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Gary A Wittert Freemasons Centre for Male Health and Wellbeing, South Australian Health and Medical Research Institute, and University of Adelaide, Adelaide, South Australia, Australia

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Mathis Grossmann Department of Medicine, The University of Melbourne and Department of Endocrinology Austin Health, Heidelberg, Australia

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Bu B Yeap Medical School, University of Western Australia, and Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia

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David J Handelsman ANZAC Research Institute, University of Sydney and Andrology Department, Concord Hospital, Sydney, New South Wales, Australia

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Testosterone acting via the androgen receptor, and via aromatisation to oestradiol, an activator of the oestrogen receptor, plays key roles in adipose tissue, bone and skeletal muscle biology. This is reflected in epidemiological studies associating obesity and disordered glucose metabolism with lower serum testosterone concentrations and an increased risk of type 2 diabetes (T2D) in men. Testosterone also modulates erythrocytosis and vascular endothelial and smooth muscle cell function, with potential impacts on haematocrit and the cardiovascular system. The Testosterone for the Prevention of Type 2 Diabetes (T4DM) study enrolled men aged 50 years and over with a waist circumference of 95 cm or over, impaired glucose tolerance or newly diagnosed T2D, and a serum testosterone concentration (as measured by chemiluminescence immunoassay) <14.0 nmol/L. The study reported that a 2-year treatment with testosterone undecanoate 1000 mg, administered 3-monthly intramuscularly, on the background of a lifestyle program, reduced the likelihood of T2D diagnosis by 40% compared to placebo. This effect was accompanied by a decrease in fasting serum glucose and associated with favourable changes in body composition, hand grip strength, bone mineral density and skeletal microarchitecture but not in HbA1c, a red blood cell-dependent measure of glycaemic control. There was no signal for cardiovascular adverse events. With the objective of informing translational science and future directions, this article discusses mechanistic studies underpinning the rationale for T4DM and translational implications of the key outcomes relating to glycaemia, and body composition, together with effects on erythrocytosis, cardiovascular risk and slow recovery of the hypothalamo–pituitary–testicular axis.

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Ulla Simanainen
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Yan Ru (Ellen) Gao
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Reena Desai
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Mark Jimenez
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Jennifer Spaliviero
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Janet R Keast ANZAC Research Institute, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales 2139, Australia

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David J Handelsman
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Neurturin (NTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family and signals through GDNF family receptor alpha 2 (GFRα2). We hypothesised that epithelial atrophy reported in the reproductive organs of Ntn (Nrtn)- and Gfr α 2 (Gfra2)-deficient mice could be due to NTN affecting the hormonal environment. To investigate this, we compared the reproductive organs of Ntn- and Gfr α 2-deficient male mice in parallel with an analysis of their circulating reproductive hormone levels. There were no significant structural changes within the organs of the knockout mice; however, serum and intratesticular testosterone and serum LH levels were very low. To reconcile these observations, we tested androgen sensitivity by creating a dihydrotestosterone (DHT) clamp (castration plus DHT implant) to create fixed circulating levels of androgens, allowing the evaluation of androgen-sensitive endpoints. At the same serum DHT levels, serum LH levels were lower and prostate and seminal vesicle weights were higher in the Ntn knockout (NTNKO) mice than in the wild-type mice, suggesting an increased response to androgens in the accessory glands and hypothalamus and pituitary of the NTNKO mice. Testicular and pituitary responsiveness was unaffected in the NTNKO males, as determined by the response to the human chorionic gonadotrophin or GNRH analogue, leuprolide, respectively. In conclusion, our results suggest that NTN inactivation enhances androgen sensitivity in reproductive and neuroendocrine tissues, revealing a novel mechanism to influence reproductive function and the activity of other androgen-dependent tissues.

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Helen E MacLean Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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Alison J Moore Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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Stephen A Sastra Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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Howard A Morris Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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Ali Ghasem-Zadeh Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia
Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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Kesha Rana Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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Anna-Maree Axell Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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Amanda J Notini Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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David J Handelsman Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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Ego Seeman Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia
Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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Jeffrey D Zajac Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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Rachel A Davey Department of Medicine, Hanson Institute, Department of Endocrinology, ANZAC Research Institute, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

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We used our genomic androgen receptor (AR) knockout (ARKO) mouse model, in which the AR is unable to bind DNA to: 1) document gender differences between males and females; 2) identify the genomic (DNA-binding-dependent) AR-mediated actions in males; 3) determine the contribution of genomic AR-mediated actions to these gender differences; and 4) identify physiological genomic AR-mediated actions in females. At 9 weeks of age, control males had higher body, heart and kidney mass, lower spleen mass, and longer and larger bones compared to control females. Compared to control males, ARKO males had lower body and kidney mass, higher splenic mass, and reductions in cortical and trabecular bone. Deletion of the AR in ARKO males abolished the gender differences in heart and cortical bone. Compared with control females, ARKO females had normal body weight, but 14% lower heart mass and heart weight/body weight ratio. Relative kidney mass was also reduced, and relative spleen mass was increased. ARKO females had a significant reduction in cortical bone growth and changes in trabecular architecture, although with no net change in trabecular bone volume. In conclusion, we have shown that androgens acting via the genomic AR signaling pathway mediate, at least in part, the gender differences in body mass, heart, kidney, spleen, and bone, and play a physiological role in the regulation of cardiac, kidney and splenic size, cortical bone growth, and trabecular bone architecture in females.

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