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      Functional Changes to Achilles Tendon and Enthesis in a Mouse Model of an Adolescent Masculine Gender-Affirming Hormone Treatment

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          Abstract

          Many transgender youth seek gender affirming care, such as puberty suppression, to prolong decision-making and to align their physical sex characteristics with their gender identity. During peripubertal growth, connective tissues such as tendon rapidly adapt to applied mechanical loads (e.g., exercise) yet if and how tendon adaptation is influenced by sex and gender affirming hormone therapy during growth remains unknown. The goal of this study was to understand the how pubertal suppression influences the structural and functional properties of the Achilles tendon using an established mouse model of transmasculine gender affirming hormone therapy. C57BL/6N female-born mice were assigned to experimental groups to mimic gender-affirming hormone therapy in human adolescents, and treatment was initiated prior to the onset of puberty (at postnatal day 26, P26). Experimental groups included controls and mice serially treated with gonadotropin release hormone analogue (GnRHa), delayed Testosterone (T), or GnRHa followed by T. We found that puberty suppression using GnRHa, with and without T, improved the overall tendon load capacity in female-born mice. Treatment with T resulted in an increase in the maximum load that tendon can withstand before failure. Additionally, we found that GnRHa, but not T, treatment resulted in a significant increase in cell density at the Achilles enthesis.

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          Standards of Care for the Health of Transgender and Gender Diverse People, Version 8

          Abstract Background: Transgender healthcare is a rapidly evolving interdisciplinary field. In the last decade, there has been an unprecedented increase in the number and visibility of transgender and gender diverse (TGD) people seeking support and gender-affirming medical treatment in parallel with a significant rise in the scientific literature in this area. The World Professional Association for Transgender Health (WPATH) is an international, multidisciplinary, professional association whose mission is to promote evidence-based care, education, research, public policy, and respect in transgender health. One of the main functions of WPATH is to promote the highest standards of health care for TGD people through the Standards of Care (SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in 2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective pathways to achieving lasting personal comfort with their gendered selves with the aim of optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods: The SOC-8 is based on the best available science and expert professional consensus in transgender health. International professionals and stakeholders were selected to serve on the SOC-8 committee. Recommendation statements were developed based on data derived from independent systematic literature reviews, where available, background reviews and expert opinions. Grading of recommendations was based on the available evidence supporting interventions, a discussion of risks and harms, as well as the feasibility and acceptability within different contexts and country settings. Results: A total of 18 chapters were developed as part of the SOC-8. They contain recommendations for health care professionals who provide care and treatment for TGD people. Each of the recommendations is followed by explanatory text with relevant references. General areas related to transgender health are covered in the chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters developed for the diverse population of TGD people include Assessment of Adults, Adolescents, Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional Environments. Finally, the chapters related to gender-affirming treatment are Hormone Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care, Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person.
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            Estrogen and bone health in men and women.

            Estrogen is the key regulator of bone metabolism in both men and women. Menopause and the accompanying loss of ovarian estrogens are associated with declines in bone mineral density (BMD): 10-year cumulative loss was 9.1% at the femoral neck and 10.6%, lumbar spine. Estradiol concentrations also predict fractures. Total estradiol levels, <5 pg/ml were associated with a 2.5-fold increase in hip and vertebral fractures in older women, an association that was independent of age and body weight. Similar associations were found in men. Despite the lower BMD and higher fracture risk in hypogonadal men, there is little association between circulating testosterone, fracture and bone loss. Nevertheless, the combination of any low sex steroid hormone and 25-hydroxyvitamin D was associated with an increased fracture risk. Menopausal hormone therapy has been shown to reduce hip and all fractures in the Women's Health Initiative with little difference between the estrogen-alone and the estrogen plus progestin trials. The risk reductions were attenuated in both trials post intervention; however, a significant hip fracture benefit persisted over 13 years for women assigned to the combination therapy. Clinical trials of testosterone replacement in older men give tantalizing but inconclusive results. The results suggest that testosterone treatment probably improves BMD, but the results are less conclusive in older versus younger men. The Testosterone Trial is designed to test the hypothesis that testosterone treatment of men with unequivocally low serum testosterone (<275 ng/dL) will increase volumetric BMD (vBMD) of the spine. Results of the Testosterone Trials are expected in 2015.
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              Tenomodulin is necessary for tenocyte proliferation and tendon maturation.

              Tenomodulin (Tnmd) is a member of a new family of type II transmembrane glycoproteins. It is predominantly expressed in tendons, ligaments, and eyes, whereas the only other family member, chondromodulin I (ChM-I), is highly expressed in cartilage and at lower levels in the eye and thymus. The C-terminal extracellular domains of both proteins were shown to modulate endothelial-cell proliferation and tube formation in vitro and in vivo. We analyzed Tnmd function in vivo and provide evidence that Tnmd is processed in vivo and that the proteolytically cleaved C-terminal domain can be found in tendon extracts. Loss of Tnmd expression in gene targeted mice abated tenocyte proliferation and led to a reduced tenocyte density. The deposited amounts of extracellular matrix proteins, including collagen types I, II, III, and VI and decorin, lumican, aggrecan, and matrilin-2, were not affected, but the calibers of collagen fibrils varied significantly and exhibited increased maximal diameters. Tnmd-deficient mice did not have changes in tendon vessel density, and mice lacking both Tnmd and ChM-I had normal retinal vascularization and neovascularization after oxygen-induced retinopathy. These results suggest that Tnmd is a regulator of tenocyte proliferation and is involved in collagen fibril maturation but do not confirm an in vivo involvement of Tnmd in angiogenesis.
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                Author and article information

                Contributors
                Role: conceived and designed researchRole: performed experimentsRole: analyzed dataRole: interpreted results of experimentsRole: prepared figuresRole: drafted the manuscriptRole: edited the manuscript
                Role: performed experiments
                Role: performed experiments
                Role: performed experimentsRole: edited the manuscript
                Role: performed experimentsRole: analyzed data
                Role: interpreted results of experimentsRole: edited the manuscript
                Role: performed experimentsRole: edited the manuscript
                Role: analyzed dataRole: drafted the manuscript
                Role: performed experiments
                Role: approved final version of manuscript
                Role: approved final version of manuscript
                Role: conceived and designed researchRole: approved final version of manuscript
                Role: approved final version of manuscript
                Role: conceived and designed researchRole: interpreted results of experimentsRole: edited the manuscriptRole: approved final version of manuscript
                Journal
                bioRxiv
                BIORXIV
                bioRxiv
                Cold Spring Harbor Laboratory
                2692-8205
                12 June 2024
                : 2024.06.10.598308
                Affiliations
                [1 ]Department of Molecular and Integrative Physiology, Michigan Medicine, Ann Arbor Michigan, United States
                [2 ]Department of Orthopedic Surgery, Michigan Medicine, Ann Arbor, Michigan, United States
                [3 ]University of Toledo College of Medicine, Toledo, Ohio, United States
                [4 ]Michigan State College of Osteopathic Medicine, East Lansing, MI, United States
                [5 ]Department of Biomedical Engineering, Michigan Medicine, Ann Arbor, Michigan, United States
                [6 ]Department of Obstetrics and Gynecology, Michigan Medicine, Ann Arbor, Michigan, United States
                Author notes
                Correspondence: Megan L. Killian, PhD, mlkillia@ 123456med.umich.edu , A. Alfred Taubman Biomedical Sciences Research Building, Room 2021, Ann Arbor, MI 48109, United States
                Author information
                http://orcid.org/0009-0008-3184-4018
                http://orcid.org/0000-0002-8478-4281
                http://orcid.org/0000-0002-8443-7212
                http://orcid.org/0000-0001-9972-4938
                http://orcid.org/0000-0003-0159-6419
                http://orcid.org/0000-0003-2131-5178
                http://orcid.org/0000-0001-6868-5550
                Article
                10.1101/2024.06.10.598308
                11195120
                38915724
                cff0d582-f80d-4bde-bde3-b47d7e6d770a

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.

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                biomechanics,enthesis,estrogen,tendon,testosterone
                biomechanics, enthesis, estrogen, tendon, testosterone

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