Current Opinion in Endocrine and Metabolic Research最新文献

Sclerostin, the product of the SOST gene has primarily been studied for its profound impact on bone mass. By interacting with LRP5 and LRP6, the glycoprotein suppresses the propagation of Wnt signals to β-catenin and thereby suppresses new bone formation. In this review, we discuss emerging data which suggest that sclerostin also acts outside the skeleton to influence metabolism. In humans, serum sclerostin levels are associated with body mass index and indices of metabolic function. Likewise, genetic mouse models of Sost gene deficiency indicate sclerostin influences adipocyte development and insulin signaling. These data raise the possibility that sclerostin neutralization may be effective at treating two epidemic conditions: osteoporosis and obesity.

Natural menopause typically occurs between the ages of 46–55 years. Premature ovarian insufficiency or premature menopause results from compromised ovarian follicular activity, occurring spontaneously or because of medical interventions, prior to the age of 40 years. The premature loss of estrogen leads to bothersome menopause symptoms and predisposes the women to multiple long-term health risks including a higher mortality risk. Hormone replacement therapy used until the natural age of menopause can help manage the symptoms effectively, and can mitigate the long-term risk of estrogen deprivation. However, hormone replacement therapy is underutilized in this population due to the inappropriate extrapolation of potential risks observed with hormone therapy use in women after natural menopause. There is a large unmet need for educating patients and providers regarding the impact of premature ovarian insufficiency and its appropriate management.

Midlife in women typically includes the menopausal transition, a time of hormonal transformation, adaptation, and reorganization. Coincident with this dynamic period of physiological change, there are putatively modifiable factors that influence disease, short-term and long-term health outcomes, symptom emergence, and longevity. The menopause transition could be considered a window of vulnerability; however, it is also a window of opportunity for intervention. Thus, the menopause transition is a critical sensitive window whereby there is opportunity for turning points for healthy aging trajectories. Preclinical research can aid in this pursuit of scientific discovery for modifiable factors and treatments, and their particular parameters. Rodent menopause models include surgical and transitional variations, allowing detection of precise determinants impacting menopause-related outcomes. These models permit systematic manipulation of endogenous and exogenous hormone exposures across the lifespan, with infinite outcome measurements ranging from molecular to behavioral. This research is uniquely poised to address complex, interactive hypotheses with extensive control in a relatively short timeframe, including dissociation of age and menopause effects. To understand the many dynamic changes with menopause, iterative and reciprocal communication between clinical and preclinical domains of science is key.

Glucocorticoids are pleiotropic hormones with potent regulatory roles in tissue homeostasis, electrolyte balance, immune defence, central nervous function, stress response, growth and development, as well as fuel metabolism. Clinically, glucocorticoids are widely used for their unsurpassed anti-inflammatory and immunomodulatory effects. However, chronic exposure to excessive levels of endogenous or exogenous glucocorticoids causes insulin resistance, glucose intolerance, dyslipidaemia, central obesity, muscle wasting and bone loss. Topical studies in rodents have demonstrated that the effects of chronic hypercortisolism on systemic fuel metabolism and body composition are in part mediated through their actions on osteoblasts. Interestingly, targeted abrogation of glucocorticoid signalling in osteoblasts also attenuates the effects of high fat intake as well as ageing on body composition and systemic fuel metabolism. Here we briefly review the physiology of glucocorticoid action and discuss emerging concepts regarding the molecular mechanisms underlying the adverse effects of glucocorticoid excess.

The pulsatile release of gonadotropin-releasing hormone (GnRH) and its frequency are crucial for healthy reproductive function. To understand what drives GnRH pulses, a combination of experimental and mathematical modelling approaches has been used. Early work focussed on the possibility that GnRH pulse generation is an intrinsic feature of GnRH neurons, with autocrine feedback generating pulsatility. However, there is now ample evidence suggesting that a network of upstream neurons secreting kisspeptin, neurokinin-B and dynorphin are the source of this GnRH pulse generator. The interplay of slow positive and negative feedback via neurokinin-B and dynorphin, respectively, allows the network to act as a relaxation oscillator, driving pulsatile secretion of kisspeptin, and consequently, of GnRH and LH. Here, we review the mathematical modelling approaches exploring both scenarios and suggest that with pulsatile GnRH secretion driven by the KNDy pulse generator, autocrine feedback still has the potential to modulate GnRH output.

Overweight and obesity patterns demonstrate a sexual dimorphism, with women being more prone to weight gain and overweight/obesity compared to men. As a result, weight gain is an important concern in women, particularly during midlife, when reproductive and physiological aging coincide, altering body composition. During this time, multiple factors contribute to the accumulation of body weight and adipose tissue, inducing a decrease in lean mass. These factors include hormonal changes -mainly hypoestrogenism-, genetic and exogenous factors, poor nutritional intake and physical inactivity, all of which might act synergistically to promote weight gain. Basal metabolic rate is also reduced due to aging, muscle mass loss, and the reduction in brown tissue activity. Impairments of the circadian system are associated with reduced endogenous melatonin secretion, altered sleep–wake cycles and metabolic inflexibility. Inflammaging, gut dysbiosis and physical inactivity further promote weight gain and the loss of lean skeletal muscle, leading to sarcopenic obesity.

It is known that the menopause transition (MT) is a complex period during a woman's life, but there has been an ongoing debate on whether the increase in cardiovascular disease (CVD) during midlife is due to chronological aging or ovarian aging. The purpose of this review is to summarize the recent findings on the role of ovarian aging versus chronological aging on CVD outcomes and its risk factors in women.

Recent data from longitudinal studies have shown that menopause-related factors, such as earlier age at menopause and surgical menopause are associated with higher CVD outcomes. The MT is also associated with detrimental changes in vascular health as well as cardiometabolic risk factors including body composition, visceral fat accumulation, lipids/lipoproteins, blood pressure, and the metabolic syndrome.

The robust evidence from recent research indicating increases in CVD risk over the MT beyond aging call for immediate efforts to raise awareness among women and their health care providers of CVD risk acceleration accompanying the MT. Efforts should also be directed toward developing and testing novel preventive approaches that target women during this time period to counteract the expected increase in CVD risk.

Evidence suggests that menopausal transition can have a profound experience on women's work. However, there is a lack of contextually rich research identifying the range and diversity of factors that further details the multiplicity of women's experiences of menopausal transition at work. The review draws together four factors that provide a more detailed insight into factors that may impact working through menopausal transition. In light of this, more knowledge is needed to understand how low paid, precarious and insecure work impacts menopausal transition, as well as recognising the workplace experience of menopause transition for those identifying as LGBTQI+.