Reviews in Endocrine & Metabolic Disorders最新文献

Asprosin is a versatile protein hormone primarily produced by white adipose tissue (WAT). When secreted into the bloodstream, it exerts a range of central and peripheral effects, positioning it as a key player in metabolic processes. Since its discovery, asprosin has garnered increasing attention for its involvement in metabolic disorders, such as insulin resistance (IR) and inflammation, both of which are critical to reproductive health. Emerging evidence indicates that asprosin influences the hypothalamus-pituitary-gonadal (HPG) axis, a key neuroendocrine system regulating mammalian reproduction. Concurrently, clinical studies have revealed dysregulated asprosin expression in various reproductive diseases, including polycystic ovary syndrome (PCOS), breast cancer, ovarian cancer, and pregnancy-related disorders such as gestational diabetes mellitus (GDM) and preeclampsia. These findings suggest that asprosin plays a crucial role in reproductive events and infertility-related conditions. This review provides an overview of the latest research on asprosin's role in reproduction, female reproductive diseases, and pregnancy complications, while also outlining potential future research directions. A deeper understanding of asprosin's complex involvement in reproduction and reproductive-endocrine disorders could offer novel insights into its potential as a therapeutic target for addressing infertility in clinical settings.

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.

The regulation of growth hormone (GH) synthesis and secretion by somatotroph cells of the anterior pituitary is a highly complex process, mediated by a variety of neuroendocrine and peripheral influences. In particular, a key role is played by the hypothalamic peptides growth hormone-releasing hormone (GHRH) and somatostatin, which regulate the somatotroph axis with opposite actions, stimulating and inhibiting GH release, respectively. Since the discovery of GHRH about 50 years ago, many pathophysiological studies have explored the underlying intricate hormonal balance that regulates GHRH secretion and its interplay with the somatotroph axis. Various molecules and pathophysiological states have been shown to modulate the release of GH, GHRH, somatostatin and GH secretagogues. Collectively, the available evidence demonstrates how a vast number of neural and peripheral signals are conveyed and integrated to orchestrate a finely tuned response of the somatotroph axis that adapts to the body's varying needs for growth, metabolism, and repair. The present review aims to summarize the available evidence regarding the key regulators involved in the modulation of the somatotroph axis in humans, presenting detailed molecular insights on the signaling cascades at play. The interplay between different mechanisms governing somatotroph secretion is highlighted, underscoring the nuanced interdependence that maintains homeostasis and facilitates the body's ability to respond to internal and external stimuli.

The hypothalamic hormone growth hormone-releasing hormone (GHRH), in addition to promoting the synthesis and release of growth hormone (GH), stimulates the proliferation of human normal and malignant cells by binding to GHRH-receptor (GHRH-R) and its main splice variant, SV1. Both GHRH and GHRH-Rs are expressed in various cancers, forming a stimulatory pathway for cancer cell growth; additionally, SV1 possesses ligand independent proliferative effects. Therefore, targeting GHRH-Rs pharmacologically has been proposed for the treatment of cancer. Various classes of synthetic GHRH antagonists have been developed, endowed with strong anticancer activity in vitro and in vivo, in addition to displaying anti-inflammatory, antioxidant and immune-modulatory functions. GHRH antagonists exert indirect effects by blocking the pituitary GH/hepatic insulin-like growth factor I (IGF-I) axis, or directly inhibiting the binding of GHRH on tumor GHRH-Rs. Additionally, GHRH antagonists block the mitogenic functions of SV1 in tumor cells. This review illustrates the main findings on the antitumor effects of GHRH antagonists in experimental human cancers, along with their underlying mechanisms. The development of GHRH antagonists, with reduced toxicity and high stability, could lead to novel therapeutic agents for the treatment of cancer and inflammatory diseases.

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.

This paper provides a critical overview on GHRH and its deficiency, discussing its multiple roles in both central and peripheral tissues. Genetically engineered mice have been instrumental in elucidating the multifaceted roles of GHRH and GH, each offering unique insights into the physiological and pathological roles of these hormones, although in many of these models dissecting the direct effect of GHRH from the effect of GH is not possible. Key findings highlight the effects of GHRH deficiency on emotional behavior, including anxiety and depression, its impact on memory and learning capabilities, as well as on adipose tissue, immune system, inflammation and pain.

Growth hormone (GH) secretion is pulsatile, entropic, and nycthemeral and is mainly controlled by the hypothalamus through two neurohormones, the stimulating growth hormone releasing hormone (GHRH) and the inhibiting somatostatin. Shortly after its discovery and synthesis, GHRH was intensely investigated diagnostically to define GH secretion. The nascent enthusiasm for using GHRH as a single diagnostic tool to investigate GH deficiency (GHD) dropped down quickly due to a flawed reproducibility. The subsequent combinatory use of molecules implicated in GH secretion through inhibition of the somatostatinergic tone, such as arginine (ARG), or the synthesis of receptor-orphan pharmaceutical compounds capable of stimulating pituitary somatotrophs to release GH, such as the GH secretagogues (GHSs), improved the reproducibility of GH response to GHRH alone, thus gaining access into the clinical practice by means of different diagnostic approaches. This review will focus on the history of the GHRH test, with main emphasis on GHRH plus ARG as a dynamic testing for the diagnosis of GHD. Our attention will extend crosswise from studies aimed at validating GHRH-based tests for the clinical practice, to address main pitfall conditions capable of affecting per se GH secretion, such as obesity, hypothalamic damage, and ageing. The history of GHRH test has been progressively dismantled due to the cease of its production for business reasons, opening a gap in the diagnostic workup of patients with GHD. In the urgency to seek further robust, safe, and validated diagnostic tests or tools, we hope to stimulate attention on a so important peptide for the health of our patients suffering from pituitary diseases.

Acute myeloid leukemia (AML) is the most aggressive and prevalent form of leukemia in adults. The gold-standard intervention revolves around the use of chemotherapy, and in some cases hematopoietic stem cell transplantation. Drug resistance is a frequent complication resulting from treatment, as it stands there are limited clinical measures available for refractory AML besides palliative care. The goal of this review is to renew interest in a novel targeted hormone therapy in the treatment of AML utilizing growth hormone-releasing hormone (GHRH) antagonism, given it may provide a potential solution for current barriers to achieving complete remission post-therapy. Recapitulating pre-clinical evidence, GHRH antagonists (GHRH-Ant) have significant anti-cancer activity across experimental human AML cell lines in vitro and in vivo and demonstrate significant inhibition of cancer in drug resistant analogs of leukemic cell lines as well. GHRH-Ant act in manners that are orthogonal to anthracyclines and when administered in combination synergize to produce a more potent anti-neoplastic effect. Considering the adversities associated with standard AML therapies and the developing issue of drug resistance, MIA-602 represents a novel approach worth further investigation.

GHRH is a neuropeptide associated with a diverse variety of activities in human physiology and immune responses. The present study reviews the latest information on the involvement of GHRH in the immune system and inflammation, suggesting that GHRH antagonists may deliver a new therapeutic possibility in disorders related to immune system dysfunction and inflammation.

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.