Mechanisms of Hormone Action PDF

INTERNAL MEDICINE MECHANISMS OF HORMONE ACTION ENDOCRINOLOGY Albert Chu, MD, FPCP, FPCEDM 10.14.24 Topic Outline I. Classes of Hormones A. Hormone and Receptor Families B. Hormone Synthesis and Processing...

INTERNAL MEDICINE MECHANISMS OF HORMONE ACTION ENDOCRINOLOGY Albert Chu, MD, FPCP, FPCEDM 10.14.24 Topic Outline I. Classes of Hormones A. Hormone and Receptor Families B. Hormone Synthesis and Processing C. Hormone Secretion, Transport, and Degradation D. Hormone Action Through Receptors E. Membrane Receptors F. Nuclear Receptors II. Functions of Hormones A. Growth B. Maintenance of Homeostasis C. Reproduction III. Hormonal Feedback Regulatory Systems A. Paracrine and Autocrine Control B. Hormonal Rhythm CLASSES OF HORMONES Hormones integrate physiologic systems in the body, regulating growth, metabolism, homeostasis, and reproduction. Hormones act via receptors in target tissues to coordinate responses to internal and external stimuli. Example: The light-dark cycle modulates CRH in the hypothalamus, increasing ACTH, leading to adrenal cortisol production, which influences metabolism, cardiovascular function, behavior, and immune response. Five Major Classes of Hormones As hormone families enlarge and diverge, their receptors must coevolve to derive new biologic functions. 1. Amino Acid Derivatives ○ Related G protein-coupled receptors (GPCRs), for ○ Dopamine, catecholamine, and thyroid hormone; example, have evolved for each of the glycoprotein 2. Small Neuropeptides hormones. ○ GRH, TRH, somatostatin, and vasopressin; ○ These receptors are structurally similar, and each is coupled 3. Large Proteins predominantly to the Gsa signaling pathway. ○ Insulin, LH, and PTH; ○ However, there is minimal overlap of hormone binding. 4. Steroid Hormones ○ For example: ○ Cortisol and estrogen (cholesterol-based); ⎯ ISH interacts minimally with the LH or 5. Vitamin Derivatives FSH receptors. ○ Retinoids (vitamin A) and vitamin D ⎯ Very high levels of hCG during pregnancy stimulate the TSH receptor Amino acid derivatives and peptide hormones interact with and increase thyroid hormone levels, cell-surface membrane receptors. resulting in a compensatory decrease in Steroids, thyroid hormones, vitamin D, and retinoids are TSH. lipid-soluble and interact with intracellular nuclear receptors, ⎯ Moderate cross-talk among the although many also interact with membrane receptors or members of the insulin/IGF family, intracellular signaling proteins as well. ⎯ PTH and PTHrP Receptor cross-talk can occur within hormone families, such as hCG stimulating TSH receptors during pregnancy, affecting HORMONE AND RECEPTOR FAMILIES thyroid hormone levels. IGF family: Moderate cross-talk occurs between IGF1, IGF2, and The glycoprotein hormone family illustrates many features of insulin receptors. High concentrations of IGF2 (e.g., in tumors) related hormones. can cause hypoglycemia. ○ Thyroid-Stimulating Hormone (TSH) ○ Follicle-Stimulating Hormone (FSH) Nuclear Receptor ○ Luteinizing Hormone (LH) ○ Human Chorionic Gonadotropin (hCG) Subdivided based on their specificities for DNA binding sites: The glycoprotein hormones are heterodimers that share alpha 1. Type 1 Receptors subunits in common ⎯ (glucocorticoid receptor, mineralocorticoid ○ The ß subunits are distinct and confer specific biologic receptor, androgen receptor, estrogen receptor, actions. progesterone receptor) that bind steroids 1  AFPatalinjug, KCPabello, RARegidor 2. Type 2 Receptors ⎯ Long half-lives (e.g., T4) provide sustained action. ⎯ (thyroid hormone receptor, vitamin D receptor, Many hormones circulate in association with serum-binding retinoic acid receptor, peroxisome proliferator proteins. activated receptor) that bind thyroid hormone, ○ Examples: vitamin D, retinoic acid, or lipid derivatives. 1. T4 and T3 binding to thyroxine-binding globulin Certain functional domains in nuclear receptors, such as the zinc (TBG). finger DNA binding domains, are highly conserved. 2. Cortisol binding to cortisol-binding globulin (CBG): Selective amino acid differences within this domain confer DNA 3. Androgen and estrogen binding to sex hormone sequence specificity. binding globulin (SHBG): The hormone-binding domains are more variable, providing 4. IGF-I and -II binding to multiple IGF-binding proteins great diversity in the array of small molecules that bind to (IGFBPs). different nuclear receptors. 5. GH interactions with GH-binding protein (GHBP), a With few exceptions, hormone binding is highly specific for a circulating fragment of the GH receptor extracellular single type of nuclear receptor. domain: Exceptions: 6. Activin binding to follistatin. 1. Glucocorticoid and mineralocorticoid receptors ○ Binding proteins modulate hormone availability, 2. Relaxed nuclear receptor specificity involves the estrogen creating reservoirs and affecting free hormone receptor, which can bind an array of compounds, some of levels (e.g., TBG for thyroid hormones, SHBG for which have little apparent structural similarity to the sex hormones). high-affinity ligand estradiol. Short-term perturbations in binding proteins change the free hormone concentration, which in turn induces compensatory adaptations through feedback loops. HORMONE SYNTHESIS AND PROCESSING ○ SHBG changes in women are an exception to this self-correcting mechanism (insulin resistance / androgen Classic Pathway of Gene Expression excess) ○ Transcription → mRNA → protein → post translational Although a variety of binding protein abnormalities have been protein processing → intracellular sorting, followed by identified, most have little clinical consequence aside from membrane integration or secretion creating diagnostic problems. Many hormones are embedded within larger precursor ○ For example, TBG deficiency can reduce total thyroid polypeptides that are proteolytically processed to yield the hormone levels greatly but the free concentrations of T4 and biologically active hormone. T3 remain normal. Steroid Hormones ○ Liver disease and certain medications can also influence ○ Modifications of the precursor, cholesterol binding protein levels (e.g., estrogen increases TBG] or ⎯ Multiple regulated enzymatic steps are required for the cause displacement of hormones from binding proteins synthesis of testosterone, estradiol, cortisol, and (e.g., salsalate displaces T4 from TBG). vitamin D Short-term perturbations in binding proteins change the free Endocrine genes contain regulatory DNA elements similar to hormone concentration, which in turn induces compensatory those found in many other genes, but their exquisite control by adaptations through feedback loops. hormones reflects the presence of specific hormone response ○ SHBG changes in women are an exception to this elements. self-correcting mechanism (insulin resistance / androgen For some hormones, substantial regulation occurs at the level of excess) translational efficiency. Hormone degradation can be an important mechanism for Steroidogenesis involves complex enzymatic steps, leading to regulating concentrations locally. various genetic and acquired disorders. ○ 11ß-hydroxysteroid dehydrogenase type 2 inactivates glucocorticoids in renal tubular cells, preventing actions through the mineralocorticoid receptor HORMONE SECRETION, TRANSPORT, AND DEGRADATION ○ Thyroid hormone deiodinases convert T4 to T3 and can inactivate T3 The level of a hormone is determined by its rate of secretion and its circulating half-life. After protein processing, peptide hormones (e.g., GRH, insulin, HORMONE ACTION THROUGH RECEPTORS GH) are stored in secretory granules. ○ As these granules mature, they are poised beneath the Two major classes of receptor: plasma membrane for imminent release into the circulation. ○ Membrane Receptors ○ Peptide hormones are stored and released upon stimuli ⎯ primarily bind peptide hormones and catecholamines. Steroid hormones, in contrast, diffuse into the circulation as they ○ Nuclear Receptors are synthesized. ⎯ bind small molecules that can diffuse across the cell ○ Thus, their secretory rates are closely aligned with rates of membrane, such as steroids and vitamin D. synthesis. Certain general principles apply to hormone-receptor interactions Hormone transport and degradation dictate the rapidity with regardless of the class of receptor. which a hormonal signal decays. Hormones bind to receptors with specificity and an affinity that Circulating hormone half-life: generally coincides with the dynamic range of circulating ○ Important for achieving physiologic hormone replacement hormone concentrations. ○ T4: 7 days Receptor numbers vary greatly in different target tissues, ○ T3: 1 day providing one of the major determinants of specific tissue ○ Most protein hormones (e.g., ACTH, GH, PRL, PTH, LH) responses to circulating hormones. have relatively short half-lives (