{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T15:51:55Z","timestamp":1781797915987,"version":"3.54.5"},"reference-count":29,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate the efficacy and safety of letrozole for improving sperm concentration categories in men with SPGF.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n 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%];\n P<\/jats:italic>\n \u2009=\u2009.01). 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];\n P<\/jats:italic>\n \u2009=\u2009.008). 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%];\n P<\/jats:italic>\n \u2009=\u2009.04) was more frequent with letrozole than with control.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n chictr.org.cn Identifier:\n ChiCTR2300073861<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2026.18422","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T15:00:35Z","timestamp":1781794835000},"page":"e2618422","source":"Crossref","is-referenced-by-count":0,"title":["Letrozole and Infertility Among Males With Spermatogenic 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Children\u2019s Hospital: Wuhan Women and Children Medical Care Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"},{"name":"Wuhan Huake Reproductive Hospital, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honggang","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Qu","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Henan Provincial People\u2019s Hospital, Zhengzhou, Henan, China"},{"name":"Reproductive Medicine Center, Zhengzhou University People\u2019s Hospital, Zhengzhou, Henan, China"},{"name":"Henan Joint International Research Laboratory of Reproductive Bioengineering, Zhengzhou, Henan, 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