Letrozole may be an option for infertility in males with spermatogenic failure

Infertility affects approximately one in six adults globally. Male factors contribute to nearly half of these cases, with spermatogenic failure representing the most severe spectrum of phenotypes, including nonobstructive azoospermia, cryptozoospermia and severe oligozoospermia. Spermatogenic failure has limited evidence-based medical treatment options. Severe sperm deficiency typically requires invasive assisted reproductive technologies, which are high-complexity procedures that impose significant physical and financial burdens on both partners. The availability of a pharmacotherapy capable of restoring spermatogenesis could transform clinical management. Aromatase inhibitors, including letrozole, are a promising therapeutic strategy. They inhibit the conversion of testosterone to estradiol, thereby relieving negative feedback on the hypothalamic-pituitary-gonadal axis. Aromatase inhibitors have been widely used off-label in male infertility. However, high-quality evidence remains limited and guideline endorsement is lacking.To explore this issue, researchers recently evaluated the efficacy and safety of letrozole for improving sperm concentration categories in men with spermatogenic failure. They conducted a multicentre, open-label, assessor-blinded randomized clinical trial at 10 male infertility centres in China from July 2023 to March 2024. Men (22–50 years of age) with spermatogenic failure (nonobstructive azoospermia, cryptozoospermia or severe oligozoospermia) were enrolled. Participants were randomized to receive letrozole (2.5 mg daily) plus vitamins C and E, or vitamins C and E alone (control group) for three months. The primary outcome was World Health Organization Sperm Concentration Categories (WHO-SCC) upgrade rate at three months after randomization. The secondary outcomes were WHO-SCC grades, Dutch Society of Obstetrics and Gynecology Total Motile Sperm Count Categories (NVOG-TMSCC) upgrade rate, semen parameters and reproductive hormone levels.Key results:The study included 296 participants (mean age, 30.2 years; 73.6% with nonobstructive azoospermia).147 participants were randomized to the letrozole group and 149 to the control group); 247 (83.4%) completed the trial, and all 296 were included in the primary analysis. WHO-SCC upgrade rates were 14.3% (21 of 147 participants) in the letrozole group vs 5.4% (8 of 149 participants) in the control group (risk difference, 9.2% [95% CI, 2.5%–15.8%]; P = .01). Participants in the letrozole group had higher odds of achieving a better WHO-SCC grade than those in the control group (common odds ratio, 2.65 [95%CI, 1.28–5.47]; P = .008). The NVOG-TMSCC upgrade rate was also higher with letrozole. Letrozole significantly increased serum gonadotropins and testosterone, while decreasing estradiol. No significant between-group differences were seen in semen parameters.Decreased libido (18 [12.2%] vs 8 [5.4%]; P = .04) was a more frequent adverse effect seen in the letrozole group compared with the control group.The authors conclude that in this randomized clinical trial of men with spermatogenic failure, letrozole treatment for three months significantly improved sperm concentration categories and was generally well tolerated. These results support the use of letrozole as an option to reduce infertility severity and potentially enable less invasive reproductive management.Reference:Sun Y, Yao C, Liu G, et al. Letrozole and infertility among males with spermatogenic failure. A randomized clinical trial. JAMA Network Open. 2026;9(6):e2618422. Published online: June 18, 2026. (accessed June 23, 2026).

Letrozole may be an option for infertility in males with spermatogenic failure

Register for free access or login.

Related Topics