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Frontiers in Endocrinology 2020Hormones are largely responsible for the integrated communication of several physiological systems responsible for modulating cellular growth and development. Although... (Review)
Review
Hormones are largely responsible for the integrated communication of several physiological systems responsible for modulating cellular growth and development. Although the specific hormonal influence must be considered within the context of the entire endocrine system and its relationship with other physiological systems, three key hormones are considered the "anabolic giants" in cellular growth and repair: testosterone, the growth hormone superfamily, and the insulin-like growth factor (IGF) superfamily. In addition to these anabolic hormones, glucocorticoids, mainly cortisol must also be considered because of their profound opposing influence on human skeletal muscle anabolism in many instances. This review presents emerging research on: (1) Testosterone signaling pathways, responses, and adaptations to resistance training; (2) Growth hormone: presents new complexity with exercise stress; (3) Current perspectives on IGF-I and physiological adaptations and complexity these hormones as related to training; and (4) Glucocorticoid roles in integrated communication for anabolic/catabolic signaling. Specifically, the review describes (1) Testosterone as the primary anabolic hormone, with an anabolic influence largely dictated primarily by genomic and possible non-genomic signaling, satellite cell activation, interaction with other anabolic signaling pathways, upregulation or downregulation of the androgen receptor, and potential roles in co-activators and transcriptional activity; (2) Differential influences of growth hormones depending on the "type" of the hormone being assayed and the magnitude of the physiological stress; (3) The exquisite regulation of IGF-1 by a family of binding proteins (IGFBPs 1-6), which can either stimulate or inhibit biological action depending on binding; and (4) Circadian patterning and newly discovered variants of glucocorticoid isoforms largely dictating glucocorticoid sensitivity and catabolic, muscle sparing, or pathological influence. The downstream integrated anabolic and catabolic mechanisms of these hormones not only affect the ability of skeletal muscle to generate force; they also have implications for pharmaceutical treatments, aging, and prevalent chronic conditions such as metabolic syndrome, insulin resistance, and hypertension. Thus, advances in our understanding of hormones that impact anabolic: catabolic processes have relevance for athletes and the general population, alike.
Topics: Adaptation, Physiological; Animals; Exercise; Growth Hormone; Growth and Development; Humans; Hydrocortisone; Muscle, Skeletal; Somatomedins; Testosterone
PubMed: 32158429
DOI: 10.3389/fendo.2020.00033 -
Frontiers in Endocrinology 2022Various theories for the hormonal basis of diabetes have been proposed and debated over the past few decades. Insulin insufficiency was previously regarded as the only... (Review)
Review
Various theories for the hormonal basis of diabetes have been proposed and debated over the past few decades. Insulin insufficiency was previously regarded as the only hormone deficiency directly leading to metabolic disorders associated with diabetes. Although glucagon and its receptor are ignored in this framework, an increasing number of studies have shown that they play essential roles in the development and progression of diabetes. However, the molecular mechanisms underlying the effects of glucagon are still not clear. In this review, recent research on the mechanisms by which glucagon and its receptor contribute to the pathogenesis of diabetes as well as correlations between mutation rates in populations and the occurrence of diabetes are summarized. Furthermore, we summarize how recent research clearly establishes glucagon as a potential therapeutic target for diabetes.
Topics: Diabetes Mellitus; Glucagon; Humans; Insulin; Receptors, Glucagon
PubMed: 35784565
DOI: 10.3389/fendo.2022.928016 -
Cell Metabolism Jun 2013Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and... (Review)
Review
Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and immune function, providing a scientific basis for utilizing incretin-based therapies in the treatment of type 2 diabetes. Activation of GLP-1 and GIP receptors also leads to nonglycemic effects in multiple tissues, through direct actions on tissues expressing incretin receptors and indirect mechanisms mediated through neuronal and endocrine pathways. Here we contrast the pharmacology and physiology of incretin hormones and review recent advances in mechanisms coupling incretin receptor signaling to pleiotropic metabolic actions in preclinical studies. We discuss whether mechanisms identified in preclinical studies have potential translational relevance for the treatment of human disease and highlight controversies and uncertainties in incretin biology that require resolution in future studies.
Topics: Animals; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Islets of Langerhans; Mice; Receptors, Gastrointestinal Hormone; Signal Transduction
PubMed: 23684623
DOI: 10.1016/j.cmet.2013.04.008 -
The American Journal of Psychiatry Aug 2020Major depressive disorder is a common psychiatric disorder associated with marked suffering, morbidity, mortality, and cost. The World Health Organization projects that... (Review)
Review
Major depressive disorder is a common psychiatric disorder associated with marked suffering, morbidity, mortality, and cost. The World Health Organization projects that by 2030, major depression will be the leading cause of disease burden worldwide. While numerous treatments for major depression exist, many patients do not respond adequately to traditional antidepressants. Thus, more effective treatments for major depression are needed, and targeting certain hormonal systems is a conceptually based approach that has shown promise in the treatment of this disorder. A number of hormones and hormone-manipulating compounds have been evaluated as monotherapies or adjunctive treatments for major depression, with therapeutic actions attributable not only to the modulation of endocrine systems in the periphery but also to the CNS effects of hormones on non-endocrine brain circuitry. The authors describe the physiology of the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary thyroid (HPT), and hypothalamic-pituitary-gonadal (HPG) axes and review the evidence for selected hormone-based interventions for the treatment of depression in order to provide an update on the state of this field for clinicians and researchers. The review focuses on the HPA axis-based interventions of corticotropin-releasing factor antagonists and the glucocorticoid receptor antagonist mifepristone, the HPT axis-based treatments of thyroid hormones (T and T), and the HPG axis-based treatments of estrogen replacement therapy, the progesterone derivative allopregnanolone, and testosterone. While some treatments have largely failed to translate from preclinical studies, others have shown promising initial results and represent active fields of study in the search for novel effective treatments for major depression.
Topics: Depressive Disorder, Major; Endocrine Glands; Hormones; Humans; Neurosecretory Systems; Treatment Outcome
PubMed: 32456504
DOI: 10.1176/appi.ajp.2020.19080848 -
Molecules (Basel, Switzerland) Oct 2022There is a wide variety of kinds of lipids, and complex structures which determine the diversity and complexity of their functions. With the basic characteristic of... (Review)
Review
There is a wide variety of kinds of lipids, and complex structures which determine the diversity and complexity of their functions. With the basic characteristic of water insolubility, lipid molecules are independent of the genetic information composed by genes to proteins, which determine the particularity of lipids in the human body, with water as the basic environment and genes to proteins as the genetic system. In this review, we have summarized the current landscape on hormone regulation of lipid metabolism. After the well-studied PI3K-AKT pathway, insulin affects fat synthesis by controlling the activity and production of various transcription factors. New mechanisms of thyroid hormone regulation are discussed, receptor α and β may mediate different procedures, the effect of thyroid hormone on mitochondria provides a new insight for hormones regulating lipid metabolism. Physiological concentration of adrenaline induces the expression of extrapituitary prolactin in adipose tissue macrophages, which promotes fat weight loss. Manipulation of hormonal action has the potential to offer a new therapeutic horizon for the global burden of obesity and its associated complications such as morbidity and mortality.
Topics: Humans; Lipid Metabolism; Prolactin; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Hormones; Adipose Tissue; Insulin; Thyroid Hormones; Epinephrine; Lipids; Transcription Factors; Water
PubMed: 36296646
DOI: 10.3390/molecules27207052 -
Journal of Applied Physiology... Mar 2017The complexity and redundancy of the endocrine pathways during recovery related to anabolic function in the body belie an oversimplistic approach to its study. The... (Review)
Review
The complexity and redundancy of the endocrine pathways during recovery related to anabolic function in the body belie an oversimplistic approach to its study. The purpose of this review is to examine the role of resistance exercise (RE) on the recovery responses of three major anabolic hormones, testosterone, growth hormone(s), and insulin-like growth factor 1. Each hormone has a complexity related to differential pathways of action as well as interactions with binding proteins and receptor interactions. Testosterone is the primary anabolic hormone, and its concentration changes during the recovery period depending on the upregulation or downregulation of the androgen receptor. Multiple tissues beyond skeletal muscle are targeted under hormonal control and play critical roles in metabolism and physiological function. Growth hormone (GH) demonstrates differential increases in recovery with RE based on the type of GH being assayed and workout being used. IGF-1 shows variable increases in recovery with RE and is intimately linked to a host of binding proteins that are essential to its integrative actions and mediating targeting effects. The RE stress is related to recruitment of muscle tissue with the glandular release of hormones as signals to target tissues to support homeostatic mechanisms for metabolism and tissue repair during the recovery process. Anabolic hormones play a crucial role in the body's response to metabolism, repair, and adaptive capabilities especially in response to anabolic-type RE. Changes of these hormones following RE during recovery in the circulatory biocompartment of blood are reflective of the many mechanisms of action that are in play in the repair and recovery process.
Topics: Adaptation, Physiological; Exercise; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Muscle Fatigue; Muscle, Skeletal; Recovery of Function; Resistance Training; Testosterone; Young Adult
PubMed: 27856715
DOI: 10.1152/japplphysiol.00599.2016 -
Endocrine Reviews Apr 2010Cellular actions of thyroid hormone may be initiated within the cell nucleus, at the plasma membrane, in cytoplasm, and at the mitochondrion. Thyroid hormone nuclear... (Review)
Review
Cellular actions of thyroid hormone may be initiated within the cell nucleus, at the plasma membrane, in cytoplasm, and at the mitochondrion. Thyroid hormone nuclear receptors (TRs) mediate the biological activities of T(3) via transcriptional regulation. Two TR genes, alpha and beta, encode four T(3)-binding receptor isoforms (alpha1, beta1, beta2, and beta3). The transcriptional activity of TRs is regulated at multiple levels. Besides being regulated by T(3), transcriptional activity is regulated by the type of thyroid hormone response elements located on the promoters of T(3) target genes, by the developmental- and tissue-dependent expression of TR isoforms, and by a host of nuclear coregulatory proteins. These nuclear coregulatory proteins modulate the transcription activity of TRs in a T(3)-dependent manner. In the absence of T(3), corepressors act to repress the basal transcriptional activity, whereas in the presence of T(3), coactivators function to activate transcription. The critical role of TRs is evident in that mutations of the TRbeta gene cause resistance to thyroid hormones to exhibit an array of symptoms due to decreasing the sensitivity of target tissues to T(3). Genetically engineered knockin mouse models also reveal that mutations of the TRs could lead to other abnormalities beyond resistance to thyroid hormones, including thyroid cancer, pituitary tumors, dwarfism, and metabolic abnormalities. Thus, the deleterious effects of mutations of TRs are more severe than previously envisioned. These genetic-engineered mouse models provide valuable tools to ascertain further the molecular actions of unliganded TRs in vivo that could underlie the pathogenesis of hypothyroidism. Actions of thyroid hormone that are not initiated by liganding of the hormone to intranuclear TR are termed nongenomic. They may begin at the plasma membrane or in cytoplasm. Plasma membrane-initiated actions begin at a receptor on integrin alphavbeta3 that activates ERK1/2 and culminate in local membrane actions on ion transport systems, such as the Na(+)/H(+) exchanger, or complex cellular events such as cell proliferation. Concentration of the integrin on cells of the vasculature and on tumor cells explains recently described proangiogenic effects of iodothyronines and proliferative actions of thyroid hormone on certain cancer cells, including gliomas. Thus, hormonal events that begin nongenomically result in effects in DNA-dependent effects. l-T(4) is an agonist at the plasma membrane without conversion to T(3). Tetraiodothyroacetic acid is a T(4) analog that inhibits the actions of T(4) and T(3) at the integrin, including angiogenesis and tumor cell proliferation. T(3) can activate phosphatidylinositol 3-kinase by a mechanism that may be cytoplasmic in origin or may begin at integrin alphavbeta3. Downstream consequences of phosphatidylinositol 3-kinase activation by T(3) include specific gene transcription and insertion of Na, K-ATPase in the plasma membrane and modulation of the activity of the ATPase. Thyroid hormone, chiefly T(3) and diiodothyronine, has important effects on mitochondrial energetics and on the cytoskeleton. Modulation by the hormone of the basal proton leak in mitochondria accounts for heat production caused by iodothyronines and a substantial component of cellular oxygen consumption. Thyroid hormone also acts on the mitochondrial genome via imported isoforms of nuclear TRs to affect several mitochondrial transcription factors. Regulation of actin polymerization by T(4) and rT(3), but not T(3), is critical to cell migration. This effect has been prominently demonstrated in neurons and glial cells and is important to brain development. The actin-related effects in neurons include fostering neurite outgrowth. A truncated TRalpha1 isoform that resides in the extranuclear compartment mediates the action of thyroid hormone on the cytoskeleton.
Topics: Animals; Humans; Receptors, Thyroid Hormone; Thyroid Hormones; Thyroxine; Triiodothyronine
PubMed: 20051527
DOI: 10.1210/er.2009-0007 -
Asian Journal of Andrology 2016Traditionally, testosterone and estrogen have been considered to be male and female sex hormones, respectively. However, estradiol, the predominant form of estrogen,... (Review)
Review
Traditionally, testosterone and estrogen have been considered to be male and female sex hormones, respectively. However, estradiol, the predominant form of estrogen, also plays a critical role in male sexual function. Estradiol in men is essential for modulating libido, erectile function, and spermatogenesis. Estrogen receptors, as well as aromatase, the enzyme that converts testosterone to estrogen, are abundant in brain, penis, and testis, organs important for sexual function. In the brain, estradiol synthesis is increased in areas related to sexual arousal. In addition, in the penis, estrogen receptors are found throughout the corpus cavernosum with high concentration around neurovascular bundles. Low testosterone and elevated estrogen increase the incidence of erectile dysfunction independently of one another. In the testes, spermatogenesis is modulated at every level by estrogen, starting with the hypothalamus-pituitary-gonadal axis, followed by the Leydig, Sertoli, and germ cells, and finishing with the ductal epithelium, epididymis, and mature sperm. Regulation of testicular cells by estradiol shows both an inhibitory and a stimulatory influence, indicating an intricate symphony of dose-dependent and temporally sensitive modulation. Our goal in this review is to elucidate the overall contribution of estradiol to male sexual function by looking at the hormone's effects on erectile function, spermatogenesis, and libido.
Topics: Aromatase; Estradiol; Germ Cells; Humans; Hypothalamo-Hypophyseal System; Leydig Cells; Libido; Male; Penile Erection; Sertoli Cells; Spermatogenesis; Testis; Testosterone
PubMed: 26908066
DOI: 10.4103/1008-682X.173932 -
Drugs Aug 2022Linzagolix (Yselty) is an orally administered, selective, non-peptide small molecule gonadotrophin releasing hormone (GnRH) receptor antagonist that is being developed... (Review)
Review
Linzagolix (Yselty) is an orally administered, selective, non-peptide small molecule gonadotrophin releasing hormone (GnRH) receptor antagonist that is being developed by Kissei Pharmaceutical for the treatment of uterine fibroids and endometriosis in women of reproductive age. Linzagolix binds to and blocks the GnRH receptor in the pituitary gland, modulating the hypothalamic pituitary-gonadal axis and dose-dependently reducing serum luteinising hormone and follicle-stimulating hormone production and serum estradiol levels. In June 2022, linzagolix was approved for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age in the EU. Linzagolix is under regulatory review the USA for this indication and is in phase 3 clinical development in the treatment of pain associated with endometriosis. This article summarizes the milestones in the development of linzagolix leading to this first approval for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.
Topics: Adult; Carboxylic Acids; Endometriosis; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leiomyoma; Luteinizing Hormone; Pharmaceutical Preparations; Pyrimidines; Receptors, LHRH
PubMed: 35997940
DOI: 10.1007/s40265-022-01753-9 -
Endocrinology Jul 2021The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even... (Review)
Review
The incretin effect-the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance-was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Homeostasis; Humans; Incretins; Insulin; Insulin Secretion; Postprandial Period; Receptors, Gastrointestinal Hormone
PubMed: 33782700
DOI: 10.1210/endocr/bqab065