Letrozole and Infertility Among Males With Spermatogenic Failure: A Randomized Clinical Trial.

Yifan Sun, Chencheng Yao, Gang Liu, Zheng Li, Xiaoyu Yang, Qigui Chen, Zhen Ye, Honggang Li, Xiaowei Qu, Haibin Guo, Jun Yang, Tao Wang, Guoqing Liang, Xiaobin Zhu, Yichang Lu, Weikang Chen, Fengbin Zhang, Ruhui Tian, Erlei Zhi, Huirong Chen, Fujun Zhao, Furong Bai, Hongfang Sun, Jianxiong Zhang, Xinjie Bu, Dewei Qian, Sicheng Wu, Yan Qiu, Zheng Li, Peng Li

Journal: JAMA network open 2026;9(6):e2618422

PMID: 42313386

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Abstract

IMPORTANCE

Spermatogenic failure (SPGF) is a severe form of male infertility with limited evidence-based medical treatment options. Aromatase inhibitors represent a promising therapeutic strategy for SPGF, but high-quality evidence is lacking.

OBJECTIVE

To evaluate the efficacy and safety of letrozole for improving sperm concentration categories in men with SPGF.

DESIGN, SETTING, AND PARTICIPANTS

This multicenter, open-label, assessor-blinded randomized clinical trial was conducted at 10 male infertility centers in China from July 2023 to March 2024. Men with SPGF (nonobstructive azoospermia [NOA], cryptozoospermia, or severe oligozoospermia) were enrolled. Follow-up for the primary outcome was completed in June 2024. Data were analyzed from July 2024 to March 2025.

INTERVENTIONS

Participants were randomized to receive letrozole (2.5 mg daily) plus vitamins C and E or vitamins C and E alone (control group) for 3 months.

MAIN OUTCOMES AND MEASURES

The primary outcome was World Health Organization Sperm Concentration Categories (WHO-SCC) upgrade rate at 3 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.

RESULTS

Among 296 participants (mean [SD] age, 30.2 [3.9] years; 218 [73.6%] with NOA; 147 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) with letrozole vs 5.4% (8 of 149 participants) with control (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. There were no significant between-group differences in semen parameters. Decreased libido (18 [12.2%] vs 8 [5.4%]; P = .04) was more frequent with letrozole than with control.

CONCLUSIONS AND RELEVANCE

In this randomized clinical trial of men with spermatogenic failure, letrozole significantly improved sperm concentration categories and was well tolerated, supporting its use as an option to downstage infertility severity and potentially enable less invasive reproductive management.

TRIAL REGISTRATION

chictr.org.cn Identifier: ChiCTR2300073861.

Address: Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Department of Andrology, The Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China.; State Key Laboratory of Reproductive Medicine and Offspring Health, Clinical Center of Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Center for Reproductive Medicine, Wuhan Children's Hospital: Wuhan Women and Children Medical Care Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.; Wuhan Huake Reproductive Hospital, Wuhan, Hubei, China.; Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.; Reproductive Medicine Center, Henan Provincial People's Hospital, Zhengzhou, Henan, China.; Reproductive Medicine Center, Zhengzhou University People's Hospital, Zhengzhou, Henan, China.; Henan Joint International Research Laboratory of Reproductive Bioengineering, Zhengzhou, Henan, China.; Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.; Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.; Department of Gynecology and Obstetrics, Reproductive Medical Center, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China.; Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.; Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China.; Clinical Research Unit, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China.

DOI: 10.1001/jamanetworkopen.2026.18422

MeSH Terms: Humans, Male, Letrozole, Adult, Infertility, Male, Aromatase Inhibitors, Sperm Count, China, Spermatogenesis, Azoospermia, Treatment Outcome