Background

: Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is first choice therapy, with several side-effects, including negative feedback of the hypothalamic-pituitary-gonadal axis, resulting in suppression of intratesticular testosterone production and spermatogenesis. To preserve these testicular functions while treating male hypogonadism clomiphene citrate (CC) is used as off-label therapy. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of CC therapy for men with hypogonadism.

Methods

: The EMBASE, PubMed, Cochrane databases were searched in May 2021, for effectiveness studies of men with hypogonadism treated with CC. Both intervention and observational studies were included. The Effective Public Health Practice Project Quality Assessment Tool, a validated instrument was used to assess methodological study quality. The primary outcome measure was the evaluation of serum hormone concentration. Secondary outcomes were symptoms of hypogonadism, metabolic- and lipid profile, side-effects, safety aspects.

Results

: We included 19 studies, comprising four randomized controlled trials and 15 observational studies, resulting in 1642 patients. Seventeen studies were included in the meta-analysis, with a total of 1279 patients. Therapy and follow-up duration varied between one and a half and 52 months. Total testosterone (TT) increased with 2.60 (95% CI 1.82 – 3.38) during CC treatment. An increase was also seen in free testosterone, luteinizing hormone, follicle stimulating hormone, sex hormone-binding globulin and estradiol. Different symptom scoring methods were used in the included studies. The most frequently used instrument was the Androgen Deficiency in Aging Males-questionnaire, which score improved during treatment. Reported side-effects were only prevalent in less than 10% of the study populations and no serious adverse events were reported.

Conclusion

: CC is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism. CC has few reported side-effects and good safety aspects.

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