Chapter 16

1. Chapter 16 The Endocrine System J.F. Thompson, Ph.D. & J.R. Schiller, Ph.D. & G.R. Pitts, Ph.D.

2. Endocrine System: An Overview • The body’s second homeostatic control system • Uses hormones as control agents • Hormones: chemical messengers released into the blood to regulate specific body functions • Hormones are secreted by endocrine (ductless) glands and tissues • Endocrinology: the scientific study of hormones and the endocrine organs

3. Hormones Regulate: • Volume & chemical composition of the extracellular fluid (ECF) • Metabolism and energy balance • Contraction of smooth and cardiac muscle fibers and many glandular secretions • Homeostasis during normal and emergency conditions • Some immune system activities • Coordinated, sequential growth, development, and maturation • Reproduction by regulating: • gamete production • fertilization • nourishment of the embryo and fetus • labor and delivery • lactation for nourishment of the infant

4. Nervous vs. Endocrine Systems rapid action potentials (nerve impulses) propagated via nerve fibers neurotransmitters released at specific effector(s) nerve impulses are brief (msecs/seconds), although control can be sustained response of effectors is of relatively short duration (seconds/minutes) slower hormones released into body fluids; circulated throughout the body in the blood all body cells exposed; only target cells with receptors respond hormones persist for seconds/hours/days responses of target cells may last seconds/hours/days, even weeks/months

5. Endocrine versus Exocrine Glands • All glands • have extensive capillary blood supply • form a discrete structure/organ • Endocrine glands • secrete hormones into surrounding tissue fluid by exocytosis and the blood transports them to target cells • Exocrine glands • secrete various compounds by exocytosis into a duct system • Mixed glands • both endocrine and exocrine functions

6. Six Pure Endocrine Glands • pineal • pituitary • thyroid • parathyroid • adrenal cortex/medulla • thymus

7. Other Endocrine System Components • mixed glands: • pancreas • gonads: ovaries & testes • other endocrine tissue: • stomach and intestines • skin and adipose tissue • heart • kidneys • placenta • neuroendocrine “organs”: • Hypothalamus/Pituitary gland

8. Types of Chemical Regulators • Circulating hormones (endocrines): travel via the blood to reach all tissues, and may affect distant target cells • Local hormones – diffuse into local interstitial fluid, reach and affect only local target cells • paracrine - acts on target cells close to the site of release • autocrine - acts on the same cell which secreted it • for the various immune system local hormones, see Chapter 21 (cytokines, lymphokines, etc.)

9. Circulating vs. Local Hormones • Local hormone molecules are usually short lived, and inactivated quickly • Circulating hormone molecules linger in the bloodstream, and exert their effects for minutes or hours • inactivated by enzymes in the target tissues or in the bloodstream or in the liver; some hormones are also eliminated by the kidneys • kidney or liver disease – may cause problems due to increased hormone levels

10. The Chemistry of Hormones • Two main chemical classes of circulating hormones: • Amino acid based: amines - from single amino acids peptides – short sequences of amino acids proteins - long chains of amino acids • Steroids: synthesized from cholesterol • A third category exists, if local hormones are included: eicosanoids: synthesized from a cell membrane fatty acid (arachidonic acid)

11. Mechanisms of Hormone Action • Hormones may alter cell activities and metabolism by: • Changing membrane permeability or membrane potential by opening or closing gated ion channels • Synthesis of proteins, lipids, or carbohydrates or certain regulatory molecules within the cell • Enzyme activation or deactivation • Induction or suppression of secretory activities • Stimulation of mitosis (and meiosis in the stem cells in the gonads)

12. Second Messenger Systems • Most amino acid, peptide and protein hormones: • Are water soluble/lipid insoluble (hydrophilic) • Cannot cross the cell membrane • Need a second messenger to exert their effects

13. Second Messenger Systems • Since amino acid based hormones cannot enter cells, a 2nd messenger must convey the hormone signal to the inside of the cell (the hormone is the 1st messenger) • Molecules that serve as second messengers include: • cyclic AMP activates protein kinases • cyclic GMP inactivates protein kinases • IP3 (inositoltriphosphate) Ca2+ ions released • Ca2+ ions that may bind to calmodulin

14. Cyclic AMP (cAMP) • Hormone A (excitatory) binds membrane receptor, activating Gs • Gs stimulates adenylate cyclase (AC) • AC forms cAMP from ATP • cAMP activates Protein Kinase A • PKA: activates/deactivates other enzymes; stimulates cell secretion; opens ion channels, etc. Hormone B (inhibitory) binds its membrane receptor, activating Gi Gi inhibits adenylate cyclase Antagonistic control

15. Second Messengers (cont.) • Two second messengers may work together (e.g., IP3 & Ca2+) • Twice as much activation • Activate enzymes and trigger other intracellular activities

16. Amplification by Hormones • Hormones are in very low concentrations in body fluids • They bind reversibly to target cell membrane receptors • Second messengers initiate a cascade of events (a “snowball” effect) because they activate enzymes that act on other enzymes • This cascade effect amplifies the effect of small quantities of hormone binding to cells

17. Amplification: the Cascade Effect • For instance, consider a single hormone molecule binding to a specific receptor on a cell surface • It may activate 10 membrane proteins • Each membrane protein may activate 10 adenylate cyclase enzymes to produce 1000 cAMP’s • This produces a total of 100,000 second messengers in the cell which act on various cytoplasmic enzymes • Each enzyme may then activate hundreds/thousands of other protein molecules

18. Steroid Hormone Action • Steroid hormones (derived from cholesterol) are lipid soluble and penetrate the cell membrane • Bind to cytoplasmic receptors inside the cell • Hormone-receptor (h-r) complex enters the nucleus, binds to a DNA receptor protein • This causes transcription of certain genes, and thus produces specific proteins • This direct gene activation is a slower process, but with longer lasting effects

19. Target Cell Specificity • Target cells have specific cell surface or cytoplasmic receptors which bind to a specific hormone • A target cell has 2,000 to 100,000 receptors for each hormone to which they respond • down-regulation: reduction in the number of receptorswhen a hormone is present in excess so target tissues become less sensitive • up-regulation: increase in the number of receptors when hormone is deficient so that target tissues become more sensitive

20. Hormone Interactions at Targets • Permissveness: one hormone allows another hormone to cause an effect • ex: thyroid hormone permits reproductive hormones to cause their effects on reproductive development • Synergism: effect of two hormones acting together is greater than either acting alone • ex: glucagon and epinephrine together cause more increase in blood glucose than either alone • Antagonism: one hormone has an opposite effect to another hormone • ex: glucagon elevates blood glucose, insulin lowers blood glucose

21. Control of Hormone Release • Humoral Control/Autocontrol: levels of substances in the blood regulate the release of the hormone, e.g.: • Ca2+ levels in blood regulate PTH release by the parathyroid gland • Glucose levels in blood regulate insulin and glucagon release by the pancreatic islets • Na+ and K+ levels in the blood regulate aldosterone release by the adrenal cortex

22. Control of Hormone Release • Nervous System Control: neural input stimulates the release of specific hormones, e.g.: • Sympathetic ANS stimulation of the adrenal glands cause them to release epinephrine and norepinephrine • Nerve impulses from the hypothalamus cause oxytocin release from the posterior pituitary during labor or breast feeding • Nerve impulses from hypothalamus cause ADH release from the posterior pituitary when water concentration of blood declines

23. Control of Hormone Release • Hormonal Control: hormones stimulate the release of other hormones • Neurohormones from the hypothalamus stimulate the anterior pituitary to release hormones which, in turn, stimulate the thyroid gland, the adrenal cortex, and the gonads, respectively, to release their hormones

24. What To Know About Every Endocrine Organ For The Exam • Name and location of each endocrine gland • Names and acronyms of hormones secreted by each endocrine gland • Chemical class of the hormone(s) (amine, peptide/protein, or steroid) • Release mechanisms for the hormone(s) • Antagonistic control to reduce the release of the hormone(s) • Target tissues or cells for each hormone • Major responses of the target tissues or cells to each hormone

25. The Pituitary Gland • Two structural components with different embryological origins Anterior Lobe (Adenohypophysis) Posterior Lobe (Neurohypophysis)

26. “The Master Gland” • The pituitary gland has two functional components • Anterior pituitary • Adenohypophysis • Primarily glandular tissue • Synthesizes protein hormones • Posterior pituitary • Neurohypophysis • Primarily neuosecretory cells (their cell bodies in the hypothalamus) • Secretes peptide hormones • Some support/glial cells

27. The Pituitary Gland • Connected to the hypothalamus by the infundibulum • Vascular linkage • hypothalamus to the anterior pituitary • two capillary beds – the hypophyseal portal system • Nervous linkage • hypothalamus to the posterior pituitary • hypothalamic neuron axons

28. Regulation of Pituitary Hormone Release • Anterior pituitary • hypothalamic releasing and inhibiting hormones/factors transported via blood in the hypophyseal portal system • Posterior pituitary • neuroendocrine release from neurosecretory cells • hormones produced in hypothalamus and released from axon end bulbs in the posterior lobe

29. Anterior Lobe / Adenohypophysis • Growth Hormone = human growth hormone (hGH) • Release • stimulated by GHRH from the hypothalamus • negative feedback regulation by low blood levels of GH • inhibited by GHIH (somatostatin) from the hypothalamus • Actions • targets especially liver, muscle, bone, cartilage; also most tissues • stimulates growth, mobilizes fats, elevates blood glucose (insulin antagonist)

30. Anterior Lobe / Adenohypophysis • Growth Hormone • pathologies • hyposecretion – pituitary dwarfism (normal trunk/limb proportions) • hypersecretion • childhood – pituitary gigantism • adulthood - acromegaly

31. Anterior Lobe / Adenohypophysis • Thyroid Stimulating Hormone (TSH) • Release • stimulated by: • TRH from hypothalamus • indirectly by pregnancy and body temperature • inhibited by negative feedback from the thyroid hormones and GHIH (somatostatin) • Actions • targets thyroid gland • stimulates thyroid hormone release (T3 and T4)

32. Anterior Lobe / Adenohypophysis • Thyroid Stimulating Hormone (TSH) • pathologies • hyposecretion – hypothyroidism • hypersecretion -- hyperthyroidism myxedema thyroid cretinsim exophthalmia

33. Anterior Lobe / Adenohypophysis • Adrenocorticotropic Hormone (ACTH) • Release • stimulated by corticotropin releasing hormone (CRH) from hypothalamus • inhibited by negative feedback by glucocorticoids from adrenal gland (and by chronic use of therapeutic anti-inflammatory steroids) • Actions • targets adrenal cortex • stimulates release of glucocorticoids (and to a lesser degree -- gonadocorticoids, and mineralocorticoids)

34. Anterior Lobe / Adenohypophysis • Adrenocorticotropic Hormone (ACTH) • pathologies • hyposecretion – Addison’s Disease • hypersecretion – Cushing’s Disease (pituitary tumor) hyperpigmentation Cushing’s Disease - edema

35. Anterior Lobe / Adenohypophysis • Follicle Stimulating Hormone (FSH) • Release • stimulated by gonadotropin releasing hormone (GnRH) from hypothalamus • inhibited by negative feedback • estrogen and inhibin in females • testosterone and inhibin in males • Actions • targets ovaries and testes • female • stimulates ovarian follicle to mature • stimulates production of estrogen • male - stimulates sperm production

36. Anterior Lobe / Adenohypophysis • Luteinizing Hormone (LH) [Interstitial Cell Stimulating Hormone (ICSH) in males] • Release • stimulated by GnRH • inhibited by negative feedback • estrogen and progesterone in females (except during LH surge) • testosterone in males • Actions • targets ovaries and testes • stimulates • females - ovulation and production of estrogen and especially progesterone • males – production of androgens, e.g., testosterone

37. Anterior Lobe / Adenohypophysis • Prolactin • Release • stimulated by an unidentified Prolactin Releasing Hormone (PRH) from the hypothalamus • enhanced by estrogens, birth control pills and breast feeding • inhibited by: • dopamine = Prolactin Inhibiting Hormone (PIH) • lack of neural stimulation (no suckling) • Actions • targets breast secretory tissue • stimulates milk production for lactation [Note: The seventh anterior pituitary hormone, Melanocyte Stimulating Hormone = MSHis of limited importance in humans.]

38. Posterior Lobe / Neurohypophysis • Oxytocin • Release • positive feedback • uterine stimulation (stretch) and suckling stimulate the hypothalamus to release oxytocin from the posterior pituitary • stimulates uterine contractions (labor) and milk letdown • increases feedback for more oxytocin release • inhibited by lack of these stimuli • Actions • targets smooth muscle of the uterus and the breast • stimulates uterine contractions and milk ejection/letdown

39. Posterior Lobe / Neurohypophysis • Antidiuretic Hormone (ADH) or Vasopressin • Release • stimulated by impulses from hypothalamus in response to: • increased osmolarity (dehydration) • decreased blood volume or blood pressure • stress • inhibited by adequate hydration or ethanol ingestion • Actions • (1) targets kidney (ADH effect) • stimulates kidney tubule cells to reabsorb water • NaCl (salt) will be conserved passively to some degree • (2) targets vascular smooth muscle to constrict • elevates blood pressure (vasopressin effect)

40. Thyroid Gland • Located in the anterior neck inferior to the larynx (“Adam’s apple”) • Two lateral lobes connected by isthmus • The largest pure endocrine gland in the body • Has a rich blood supply

41. Thyroid gland (continued) • Structure • Spherical follicles • lined with cuboidal follicular cells • site of production of thyroid hormones • thyroxine (T4) (tetraiodo- thyronine) • triiodothyronine (T3) • amine hormones • Parafollicular (C cells) • between follicles • produce calcitonin (thyrocalcitonin) • a protein hormone The interior of the follicle contains the thyroid “colloid” which is the inactive storage form of thyroid hormones, called thyroglobulin.

42. Thyroid Gland (continued) • Thyroid Hormones • thyroxine (T4) and triiodothyronine (T3) • amine hormones – unusual in penetrating its target cells to bind with cytoplasmic receptors • formed from an amino acid (AA) – tyrosine • two linked tyrosines with iodine atoms covalently bound • 4 iodine atoms - thyroxine (T4) = tetraiodothyronine • 3 iodine atoms - triiodothyronine (T3)

43. Thyroid Hormones (continued) • Actions • targets all tissues except adult brain, spleen, testes, uterus and thyroid gland • carried in blood attached to a transport protein, only active when freed from the transport protein to diffuse into the tissues • stimulates glucose metabolism • increases basal metabolic rate • increases body heat = thermogenesis • important regulator of growth and development in conjunction with hGH • Regulation • decreased levels of thyroid hormones stimulate TRH and TSH • hypothalamic TRH stimulates the anterior pituitary to release TSH which stimulates the thyroid to release thyroid hormones

44. Thyroid Gland Pathologies • Hypothyroidism* • adults – myxedema • lethargic, low metabolism, puffy eyes, easily chilled, mental impairment • if due to lack of iodine, then a goiter - increased thyroid size • infants – cretinism • short, thick body, mental retardation • improper development * Note: the defect may be in the pituitary gland or in the thyroid gland itself

45. Thyroid Gland Pathologies • Hyperthyroidism: Graves disease among others • body produces autoantibodies which bind and stimulate the TSH receptor inappropriately • stimulates excess thyroid hormone production • causes elevated metabolic rate, sweating, rapid heartbeat, high blood pressure, nervousness, bulging eyes (exophthalmia) * Note: the defect may be in the pituitary gland or in the thyroid gland itself

46. Thyroid Hormones (continued) • (Thyro)Calcitonin • A protein hormone • Release • from parafollicular (C) cells in thyroid tissue (between the follicles) • triggered by elevated blood calcium levels • Actions • targets bones, primarily in childhood • inhibits osteoclast activity (stops bone resorption) • stimulates osteoblasts for calcium uptake and incorporation into hydroxyapatite in the bone matrix • Net effect: decreases blood Ca2+ levels

47. Parathyroid Glands • Typically four small glands on the posterior surface of the thyroid gland • Filled with chief (principal) cells which secrete parathyroid hormone (PTH or parathormone) • Oxyphil cells – larger cells, function unknown • PTH is a protein hormone

48. Parathyroid Hormone (PTH) • Release - negative feedback • stimulated by low blood Ca2+ levels • inhibited by high blood Ca2+ levels • Targets: • Bone: osteoclasts dissolve matrix liberating Ca2+ and PO4- ions • Intestine: absorb Ca2+ and PO4- ions • Kidney: reabsorb Ca2+ and eliminate PO4- ions • activates vitamin D to active vitamin D3 (calcitriol), enhances Ca2+ absorption at the intestine • Net effect: elevates blood Ca2+ levels

49. The Adrenal Glands • Paired glands near the tops of the kidneys • Two separate parts: • adrenal medulla • interior of the gland • derived from nervous tissue – works with the sympathetic division of the ANS • adrenal cortex • exterior region of gland • made up of three layers • zona glomerulosa • zona fasciculata • zona reticularis • glandular epithelial tissue

50. The Adrenal Cortex • Multi-enzyme pathways convert cholesterol into the various steroid hormones • Synthetic enzymes are organized in the layers of the cortex • zona glomerulosa (outer) • produces mineralocorticoids (aldosterone) • controls homeostasis of electrolytes (ions) and water • zona fasciculata (middle) • produce glucocorticoids (cortisol) • involved in glucose metabolism and overall metabolism • zona reticularis (inner) • produce male and female gonadocorticoids in small quantities • insignificant contribution to reproductive functions