Letrozole Shows Promise for Male Infertility Treatment: JAMA
China: A randomized clinical trial demonstrated that letrozole significantly improved sperm concentration in men with spermatogenic failure and was well tolerated.
By increasing sperm counts and shifting patients into more favorable sperm concentration categories, letrozole may help reduce the severity of male infertility. These improvements could expand reproductive options and potentially allow some couples to pursue less invasive fertility treatments. The findings support letrozole as a promising therapeutic strategy for selected men with impaired sperm production.
The study was published in JAMA Network Open by Yifan Sun from the Department of Andrology, Center for Men’s Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China, and colleagues.
Spermatogenic failure is a severe form of male infertility marked by reduced sperm production and limited treatment options. Letrozole, an aromatase inhibitor that modifies hormone levels, has been proposed as a potential therapy, but high-quality evidence has been scarce.
To assess its effectiveness and safety, researchers conducted a multicenter, assessor-blinded randomized clinical trial across 10 infertility centers in China. Men with spermatogenic failure were assigned to receive either letrozole (2.5 mg daily) plus vitamins C and E or vitamins C and E alone for three months.
The study enrolled 296 men with a mean age of 30.2 years, including a majority with nonobstructive azoospermia. While 247 participants completed the trial, all enrolled men were included in the primary analysis.
The primary outcome was the rate of improvement in World Health Organization Sperm Concentration Categories (WHO-SCC) after three months of treatment.
The trial revealed the following findings:
- A total of 14.3% of men treated with letrozole achieved an upgrade in sperm concentration category, compared with 5.4% in the control group.
- Men receiving letrozole were more than twice as likely to improve to a higher sperm concentration category than those receiving vitamins C and E alone.
- Letrozole treatment resulted in higher rates of improvement in total motile sperm count categories.
- The therapy significantly increased serum testosterone levels.
- Letrozole significantly increased gonadotropin levels.
- Treatment was associated with a reduction in estradiol concentrations.
- No significant differences were observed between groups in conventional semen parameters.
- Improvements in sperm concentration categories suggest a potential reduction in infertility severity.
- The observed benefits may increase the possibility of less invasive fertility treatments for some couples.
- Letrozole was generally well tolerated throughout the study.
- Decreased libido was reported more frequently in the letrozole group than in the control group.
- No major safety concerns were identified during the trial.
The researchers noted limitations, including the short three-month treatment duration, the predominantly Han Chinese study population, and the high proportion of men with nonobstructive azoospermia, who generally have lower treatment response rates. Despite these limitations, they concluded that letrozole may help reduce the severity of male infertility and expand reproductive options for men with spermatogenic failure.
Reference:
Sun Y, Yao C, Liu G, et al. Letrozole and Infertility Among Males With Spermatogenic Failure: A Randomized Clinical Trial. JAMA Netw Open. 2026;9(6):e2618422. doi:10.1001/jamanetworkopen.2026.18422
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