Empirical hormonal treatments for idiopathic male infertility: a network meta-analysis comparing antiestrogens and FSH

Background: Idiopathic male infertility, characterized by impaired spermatogenesis without identifiable etiology, lacks targeted therapeutic strategies. Empirical hormonal treatments such as aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and follicle-stimulating hormone (FSH) are commonly employed, despite limited high-quality evidence. Objective: To compare the efficacy of AIs, SERMs, and FSH in improving semen parameters among men with idiopathic oligozoospermia and/or asthenozoospermia, using a network meta-analysis (NMA) approach. Methods: This systematic review and NMA included 24 controlled studies (n = 1676 men). Eligible trials compared FSH, SERMs, or AIs (eg, clomiphene, tamoxifen) to placebo or active comparators. Outcomes included post-treatment sperm concentration, total sperm number, and progressive motility. A frequentist random-effects model was used. Treatments were ranked using P-scores, with inconsistency assessed via node-splitting. Results: Clomiphene citrate (CC) 25 mg every other day showed the greatest improvement in sperm concentration (mean difference [MD] = 22.00; 95% CI: 14.75-29.25; P-score = 99%). FSH 300 IU every other day also significantly improved sperm concentration (MD = 9.34; 95% CI: 5.14-13.53). For total sperm number, CC 25 mg every other day again ranked highest (MD = 66.70; 95% CI: 27.53-105.87). No intervention showed a significant effect on progressive motility in the NMA. A dose–response trend was observed for FSH (direct relationship) and SERMs (inverse relationship). Conclusions: Both SERMs and FSH improve sperm concentration and count compared to placebo. Clomiphene at low doses and high-dose FSH may offer the greatest benefit. These findings support a personalized empirical treatment approach and emphasize the need for future trials stratified by clinical phenotype, such as the recently proposed APHRODITE criteria.