SynthesisEuropean journal of clinical pharmacology2026
Clomiphene citrate versus testosterone replacement therapy in male hypogonadism: a systematic review of literature and meta-analysis.
Synthesis in European journal of clinical pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
introductionMale 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.
methodsWe 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'. 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.
resultsA 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 = 6.64 ng/dL; 95% CI -35.35 to 48.63; I² = 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 = 24.29; 95% CI -18.91 to 67.48; I² = 76.1%). For sexual function, three studies (199 patients; 85 on clomiphene; 114 on TRT) assessing post-treatment libido (ADAM 1-5) showed lower libido scores with clomiphene than TRT (MD = - 0.54; 95% CI - 0.87 to - 0.21; P = 0.009; I² = 18.8%).
conclusionsNo 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.
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