Clomiphene raised testosterone about as well as TRT gel in 1,512 men, but libido scores came out lower
Journal: European Journal of Clinical Pharmacology | Published: 2026-07-11 | Type: Systematic Review, Meta-Analysis, Comparative Study | PMID: 42435198 Authors: Constantinou Beatriz T, Benedicto Bianca C, Galligani Lilian, et al. (Department of Urology, Ninth of July University, Sao Bernardo do Campo, Brazil; Federal University of São Paulo School of Medicine) Funding/COI: No funding source listed; authors declare no competing interests
This meta-analysis pooled 11 studies (1,512 hypogonadal men) comparing clomiphene citrate, a pill that stimulates the body's own testosterone production, against testosterone replacement therapy (TRT), which raises testosterone directly but suppresses sperm production. Pooled results showed no statistically significant difference in serum testosterone between the two overall, though TRT scored better on libido. The trial's own stated rationale for clomiphene, preserving fertility, was never actually tested: no fertility or semen outcomes were pooled.
The headline "no difference" finding on testosterone is undercut by its own numbers: I² = 80.6% overall and 76.1% within the gel subgroup indicates substantial heterogeneity, meaning the 11 studies did not agree with each other, likely reflecting differences in dosing, assay methods, and baseline patient profiles across trials. The authors' own conclusion flags "some concerns to high risk of bias" across the included studies, but the abstract gives no breakdown of which studies carried that risk or why, making it hard to judge how much the pooled estimate should be trusted.
The injectable-TRT-beats-clomiphene subgroup result, the largest effect size in the paper, comes from a single 62-patient study. A one-study subgroup with a wide confidence interval (-518.78 to -62.22) is not a basis for a generalizable claim, despite the size of the point estimate. Perhaps the bigger gap: clomiphene's entire appeal in this context is fertility preservation, since TRT suppresses spermatogenesis, yet the review pooled no semen parameters or fertility outcomes at all. A comparison built around a fertility-sparing rationale that never measures fertility is a significant scope gap.
This is a modestly sized meta-analysis whose central claim, that clomiphene and TRT gel raise testosterone similarly, is weakened by heterogeneity so high the pooled number is barely interpretable, and whose more dramatic finding (injectable TRT beating clomiphene) leans entirely on one small study. The libido finding favoring TRT is the most solid result here, with lower heterogeneity and a clear p-value. But the paper never touches the actual reason clinicians reach for clomiphene in younger men, fertility preservation, which limits how useful this comparison is for the population it's ostensibly written for.