Selective modulation of estrogen receptor in obese men with androgen deficiency: A systematic review and meta-analysis

Background: Although selective estrogen receptor modulators have been proposed as a treatment for men with central functional hypogonadism, only a few data have been produced in men with obesity-related functional androgen deficiency. Objective: To determine whether and to what extent selective estrogen receptor modulators are an effective and safe therapy in men with obesity-related functional androgen deficiency. Materials and methods: A thorough search of PubMed, Web of Science, Scopus, and Cochrane Library databases was performed to identify studies comparing testosterone levels before and after treatment. Mean differences with 95% coefficient intervals were combined using random effects models. Funnel plot, Egger's test, and trim-and-fill analysis were used to assess publication bias. Results: Seven studies met the inclusion criteria providing information on 292 men with obesity-related functional androgen deficiency treated with clomiphene citrate (12.5-50 mg daily) or enclomiphene citrate (12.5-25 mg daily) for 1.5-4 months. The pooled estimates indicated a significant increase in testosterone levels both with clomiphene (mean difference: 11.56 nmol/L; 95% coefficient interval: 9.68, 13.43; I2  = 69%, pfor heterogeneity  = 0.01) and enclomiphene citrate (mean difference: 7.50 nmol/L; 95% coefficient interval: 6.52, 8.48; I2  = 4%, pfor heterogeneity  = 0.37). After the exclusion of one study on severely obese men, who exhibited the highest response rate to clomiphene citrate, the heterogeneity disappeared (mean difference: 10.27 nmol/L; 95% coefficient interval: 9.39, 11.16; I2  = 0%, pfor heterogeneity  = 0.66). No publication bias was revealed by Egger's test and trim-and-fill analysis. No treatment-related unexpected findings regarding safety profile were registered. Discussion and conclusion: Treatment with clomiphene citrate and enclomiphene citrate may be an effective and safe alternative to testosterone replacement therapy in men with obesity-related functional androgen deficiency. Further long-term studies are warranted to define clinical reflections of the selective estrogen receptor modulators-induced increase in testosterone levels and to better clarify the safety profile.