Nature Reviews Endocrinology

Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and is associated with a substantially increased lifetime risk of comorbidities, including type 2 diabetes mellitus, psychiatric disorders and gynaecological cancers. Despite its high prevalence (~15%) and substantial economic burden, the aetiology of PCOS remains elusive. The genetic loci linked to PCOS so far account for only ~10% of its heritability, which is estimated at 70%. However, growing evidence suggests that altered epigenetic and developmental programming resulting from hormonal dysregulation of the maternal uterine environment contributes to the pathogenesis of PCOS. Male as well as female relatives of women with PCOS are also at an increased risk of developing PCOS-associated reproductive and metabolic disorders. Although PCOS phenotypes are highly heterogenous, hyperandrogenism is thought to be the principal driver of this condition. Current treatments for PCOS are suboptimal as they can only alleviate some of the symptoms; preventative and targeted treatments are sorely needed. This Review presents an overview of the current understanding of the aetiology of PCOS and focuses on the developmental origin and epigenetic inheritance of this syndrome.

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Type 2 diabetes mellitus in older adults: clinical considerations and management

Srikanth Bellary, Ioannis Kyrou, James E. Brown & Clifford J. Bailey

doi : 10.1038/s41574-021-00512-2

Nature Reviews Endocrinology volume 17, pages534–548 (2021)

The past 50 years have seen a growing ageing population with an increasing prevalence of type 2 diabetes mellitus (T2DM); now, nearly half of all individuals with diabetes mellitus are older adults (aged ?65 years). Older adults with T2DM present particularly difficult challenges. For example, the accentuated heterogeneity of these patients, the potential presence of multiple comorbidities, the increased susceptibility to hypoglycaemia, the increased dependence on care and the effect of frailty all add to the complexity of managing diabetes mellitus in this age group. In this Review, we offer an update on the key pathophysiological mechanisms associated with T2DM in older people. We then evaluate new evidence relating particularly to the effects of frailty and sarcopenia, the clinical difficulties of age-associated comorbidities, and the implications for existing guidelines and therapeutic options. Our conclusions will focus on the effect of T2DM on an ageing society.

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Potential gut–brain mechanisms behind adverse mental health outcomes of bariatric surgery

Robyn M. Brown, Eva Guerrero-Hreins, Wendy A. Brown, Carel W. le Roux & Priya Sumithran

doi : 10.1038/s41574-021-00520-2

Nature Reviews Endocrinology volume 17, pages549–559 (2021)

Bariatric surgery induces sustained weight loss and metabolic benefits via notable effects on the gut–brain axis that lead to alterations in the neuroendocrine regulation of appetite and glycaemia. However, in a subset of patients, bariatric surgery is associated with adverse effects on mental health, including increased risk of suicide or self-harm as well as the emergence of depression and substance use disorders. The contributing factors behind these adverse effects are not well understood. Accumulating evidence indicates that there are important links between gut-derived hormones, microbial and bile acid profiles, and disorders of mood and substance use, which warrant further exploration in the context of changes in gut–brain signalling after bariatric surgery. Understanding the basis of these adverse effects is essential in order to optimize the health and well-being of people undergoing treatment for obesity.

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Drug resistance in pituitary tumours: from cell membrane to intracellular signalling

Erika Peverelli, Donatella Treppiedi, Federica Mangili, Rosa Catalano, Anna Spada & Giovanna Mantovani

doi : 10.1038/s41574-021-00514-0

Nature Reviews Endocrinology volume 17, pages560–571 (2021)

The pharmacological treatment of pituitary tumours is based on the use of stable analogues of somatostatin and dopamine. The analogues bind to somatostatin receptor types 2 and 5 (SST2 and SST5) and dopamine receptor type 2 (DRD2), respectively, and generate signal transduction cascades in cancerous pituitary cells that culminate in the inhibition of hormone secretion, cell growth and invasion. Drug resistance occurs in a subset of patients and can involve different steps at different stages, such as following receptor activation by the agonist or during the final biological responses. Although the expression of somatostatin and dopamine receptors in cancer cells is a prerequisite for these drugs to reach a biological effect, their presence does not guarantee the success of the therapy. Successful therapy also requires the proper functioning of the machinery of signal transduction and the finely tuned regulation of receptor desensitization, internalization and intracellular trafficking. The present Review provides an updated overview of the molecular factors underlying the pharmacological resistance of pituitary tumours. The Review discusses the experimental evidence that supports a role for receptors and intracellular proteins in the function of SSTs and DRD2 and their clinical importance.

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Timing of puberty — body size or reproductive optimization?

Yehuda Limony & Slawomir Koziel

doi : 10.1038/s41574-021-00501-5

Nature Reviews Endocrinology volume 17, page573 (2021)

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Reply to: Timing of puberty — body size or reproductive optimization?

Gillian R. Bentley, Barry A. Bogin, Ben Bar-Sadeh, Reinhard Stöger & Philippa Melamed

doi : 10.1038/s41574-021-00502-4

Nature Reviews Endocrinology volume 17, pages573–574 (2021)

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