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

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.

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.

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.

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).

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.