Endocrine Reviews

Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or non-syndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and non-coding RNAs, such as microRNA, long noncoding RNAs and circular RNAs...

Mitochondrial damage is implicated as a major contributing factor for a number of noncommunicable chronic diseases such as cardiovascular diseases, cancer, obesity, and insulin resistance/type 2 diabetes. Here, we discuss the role of mitochondria in maintaining cellular and whole-organism homeostasis, the mechanisms that promote mitochondrial dysfunction and the role of this phenomenon in noncommunicable chronic diseases. We also review the state of the art regarding the pre-clinical evidence associated with the regulation of the mitochondrial function and the development of current mitochondrial-targeted therapeutics to treat non communicable chronic diseases...

Obesity contributes to reduced life expectancy, impaired quality of life and disabilities mainly in those individuals who develop cardiovascular diseases, type 2 diabetes, osteoarthritis and cancer. However, there is large variation in the individual risk to develop obesity-associated comorbid diseases which cannot simply be explained by the extent of adiposity. Observations that a proportion of individuals with obesity have a significantly lower risk for cardiometabolic abnormalities led to the concept of metabolically healthy obesity (MHO)...

We provide an in-depth review of the role of androgens in male maturation and development from the fetal stage through adolescence into emerging adulthood and discuss the treatment of disorders of androgen production throughout these time periods. Testosterone, the primary androgen produced by males, has both anabolic and androgenic effects. Androgen exposure induces virilization and anabolic body composition changes during fetal development, influences growth and virilization during infancy and stimulates development of secondary sexual characteristics, growth acceleration, bone mass accrual, and alterations of body composition during puberty...

The past decade has seen several critical advances in our understanding of hypothalamic-pituitary-adrenal (HPA) axis regulation. Homeostatic physiological circuits need to integrate multiple internal and external stimuli and provide a dynamic output appropriate for the response parameters of their target tissues. The HPA axis is an example of such a homeostatic system. Recent studies have shown that circadian rhythmicity of the major output of this system - the adrenal glucocorticoid hormones corticosterone in rodent and predominately cortisol in man - is comprised of varying amplitude pulses that exist due to a sub-hypothalamic pulse generator...

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Neuroendocrine neoplasms constitute a diverse group of tumors that derive from the sensory and secretory neuroendocrine cells and predominantly arise within the pulmonary and gastrointestinal tracts. The majority of these neoplasms have a well-differentiated grade and are termed neuroendocrine tumors (NETs). This subgroup is characterized by limited proliferation and patients affected by these tumors carry a good to moderate prognosis. A substantial subset of patients presenting with a NET suffer from the consequences of endocrine syndromes as a result of the excessive secretion of amines or peptide hormones, which can impair their quality of life and prognosis...

Neurodegenerative diseases (NDs) are a wide class of disorders of the central nervous system (CNS) with unknown etiology. Several factors were hypothesized to be involved in the pathogenesis of these diseases, including genetic and environmental factors. Many of these diseases show a sex prevalence and sex steroids were shown to have a role in the progression of specific forms of neurodegeneration. Estrogens were reported to be neuroprotective through their action on cognate nuclear and membrane receptors, while adverse effects of male hormones have been described on neuronal cells, although some data also suggest neuroprotective activities...

Obesity and diabetes have both been associated with an increased risk of cancer. In the face of increasing obesity and diabetes rates worldwide, this is a worrying trend for cancer rates. Factors such as hyperinsulinemia, chronic inflammation, antihyperglycemic medications, and shared risk factors have all been identified as potential mechanisms underlying the relationship. The most common obesity- and diabetes-related cancers are endometrial, colorectal, and postmenopausal breast cancers. In this review, we summarize the existing evidence that describes the complex relationship between obesity, diabetes, and cancer, focusing on epidemiological and pathophysiological evidence, and also reviewing the role of antihyperglycemic agents, novel research approaches such as Mendelian Randomization, and the methodological limitations of existing research...

Androgen deficiency (hypogonadism) affects males of all ages. Testosterone replacement therapy (TRT) is effective in restoring serum testosterone and relieving symptoms. TRT, however, is reported to have possible adverse effects in part because administered testosterone is not produced in response to the hypothalamic-pituitary-gonadal (HPG) axis. Progress in stem cell biology offers potential alternatives for treating hypogonadism. Adult Leydig cells (ALCs) are generated by stem Leydig cells (SLCs) during puberty...

Infants rely on brown adipose tissue (BAT) as a primary source of thermogenesis. In some adult humans, residuals of brown adipose tissue are adjacent to the central nervous system and acute activation increases metabolic rate. Brown adipose tissue (BAT) recruitment occurs during cold acclimation and includes secretion of factors, known as batokines, which target several different cell types within BAT, and promote adipogenesis, angiogenesis, immune cell interactions, and neurite outgrowth. All these processes seem to act in concert to promote an adapted BAT...

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disease, extending from simple steatosis to inflammation and fibrosis with a significant risk for the development of cirrhosis. It is highly prevalent and is associated with significant adverse outcomes both through liver-specific morbidity and mortality but, perhaps more important, through adverse cardiovascular and metabolic outcomes. It is closely associated with type 2 diabetes and obesity, and both of these conditions drive progressive disease toward the more advanced stages...

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is associated with obesity in human genome-wide association studies. Similarly, mouse genetic studies indicate that loss of function alleles and glucose-dependent insulinotropic polypeptide overexpression both protect from high-fat diet-induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity. Further, both antagonists and agonists alone prevent weight gain, but result in remarkable weight loss when codosed or molecularly combined with glucagon-like peptide-1 analogs preclinically...

There is growing evidence that oxytocin (OXT), a hypothalamic hormone well recognized for its effects in inducing parturition and lactation, has important metabolic effects in both sexes. The purpose of this review is to summarize the physiologic effects of OXT on metabolism and to explore its therapeutic potential for metabolic disorders. In model systems, OXT promotes weight loss by decreasing energy intake. Pair-feeding studies suggest that OXT-induced weight loss may also be partly due to increased energy expenditure and/or lipolysis...

Differences/disorders of sex development (DSD) are a heterogeneous group of congenital conditions that result in discordance between an individual's sex chromosomes, gonads, and/or anatomic sex. Advances in the clinical care of patients and families affected by 46,XY DSD have been achieved since publication of the original Consensus meeting in 2006. The aims of this paper are to review what is known about morbidity and mortality, diagnostic tools and timing, sex of rearing, endocrine and surgical treatment, fertility and sexual function, and quality of life in people with 46,XY DSD...

An ever-increasing population of patients with papillary thyroid cancer is engaging with health care systems around the world. Numerous questions about optimal management have arisen that challenge conventional paradigms. This is particularly the case for patients with low-risk disease, who comprise most new patients. At the same time, new therapies for patients with advanced disease are also being introduced, which may have the potential to prolong life. This review discusses selected controversial issues in adult papillary thyroid cancer management at both ends of the disease spectrum...

During the last decade, there have been substantial advances in the identification and characterization of DNA sequence variants associated with individual predisposition to type 1 and type 2 diabetes. As well as providing insights into the molecular, cellular, and physiological mechanisms involved in disease pathogenesis, these risk variants, when combined into a polygenic score, capture information on individual patterns of disease predisposition that have the potential to influence clinical management. In this review, we describe the various opportunities that polygenic scores provide: to predict diabetes risk, to support differential diagnosis, and to understand phenotypic and clinical heterogeneity...

The treatment of advanced thyroid cancer has undergone rapid evolution in the last decade, with multiple kinase inhibitor drug approvals for each subtype of thyroid cancer and a number of other commercially available drugs that have been studied for this indication. Although most of the US Food and Drug Administration (FDA)-approved drugs are antiangiogenic multikinase inhibitors-vandetanib, cabozantinib, sorafenib, lenvatinib-there are two FDA indications that are mutation specific-dabrafenib/trametinib for BRAF-mutated anaplastic thyroid cancer and larotrectinib for NTRK-fusion thyroid cancer...

Steroid biosynthesis and metabolism are reflected by the serum steroid metabolome and, in even more detail, by the 24-hour urine steroid metabolome, which can provide unique insights into alterations of steroid flow and output indicative of underlying conditions. Mass spectrometry-based steroid metabolome profiling has allowed for the identification of unique multisteroid signatures associated with disorders of steroid biosynthesis and metabolism that can be used for personalized approaches to diagnosis, differential diagnosis, and prognostic prediction...

Recent, rapid changes in the treatment of type 1 diabetes have allowed for commercialization of an "artificial pancreas" that is better described as a closed-loop controller of insulin delivery. This review presents the current state of closed-loop control systems and expected future developments with a discussion of the human factor issues in allowing automation of glucose control. The goal of these systems is to minimize or prevent both short-term and long-term complications from diabetes and to decrease the daily burden of managing diabetes...