC3200249","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"4134_CR3","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1093\/eurheartj\/ehq009","volume":"31","author":"R Haring","year":"2010","unstructured":"Haring R, V\u00f6lzke H, Steveling A, Krebs A, Felix SB, Sch\u00f6fl C, D\u00f6rr M, Nauck M, Wallaschofski H (2010) Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20\u201379. Eur Heart J 31(12):1494\u20131501. https:\/\/doi.org\/10.1093\/eurheartj\/ehq009 Epub 2010 Feb 17. PMID: 20164245","journal-title":"Eur Heart J"},{"issue":"6","key":"4134_CR4","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1111\/andr.274","volume":"2","author":"V Zarotsky","year":"2014","unstructured":"Zarotsky V, Huang MY, Carman W, Morgentaler A, Singhal PK, Coffin D, Jones TH (2014) Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men. Andrology 2(6):819\u2009\u2013\u200934. https:\/\/doi.org\/10.1111\/andr.274. Epub 2014 Oct 1. PMID: 25269643","journal-title":"Andrology"},{"issue":"2","key":"4134_CR5","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.juro.2018.03.115","volume":"200","author":"JP Mulhall","year":"2018","unstructured":"Mulhall JP, Trost LW, Brannigan RE et al (2018) Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol 200(2):423\u2013432. https:\/\/doi.org\/10.1016\/j.juro.2018.03.115","journal-title":"J Urol"},{"issue":"5","key":"4134_CR6","doi-asserted-by":"publisher","first-page":"1715","DOI":"10.1210\/jc.2018-00229","volume":"103","author":"S Bhasin","year":"2018","unstructured":"Bhasin S, Brito JP, Cunningham GR et al (2018) Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 103(5):1715\u20131744. https:\/\/doi.org\/10.1210\/jc.2018-00229","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"4134_CR7","doi-asserted-by":"publisher","first-page":"256","DOI":"10.5534\/wjmh.190061","volume":"38","author":"G Corona","year":"2020","unstructured":"Corona G, Rastrelli G, Morelli A et al (2020) Treatment of Functional Hypogonadism Besides Pharmacological Substitution. World J Mens Health 38(3):256\u2013270. https:\/\/doi.org\/10.5534\/wjmh.190061","journal-title":"World J Mens Health"},{"issue":"6","key":"4134_CR8","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1111\/andr.12725","volume":"8","author":"M Awouters","year":"2020","unstructured":"Awouters M, Vanderschueren D, Antonio L (2020) Aromatase inhibitors and selective estrogen receptor modulators: Unconventional therapies for functional hypogonadism? Andrology 8(6):1590\u20131597. https:\/\/doi.org\/10.1111\/andr.12725","journal-title":"Andrology"},{"issue":"9","key":"4134_CR9","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1053\/meta.2000.8625","volume":"49","author":"JE Morley","year":"2000","unstructured":"Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, Perry HM (2000) Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 49(9):1239\u20131242","journal-title":"Metabolism"},{"issue":"3","key":"4134_CR10","doi-asserted-by":"publisher","first-page":"236","DOI":"10.4103\/iju.IJU_372_16","volume":"33","author":"P Dadhich","year":"2017","unstructured":"Dadhich P, Ramasamy R, Scovell J, Wilken N, Lipshultz L (2017) Testosterone versus clomiphene citrate in managing symptoms of hypogonadism in men. Indian J Urol 33(3):236\u2013240. https:\/\/doi.org\/10.4103\/iju.IJU_372_16 PMID: 28717276; PMCID: PMC5508437","journal-title":"Indian J Urol"},{"issue":"4","key":"4134_CR11","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/j.juro.2016.10.068","volume":"197","author":"KM Wheeler","year":"2017","unstructured":"Wheeler KM, Smith RP, Kumar RA, Setia S, Costabile RA, Kavoussi PK (2017) A comparison of secondary polycythemia in hypogonadal men treated with clomiphene citrate versus testosterone replacement: a multi-institutional study. J Urol 197(4):1127\u20131131. https:\/\/doi.org\/10.1016\/j.juro.2016.10.068","journal-title":"J Urol"},{"issue":"4 Suppl","key":"4134_CR12","first-page":"e413","volume":"193","author":"A McCullough","year":"2015","unstructured":"McCullough A, Kim E, Wyllie M (2015) In two phase III studies, Androxal\u2122 (enclomiphene citrate) significantly improves total testosterone levels compared to AndroGel 1.62%, without suppression of spermatogenesis and testicular function in overweight males with secondary hypogonadism. J Urol 193(4 Suppl):e413","journal-title":"J Urol"},{"issue":"4","key":"4134_CR13","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1111\/bju.13337","volume":"117","author":"ED Kim","year":"2016","unstructured":"Kim ED, McCullough A, Kaminetsky J (2016) Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int 117(4):677\u2013685. https:\/\/doi.org\/10.1111\/bju.13337 Epub 2015 Oct 23. PMID: 26496621","journal-title":"BJU Int"},{"issue":"4 Suppl","key":"4134_CR14","first-page":"e904","volume":"193","author":"CR Mazzola","year":"2015","unstructured":"Mazzola CR, Miranda E, Narus J, Mulhall JP (2015) A comparison of estradiol levels and gynecomastia rates in hypogonadal men using clomiphene citrate versus transdermal testosterone. J Urol 193(4 Suppl):e904","journal-title":"J Urol"},{"issue":"Suppl","key":"4134_CR15","first-page":"50","volume":"3","author":"R Wiehle","year":"2015","unstructured":"Wiehle R, Fontenot G, Sandel M, Thompson J, McCullough A (2015) Enclomid and topical testosterone elevate testosterone in hypogonadal men but enclomid does not decrease testes size. Andrology 3(Suppl):50","journal-title":"Andrology"},{"issue":"4 Suppl","key":"4134_CR16","first-page":"e904","volume":"193","author":"D Lee","year":"2015","unstructured":"Lee D, Bernstein A, Sarkisian A, Wosnitzer M, Winter A, Paduch D (2015) Comparison of clomiphene citrate and transdermal testosterone replacement therapy in their influence on hormonal and metabolic changes in the treatment of hypogonadism. J Urol 193(4 Suppl):e904\u2013e905","journal-title":"J Urol"},{"issue":"3","key":"4134_CR17","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1016\/j.juro.2014.03.089","volume":"192","author":"R Ramasamy","year":"2014","unstructured":"Ramasamy R, Scovell JM, Kovac JR, Lipshultz LI (2014) Testosterone supplementation versus clomiphene citrate for hypogonadism: an age matched comparison of satisfaction and efficacy. J Urol 192(3):875\u2013879","journal-title":"J Urol"},{"issue":"6","key":"4134_CR18","doi-asserted-by":"publisher","first-page":"1628","DOI":"10.1111\/jsm.12116","volume":"10","author":"J Kaminetsky","year":"2013","unstructured":"Kaminetsky J, Werner M, Fontenot G, Wiehle R (2013) Oral Enclomiphene Citrate Stimulates the Endogenous Production of Testosterone and Sperm Counts in Men with Low Testosterone: Comparison with Testosterone Gel. J Sex Med 10(6):1628\u20131635. https:\/\/doi.org\/10.1111\/jsm.12116","journal-title":"J Sex Med"},{"key":"4134_CR19","unstructured":"Berg J. The effect on Androxal Versus AndroGel on morning testosterone in men with secondary Hypogonadism (Low Testosterone). ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2011. Identifier: NCT01386606. Available from: https:\/\/clinicaltrials.gov\/study\/NCT01386606"},{"issue":"1 Pt 1","key":"4134_CR20","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1111\/j.1743-6109.2009.01454.x","volume":"7","author":"F Taylor","year":"2010","unstructured":"Taylor F, Levine L (2010) Clomiphene citrate and testosterone gel replacement therapy for male hypogonadism: efficacy and treatment cost. J Sex Med 7(1 Pt 1):269\u2013276. https:\/\/doi.org\/10.1111\/j.1743-6109.2009.01454.x","journal-title":"J Sex Med"},{"issue":"3","key":"4134_CR21","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1111\/andr.13146","volume":"10","author":"M Huijben","year":"2022","unstructured":"Huijben M, Lock MTWT, de Kemp VF, de Kort LMO, van Breda HMK (2022) Clomiphene citrate for men with hypogonadism: a systematic review and meta-analysis. Andrology 10(3):451\u2013469. https:\/\/doi.org\/10.1111\/andr.13146","journal-title":"Andrology"},{"issue":"9","key":"4134_CR22","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.3390\/ph17091233","volume":"17","author":"YC Wu","year":"2024","unstructured":"Wu YC, Sung WW (2024) Clomiphene Citrate Treatment as an Alternative Therapeutic Approach for Male Hypogonadism: Mechanisms and Clinical Implications. Pharmaceuticals 17(9):1233. https:\/\/doi.org\/10.3390\/ph17091233","journal-title":"Pharmaceuticals"},{"issue":"5","key":"4134_CR23","doi-asserted-by":"publisher","first-page":"e250093","DOI":"10.20945\/2359-4292-2025-0093","volume":"69","author":"A Hohl","year":"2025","unstructured":"Hohl A, Chavez MP, Pasqualotto E, Ferreira ROM, Sande-Lee S, Ronsoni MF (2025) Clomiphene or enclomiphene citrate for the treatment of male hypogonadism: a systematic review and meta-analysis of randomized controlled trials. Arch Endocrinol Metab 69(5):e250093","journal-title":"Arch Endocrinol Metab"},{"issue":"5","key":"4134_CR24","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1097\/JU.0000000000000396","volume":"202","author":"SC Krzastek","year":"2019","unstructured":"Krzastek SC, Sharma D, Abdullah N, Sultan M, Machen GL, Wenzel JL et al (2019) Long-term safety and efficacy of clomiphene citrate for the treatment of hypogonadism. J Urol 202(5):1029\u20131035","journal-title":"J Urol"}],"container-title":["European Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-026-04134-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00228-026-04134-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-026-04134-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T06:55:33Z","timestamp":1787036133000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00228-026-04134-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,11]]},"references-count":24,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["4134"],"URL":"https:\/\/doi.org\/10.1007\/s00228-026-04134-3","relation":{},"ISSN":["0031-6970","1432-1041"],"issn-type":[{"value":"0031-6970","type":"print"},{"value":"1432-1041","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,11]]},"assertion":[{"value":"4 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"204"}}