Nature Reviews Endocrinology

An increasing number of transgender and gender-diverse (TGD) youth (early pubertal through to late adolescent, typically 9–10 through to 18 years of age) are seeking medical services to bring their physical sex characteristics into alignment with their gender identity — their inner sense of self as male or female or somewhere on the gender spectrum. Compelling research has demonstrated the clear mental health — even life-saving — benefits of gender-affirming care, but current clinical practice guidelines and standards of care are based on only several short-term and a few medium-term outcomes studies complemented by expert opinion. Nevertheless, although the relative paucity of outcomes data raises concerns, the stance of not intervening until more is known is not a neutral option, and large observational studies evaluating current models of care are necessary and are now underway. This Review highlights key advances in our understanding of transgender and gender-diverse youth, the challenges of providing gender-affirming care, gaps in knowledge and priorities for research.

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GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease

Dongdong Wang, Emily A. Day, Logan K. Townsend, Djordje Djordjevic, Sebastian Beck Jørgensen & Gregory R. Steinberg

doi : 10.1038/s41574-021-00529-7

Nature Reviews Endocrinology volume 17, pages592–607 (2021)

Growth differentiation factor 15 (GDF15) is a member of the TGF? superfamily whose expression is increased in response to cellular stress and disease as well as by metformin. Elevations in GDF15 reduce food intake and body mass in animal models through binding to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and the recruitment of the receptor tyrosine kinase RET in the hindbrain. This effect is largely independent of other appetite-regulating hormones (for example, leptin, ghrelin or glucagon-like peptide 1). Consistent with an important role for the GDF15–GFRAL signalling axis, some human genetic studies support an interrelationship with human obesity. Furthermore, findings in both mice and humans have shown that metformin and exercise increase circulating levels of GDF15. GDF15 might also exert anti-inflammatory effects through mechanisms that are not fully understood. These unique and distinct mechanisms for suppressing food intake and inflammation makes GDF15 an appealing candidate to treat many metabolic diseases, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular disease and cancer cachexia. Here, we review the mechanisms regulating GDF15 production and secretion, GDF15 signalling in different cell types, and how GDF15-targeted pharmaceutical approaches might be effective in the treatment of metabolic diseases.

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Advances in differential diagnosis and management of growth hormone deficiency in children

Camille Hage, Hoong-Wei Gan, Anastasia Ibba, Giuseppa Patti, Mehul Dattani, Sandro Loche, Mohamad Maghnie & Roberto Salvatori

doi : 10.1038/s41574-021-00539-5

Nature Reviews Endocrinology volume 17, pages608–624 (2021)

Growth hormone (GH) deficiency (GHD) in children is defined as impaired production of GH by the pituitary gland that results in growth failure. This disease might be congenital or acquired, and occurs in isolation or in the setting of multiple pituitary hormone deficiency. Isolated GHD has an estimated prevalence of 1 patient per 4000–10,000 live births and can be due to multiple causes, some of which are yet to be determined. Establishing the correct diagnosis remains key in children with short stature, as initiating treatment with recombinant human GH can help them attain their genetically determined adult height. During the past two decades, our understanding of the benefits of continuing GH therapy throughout the transition period from childhood to adulthood has increased. Improvements in transitional care will help alleviate the consequent physical and psychological problems that can arise from adult GHD, although the consequences of a lack of hormone replacement are less severe in adults than in children. In this Review, we discuss the differential diagnosis in children with GHD, including details of clinical presentation, neuroimaging and genetic testing. Furthermore, we highlight advances and issues in the management of GHD, including details of transitional care.

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Improving clinical outcomes through attention to sex and hormones in research

Michelle M. Mielke & Virginia M. Miller

doi : 10.1038/s41574-021-00531-z

Nature Reviews Endocrinology volume 17, pages625–635 (2021)

Biological sex, fluctuations in sex steroid hormones throughout life and gender as a social construct all influence every aspect of health and disease. Yet, for decades, most basic and clinical studies have included only male individuals. As modern health care moves towards personalized medicine, it is clear that considering sex and hormonal status in basic and clinical studies will bring precision to the development of novel therapeutics and treatment paradigms. To this end, funding, regulatory and policy agencies now require inclusion of female animals and women in basic and clinical studies. However, inclusion of female animals and women often does not mean that information regarding potential hormonal interactions with pharmacological treatments or clinical outcomes is available. All sex steroid hormones can interact with receptors for drug targets, metabolism and transport. Genetic variation in receptors or in enzymatic function might contribute to sex differences in therapeutic efficacy and adverse drug reactions. Outcomes from clinical trials are often not reported by sex, and, if the data are available, they are not translated into clinical practice guidelines. This Review will provide a historical perspective for the current state of research related to hormone trials and provide concrete strategies that, if implemented, will improve the health of all people.

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