Milestones in CRH research

The Corticotropin-releasing Hormone (CRH) mammalian family members include CRH, urocortin I, Stresscopin (SCP) and Stresscopin-related peptide (SRP), along with the CRH receptors type 1 (CRHR1) and type 2 (CRHR2), and CRH-binding protein (CRH-BP). These family members differ in their tissue distribution and pharmacology. Several studies have provided evidence supporting an important role of this family in the regulation of the neuroendocrine and behavioral responses to stress. Regulation of the relative contribution of CRH and its homologs and the two CRH receptors in brain CRH pathways may be essential in coordinating physiologic responses to stress. The development of disorders related to heightened stress sensitivity and dysregulation of stress-coping mechanisms appears to involve regulatory mechanisms of the CRH family members. Therapeutic agents that target CRH family members may offer a new approach to the treatment of these disorders. The purpose of this review is to summarize the most significant discoveries related to CRH over time. © 2017 Bentham Science Publishers

CRF receptor antagonists: Utility in research and clinical practice

CRF, CRF-relatcd peptides and CRF receptors constitute a complex physiological system which has a key role in facilitating the adaptation of the organism to the stressful stimuli of the environment. The behavioral, endocrine. autonomic and immune branches or stress response are considered to be under the coordinating effects of CRF and its related peptides. The effects of these peptides are mediated through two distinct receptors, types 1 and 2 CRF receptors (CRF, and CRF2). The two receptors are encoded by separate genes and belong to the G-coupled receptor superfamily. The wide influence of the CRF system on physiological processes in both brain and periphery, suggests the implication of the respective peptides in the pathophysiology of numerous disorders which involve dysregulated stress responses. The potential use of CRF antagonists in such disorders is currently under intense investigation. Furthermore, such compounds have been invaluable in elucidating the physiology of the CRF system. This review will focus on existing data on the structural and pharmacological characteristics as well as the experimental and potential clinical uses of non-peptide, small molecule CRF antagonists

CRH-Like Peptides in Human Reproduction

CRH and Urocortins 1, 2 and 3 comprise the, so far identified, members of the CRH family of peptides in humans. Their actions are mediated through two distinct receptors, CRHR1 and CRHR2, encoded by different genes. CRH-like peptides and their receptors have been identified in reproductive tissues, such as the ovary, uterus as well as fetal and placental membranes. The participation of the “CRH family” of peptides and receptors in the physiology of these organs is currently under intense investigation. During the estrus cycle, endometrial CRH acts as a fine tuner of stromal cells decidualization. CRH is produced by embryonic trophoblast and maternal decidual cells and plays important roles in implantation. CRH also participates in the control of trophoblast invasion. Furthermore, placental CRH and Urocortin are involved in the mechanisms controlling maintenance of pregnancy and the onset of labor. The level of participation of urocortins 2 and 3 in these phenomena is currently under investigation. This review will focus on existing data on the expression and regulation of the CRH family of peptides and their receptors in the female reproductive system, as well as in their potential biologic role(s) in human reproductive functions

CRH receptors in human reproduction

Background: Corticotropin releasing hormone (CRH), the main peptide-mediator of stress, has been found in the female reproductive system. Objective: Herein, the role of CRH receptors in the female reproductive system is presented. Results: It is clear that CRH receptors are involved in the regulation of the hypothalamic-pituitary-ovarian axis, while locally are associated with decidualization, embryonic implantation, early fetal development and triggering of parturition. Conclusion: Abnormal CRH signaling may contribute to obstetrical pathophysiology, such as pre-eclampsia, abnormal placenta invasion, endometrial growth retardation and preterm delivery. © 2018 Bentham Science Publishers

Peripheral corticotropin-releasing hormone is produced in the immune and reproductive systems: Actions, potential roles and clinical implications

Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamic-pituitary-adrenal axis, has been identified in various organ systems, including the immune and the female and male reproductive systems. CRH-like immunoreactivity has been reported in peripheral inflammatory sites and in a number of reproductive organs, including the ovaries, endometrial glands, decidualized endometrial stroma, placenta, decidua, and the testes. Therefore, "immune" and "reproductive" CRH are forms of "tissue" CRH; i.e., CRH found in peripheral tissues. Immune CRH plays a direct immunomodulatory role as an autocrine/paracrine mediator of inflammation. Immune CRH participates in several experimental inflammations and, in humans, in inflamed tissues from patients with autoimmune and inflammatory diseases. One of the early effects of immune CRH is the degranulation of mast cells and the release of histamine and several inflammatory cytokines. Reproductive CRH is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period

Corticotropin-releasing hormone receptor antagonists

Corticotropin-releasing hormone (CRH), CRH-related peptides, and CRH receptors play major roles in coordinating the behavioral, endocrine, autonomic, and immune responses to stress. The wide influence of the CRH system on physiological processes in both brain and periphery implicates the respective peptides in the pathophysiology of numerous disorders characterized by dysregulated stress responses. The potential use of CRH antagonists is presently under intense investigation. Selective antagonists have been used experimentally to elucidate the role of CRH-related peptides in disease processes, such as anxiety and depression, sleep disorders, addictive behavior, inflammatory disorders, acute and chronic neurodegeneration, and preterm labor

Preterm Birth as a Risk Factor for Metabolic Syndrome and Cardiovascular Disease in Adult Life: A Systematic Review and Meta-Analysis

Objective: To determine if preterm birth is associated with components of the metabolic syndrome in adult life. Study design: A structured literature search was performed using PubMed. All comparative studies reported metabolic and cardiovascular outcomes in adults (≥18 years of age) born preterm (<37 weeks of gestation) compared with adults born at term (37-42 weeks of gestation) and published through March 2018 were included. The major outcomes assessed were body mass index, waist circumference, waist-to-hip ratio, fat mass, systolic blood pressure (SBP), diastolic blood pressure (DBP), 24-hour SBP, 24-hour DBP, endothelium-dependent brachial artery flow-mediated dilation, carotid intima-media thickness, pulse wave velocity, fasting glucose and insulin, Homeostasis Model Assessment-Estimated Insulin Resistance Index, and lipid profiles. Quality appraisal was performed using a modified version of the Newcastle-Ottawa scale. A meta-analysis was performed for comparable studies which reported sufficient data. Results: Forty-three studies were included, including a combined total of 18 295 preterm and 294 063 term-born adults. Prematurity was associated with significantly higher fat mass (P = .03), SBP (P < .0001), DBP (P < .0001), 24-hour SBP (P < .001), and 24-hour DBP (P < .001). Furthermore, preterm-born adults presented higher values of fasting glucose (P = .01), insulin (P = .002), Homeostasis Model Assessment-Estimated Insulin Resistance Index (P = .05), and total cholesterol levels (P = .05) in comparison with adults born at term, in random effect models. No statistically significant difference was found between preterm and term-born adults for the other outcomes studied. Conclusions: Preterm birth is strongly associated with a number of components of the metabolic syndrome and cardiovascular disease in adult life. © 2019 Elsevier Inc

Morphological and binding properties of interleukin-6 on thin ZnO films grown on (1 0 0) silicon substrates for biosensor applications

To develop effective protein immobilization technology with minimal amounts of protein for high sensitivity surface acoustic wave biosensors, we determined the binding properties, and morphological characteristics of human interleukin-6 (IL-6), a pro-inflammatory cytokine, on the surface of ZnO, and SiO2 films grown onto (1 0 0) Si substrates, for the first time. Interleukin-6 was immobilized in the range of 0.276-10 pg/ml on the surface of ZnO and SiO2, and visualized at each stage, while protein-protein interactions were measured with the antigen/antibody immunoassay of solid-phase ELISA, which we modified for these types of substrates. A relative mass value was determined in each case. ELISA detected upward of 1 and 6 ng/ml of protein applied on ZnO and SiO2, respectively. It is concluded that the more reactive ZnO surface is a new and more effective template for protein immobilization. © 2006 Elsevier B.V. All rights reserved

The role of HCG in implantation: A mini-review of molecular and clinical evidence

Embryo implantation is a complex process involving continuous molecular cross-talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, a brief overview of the molecular mechanisms regulated by HCG is presented. Furthermore, we summarize the existing evidence regarding the clinical impact on reproductive outcomes after endometrial priming with HCG prior to embryo transfer. Although promising, further evidence is needed to clarify the protocol that would lead to beneficial outcomes. © 2017 by the authors. Licensee MDPI, Basel, Switzerland

Stress and the female reproductive system

The hypothalamic-pituitary-adrenal (HPA) axis, when activated by stress, exerts an inhibitory effect on the female reproductive system. Corticotropin-releasing hormone (CRH) inhibits hypothalamic gonadotropin- releasing hormone (GnRH) secretion, and glucocorticoids inhibit pituitary luteinizing hormone and ovarian estrogen and progesterone secretion. These effects are responsible for the "hypothalamic" amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome. In addition, corticotropin-releasing hormone and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, corticotropin-releasing hormone is secreted in peripheral inflammatory sites where it exerts inflammatory actions. Reproductive corticotropin-releasing hormone is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period. © 2004 Elsevier Ireland Ltd. All rights reserved