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Some of them receive long-term puberty suppression with gonadotropin-releasing hormone analogues (GnRHa) before starting gender-affirming hormones (GAH). The impact of GnRHa use started in early puberty on bone composition and bone mass accrual is unexplored. It is furthermore unclear whether subsequent GAH fully restore GnRHa effects and whether the timing of GAH introduction matters. To answer these questions, we developed a mouse model mimicking the clinical strategy applied in trans boys. Prepubertal 4-week-old female mice were treated with GnRHa alone or with GnRHa supplemented with testosterone (T) from 6\u2009weeks (early puberty) or 8\u2009weeks (late puberty) onward. Outcomes were analyzed at 16\u2009weeks and compared with untreated mice of both sexes. GnRHa markedly increased total body fat mass, decreased lean body mass, and had a modest negative impact on grip strength. Both early and late T administration shaped body composition to adult male levels, whereas grip strength was restored to female values. GnRHa-treated animals showed lower trabecular bone volume and reduced cortical bone mass and strength. These changes were reversed by T to female levels (cortical bone mass and strength) irrespective of the time of administration or even fully up to adult male control values (trabecular parameters) in case of earlier T start. The lower bone mass in GnRHa-treated mice was associated with increased bone marrow adiposity, also reversed by T. In conclusion, prolonged GnRHa use started in prepubertal female mice modifies body composition toward more fat and less lean mass and impairs bone mass acquisition and strength. Subsequent T administration counteracts GnRHa impact on these parameters, shaping body composition and trabecular parameters to male values while restoring cortical bone architecture and strength up to female but not male control levels. These findings could help guide clinical strategies in transgender care. \u00a9 2023 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>\n                  <jats:p>Abstract<\/jats:p>\n                  <jats:p>Prolonged puberty suppression with gonadotropin-releasing hormone analogue (GnRHa) impacts body composition and skeletal characteristics in a mouse model mimicking the clinical strategy in trans boys. Some parameters are fully reversed to control male levels by gender-affirming hormone (GAH), for trabecular bone volume upon early but not late addition, whereas other parameters including cortical bone mass and strength only reach female values, irrespective of the time of testosterone administration.<\/jats:p>","DOI":"10.1002\/jbmr.4832","type":"journal-article","created":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T04:15:25Z","timestamp":1684901725000},"page":"1497-1508","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8894-2980","authenticated-orcid":false,"given":"Vanessa","family":"Dubois","sequence":"first","affiliation":[{"name":"Basic and Translational Endocrinology (BaTE), Department of Basic and Applied Medical Sciences Ghent University Ghent Belgium"},{"name":"Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (Chrometa) KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0874-4648","authenticated-orcid":false,"given":"Silvia","family":"Ciancia","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Pediatrics Ghent University Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8096-9310","authenticated-orcid":false,"given":"Stefanie","family":"Doms","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (Chrometa) KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1444-2531","authenticated-orcid":false,"given":"Sarah","family":"El Kharraz","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology KU Leuven and Leuven Cancer Institute (LKI) Leuven Belgium"},{"name":"Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB Leuven Belgium"},{"name":"Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Sommers","sequence":"additional","affiliation":[{"name":"Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na Ri","family":"Kim","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (Chrometa) KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6050-6677","authenticated-orcid":false,"given":"Karel","family":"David","sequence":"additional","affiliation":[{"name":"Department of Endocrinology University Hospitals Leuven Leuven Belgium"},{"name":"Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (Chrometa) KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien","family":"Van Dijck","sequence":"additional","affiliation":[{"name":"Laboratory of Skeletal Cell Biology and Physiology (SCEBP), Skeletal Biology and Engineering Research Center (SBE), Department of Development and Regeneration KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0187-1460","authenticated-orcid":false,"given":"Roger","family":"Valle-Tenney","sequence":"additional","affiliation":[{"name":"Laboratory of Skeletal Cell Biology and Physiology (SCEBP), Skeletal Biology and Engineering Research Center (SBE), Department of Development and Regeneration KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4243-5486","authenticated-orcid":false,"given":"Christa","family":"Maes","sequence":"additional","affiliation":[{"name":"Laboratory of Skeletal Cell Biology and Physiology (SCEBP), Skeletal Biology and Engineering Research Center (SBE), Department of Development and Regeneration KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1079-2860","authenticated-orcid":false,"given":"Leen","family":"Antonio","sequence":"additional","affiliation":[{"name":"Department of Endocrinology University Hospitals Leuven Leuven Belgium"},{"name":"Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (Chrometa) KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4153-4757","authenticated-orcid":false,"given":"Brigitte","family":"Decallonne","sequence":"additional","affiliation":[{"name":"Department of Endocrinology University Hospitals Leuven Leuven Belgium"},{"name":"Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (Chrometa) KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8324-4462","authenticated-orcid":false,"given":"Geert","family":"Carmeliet","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (Chrometa) KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8676-7709","authenticated-orcid":false,"given":"Frank","family":"Claessens","sequence":"additional","affiliation":[{"name":"Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9552-4899","authenticated-orcid":false,"given":"Martine","family":"Cools","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Service, Department of Pediatrics Ghent University Hospital Ghent 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