The Endocrine PhysiologyIntroduction to Endocrinology Dr. Khalid Alregaiey
Learning Objectives • Describe autocrine, paracrine, and endocrine signaling. • List the endocrine glands in the body and their secreted hormones. • Define the terms hormone, target cell, and receptor. • Classify hormones based on their chemical nature. • Discuss the mechanisms of hormone actions and second messengers. • Outline regulation of hormone receptors. • Discuss regulation of hormone secretion. • Compare and contrast negative and positive feedback control mechanisms in hormone secretion regulation. • Understand the basis of hormone measurements (RIA and immunmetric assays) and their interpretation.
Endocrine System: Overview • Endcocrinology: It is study of homeostatic functions of substances called HORMONES, that are released from glands called endocrine glands distributed throughout the body. • Hormones: Are secretions of ductless glands that are directly released into the blood stream. They can act on cells in the vicinity or on distant target cells. • Endocrine system – the body’s second great controlling system which influences metabolic activities of cells by means of hormones
Endocrine System: Overview • Endocrine glands – pituitary, thyroid, parathyroid, adrenal, and pineal. • The pancreas and gonads produce both hormones and exocrine products • The hypothalamus has both neural functions and releases hormones • Other tissues and organs that produce hormones – adipose cells, pockets of cells in the walls of the small intestine, stomach, kidneys, and heart
Autocrines and Paracrines • Autocrines – chemicals that exert their effects on the same cells that secrete them • Paracrines – locally acting chemicals that affect cells other than those that secrete them • These are not considered hormones since hormones are long-distance chemical signals
Types of Hormones • Amino acid based – most hormones belong to this class, including: • Amines (Tyrosine: Caecholamines and Thyroid hormones, Tryptophan: Melatonin) • Polypeptide hormones • protein hormones • Steroids – Derived from Cholesterol: gonadal and adrenocortical hormones • Fatty acid derived: Eicosanoids, derived from arachidonic acid: leukotrienes and prostaglandins
Transport of Hormones in the Blood • Water-soluble hormones (peptides and catecholamines) are dissolved in the plasma and transported to target cells. • Steroid and thyroid hormones, in contrast, circulate in the blood mainly bound to plasma proteins. Usually less than 10 percent of steroid or thyroid hormones in the plasma exist free in solution.
Correlation of Plasma Half-Life & Metabolic Clearance of Hormones with Degree of Protein Binding Hormone Protein binding (%) Plasma half-life Metabolic clearance (ml/minute) 99.97 99.7 94 89 15 little little little Thyroid Thyroxine Triiodothyronine Steroids Cortisol Testosterone Aldosterone Proteins Thyrotropin Insulin Antidiuretic hormone 6 days 1 day 100 min 85 min 25 min 50 min 8 min 8 min 0.7 18 140 860 1100 50 800 600 MCR = (mg/minute removed)/(mg/ml of plasma) = ml cleared/minute
Circulating Transport Proteins Principle Hormone Transported Transport Protein Specific Corticosteroid binding globulin (CBG, transcortin) Thyroxine binding globulin (TBG) Sex hormone-binding globulin (SHBG) Nonspecific Albumin Transthyretin (prealbumin) Cortisol, aldosterone Thyroxine, triiodothyronine Testosterone, estrogen Most steroids, thyroxine, triiodothyronine Thyroxine, some steroids
Determinants of Free Hormone Receptor Binding Carrier-bound hormone Free Hormone Hormone receptor Endocrine cell Hormone degradation Biological effects
Hormone Action • Hormones alter target cell activity by one of the following mechanisms: • Ion Channel–Linked Receptors. • G Protein–Linked Hormone Receptors. • Enzyme-Linked Hormone Receptors. • Intracellular Hormone Receptors and Activation of Genes (steroid and thyroid hormones)
Hormone Action • Hormones circulate to all tissues but only activate cells referred to as target cells • Target cells must have specific receptors to which the hormone binds
Location of receptors: • 1. In or on the surface of the cell membrane. The membrane receptors are specific mostly for the protein, peptide, and catecholamine hormones. • 2. In the cell cytoplasm. The primary receptors for the different steroid hormones are found mainly in the cytoplasm. • 3. In the cell nucleus. The receptors for the thyroid hormones are found in the nucleus and are believed to be located in direct association with one or more of the chromosomes.
Cyclic Adenosine Monophosphate (cAMP) Second Messenger Mechanism • Hormone (first messenger) binds to its receptor, which then binds to a G protein • The G protein is then activated as it binds GTP, displacing GDP • Activated G protein activates the effector enzyme adenylate cyclase • Adenylate cyclase generates cAMP (second messenger) from ATP • cAMP activates protein kinases, which then cause cellular effects
Cell Membrane Phospholipid: Second Messenger System • Hormone binds to the receptor and activates G protein • G protein binds and activates a phospholipase enzyme • Phospholipase splits the phospholipid PIP2 into diacylglycerol (DAG) and IP3 (both act as second messengers) • DAG activates protein kinases; IP3 triggers release of Ca2+ stores • Ca2+ (third messenger) alters cellular responses
Protein Hormones - Mechanisms of Action Tyrosine Kinase/Cytokine Receptor Mechanism Guanylate Cyclase Mechanism Adenylyl Cyclase Mechanism Phospholipid Mechanism
Steroid and Thyroid Hormones • Steroid hormones and thyroid hormone diffuse easily into their target cells • Once inside, they bind and activate a specific intracellular receptor • The hormone-receptor complex travels to the nucleus and binds a DNA-associated receptor protein • This interaction prompts DNA transcription to produce mRNA • The mRNA is translated into proteins, which bring about a cellular effect
Target Cell Activation • Target cell activation depends on three factors • Blood levels of the hormone • Relative number of receptors on the target cell • The affinity of those receptors for the hormone • Up-regulation – target cells form more receptors in response to the hormone • Down-regulation – target cells lose receptors in response to the hormone
Down-regulation (1) inactivation of some receptors; (2) inactivation of some of the intracellular signaling molecules; (3) temporary sequestration of the receptor to the inside of the cell; (4) destruction of the receptors by lysosomes after they are internalized; or (5) decreased production of the receptors.
Hormone Concentrations in the Blood • Hormones circulate in the blood in two forms – free or bound • Steroids and thyroid hormone are attached to plasma proteins
Hormone Concentrations in the Blood • Concentrations of circulating hormone reflect: • Rate of release • Speed of inactivation and removal from the body • Hormones are removed from the blood by: (1) binding with the tissues (receptors), (2) metabolic destruction by the tissues, (3) excretion by the liver into the bile, and (4) excretion by the kidneys into the urine.
Interaction of Hormones at Target Cells • Three types of hormone interaction • Permissiveness – one hormone cannot exert its effects without another hormone being present • Synergism – the total effect of two hormones together is greater than the sum of their individual effects • Antagonism – one or more hormones opposes the action of another hormone
Hormonal Rhythms 12 PLASMA GH (mG/L) 8 4 0 8 12 16 20 0 4 8 500 400 PLASMA CORTISOL (nmol/L) 300 200 100 0 8 12 16 20 0 4 8 CLOCK TIME
Control of Hormone Release • Blood levels of hormones: • Are controlled by negative and positive feedback systems • Vary only within a narrow desirable range • Hormones are synthesized and released in response to humoral, neural, and hormonal stimuli
+ + _ + Feedback Mechanisms Positive Feedback Negative Feedback Target cell Target cell Endocrine cell Endocrine cell Biological effects Biological effects
Feedback Control • Negative Feedback Prevents Overactivity of Hormone Systems • Negative feedback is most common: for example, LH from pituitary stimulates the testis to produce testosterone which in turn feeds back and inhibits LH secretion • Positive feedback is less common: examples include LH stimulation of estrogen which stimulates LH surge at ovulation
Humoral Stimuli • Humoral stimuli – secretion of hormones in direct response to changing blood levels of ions and nutrients • Example: concentration of calcium ions in the blood • Declining blood Ca2+ concentration stimulates the parathyroid glands to secrete PTH (parathyroid hormone) • PTH causes Ca2+ concentrations to rise and the stimulus is removed
Neural Stimuli • Neural stimuli – nerve fibers stimulate hormone release • Preganglionic sympathetic nervous system (SNS) fibers stimulate the adrenal medulla to secrete catecholamines
Hormonal Stimuli • Hormonal stimuli – release of hormones in response to hormones produced by other endocrine organs • The hypothalamic hormones stimulate the anterior pituitary • In turn, pituitary hormones stimulate targets to secrete still more hormones
Measurement of Hormone Concentrations • Radioimmunoassay (RIA) • Enzyme-Linked Immunosorbentm Assay (ELISA)