Letrozole (Femara) improves sperm concentration in men with spermatogenic failure

1. In adult male patients with spermatogenic failure (SPGF), letrozole (Femara) is well tolerated and associated with significantly greater upgrade rates of sperm concentration category compared to control.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Approximately 1 in 6 adults experience infertility in their lifetime, with male factors accounting for nearly half of these cases. SPGF, or impaired or absent sperm production, is both the most common cause of male infertility and the most severe. Many cases necessitate invasive assisted reproductive technologies, which are expensive and physically imposing. Aromatase inhibitors (AIs) such as letrozole inhibit the conversion of testosterone to estradiol, relieving estrogen-mediated negative feedback on the hypothalamic-pituitary-gonadal axis. This increases testosterone levels and supports spermatogenesis. Although AIs have been used off-label in male infertility, high-quality evidence and guidelines remain lacking.

This study was a randomized, open-label, assessor-blinded clinical trial conducted at 10 male infertility centres in China from July 2024 to March 2025. Participants included males aged 22 to 50 years with a diagnosis of SPGF. These patients were randomized 1:1 to receive oral letrozole 2.5 mg, vitamin C 100 mg, and vitamin E 100 mg once daily, or vitamin C 100 mg and vitamin E 100 mg once daily. The primary endpoint was the upgrade rate in WHO Sperm Concentration Categories (WHO-SCC) at 3 months.

Overall, this study found that patients treated with letrozole had significantly improved sperm concentration categories. This group also had significantly higher serum gonadotropins and testosterone, and while decreased libido was more frequent, letrozole was overall well-tolerated.

Click here to read this study in JAMA Network Open

Relevant reading: Clinical application of aromatase inhibitors to treat male infertility

In-Depth [randomized clinical trial]:

Patients with severe SPGF, the most common cause of male infertility, often require invasive assisted reproductive technologies, which are expensive and physically demanding. Pharmacotherapy may provide an alternative. However, while AIs are widely used off-label, there is limited evidence and guideline backing. This randomized controlled trial compared sperm production in patients with SPGF receiving either letrozole or not. The primary endpoint was the upgrade rate in WHO Sperm Concentration Categories (WHO-SCC) at 3 months.

This trial included 296 male patients (mean [SD] age, 30.2 [3.9] years who were randomized 1:1 to receive letrozole (intervention arm; n = 147; mean [SD] age, 30.4 [3.7] years) or not (control arm; n = 149; mean [SD] age, 30.0 [4.0] years). Participants had a baseline diagnosis of nonobstructive azoospermia (218 [73.6%]), cryptozoospermia (57 [19.3%]), and severe oligozoospermia (21 [7.1%]). At 3 months, primary outcome data were available for 120 participants (81.6%) in the letrozole group and 127 (85.2%) in the control group. Patients in the intervention arm were significantly more likely to achieve WHO-SCC upgrade compared to the control arm (14.3% vs. 5.4%; risk difference, 9.2% [95% CI, 2.5%-15.8%]; P = .01). Sperm concentration upgrade rate was also significantly higher using the Dutch Society of Obstetrics and Gynecology Total Motile Sperm Count Categories (NVOG-TMSCC) system (4.1% vs. 0.7%; risk difference, 4.3% [95% CI, 1.1%-7.5%]; P = .03). At 3 months, intervention arm patients had significantly higher FSH (35.0 mIU/L vs. 17.0 mIU/L; P < .001), LH (17.9 mIU/L vs 7.5 mIU/L; P < .001), and total T (716.0 ng/dL vs 333.5 ng/dL; P < .001). Decreased libido (18 [12.2%] vs 8 [5.4%]; P = .04) was more frequent with letrozole than with control; however, there were no significant differences in major adverse events.

Image: PD

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