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Stine A Holmboe Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej, Copenhagen, Denmark
The International Research Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Ravi Jasuja Research Program in Men’s Health: Aging and Metabolism, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Brian Lawney Research Program in Men’s Health: Aging and Metabolism, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Lærke Priskorn Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej, Copenhagen, Denmark
The International Research Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Niels Joergensen Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej, Copenhagen, Denmark
The International Research Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Allan Linneberg Centre for Clinical Research and Prevention, Frederiksberg Hospital, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Tina Kold Jensen Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej, Copenhagen, Denmark
The International Research Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark

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Niels Erik Skakkebæk Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej, Copenhagen, Denmark
The International Research Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Anders Juul Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej, Copenhagen, Denmark
The International Research Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Anna-Maria Andersson Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej, Copenhagen, Denmark
The International Research Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Introduction Testosterone in serum is primarily bound to proteins with only a minor fraction circulating as free unbound testosterone. The major high-affinity binding protein is sex hormone-binding globulin (SHBG) ( 1 ). Because of the short

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Milou Cecilia Madsen Department of Internal Medicine and Center of Expertise on Gender Dysphoria, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

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Martin den Heijer Department of Internal Medicine and Center of Expertise on Gender Dysphoria, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

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Claudia Pees Walaeus Library, Leiden University Medical Center, Leiden, the Netherlands

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Nienke R Biermasz Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Leontine E H Bakker Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Introduction Testosterone is the primary sex hormone and anabolic steroid in men. It is secreted primarily by the Leydig cells of the testicles and, to a much lesser extent, by the adrenal glands. Testes produce 3–10 mg of testosterone daily

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Simon Chang Unit for Thrombosis Research, Institute of Regional Health Research, University of Southern Denmark and Department of Clinical Biochemistry, Hospital of South West Denmark, Esbjerg, Denmark
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus N, Denmark

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Christian Fynbo Christiansen Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark

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Anders Bojesen Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark

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Svend Juul Department of Public Health, Aarhus University, Aarhus C, Denmark

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Anna-Marie B Münster Unit for Thrombosis Research, Institute of Regional Health Research, University of Southern Denmark and Department of Clinical Biochemistry, Hospital of South West Denmark, Esbjerg, Denmark

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Claus H Gravholt Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus N, Denmark
Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark

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Introduction Men with 47,XXY Klinefelter syndrome (KS) commonly present hypergonadotropic hypogonadism and are commonly treated with testosterone supplementation therapy ( 1 ). However, this treatment is almost entirely based on our knowledge

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Lachlan Angus Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia

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Shalem Leemaqz Robinson Research Institute, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia

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Olivia Ooi Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia

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Pauline Cundill Equinox Gender Diverse Clinic, Thorne Harbour Health, Fitzroy, Victoria, Australia

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Nicholas Silberstein Equinox Gender Diverse Clinic, Thorne Harbour Health, Fitzroy, Victoria, Australia

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Peter Locke Equinox Gender Diverse Clinic, Thorne Harbour Health, Fitzroy, Victoria, Australia

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Jeffrey D Zajac Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia

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Ada S Cheung Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia

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oestradiol as feminising gender-affirming hormone therapy ( 3 ). Goals of therapy are generally to increase serum oestradiol concentrations and lower serum total testosterone concentrations to achieve sex steroid concentrations in the female reference range

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Agnieszka Pazderska Department of Endocrinology, Newcastle-upon-Tyne Hospitals, Newcastle upon Tyne, UK
Department of Endocrinology, St James’s Hospital, Dublin, Ireland

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Yaasir Mamoojee Department of Endocrinology, Newcastle-upon-Tyne Hospitals, Newcastle upon Tyne, UK

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Satish Artham Department of Endocrinology, Newcastle-upon-Tyne Hospitals, Newcastle upon Tyne, UK

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Margaret Miller Department of Endocrinology, Newcastle-upon-Tyne Hospitals, Newcastle upon Tyne, UK

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Stephen G Ball Department of Endocrinology, Central Manchester University Hospitals, Manchester, UK
Department of Endocrinology, University of Manchester, Manchester, UK

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Tim Cheetham Endocrine Research Group, Institute of Genetic Medicine, University of Newcastle-upon-Tyne, Newcastle upon Tyne, UK
Department of Paediatric Endocrinology & Diabetes, Newcastle-upon-Tyne Hospitals, Newcastle upon Tyne, UK

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Richard Quinton Department of Endocrinology, Newcastle-upon-Tyne Hospitals, Newcastle upon Tyne, UK
Endocrine Research Group, Institute of Genetic Medicine, University of Newcastle-upon-Tyne, Newcastle upon Tyne, UK

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remainder being identifiable later during the process of pubertal induction through failure to normalise testicular volume with testosterone therapy ( 1 ). Given the aforementioned factors, the diagnostic evaluation and management of pubertal delay should

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Hans Valdemar López Krabbe Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Jørgen Holm Petersen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark

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Louise Laub Asserhøj Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Department of Fertility, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

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Trine Holm Johannsen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Peter Christiansen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Rikke Beck Jensen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

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Line Hartvig Cleemann Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Casper P Hagen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Lærke Priskorn Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Niels Jørgensen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Katharina M Main Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

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Anders Juul Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

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Lise Aksglaede Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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well as an increased risk of developing insulin resistance, metabolic syndrome, and osteoporosis ( 1 ). Low to low-normal serum concentrations of testosterone are seen in most adults with KS, but nearly all have highly elevated concentrations of

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Peter Bond P Bond, Department of Internal Medicine, Elisabeth TweeSteden Hospital, Tilburg, Netherlands

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Tijs Verdegaal T Verdegaal, Department of Internal Medicine, Spaarne Gasthuis, Haarlem, Netherlands

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Diederik L Smit D Smit, Department of Internal Medicine, Elisabeth TweeSteden Hospital, Tilburg, Netherlands

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Erythrocytosis, or elevated hematocrit, is a common side effect of testosterone therapy (TTh) in male hypogonadism. Testosterone stimulates erythropoiesis through an initial rise in erythropoietin (EPO), establishment of a new EPO/hemoglobin ‘set point’, and a parallel decrease in the master iron regulator protein hepcidin, as well as several other potential mechanisms. Evidence shows an increased thrombotic risk associated with TTh–induced erythrocytosis. Several guidelines for the treatment of male hypogonadism by endocrine organizations recommend against starting TTh in patients presenting with elevated hematocrit at baseline or to stop TTh when its levels cannot be controlled by dose-adjustments. Importantly, therapeutic phlebotomy or venesection is mentioned as a means of reducing hematocrit in these patients. However, evidence supporting the efficacy or safety of therapeutic phlebotomy in lowering hematocrit in TTh–induced erythrocytosis is lacking. In light of this dearth of evidence, the recommendation to lower hematocrit using therapeutic phlebotomy is notable, as phlebotomy lowers tissue oxygen partial pressure (pO2) and, eventually, depletes iron stores, thereby triggering various biological pathways which might also increase thrombotic risk. The potential pros and cons should therefore be carefully weighed against each other and shared decision making is recommended for initiating therapeutic phlebotomy as a treatment in patients on TTh who present with increased hematocrit.

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Angelica Lindén Hirschberg Division of Obstetrics and Gynaecology, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden.

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estradiol, progesterone and testosterone, as well as subsequent anovulation and amenorrhea ( 3 ). Several mechanisms underlie such inhibition of the HPG axis ( Fig. 1 ), including exercise-induced activation of the hypothalamic-pituitary-adrenal axis and a

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Mikkel Andreassen Department of Endocrinology, Faculty of Health Science, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Anders Juul Department of Growth and Reproduction, Faculty of Health Science, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Ulla Feldt-Rasmussen Department of Endocrinology, Faculty of Health Science, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Niels Jørgensen Department of Growth and Reproduction, Faculty of Health Science, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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testosterone secretion. FSH primarily stimulates Sertoli cells adjacent to germ cells within the seminiferous tubules. Intratesticular testosterone stimulated by LH, and stimulation of Sertoli cells by FSH seems both important for induction of spermatogenesis

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Sidsel Mathiesen Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Kaspar Sørensen Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Marianne Ifversen Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Casper P Hagen Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Jørgen Holm Petersen Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark

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Anders Juul Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Klaus Müller Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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due to increasing survival rates and longer follow-up time ( 1 ). HSCT interferes with the male reproductive axis, potentially causing testosterone deficiency and impaired spermatogenesis due to the detrimental effects of high-dose chemotherapy and

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