Clomiphene citrate for male infertility: A systematic review and meta-analysis.

BACKGROUND: Male infertility is a prevalent and worldwide problem with various difficulties in treatment. Clomiphene citrate is a selective estrogen receptor modulator and may improve semen quality by stimulating hormone synthesis and spermatogenesis. There is lack of evidence on the efficacy of clomiphene citrate as therapy for male infertility. OBJECTIVES: Therefore, a systematic review and meta-analysis was performed to assess the efficacy of clomiphene citrate on sperm quality in infertile men. METHODS: A search was conducted in the PubMed, EMBASE and Cochrane databases for effectiveness in infertile males treated with clomiphene citrate. Both intervention and observational studies were included. Primary outcome measures were semen parameters (concentration, motility and morphology). Secondary outcomes included hormonal evaluation, pregnancy rate and side effects. Studies were included for meta-analysis if they provided absolute numbers for outcomes before and during treatment with appropriate SD or SE. RESULTS: Total 1799 studies were identified during the search, 18 studies remained for qualitative analysis (n = 731) and 15 studies for meta-analysis (n = 566). Study populations ranged between 11 and 140 participants. Sperm concentration was higher during treatment, with a mean difference 8.38 × 106 /ml (95% confidence interval: 5.17-11.59; p < 0.00001; I2  = 87%). Total sperm motility was higher during treatment, with a mean difference of 8.14% (95% confidence interval: 3.83-12.45; p < 0.00001; I2  = 76%). There was no difference in sperm morphology before and during treatment. Total testosterone, follicle-stimulating hormone, luteinizing hormone and estradiol were higher during clomiphene citrate treatment. During follow-up, no serious adverse effects occurred. In 10 studies, pregnancy rate was reported and yielded a mean of 17% during clomiphene citrate treatment (range: 0%-40%). CONCLUSIONS: Clomiphene citrate increased sperm concentration and motility and could be considered as a safe therapy for improving sperm parameters in infertile males.

Clomiphene citrate for men with hypogonadism: a systematic review and meta-analysis.

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 is used as off-label therapy. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of clomiphene citrate 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 clomiphene citrate. 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 increased with 2.60 (95% CI 1.82-3.38) during clomiphene citrate 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, whose 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: Clomiphene citrate is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism. Clomiphene citrate has few reported side effects and good safety aspects.