Clomiphene or enclomiphene citrate for the treatment of male hypogonadism: a systematic review and meta-analysis of randomized controlled trials.

Objective: This study aimed to evaluate the efficacy and safety of selective estrogen receptor modulators (SERMs), specifically clomiphene and enclomiphene, in treating men with functional hypogonadism.

Materials and methods: A systematic search was conducted in PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials comparing SERMs with placebo, testosterone (T) gel, or human chorionic gonadotropin (hCG), up to July 2024. The primary endpoints were total testosterone (TT), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Weighted mean differences (MDs) and risk ratios (RRs) were calculated for continuous and binary endpoints, respectively, with 95% confidence intervals (CIs).

Results: SERM therapy significantly improved TT (MD: 273.76 ng/dL; 95% CI: 191.87-355.66 ng/dL; p < 0.01; I2 = 89%), LH (MD: 4.66 IU/L; 95% CI: 3.37-5.94 IU/L; p < 0.01; I2 = 55%), and FSH (MD: 4.59 IU/L; 95% CI: 2.88-6.30 IU/L; p < 0.01; I2 = 68%) compared to placebo. No significant difference in TT was observed between the SERM and T gel groups. TT levels were significantly higher with SERM therapy and the combined treatment of SERM and hCG compared to hCG alone (158 vs. 153 vs. 134 ng/dL, respectively; p < 0.002 for both comparisons).

Conclusion: SERM therapy is associated with significantly improved levels of TT, LH, and FSH in hypogonadal men compared to placebo, and significantly enhanced levels of LH and FSH compared to T gel. The findings suggest that SERM therapy effectively increases TT levels in men with functional hypogonadism and should be considered as an alternative to T gel therapy.