THE ENDOCRINE SYSTEM

1. THE ENDOCRINE SYSTEM

2. ENDOCRINE ORGANS

3. AN OVERVIEW • Endocrine glands are ductless glands that produce and release hormones to the surrounding tissue, and they typically have a rich vascular (blood) and lymphatic (lymph) drainage that receives their hormones • Endocrine glands may be strictly endocrine, such as the pituitary, thyroid, parathyroid, adrenal, pineal and thymus; or they may be organs that have hormone production as one of many functions, such as the pancreas (exocrine) , gonads (exocrine), hypothalamus (neural), and others • Adipose cells: leptin • Cells of small intestine, stomach, kidneys, and heart

4. AN OVERVIEW • Hormones: long-distance chemical signals that travel in blood or lymph throughout the body • Local hormones: • Autocrines: • Chemicals that exert their effects on the same cells that secrete them • Example: prostaglandins released by smooth muscle cells cause the smooth muscle cells to contract • Paracrines: • Also act locally but affect cell types other than those releasing the paracrine chemicals • Somatostatin released by one type of pancreatic cells inhibits the release of insulin by a different type of pancreatic cells • Study of hormones and the endocrine organs is called endocrinology

5. HOMEOSTATIC IMBALANCE • Certain tumor cells, such as those of some cancers of the lungs or pancreas, synthesize hormones identical to those made in normal endocrine glands • However, they do so in an excessive and uncontrolled fashion

6. HORMONES • Chemistry of Hormones: • Hormones are chemical messengers released into the blood to be transported throughout the body • Hormones are long-distance chemical signals that are secreted by the cells to the extracellular fluid and regulate the metabolic functions of other cells • Responses to hormones typically occur after a lag period of seconds or even days • Responses tend to be much more prolonged than those induced by the nervous system • Most hormones are amino acid bases, but gonadal and adrenocortical hormones are steroids, derived from cholesterol

7. HORMONES • Hormones: • Amino acid based • Steroids • Eicosanoids: local hormones that are biologically active lipids released by nearly all cell membranes • Leukotrienes: signaling chemicals that mediate inflammation and some allergic reactions • Prostaglandins: have multiple targets and effects, ranging from raising blood pressure and increasing the expulsive uterine contractions of birth to enhancing blood clotting, pain, and inflammation

8. HORMONES • Mechanisms of Hormone Action: • Even though all major hormones circulate to virtually all tissues, a given hormone influences the activity of only certain tissue cells, referred to as its target cells • Hormones bring about their characteristic effects on target cells by altering cell activity; that is, they increase or decrease the rates of normal cellular processes • Precise response depends on the target cell • Hormones typically produce: • Changes in membrane permeability or potential , or both, by opening or closing ion channels • Stimulate synthesis of proteins or regulatory molecules such as enzymes within the cell • Activate or deactivate enzymes • Induce secretory activity • Stimulate mitosis

9. HORMONES • Mechanisms of Hormone Action: • Nearly all amino acid-based hormones exert their effects through an intracellular second messenger(G protein that is activated when a hormone binds to a membrane receptor) • Steroid hormones are lipid soluble and diffuse into the cell, where they bind to intracellular receptors, migrate to the nucleus, and activate specific target sequences of DNA • Involves direct gene activation by the hormone

10. Amino Acid-Based Hormones and Second-messenger Systems • Because proteins and peptides cannot penetrate the plasma membranes of tissue cells, virtually all amino acid-based hormones exert their signaling effects through intracellular second messenger generated when a hormone binds to a receptor on the plasma membrane • Cyclic AMP is the best understood today

11. Cyclic AMP Signaling Mechanism • Three plasma membrane components interact to determine intracellular levels of cyclic AMP (cAMP): • Hormone receptor • Signal transducer (G protein) • Effector enzyme (adenylate cyclase)

12. Cyclic AMP Signaling Mechanism • 1. Hormone, acting as the first messenger, binds to its receptor: • Receptor changes shape and binds with a nearby inactive G protein • 2. G protein is activated • Guanosine diphosphate (GDP) bound to it is displaced by the high-energy compound guanosine triphosphate (GTP) • G protein behaves like a light switch • It is “off” when GDP is bound to it • It is “on” when GTP is bound to it

13. Cyclic AMP Signaling Mechanism • 3. The activated G protein (moving along the membrane) binds to and activates the effector enzyme adenylate cyclase • At this point the GTP bound to the G protein is hydrolyzed to GDP and the G protein becomes inactive once again • 4. The activated adenylate cyclase generates the second-messenger cAMP from ATP

14. Cyclic AMP Signaling Mechanism • 5. cAMP, which is free to diffuse throughout the cell, triggers a cascade of chemical reactions in which one or more enzymes (protein kinases) are activated • The protein kinases phosphorylate (add a phosphate group to) various proteins, many of which are other proteins • Because phosphorylation activates some of these proteins and inhibits others, a variety of reactions may occur in the same target cell at the same time

15. Cyclic AMP Signaling Mechanism • This type of intracellular enzymatic cascade has a huge amplification effect. Each activated adenylate cyclase generates large numbers of cAMP molecules, and a single kinase enzyme can catalyze hundreds of reactions.Hence, as the reaction cascades through one enzyme intermediate after another, the number of product molecules increases dramatically at each step. Theoretically receptor binding of a single hormone molecule could generate millions of final product molecules

16. Cyclic AMP Signaling Mechanism • The sequnce of reactions set into motion by cAMP depends on the: • Type of target cell (e.g thyroid, bone) • The specific protein kinases it contains • The hormone acting as first messenger (e.g. thyroid stimulating hormone, growth hormone)

17. Cyclic AMP Signaling Mechanism • Notice that on the right side of this diagram that some G proteins inhibit rather than activate adenylate cyclase, thus reducing the cytoplasmic concentration of cAMP • Such opposing effects permit even slight changes in levels of antagonistic hormones to influence a target cell’s activity

18. Cyclic AMP Signaling Mechanism • Because cAMP is rapidly degraded by the intracellular enzyme phosphodieterase, its action persists only briefly. This might seem a problem but because of the amplification effect, most hormones need to be present only briefly to cause the desired results. • Continued production of hormones then prompts continued cellular activity • No extracellular controls are necessary to stop the activity (self-limiting)

19. Second-Messenger Mechanisms of Amino Acid-Based Hormones

20. Second-Messenger Mechanisms of Amino Acid-Based Hormones • PIP-Calcium Signal Mechanism • Although cyclic AMP is the activating second messenger in some tissues for at least 10 amino acid-based hormones, some of the same hormones (.g., epinephrine) act through a different second-messenger system in other tissues • One such mechanism, called the PIP-calcium signal mechanism, intracellular calcium ions act as the final mediator

21. PIP-Calcium Signal Mechanism • 1. Hormone docking on the receptor causes it to bind the nearby inactive G protein • 2. The protein is activated as GTP binds, displacing GDP • 3. The activated G protein then binds to and activates membrane-bound phospholipase (the effector enzyme) • The G protein then becomes inactive

22. PIP-Calcium Signal Mechanism • 4. Phospholipase splits a plasma-membrane phospholipid calledPIP2(phosphatidyl inositol biphosphate) into diacylglycerol (DAG) and inositol triphosphate (IP3), and both these molecules act as second messangers • 5. DAG activates specific protein kinases, and IP3 triggers the release of Ca2+ from the endoplasmic reticulum and other intracellular storage sites

23. PIP-Calcium Signal Mechanism • 6. The liberated Ca2+ takes on a second messenger role, either by directly altering the activity of specific enzymes and plasma membrane Ca2+ channels or by binding to the intracellular regulatory protein calmodulin • Once Ca2+ binds to calmodulin, enzymes are activated that amplify the cellular response

24. Second-Messenger Mechanisms of Amino Acid-Based Hormones • Other hormones (not listed in the previous two diagrams) act on their target cells through different mechanisms • Some unknown • Insulin and other growth factors appear to work without second messengers • Insulin receptor is a tyrosine kinase enzyme that is activated by autophosphorylation (addition of phosphate to several of its own tyrosines) when insulin binds

25. STEROID HORMONESandDIRECT GENE ACTIVATION • Being lipid soluble, steroid hormones (and, strangely, thyroid hormone, a small iodinated amine) can diffuse into their target cells • Once inside, they bind to an intracellular receptor that is activated by the coupling • The activated hormone-receptor complex then makes its way to the nuclear chromatin, where the hormone binds to a DNA associated receptor protein specific for it • Exception: thyroid hormone receptors are always bound to DNA even in the absence of thyroid hormone

26. STEROID HORMONESandDIRECT GENE ACTIVATION • The interaction between DNA and hormone-receptor complex “turns on” a gene • Prompts transcription of DNA to produce a messenger RNA (mRNA) • mRNA is then translated on the cytoplasmic ribosomes, producing specific protein molecules (enzymes)

27. Direct Gene Activation Mechanism of Steroid Hormones

28. HORMONES • Target Cell Specificity • Cells must have specific membrane or intracellular receptors to which hormones can bind • Target cell response depends on three factors: • Blood levels of the hormone • Relative numbers of target cell receptors • Affinity (strength) of the receptor for the hormone • Target cells can change their sensitivity to a hormone by changing the number of receptors

29. HORMONES • Target Cell Specificity • Up-regulation: phenomenon in which target cells form more receptors in response to rising blood levels of the specific hormones to which they respond • Down-regulation: phenomenon in which prolonged exposure to high hormone concentrations desensitizes the target cells, so that they respond less vigorously to hormonal stimulation • Involves loss of receptors • Prevents the target cells from overreacting to persistently high hormone levels

30. HORMONES • Hormones influence the number and affinity not only of their own receptors but also of receptors that respond to other hormones • Example: • Progesterone induces a loss of estrogen receptors in the uterus, thus antagonizing estrogen’s actions • However, estrogen causes the same cells to produce more progesterone receptors, enhancing their ability to respond to progesterone

31. HORMONES • Potent chemicals, and they exert profound effects on their target organs at very low concentrations • Circulate in the blood in two forms: • Free: most circulate unencumbered • Bound to a protein carrier • In general, lipid-soluble hormones (steroids and thyroid hormones) travel in the bloodstream attached to plasma proteins • The concentration of a hormone reflects its: • Rate of release • Rate of inactivation and removal from the body • Most are removed from the blood by the kidneys or liver, and their breakdown products are excreted from the body in urine or feces

32. HALF-LIFE • Length of time a hormone remains in the blood • Duration of time a hormone remains in the blood • Usually brief • Fraction of a minute to 30 minutes • Shortest for water-soluble hormones

33. ONSET • Time required for hormone effects to appear varies greatly • Some hormones provoke target organ responses almost immediately, while others, particularly the steroid hormones, require hours to days before their effects are seen • Some hormones are secreted in a relatively inactive form and must be activated in the target cells

34. DURATION • Duration of hormone action varies from seconds to several hours, depending on the hormone • Because of these variations, hormonal blood levels must be precisely and individually controlled to meet the continuously changing needs of the body

35. Interaction of Hormones at Target Cells • Understanding hormonal effects is a bit more complicated than you might expect because multiple hormones may act on the same target cells at the same timeand in many cases the results of such an interaction is not predictable even when you know the effects of the individual hormones

36. Interaction of Hormones at Target CellsTypes of Hormone Interaction • Permissiveness occurs when one hormone cannot exert its full effect without another hormone being present • Example: Thyroid hormone is necessary for normal timely development of reproductive structure by reproductive hormones. Without thyroid hormone, reproductive system development is delayed • Synergism occurs when more than one hormone produces the same effects in a target cell, and their combined effects are amplified • Example: Glucagon (pancreas) and epinephrine (adrenal medulla) cause the liver to release glucose to the blood. When they act together, the amount of glucose released is about 150% of what is released when each hormone acts alone. • Antagonism occurs when one hormone opposes the action of another hormone • Example: Insulin, which lowers blood sugar levels, is antagonized by the action of glucagon, which acts to raise blood sugar levels • May compete for the same receptors • May act through different metabolic pathways • May cause down-regulation of the receptors for the antagonistic hormone

37. HORMONES • Control of Hormone Release • Most hormone synthesis and release is regulated through negative feedback mechanisms • Endocrine gland stimuli may be: • Humoral • Neural • Hormonal

38. Three Different Mechanisms of Endocrine Gland Stimuli

39. HUMORAL STIMULI • Term humoral refers back to the ancient use of the term humor (viscous body fluids: blood, bile, etc.) • Simplest of the endocrine control systems • Endocrine glands that secrete their hormones in direct response to changing blood levels of certain ions and nutrients • These stimuli are called humoral stimuli to distinguish them from hormonal stimuli, which are also blood-borne chemicals • Examples: • Parathyroid: Ca2+ • Pancreas: glucose • Adrenal cortex: K, Cl-,HCO3-

40. NEURAL STIMULI • In a few cases, nerve fibers stimulate hormone release • Example: • Sympathetic nervous system stimulation of the adrenal medulla to release catecholamines (norepinephrine and epinephrine) during periods of stress

41. HORMONAL STIMULI • Many endocrine glands release their hormones in response to hormones produced by other endocrine organs, and the stimuli in these cases are called hormonal stimuli • Example: • Release of most anterior pituitary hormones is regulated by the releasing and inhibiting hormones produced by the hypothalamus • Many anterior pituitary hormones stimulate other endrocine glands to release their hormones • The hypothalamus-pituitary-target endocrine organ feedback loop lies at the very core of endocrinology

42. NEURAL SYSTEM MODULATION • Both “turn on” factors (humoral, neural, and hormonal stimuli) and “turn off” factors (feedback inhibition and others) may be modified by the nervous system • Endocrine system is NOT strictly like a thermostat • The endocrine system can make fine adjustments • Example: if someone in the house is cold, the thermostat will not adjust itself • The nervous system can, in certain cases, override normal endocrine controls as needed to maintain homeostasis • Allows hormone secretion to be modified by the nervous stimulation in response to changing body needs • Example: • The action of insulin and several other hormones normally keeps blood sugar levels in the range of 90-110 mg glucose per 100 ml of blood • Under stress, blood sugar levels rise because the hypothalamus and sympathetic nervous system centers are strongly activated ensuring that the body has sufficient fuel for vigorous activity

43. ENDOCRINE ORGANS

44. PITUITARY GLAND(HYPOPHYSIS) • Size an shape of a pea (pea on a stalk) • The stalk, funnel-shaped infundibulum, connects the gland to the hypothalamus superiorly

45. PITUITARY GLAND(HYPOPHYSIS) • Two major lobes (well-defined part of an organ separated by boundaries): • One is glandular tissue (anterior pituitary) • One is neural tissue (posterior pituitary)

46. Pituitary-Hypothalamic Relationship • The contrasting histology of the two pituitary lobes reflects the dual origin of this organ • Posterior Lobe (neurohypophysis) actually is derive from a downgrowth of the hypothalamus and maintains its neural connection to the brain • Neurosecretory cells in the hypothalamus synthesize two neurohormones and transport them along their axons to the posterior pituitary storing them in capillary beds for distribution throughout the body • Anterior Lobe (glandular)(adenohypophysis) originates from a superior outpocketing of the oral mucosa and is formed from epithelial tissue • Releasing and inhibiting hormones (amino acid based) secreted by neurons in the ventral hypothalamus circulate to the adenohypophysis, where they regulate secretion of its hormones • No direct neural connection between the two, but there is vascular connection

47. ANTERIOR PITUITARY • The Pituitary Gland (Hypophysis) • The pituitary gland is connected to the hypothalamus via a stalk, the infundibulum, and consists of two lobes: the anterior pituitary, or adenohypophysis, and the posterior pituitary, or neurohypophysis • Anterior Pituitary: There are six adenohypophyseal hormones (all protein) and one prohormone • Growth hormone (GH) stimulates body cells to increase in size and divide • Thyroid stimulating hormone (TSH) is a tropic hormone that stimulates normal development and secretion of the thyroid gland • Adrenocorticotropic hormone (ACTH) stimulates the adrenal cortex to release corticosteroid hormones • Follicle-stimulating hormone (FSH) stimulates gamete production • Leutinizing hormone (LH) promotes ovulation in females and production of gonadal hormones • Prolactin stimulates milk production in females, and may enhance testosterone in males • Pro-opiomelanocortin (POMC) is a prohormone that is the source of adrenocorticotropic hormone and two opiates (pain killing neurotransmitters)(enkephalin and beta endorphin which reduce our perception of pain under certain stressful conditions) • Enkephalin activity increases dramatically in pregnant women in labor • Endorphin release is enhanced when an athlete gets a so-called second wind and is probably responsible for the “runner’s high”

48. ADENOHYPOPHYSEAL HORMONES • When the adenohypophysis (anterior pituitary) receives an appropriate chemical stimulus from the hypothalamus, one or more of its hormone are released by certain cells. • Although many different hormones pass from the hypothalamus to the anterior lobe, each target cell in the anterior lobe distinguishes the message directed to it and responds in kind—secreting the proper hormone in response to specific releasing hormones, and shutting off hormone release in response to specific inhibiting hormones • The hypothalamic releasing hormones are far more important as regulatory factors because only very little hormone is stored by secretory cells of the anterior lobe • 4 of the 6 are tropins (tropic hormones) which regulate the secretory action of other endocrine glands: • Thyroid-stimulating hormone • Follicle-stimulating hormone • Adrenocorticotropic hormone • Luteinizing hormone • All 6 hormones affect their target cells via a cyclic AMP second-messenger system

49. GROWTH HORMONES(GH) • Produced by the somatotropic cells of the anterior lobe • Stimulates most body cells to increase in size and divide • Major targets are the bones and skeletal muscles • Essentially an anabolic (tissue building) hormone • Promotes protein synthesis • Encourages the use of fats for fuel, thus conserving glucose • Most growth-promoting effects of GH are mediated indirectly by insulin-like growth factors (IGFs)(somatomedins) • Family of growth-promoting proteins produced by the liver, skeletal muscle, bone, and other tissues • Stimulate uptake of amino acids from the blood and their incorporation into cellular proteins throughout the body • Stimulate uptake of sulfur into cartilage matrix

50. GROWTH HORMONES(GH) • Mobilizes fats from fat depots for transport to cells, increasing blood levels of fatty acids • Decreases the rate of glucose uptake and metabolism: • Because these actions antagonize those of the pancreatic hormone insulin, they are referred to as anti-insulin actions • In the liver, it encourages glycogen breakdown and release of glucose to the blood • The elevation in blood sugar levels that occurs as a result of this glucose sparing is called the diabetogenic effect of GH, because it mimics the high blood sugar levels typical of diabetes mellitus