Reviews in Endocrine & Metabolic Disorders最新文献

Growth hormone-releasing hormone (GHRH) is a crucial endocrine hormone that exerts its biological effects by binding to specific receptors on the cell surface, known as GHRH receptors (GHRH-R). This binding activates downstream signaling pathways. In addition to promoting growth hormone secretion by the pituitary gland, GHRH also functions to maintain multisystem homeostasis by interacting with peripheral tissues that express GHRH-R. Due to the multiple roles of GHRH in body development and tissue repair, a variety of GHRH analogue peptides have been synthesized. Based on their effects on GHRH-R, these GHRH analogues can be classified as GHRH-R agonists and antagonists. Recently, the interaction of GHRH and its analogues with blood vessels, such as promoting angiogenesis and inhibiting vascular calcification (VC), has gained significant attention. This article reviews the effects of GHRH and its analogues on blood vessels.

Despite over a century of insulin therapy and recent advances in glucose monitoring, diabetes and its complications remain a significant burden. Current medications are not durable, with symptoms often returning after treatment ends, and responses vary between patients. Additionally, the effectiveness of many medications diminishes over time, highlighting the need for alternative approaches. Maintaining β-cell mass and promoting β-cell regeneration offer more curable treatments, while cell replacement therapies could be an option if regeneration is not feasible. For both strategies, enhancing β-cell survival is crucial. Growth hormone-releasing hormone (GHRH) was originally discovered for its ability to stimulate the production and release of growth hormone (GH) from the pituitary. Beyond the hypothalamus, GHRH is produced in peripheral tissues, with its receptor, GHRHR, expressed in tissues such as the pituitary, pancreas, adipose tissue, intestine, and liver. Several studies have shown that GHRH and its analogs enhance the survival of insulin-producing pancreatic β-cells both in vitro and in animal models. These beneficial effects strongly support the potential of GHRH agonists and antagonists for the clinical treatment of human metabolic diseases or for enhancing β-cell survival in cells used for transplantation. In the current review, we will discuss the roles of hypothalamic and extrahypothalamic GHRH in metabolism in physiological and pathological contexts, along with the underlying mechanisms. Furthermore, we will discuss the potential beneficial effects of GHRH analogs for the treatment of metabolic diseases.

Prolactin is a 23 kDa protein synthesised and released by lactotrophs located in the anterior pituitary gland. The main function of prolactin is the development of the mammary glands and the production and maintenance of milk secretion during pregnancy and lactation. Prolactin is present in 3 forms in the circulation monomeric, dimeric and macroprolactin which is one of the causes of variability between assay manufacturers. Although most assays have been standardised using the WHO's 3rd international standard there is still considerable variability between commercially available assays and as such laboratories need to establish their own reference intervals. Clinicians use reference intervals to distinguish between healthy and diseased individuals. Direct methods to establish reference intervals are expensive and time consuming and are impractical for most routine clinical laboratories. Indirect methods using the laboratories own data are more commonly used but also have drawbacks. Determination of reference intervals for prolactin is particularly difficult due to various physiological causes for variation in prolactin levels including age, sex and menopause. The presence of macroprolactin, its detection and methods for reporting its presence adds to reference interval determination complexity and harmonisation of these methods may improve clinical care.

Individuals in the United States with lower economic resources face a disproportionate burden of obesity and co-morbid conditions. This review summarizes the efficacy of MR programs for the treatment of obesity and diabetes and alerts clinicians to potential barriers and facilitators to the uptake of such programs so they may tailor their prescriptive approach. Implementation of effective behavioral and lifestyle interventions for obesity and diabetes in low-income settings is fraught with barriers and under-studied. The dearth of data on the use of MR programs in populations with low economic resources highlights a key area for future investigation.

Pasireotide long-acting release (PAS-LAR) is a second-generation somatostatin receptor ligand (SRL) approved for acromegaly treatment. This meta-analysis aimed to evaluate the real-world effectiveness and safety of PAS-LAR in patients with acromegaly resistant to first-generation somatostatin receptor ligands (fgSRL). A systematic literature search was conducted in PubMed and Web of Science for real-world studies on PAS-LAR in acromegaly published between 2014 and 2023. Random-effects meta-analyses were performed on biochemical control rates, tumor shrinkage, and metabolic parameters. Twelve studies comprising 409 patients were included. The pooled rate of insulin-like growth factor 1 (IGF-1) control was 57.9% [95% CI: 48.4-66.8] and the percentage of patients with tumor shrinkage was 33.3% [95%CI: 19.7-50.4]. Significant reductions were observed in growth hormone standardized mean difference (SMD) 0.6 ng/mL [95% CI: 0.3 to 1.0] and IGF-1 levels SMD 0.9 ULN [95% CI: 0.4 to 1.4]. However, as expected, a worsening in glucose metabolism was noted as an increase in fasting glucose SMD - 0.8 mg/dL [95% CI: -1.0 to -0.5, p < 0.01], glycated hemoglobin SMD - 0.5% [95% CI: -0.7 to -0.2]. and type 2 diabetes mellitus prevalence SMD - 11.5% (95% CI: -17.5 to -5.5). PAS-LAR demonstrated higher effectiveness in real-world settings, with over 60% of patients achieving IGF-1 control compared to the around 30% efficacy observed in clinical trials. These findings suggest that PAS-LAR is an effective option for acromegaly patients resistant to fgSRL, but careful monitoring of glucose levels is essential. The high heterogeneity observed across studies emphasizes the need for identifying PAS-LAR response biomarkers to set-up individualized treatment approaches for optimizing patient outcomes.

In the late 1960s and early 1970s, hypothalamic regulatory hormones were isolated, characterized and sequenced. Later, it was demonstrated hypothalamic and ectopic production of growth hormone-releasing hormone (GHRH) in normal and tumor tissues, of both humans and animals. Pituitary-type GHRH receptors (pGHRH-R) had been demonstrated to be expressed predominantly in the anterior pituitary gland but also found in other somatic cells, and significantly present in various human cancers; in addition, the expression of splice variants (SVs) of GHRH receptor (GHRH-R) has been found not only in the pituitary but in extrapituitary tissues, including human neoplasms. In relation to the prostate, besides the pGHRH-R, it has been detected the presence of truncated splice variants of GHRH-R (SV1-SV4) in normal human prostate and human prostate cancer (PCa) specimens; lastly, a novel SV of GHRH-R has been detected in human PCa. Signaling pathways activated by GHRH include AC/cAMP/PKA, Ras/Raf/ERK, PI3K/Akt/mTOR and JAK2/STAT3, which are involved in processes such as cell survival, proliferation and cytokine secretion. The neuropeptide GHRH can also transactivate the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER)-2. Thus, GHRH-Rs have become drug targets for several types of clinical conditions, including prostate-related conditions such as prostatitis, benign hyperplasia and cancer. Over the last fifty years, the development of GHRH-R receptor antagonists has been unstoppable, improving their potency, stability and affinity for the receptor. The last series of GHRH-R antagonists, AVR, exhibits superior anticancer and anti-inflammatory activities in both in vivo and in vitro assays.

HOXA10 belongs to the homeobox gene family and is essential for uterine biogenesis, endometrial receptivity, embryo implantation, and stromal cell decidualization. Available evidence suggests that the expression of HOXA10 is dysregulated in different endometrial disorders like endometrial hyperplasia, endometrial cancer, adenomyosis, endometriosis, recurrent implantation failure, and unexplained infertility. The downregulation of HOXA10 occurs by genetic changes in the HOXA10 gene, methylation of the HOXA10 locus, or selected miRNAs. Endocrine disruptors and organic pollutants also cause the reduced expression of HOXA10 in these conditions. In vivo experiments in mouse models and in vitro studies in human cell lines demonstrate that downregulation of HOXA10 leads to endometrial epithelial cell proliferation, failure of stromal cell decidualization, altered expression of genes involved in cell cycle regulation, immunomodulation, and various signaling pathways. These disruptions are speculated to cause infertility associated with the disorders of the endometrium.

This special issue of Reviews in Endocrine and Metabolic Disorders is dedicated to hypoprolactinemia. Prolactin is known for its actions on the mammary gland including development, preparation for postpartum lactation, as well as synthesis and maintenance of milk secretion. However, prolactin has many other physiological effects on reproduction, embryonic and fetal development, homeostasis, neuroprotection, behavior, and immunoregulation. In clinical practice, physiopathology and clinical consequences of increased prolactin secretion are generally well understood, and medical treatment to decrease prolactin levels is available and effective in most cases. Unlike prolactin excess, hypoprolactinemia has been a neglected endocrine disorder and nospecific replacement therapy is commercially available. Prolactin is the only anterior pituitary hormone not addressed by clinical hypopituitarism guidelines. In recent years, human studies have revealed that hypoprolactinemia is associated with metabolic, sexual and neuropsychologic alterations. Therefore, this special issue of Reviews in Endocrine and Metabolic Disorders is aimed to enhance our incomplete understanding of hypoprolactinemia. A total of 17 articles were authored by respected scientists and clinicians from a variety of disciplines including adult and pediatric endocrinology, pathology, gynecology, reproductive medicine, oncology, and neurosurgery.

Prolactin (PRL) is a 23-kDa protein synthesized and secreted by lactotroph cells of the anterior pituitary gland but also by other peripheral tissues. PRL binds directly to a unique transmembrane receptor (PRLR), and the JAK2/signal transducer and activator of transcription 5 (Stat5) pathway is considered the major downstream pathway for PRLR signaling. To a lesser extent, PRL may be cleaved into the shorter 16-kDa PRL, also called vasoinhibin, whose signaling is not fully known. According to rodent models of PRL signaling inactivation and the identification of human genetic alterations in PRL signaling, a growing number of biological processes are partly mediated by PRL or its downstream effectors. In this review, we focused on PRL structure and signaling and its canonical function in reproduction. In addition to regulating reproductive functions, PRL also plays a role in behavior, notably in initiating nurturing and maternal behavior. We also included recent insights into PRL function in several fields, including migraines, metabolic homeostasis, inflammatory and autoimmune disease, and cancer. Despite the complexity of understanding the many functions of PRL, new research in this field offers interesting perspectives on physiological and pathophysiological processes.

Growth hormone-releasing hormone (GHRH) is primarily produced by the hypothalamus and stimulates the release of growth hormone (GH) in the anterior pituitary gland, which subsequently regulates the production of hepatic insulin-like growth factor-1 (IGF-1). GH and IGF-1 have potent effects on promoting cell proliferation, inhibiting cell apoptosis, as well as regulating cell metabolism. In central nerve system (CNS), GHRH/GH/IGF-1 promote brain development and growth, stimulate neuronal proliferation, and regulate neurotransmitter release, thereby participating in the regulation of various CNS physiological activities. In addition to hypothalamus-pituitary gland, GHRH and GHRH receptor (GHRH-R) are also expressed in other brain cells or tissues, such as endogenous neural stem cells (NSCs) and tumor cells. Alternations in GHRH/GH/IGF-1 axis are associated with various CNS diseases, for example, Alzheimer's disease, amyotrophic lateral sclerosis and emotional disorders manifest GHRH, GH or IGF-1 deficiency, and GH or IGF-1 supplementation exerts beneficial therapeutic effects on these diseases. CNS tumors, such as glioma, can express GHRH and GHRH-R, and activating this signaling pathway promotes tumor cell growth. The synthesized GHRH antagonists have shown to inhibit glioma cell growth and may hold promising as an adjuvant therapy for treating glioma. In addition, we have shown that GHRH agonist MR-409 can improve neurological sequelae after ischemic stroke by activating extrapituitary GHRH-R signaling and promoting endogenous NSCs-derived neuronal regeneration. This article reviews the involvement of GHRH/GH/IGF-1 in CNS diseases, and potential roles of GHRH agonists and antagonists in treating CNS diseases.