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Home , Calcitriol, Parathyroid hormone

Endocrine System Human Physiology Unit 3

• Various glands located throughout the body • Some organs may also have endocrine functions • Endocrine glands/organs synthesize and release • Hormones travel in plasma to target cells Functions of the Endocrine System

• Differentiation of nervous and reproductive system during fetal development • Regulation of growth and development • Regulation of the reproductive system • Maintains • Responds to changes from resting state Mechanisms of Regulation

• Hormones have different rates and rhythms of secretion

• Hormones are regulated by feedback systems to maintain homeostasis

• Receptors for hormones are only on specific effector cells

• of hormones vary for hormones and hormones Regulation of Hormone Secretion

• Release of hormones occurs in response to • A change from resting conditions • Maintaining a regulated level of hormones or substances

• Hormone release is regulated by • Chemical factors (glucose, ) • Endocrine factors (tropic hormones, HPA) HPA = Hypothalamic-Pituitary Axis • Neural controls (sympathetic activation) Hormone Feedback Systems

Negative feedback maintains hormone concentrations within physiological ranges

• Negative feedback • Feedback to one level Loss of • Long-loop Negative Feedback feedback • Feedback to two levels control often leads to • -Pituitary-Gland Axis pathology Negative Feedback

Short-Loop Negative Feedback Long-Loop Negative Feedback Hormone Transport

Peptide/Protein Hormones Lipid Soluble Hormones

• Circulate in free forms • Circulate bound to carrier or (unbound) transport proteins (albumins) • • Short half life Remain in blood from hours to days • Degraded by circulating • Examples • • Examples • , • • : t ½ = 3-5 minutes • Hypolthalamic hormones • Mineralcorticoids • D • Pituitary hormones • hormone • (PTH) • Arachidonic acid derivatives Hormone Receptors

• A hormone released in to plasma circulates throughout the entire body • Only cells with the receptors for those hormones can respond • Cell receptors have 2 functions • Recognize and bind to hormone with high affinity • Initiate a signal to intracellular effectors Hormone Receptors

• Sensitivity is related to the number of receptors • Plasma membrane receptors are constantly being synthesized and degraded • Regulation as a response • Changes in [receptor] may occur within hours

• Physiological conditions affect receptor number and affinity • pH • Temperature • Ion concentration • Diet • Other chemicals (drugs) Plasma Membrane Receptors Signal Transduction

2nd Messenger Associated Hormones 2nd Messenger Associated Hormones cAMP Adrenocorticotropic Hormone (ACTH) Calcium Angiotensin II (LH) -Releasing Hormone (GnRH) Human Chorionic Gonadotropin (hCG) Antidiuretic Hormone (ADH) Follicle-stimulating Hormone (FSH) Thyroid Stimulating Hormone (TSH) IP3 and DAG Angiotensin II Antidiuretic Hormone (ADH) Antidiuretic Hormone (ADH) Thyrotropin Releasing Hormone (TRH) Parathyroid Hormone (PTH) Tyrosine Kinase Insulin JAK (GH) cGMP Atrial (ANP) Hormone Effects

• Binding of hormones t their receptors trigger 3 types of responses 1. Acts on pre-existing channel-forming proteins to change membrane permeability 2. Activating pre-existing proteins by a 2nd messenger 3. Activating genes resulting in protein synthesis • Direct Effects • Changes in cell function result from hormone binding • Insulin causes cellular glucose/ uptake • Permissive Effects • Hormone induced changes that facilitate the maximal response of a cell • Insulin has a permissive effect on cells, facilitating their response to prolactin Hormone Excretion

• Excretion • Excreted directly by the kidneys • Metabolized (conjugated) by the which inactivates them and makes them more water soluble

• Excretion • Deactivated by enzymes and excreted in or feces Hypothalamic-Pituitary Axis

• Neurosecretory cells in the • Hypothalamic neurons extend into hypothalamus communicate the posterior pituitary with endocrine cells in the • Hypothalamohypophysial nerve tract anterior pituitary • Neurons of the Supraoptic Nucleus • Hypothalamo-pituitary portal and Paraventricular Nucleus vessels • Hormones are stored and released • Endocrine cells of the anterior from the posterior pituitary into pituitary secrete their hormones general circulation into general circulation Hypothalamic-Pituitary Axis

Hypothalamo-pituitary portal vessels

Capillaries in Infundibulum ↓ Venule ↓ Capillaries in Anterior Lobe ↓ Hypothalamohypophysial Nerve Tract Venule ↓ General Circulation Hypothalamus Hypothalamus

• Neural input to the neurosecretory cells of the hypothalamus control their actions • Neurons from other parts of the • Sensory feedback to the hypothalamus

• Neurosecretory cells secrete releasing and inhibiting hormones

• Hypophysiotropic Hormones • Tropic hormones cause other hormones to be produced • Tropic Hormones released by the hypothalamus that cause hormones to be released by the anterior pituitary Hypothalamus

Hypothalamus Hormone Target Tissue Actions Thyrotropin-Releasing Hormone (TRH) Anterior Pituitary (+) Thyroid stimulating Hormone (TSH) Gonadotropin-Releasing Hormone (GnRH) Anterior Pituitary (+) Follicle Stimulating Hormone (FSH) (+) Luteinizing Hormone (LH) Growth Hormone Releasing Hormone (GHRH) Anterior Pituitary (+) Growth Hormone (GH) Somatocrinin Anterior Pituitary (-) Growth Hormone (GH) (-) Thyroid Stimulating Hormone (TSH) Corticotropin-Releasing Hormone (CRH) Anterior Pituitary (+) Adrenocorticotropic Hormone (ACTH) (+) β endorphin Substance P Anterior Pituitary (+) Growth Hormone (GH) (+) Follicle Stimulating Hormone (FSH) (+) Luteinizing Hormone (+) Prolactin (-) Adrenocorticotropic Hormone (ACTH) Prolactin-Releasing Factor (PRF) Anterior Pituitary (+) Prolactin (DA) Anterior Pituitary (-) Prolactin Anterior Pituitary Anterior Pituitary

• Also called adenohypophysis • Chromophils are the secretory cells of the anterior pituitary • 7 different sub-types • Secretes tropic hormones • Causes target glands to secrete hormones

• Regulation of the anterior pituitary • Feedback of the releasing/inhibiting hormones • Feedback from target gland hormones • Direct effects of neurotransmitters Anterior Pituitary

Anterior Pituitary Hormone Target Organ Actions Adrenocorticotropic Hormone (ACTH) Adrenal Cortex (+) , DHEA Melanocyte Stimulating Hormone (MSH) Anterior Pituitary (+) Secretion of Growth Hormone (GH) Liver (and Muscle, ) (+) Insulin-Like Growth Factor (IGF-1) Prolactin Mammary Glands (+) production of milk Thyroid-Stimulating Hormone (TSH) Thyroid Gland (+) Thyroid Hormone (T3, T4) (+) iodide uptake Luteinizing Hormone (LH) Gonads (+) progesterone Women – granulosa cells Ovulation Men – Leydig cells (+) Testicular growth Follicle Stimulating Hormone (FSH) Gonads (+) estrogen Women – granulosa cells Follicle development Men – Sertoli cells Spermatogenesis β- Adipocytes Lipolysis β- Adipocytes Analgesia, food and water intake, (Brain opioid receptors) body temperature regulation Posterior Pituitary Posterior Pituitary

• Also called neurohypophysis • Secretes 2 peptide hormones • • Antidiuretic Hormone (ADH) • Secreted from the hypothalamus • Supraoptic nucleus • Paraventricular nucleus Posterior Pituitary

Posterior Pituitary Hormone Target Gland Actions Oxytocin Uterine smooth muscle Causes uterine contraction Mammary Glands Causes the “milk ejection” reflex Antidiuretic Hormone (ADH) tubules Controls plasma osmolality Pineal Gland

• Contains photoreceptor cells that secrete Melatonin • Synthesized from tryptophan • tryptophan→serotonin→melatonin • Melatonin release: • Stimulated by exposure to dark • Inhibited by exposure to light • Melatonin regulates circadian rhythms and reproductive systems Thyroid Gland Thyroid Gland

• Neurons of the ANS terminate on blood vessels of the thyroid • ACh • Catecholamines

• Thyroid gland secretes 2 Actions of TSH on the Thyroid 1. Immediate release of stored hormone • Thyroid hormone 2. Increased iodide uptake and oxidation 3. Increase in thyroid hormone synthesis • 4. Increase in the synthesis and secretion of by the thyroid 5. Stimulates the growth and maintenance of the thyroid Thyroid Gland Thyroid Gland Feedback • Regulation of thyroid hormone

by long-loop negative feedback Thyroxine (T4) • Stimulus for secretion of TRH is monitored in from the hypothalamus plasma for • Sleep feedback • Extreme cold • Exercise • • Low plasma glucose Thyroid Hormone Thyroid Gland Thyroid Hormone produced: Synthesis 90% T4 10% T3

• Follicular cells form thyroid follicles • Thyroid Hormone is synthesized inside the follicles • (T3) • Thyroxine (T4) • Iodide is attached to tyrosine rings bound to thyroglobulin inside the follicle • MIT+DIT = T3 • DIT+DIT = T4 MCT: Thyroid hormone transporter Thyroid Gland Thyroid Hormone TH Receptors

• In the tissues, T4 is converted to T3 which binds to nuclear hormone receptors • Thyroid beta receptor (THβ1, THβ2) • Liver, brain • Modulates cholesterol and triglyceride levels • Thyroid alpha receptor (THα1) • • Modulates heart rate, contraction Thyroid Gland Thyroid Hormone Direct Actions Permissive Actions

• Regulates cell • Stimulates • Protein metabolism • Triglyceride metabolism • Fetal neurologic development • Glucose metabolism • Neurologic functioning in adults • Increased cellular metabolism increases • Oxygen consumption • Growth hormone secretion • Heat production • Skeletal maturation • Maintains • Healthy metabolic processes • And more……… • Normal growth and maturation • Activity of Na+/K+/ATPase pumps Thyroid Gland Thyroid Hormone Pathologies • Within physiological ranges, the permissive effects are modest • The permissive effects of TH become pronounced when there are high/low circulating levels • Hyperthyroidism • Hypothyroidism Thyroid Gland Calcitonin

• Parafollicular Cells (C Cells) • Secrete Calcitonin • Causes serum calcium levels to decrease • Inhibits • Used to treat • • Osteoarthritis • Paget bone disease • Hypercalcemia • Metastatic bone cancer Parathyroid Gland

• Produce Parathyroid Hormone (PTH) • Works with to increase serum Calcium levels • Concomitant decrease in serum levels • Water soluble hormone • GPCR + cAMP receptors • Acts on bone • activity, proliferation • Acts on kidneys • Acts on DCT to increase calcium reabsorption Pancreas

• Islets of Langerhans have 4 secretory cell types • Pancreatic hormones regulate carbohydrate, fat and protein metabolism • Alpha cells • Glucagon • Beta cells • Insulin • Delta cells • Somatostatin • F cells • Polypeptide regulating Pancreas Insulin

• A peptide hormone Actions of Insulin • Secretion is regulated by • Chemical control: serum glucose, • Facilitates the rate of glucose amino acids and amino acid uptake • Neural control: ANS • Hormonal control: GI hormones • Cellular glucose uptake by • Insulin (feedback) glucose transporters • Glucagon • GLUT transporters • • Primary transporter: GLUT4 • • • Cellular amino acid uptake by amino acid transporters Pancreas Insulin Receptors • Tyrosine Kinase receptor • Receptors on liver, muscle, adipocytes • Receptor activation leads to the insertion of glucose transporters in the cell membrane • Cell takes in glucose • Promotes all of the actions on glucose Pancreas Insulin Actions

Actions Liver Cells Muscle Cells Adipocytes Glucose uptake Increased Increased Increased Glycogenesis Increased Increased ------Glycogenolysis Decreased Decreased ------Glycolysis Increased Increased Increased Gluconeogenesis Increased ------Other ↑ fatty acid synthesis ↑ amino acid uptake ↑ fat esterification ↓ ketogenesis ↑ protein synthesis ↓ lipolysis ↓ urea cycle activity ↓proteolysis ↑ fat storage Pancreas Glucagon

• Produced by pancreatic α cells Actions of Glucagon and cells lining the GI tract • Stimulus for glucagon release • Liver • Low serum glucose • ↑ glycogenolysis • Sympathetic stimulation • ↑ gluconeogenesis • Some amino acids • Protein rich meal • Adipocytes • ↑ lipolysis • Inhibition of glucagon release • High serum glucose Pancreas Somatostatin

• Essential in carbohydrate, fat and protein metabolism • Homeostasis of ingested nutrients • Regulates pancreatic alpha and beta cells

• NOT the same as hypothalamic somatostatin Adrenal Glands Adrenal Glands

Stimulated Derived by ACTH from Cholesterol

Region of Adrenal Cortex % of Cortex Hormones Released Example

Zona Glomerulosa 15% Mineral Corticoids * Zona Fasciculata 78% Glucocorticoids Cortisol Zona Reticularis Mineral Corticoids Aldosterone* 7% Androgens Adrenal androgens* Glucocorticoids *

* We will discuss these hormones when we discuss renal and reproductive physiology Adrenal Glands Adrenal Glands Glucocorticoids • Glucocorticoids Regulation of ACTH • Direct effect on carbohydrate • Serum cortisol levels metabolism • Diurnal rhythms • People. With regular sleep/wake • Glucocorticoids have various patterns, ACTH peaks 3-5 hours effects: after sleep begins and declines • Metabolic actions throughout the day • Neurologic actions • Psychologic and physiologic • Anti-inflammatory actions stress • Growth-suppressing actions Adrenal Glands Adrenal Glands Cortisol • Most potent Actions of Cortisol • • Increase blood glucose levels Main secretory product of the • Promote gluconeogenesis in the liver adrenal glands • Decreasing uptake of glucose by muscle and lymphatic cells • Necessary for the maintenance • Ultimate effect on the body is protein of life and for protection from breakdown stress • Suppression of • • Half life of 90 minutes (-) bone formation • (-) ADH secretion • Deactivated by the liver • (+) gastric acid secretion • Depress nerve cell function Adrenal Glands Adrenal Glands Cortisol Adrenal Glands Adrenal Glands Cortisol – Stress Response Organs That Have Endocrine Function

• Some organs have endocrine function in addition to their role as part of an organ system

Organ Hormone Hormone Actions Liver Insulin-like Growth Factor (IGF1) Postnatal growth Thrombopoietin (THPO) Platelet production Hepcidin Iron homeostasis Gastrointestinal Organs MANY Hormones Regulation of motility (Entetric endocrine system) Kidneys RBC production Vitamin D activation Heart Atrial Natriuretic Peptide (ANP) Decreases blood pressure Adipocytes Leptin Energy balance