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Mathis Grossmann

A wealth of observational studies show that low testosterone is associated with insulin resistance and with an increased risk of diabetes and the metabolic syndrome. Experimental studies have identified potential mechanisms by which low testosterone may lead to insulin resistance. Visceral adipose tissue is an important intermediate in this relationship. Actions of testosterone or its metabolite oestradiol on other tissues such as muscle, liver, bone or the brain, and body composition-independent effects may also play a role. However, definitive evidence from randomised controlled trials (RCTs) to clarify whether the association of low testosterone with disordered glucose metabolism is causative is currently lacking. It therefore remains possible that this association is due to reverse causation, or simply originates by association with common health and lifestyle factors. RCTs of testosterone therapy in men with or without diabetes consistently show modest metabolically favourable changes in body composition. Despite this, testosterone effects on glucose metabolism have been inconsistent. Recent evidence suggests that the hypothalamic–pituitary–testicular axis suppression in the majority of obese men with metabolic disorders is functional, and may be, at least in part, reversible with weight loss. Until further evidence is available, lifestyle measures with emphasis on weight reduction, treatment of comorbidities and optimisation of diabetic control should remain the first-line treatment in these men. Such measures, if successful, may be sufficient to normalise testosterone levels in men with metabolic disorders, who typically have only modest reductions in circulating testosterone levels.

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Sabashini K Ramchand, Yee-Ming Cheung, Belinda Yeo, and Mathis Grossmann

In women with oestrogen receptor (ER)-positive early breast cancer, oestradiol is important for breast cancer development and progression. Endocrine therapy prevents the deleterious effects of oestradiol in breast tissue by systemically depleting oestradiol concentration (aromatase inhibitors) or preventing its local action in breast tissue (selective oestrogen receptor modulators i.e. tamoxifen), thereby improving oncological outcomes. Use of aromatase inhibitors in postmenopausal women and ovarian function suppression with either tamoxifen or aromatase inhibition in premenopausal women, consequent to systemic oestradiol depletion, exerts detrimental effects on skeletal health. The oestradiol-deficient state causes increased bone remodelling and a negative bone balance. This results in bone loss, microstructural deterioration and bone fragility predisposing to fractures. Similar effects are also seen with tamoxifen in premenopausal women. In contrast, use of tamoxifen in postmenopausal women appears to exert protective effects on bone but studies on fracture risk are inconclusive. The longevity of women with ER-positive breast cancer treated with adjuvant endocrine therapy emphasises the need to mitigate the adverse skeletal effects of these therapies in order to maximise benefit. In general, fractures are associated with increased morbidity, mortality and are a high socioeconomic burden. Whilst the efficacy of antiresorptive therapy in preventing bone mineral density loss in postmenopausal women has been established, further clinical trial evidence is required to provide guidance regarding fracture risk reduction, when to initiate and stop treatment, choice of agent and optimal management of bone health in premenopausal women receiving endocrine therapy. In addition, potential oncological benefits of antiresorptive therapies will also need to be considered.

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Gary A Wittert, Mathis Grossmann, Bu B Yeap, and David J Handelsman

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 95cm 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 2 years treatment with testosterone undecanoate 1000mg, 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 commentary 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, and cardiovascular risk and slow recovery of the hypothalamo-pituitary-testicular axis.