Endocrine Reviews

The initiation and maintenance of reproductive capacity in humans is dependent upon pulsatile secretion of the hypothalamic hormone gonadtropin-releasing hormone, GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in more than 30 genes identified to date acting either alone or in combination...

Glucose homeostasis requires an organism to rapidly respond to changes in plasma glucose concentrations. Iatrogenic hypoglycemia as a result of treatment with insulin or sulfonylureas is the most common cause of hypoglycemia in humans and is generally only seen in patients with diabetes who take these medications. The first response to a fall in glucose is the detection of impending hypoglycemia by hypoglycemia detecting sensors including glucose sensing neurons in the hypothalamus and other regions. This detection is then linked to a series of neural and hormonal responses that serve to prevent the fall in blood glucose and restore euglycemia...

Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) are heterogeneous regarding site of origin, biological behavior and malignant potential. There has been a rapid increase in data publication over the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal NETs. This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway-based overview. This provided a summary of the critical alterations sustaining neoplastic cells...

Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and viceversa. This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic beta cells and skeletal muscle) to explain the mechanism linking overt and subclinical hypothyroidism to type 2 diabetes and metabolic syndrome...

The re-discovery of the group of thyronamines (TAM), especially the first detailed description of their most prominent congener 3-iodothyronamine (3T1AM) fourteen years ago boosted research on this thyroid hormone metabolite tremendously. TAM exert actions partly opposite to and distinct from known functions of thyroid hormones. These fascinating metabolic, anapyrexic, cytoprotective and brain effects quickly evoked the hope to use hormone-derived TAM as therapeutic option. The G-protein coupled receptor (GPCR) TAAR1, a member of the trace amine-associated receptor family (TAAR), was identified as first target and effector of TAM action...

Production of sperm and androgens is the main function of the testis. This depends on normal development of both testicular somatic cells and germ cells. Genetic program initiated from the Y chromosome gene SRY (sex-determining region Y) directs somatic cell specification to Sertoli cells that orchestrate further development. They first guide fetal germ cell differentiation towards spermatogenic destiny, and then take care of the full service to spermatogenic cells during spermatogenesis. The number of Sertoli cells sets the limits of sperm production...

Increasingly, primary hypertension is being considered a syndrome and not a disease, with the individual causes (diseases) having a common sign---an elevated blood pressure. To determine these causes, genetic tools are increasingly employed. This review identified 62 proposed genes. However, only 21 of them met our inclusion criteria: 1) primary hypertension, 2) two or more supporting cohorts from different publications or within a single publication or one supporting cohort with a confirmatory genetically modified animal study, 3) 600 or more subjects in the primary cohort; and exclusion criteria: 1) meta-analyses or reviews, 2) secondary and monogenic hypertension, 3) only hypertensive complications, 4) genes related to blood pressure but not hypertension per se, 5) non-supporting studies more common than supporting ones, 5) studies that did not perform a Bonferroni, or similar multi-assessment, correction...

The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH-deficiency (GHD) or GH-resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH-R mutations, combined deficiency of GH, PRL, and TSH, or global deletion of GH receptors live longer than their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes...

Pancreatic islet transplantation has become an established approach to β-cell replacement therapy for the treatment of insulin deficient diabetes. Recent progress in techniques for islet isolation, islet culture, and peri-transplant management of the islet transplant recipient have resulted in substantial improvements in metabolic and safety outcomes for patients. For patients requiring total or sub-total pancreatectomy for benign disease of the pancreas, isolation of islets from the diseased pancreas with intrahepatic transplantation of autologous islets can prevent or ameliorate post-surgical diabetes, and for patients previously experiencing painful recurrent acute or chronic pancreatitis, quality-of-life is substantially improved...

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The liver and the reproductive system interact in a multifaceted bidirectional fashion. Sex steroid signaling influences hepatic endobiotic and xenobiotic metabolism and contributes to the pathogenesis of functional and structural disorders of the liver. In turn, liver function impacts on the reproductive axis via modulating sex steroid metabolism and transport to tissues via sex hormone binding globulin (SHBG). The liver senses the body's metabolic status and adapts its energy homeostasis in a sex-dependent fashion, a dimorphism signaled by the sex steroid milieu and possibly related to the metabolic costs of reproduction...

Several components of the GH axis are involved in tumor progression and GH-induced intracellular signaling has been strongly associated with breast cancer susceptibility in genome-wide association studies. In the general population, high IGF-I levels and low IGFBP-3 levels within the normal range are associated with the development of common malignancies, and components of the GH-IGF signaling system exhibit correlations with clinical, histopathological and therapeutic parameters in cancer patients. Despite promising findings in preclinical studies, anti-cancer therapies targeting the GH-IGF signaling system have led to disappointing results in clinical trials...

The midcycle surge of luteinizing hormone (LH) sets in motion interconnected networks of signaling cascades to bring about rupture of the follicle and release of the oocyte during ovulation. Many mediators of these LH-induced signaling cascades are associated with inflammation, leading to the postulate that ovulation is similar to an inflammatory response. First responders to the LH surge are granulosa and theca cells, which produce steroids, prostaglandins, chemokines, and cytokines, which are also mediators of inflammatory processes...

Levothyroxine, a largely prescribed drug with a narrow therapeutic index, is often a lifelong treatment. The therapeutic efficacy of thyroxine may be marred by behavioral, pharmacologic and pathologic issues acting as interfering factors. Despite a continuous search for an optimal thyroxine treatment, a significant number of patients fail to show a complete chemical and/or clinical response to this reference dose of thyroxine. Gastrointestinal malabsorption of oral thyroxine represents an emerging cause of refractory hypothyroidism and may be more frequent than previously reputed...

The number of patients surviving five or more years after initial cancer diagnosis has significantly increased over the last decades due to considerable improvements in the treatment of many cancer entities. A negative consequence of this is the emergence of long-term sequelae and endocrine disorders account for a high proportion of these. These late effects can occur decades after cancer treatment and affect up to 50% of childhood cancer survivors. Multiple predisposing factors for endocrine late effects have been identified; including radiation, gender and age at the time of diagnosis...

Nutrient handling by higher organisms is a complex process that is regulated at the transcriptional level. Studies over the past 15 years have highlighted the critical importance of a family of transcriptional regulators termed the Krüppel-like factors (KLFs) in metabolism. Within an organ, distinct KLFs direct networks of metabolic gene targets to achieve specialized functions. This regulation is often orchestrated in concert with recruitment of tissue-specific transcriptional regulators, particularly members of the nuclear receptor family...

Gender-affirming treatment of transgender people requires a multidisciplinary approach in which endocrinologists play a crucial role. The aim of this paper is to review recent data on hormonal treatment of this population and its effect on physical, psychological, and mental health. The Endocrine Society guidelines for transgender women include estrogens in combination with androgen-lowering medications. Feminizing treatment with estrogens and antiandrogens has desired physical changes, such as enhanced breast growth, reduction of facial and body hair growth, and fat redistribution in a female pattern...

Diabetic neuropathy, with its major clinical sequels, notably neuropathic pain, foot ulcers, and autonomic dysfunction, is associated with substantial morbidity, increased risk of mortality, and reduced quality of life. Despite its major clinical impact, diabetic neuropathy remains underdiagnosed and undertreated. Moreover, the evidence supporting a benefit for causal treatment is weak at least in patients with type 2 diabetes, and current pharmacotherapy is largely limited to symptomatic treatment options...

The development of hypothalamic obesity (HO) following craniopharyngioma (CP) and other suprasellar tumors leads to reduced patient quality of life. No treatment algorithms are currently available for management of HO. Depending on which hypothalamic nuclei are destroyed, the pathophysiologic mechanisms and clinical symptoms that contribute to HO differ among patients. Herein, we review the contribution of the hypothalamus to the pathophysiologic mechanisms and symptoms underlying CP-associated HO. Additionally, we performed a systematic search of MEDLINE and Embase to identify all intervention studies for weight management in patients with CP or other suprasellar tumors published until September 2017...

Acromegaly is a chronic systemic disease with many complications and is associated with increased mortality when not adequately treated. Substantial advances in acromegaly treatment, as well as in the treatment of many of its complications, mainly diabetes mellitus, heart failure, and arterial hypertension, were achieved in the last decades. These developments allowed change in both prevalence and severity of some acromegaly complications and furthermore resulted in a reduction of mortality. Currently, mortality seems to be similar to the general population in adequately treated patients with acromegaly...