{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:24:37Z","timestamp":1790436277075,"version":"4.1.0"},"reference-count":18,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Reprod. Health"],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Idiopathic non-obstructive azoospermia (NOA) is a severe form of male infertility with limited non-surgical treatment options. Microdissection testicular sperm extraction (micro-TESE) remains the standard approach for sperm retrieval, yet success rates vary substantially, and many patients undergo surgery without successful sperm recovery. Hormonal optimization using human chorionic gonadotropin (hCG) with or without follicle-stimulating hormone (FSH) has been proposed to improve spermatogenesis in hypogonadal men, but evidence from randomized controlled trials is lacking. This multicenter trial evaluates whether gonadotropin-based hormonal optimization improves sperm availability for intracytoplasmic sperm injection (ICSI) compared with standard-of-care (SOC) management in men with idiopathic NOA and biochemical hypogonadism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This multicenter, randomized, controlled, parallel-group superiority trial will allocate participants 1:1 to hormonal therapy or SOC. Eligible participants are men with idiopathic NOA, total testosterone &amp;lt;350\u2005ng\/dL on two fasting morning tests, and FSH \u22657.6\u2005IU\/L, consistent with APHRODITE Groups 3\u20134. Key exclusion criteria include cryptorchidism, prior chemotherapy or radiotherapy, defined genetic NOA (e.g., AZFa\/complete AZFb deletions), prior micro-TESE, recent hormonal therapy use, uncontrolled endocrine disease, severe liver disease, polycythemia, active malignancy, inability to comply with the study procedures, and clinically significant varicocele. Participants assigned to the intervention arm will receive gonadotropin-based hormonal optimization using hCG and recombinant FSH, with hormonal monitoring and hCG dose titration throughout treatment. The control arm will receive standard management without hormonal therapy. The primary endpoint is a composite treatment-policy outcome defined as sperm availability suitable for ICSI at any time from randomization through Week 16, either through ejaculated sperm or through micro-TESE. Secondary outcomes include micro-TESE sperm retrieval success rate, need for surgery, embryologic outcomes, reproductive outcomes, and treatment safety. The study is designed as a pragmatic comparative effectiveness trial that intends to evaluate whether biologically informed hormonal optimization improves clinically meaningful sperm availability under routine clinical practice conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and Dissemination<\/jats:title>\n                    <jats:p>The study was approved by Institution Ethics Committee (IIVF-UA00l 00).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      (\n                      <jats:ext-link>https:\/\/clinicaltrials.gov\/study\/NCT07540611<\/jats:ext-link>\n                      ), identifier NCT07540611.\n                    <\/jats:p>\n                  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Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashank","family":"Sanagoudar","sequence":"additional","affiliation":[{"name":"Department of Clinical and Lab Operations, Indira IVF Hospital Limited","place":["Udaipur, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2193","DOI":"10.1007\/s11255-021-02979-4","article-title":"Microdissection testicular sperm extraction (micro-TESE) in men with infertility due to nonobstructive azoospermia: summary of current literature","volume":"53","author":"Achermann","year":"2021","journal-title":"Int Urol Nephrol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"6380023","DOI":"10.1155\/2024\/6380023","article-title":"Microsurgical testicular sperm extraction: predictive factors and outcomes for men with nonobstructive 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