Lecture 1 - Endocrinology Endocrine Organs (Fig 6.1) 1. Primary – pineal, hypothalamus, pituitary, thyroid, parathyroid, adrenal, pancreas, ovaries, testes. These organs consist of tissues whose primary function is to produce hormones. 2. Secondary – heart, stomach, liver, kidney, small intestine, skin. These produce hormones as well, but their principle functions are not to be hormone-producing structures. Endocrine Organs And The Hormones They Secrete (Table 6.1) 1. This very long table lists organs, hormones produced by them and their functions. It is a good reference table to refer to throughout the course. Hormones As Chemical Messengers (Fig 5.2 d,e) 1. Hormones are chemical messengers released into the bloodstream and carried throughout the body. They target organs which contain receptors for that hormone. 2. Secretory cell – endocrine cells in an endocrine organ that secrete the hormone. Target cell – contains receptor for the hormone Nontarget cell – does not contain receptors for the hormone 3. Secretory cells can be neural or nonneural. cAMP Second Messenger System (Fig 5.17a) 1. Most hormones are water-soluble proteins or peptides. They cannot penetrate the cell membrane. Instead, they must bind to a receptor on the membrane. 2. They interact through the cAMP second messenger system. (Hormone ( receptor ( G protein ( adenylate cyclase ( cAMP ( protein kinase ( phosphorylation) 3. The phosphorylation can turn a channel on or off, start or stop the transcription of a gene, turn a protein on or off, etc. Phosphatidyl-Inositol Second Messenger System (Fig 5.17b) 1. Look in the old lecture for this description. 2. The endpoint, again, is the phosphorylation of a protein. Tyrosine Kinase Receptor (Fig 5.13) 1. Hormones such as insulin bind to receptors on an enzyme. 2. This activates the enzymatic site on the inner surface. The tyrosine kinase will phosphorylate proteins. 3. In this case, the receptor and the enzyme are attached to each other. Catecholamine Synthesis (Fig 5.3) 1. Dopamine, epinephrine and norepinephrine are synthesized from tyrosine. 2. Dopamine is released by the hypothalamus onto the anterior pituitary. It inhibits the production of prolactin. 3. Epinephrine and norepinephrine are released by the adrenal medulla. 4. All of these are water-soluble, so they bind to receptors and work through G-protein. Thyroid Hormones (Online Slide 1) 1. Thyroxine and triiodothyronine are synthesized from tyrosine. 2. These two hormones are not water-soluble. They are lipid-soluble, so they can easily penetrate the cell membrane into the cytosol. Steroids (Fig 2.6) 1. Most hormones are proteins, peptides or water-soluble derivatives of tyrosine. 2. There is a small group of hormones that are lipid soluble derivatives of cholesterol. They are steroids – testosterone, aldosterone, etc. 3. They are like the thyroid hormones – lipid soluble so they diffuse across the membrane. Steroid Hormones (Online Slide 2) 1. Cholesterol a. It is a C27 steroid meaning it has 27 carbons altogether. The fundamental structure has 17 carbons in four rings, along with other carbons attached as substituents (two methyl groups and a long hydrocarbon chain at the other end. b. This is the precursor to other steroids. 2. Progestins (Progesterone) a. It is a C21 steroid. Most of the tail of the original cholesterol has been hydrolyzed. It ends up with a ketone at both ends. b. It supports uterine growth in the female during the reproductive cycle and during pregnancy. 3. Glucocorticoids (Cortisol) a. It is also a C21 steroid. Cortisol has three hydroxide groups attached to it as well as the two ketones. b. It is a metabolic hormone produced by the adrenal cortex. 4. Mineralocorticoids (Aldosterone) a. It is also a C21 steroid. Aldosterone has an aldehyde on it as well as two ketones and two hydroxide groups. b. It is concerned with regulating Na+ and K+ levels in the blood at the kidney level. 5. Testosterone is a C19 steroid. 6. Estrogens are C18 steroids. They have one less methyl group than testosterone. Hormone Transport In Blood Circulation (Fig 5.7) 1. Hydrophilic messengers can be directly released into the blood through vesicles. 2. Lipid-soluble hormones do not need to be packaged into vesicles. They can just leave the cell into the blood. However, when they enter the blood, they are bound loosely to carrier proteins. There is a small level of dissociation where the steroid will penetrate the membrane of the target cell and bind to a receptor within it. The concentration of hormone available to any target organ depends on how much is produced as well as how many carrier proteins are in the blood. Lipophilic Messengers (Fig 5.11) 1. Steroid messengers diffuse across the cell membrane and bind to receptors either in the cytosol or the nucleus. 2. The hormone-receptor complex moves into the nucleus and affects the rate of transcription of DNA. 3. This then changes the rate of mRNA production as well as protein production. 4. The rate at which this response occurs is slower than the response of target cells due to peptide hormones because protein production has to be affected before a change is seen. Peptide hormones act through the cAMP second messenger system. Hypothalamus and Pituitary Gland (Fig 6.2) 1. The hypothalamus is the master endocrine gland. It is located at the upper end of the brainstem. It is intimately connected to the pituitary gland because the hypothalamus controls the hormones that the pituitary gland produces and releases. 2. The hypothalamus is also strongly connected with the autonomic nervous system. It is concerned with integrating and bridging the endocrine and nervous systems, particularly the control and actions of the visceral organs. Hypothalamic Control Centers (Online Slide 3) 1. Body temperature – cooling vs. warming; central and cutaneous temperature receptors a. For example, there are warmth receptors present in the cooling center of the hypothalamus. So if the blood temperature rises, the warm receptors are activated, which then activate the cooling center to cool the body. 2. Food balance – feeding vs. satiety; GI, glucose and insulin receptors. a. You have receptors in many areas that tell you if you’re hungry or full. So for example, if the level of blood glucose rises, it stimulates glucose receptors in the hypothalamus and will enhance actions in the satiety center and decrease actions in the feeding center. The same thing happens with stretch receptors in the stomach, water level receptors, etc. 3. Water balance – drinking vs. excretion; blood pressure/volume and osmoreceptors a. There are blood pressure and volume receptors in major parts of the circulatory system that will allow the hypothalamus to know what is going on in the body. If blood volume and pressure are high, excretion actions are enhanced. If blood volume and pressure are low, drinking and retention actions are enhanced. Hypothalamic Neurons Innervate Posterior Pituitary Capillaries (Fig 6.3) 1. Posterior pituitary – derived from nervous tissue; does not produce hormones Anterior pituitary – derived from digestive system; produces many hormones 2. The posterior pituitary only contains a glob of capillaries where “posterior pituitary neurons” are released. The peptide hormones here are oxytocin, which causes milk release and anti- diuretic hormone (ADH) which retains water. They are produced in neurosecretory cells in the hypothalamus. Thus, they are neurohormones. They are secreted into the capillaries in the posterior pituitary gland, which sends them out into the remainder of the bloodstream. Control ADH Secretion (Fig 20.11) 1. The osmolarity of the extracellular fluid rises. Osmoreceptors in the hypothalamus are activated, which increases the activity of neurosecretory cells in the hypothalamus. They produce ADH, which acts on the kidneys to increase water absorption by increasing the permeability of the kidneys to water. This causes water excretion to decrease and conserves water in the body. 2. This entire process negatively feeds back to the osmolarity in extracellular fluid, controlling how much ADH is produced and how much water is retained. Control ADH Secretion (Fig 20.12) 1. MAP (mean arterial pressure) and blood volume also control ADH secretion. If MAP and blood volume decrease, ADH production increases. 2. This causes water to be reabsorbed into the body. 3. Ultimately, the hypothalamus regulates how much ADH is produced and released because it contains receptors for water balance. It tells the pituitary to produce or not produce ADH. Control Oxytocin Secretion (Fig 22.27) 1. The sucking of an infant causes tactile receptors in the nipple to be activated. This causes the hypothalamus to increase neurosecretory activity of prolactin-releasing hormone (PRH). It causes the anterior pituitary to release more prolactin. At the same time, the posterior pituitary releases oxytocin, which causes the contraction of myoepithelial cells in the breasts. This causes milk to be released from the breast. 2. This is a good example of the intertwining of neural and hormonal activity. 3. With ADH and oxytocin, their release is controlled by activating sensory systems, which are responded to by the hypothalamus. Hypothalamic-Pituitary Portal System (Fig 6.4) 1. The two glands are connected by a portal system of capillaries. 2. The hypothalamus has neurosecretory hormones, which activate or repress the actions of the anterior pituitary gland, which actually produces the hormones. The hypothalamic neurons control the anterior pituitary hormones, which affects the rest of the body. 3. At the base of the pituitary is a capillary bed, which is connected to a secondary capillary bed by a portal vein (vessel that connects two capillary beds). The hypothalamic releasing or inhibiting hormones are released into the first capillary bed, which are carried through the portal vein to the secondary capillary bed. They diffuse out to the endocrine cells, which produce their hormones and release them into second capillary bed again. Hypothalamic And Anterior Pituitary Hormones (Fig 6.5) 1. PRH/PIH ( Prolactin ( breasts a. Prolactin-releasing hormone or prolactin-inhibiting hormone, also known as dopamine, are both produced by the hypothalamus. They act on the anterior pituitary to either release or inhibit prolactin production. b. Prolactin causes the growth of the breasts. It is one hormone that does not cause an organ to produce another hormone. c. Its levels are regulated by the levels of PRH and PIH (antagonistic hormones). The levels of estrogen, progesterone and other hormones affect the activity of the hypothalamus, which also feeds back to prolactin levels. 2. TRH a. Thyroid-releasing hormone stimulates the anterior pituitary to produce thyroid-stimulating hormone, TSH. TSH stimulates the thyroid to produce thyroid hormones. b. Thyroid hormone (TH) controls the activity of the thyroid gland. It also feeds back on the anterior pituitary and hypothalamus to control its production. There is no inhibitory hormone. 3. CRH a. Corticotropic-releasing hormone causes the anterior pituitary to release adrenocorticotropic hormone (ACTH). It acts on the adrenal cortex, causing it to produce cortisol. b. CRH levels feed back to the hypothalamus and pituitary to control their release. There is no inhibitory hormone. 4. GHRH/GHIH a. Growth hormone-releasing hormone or growth hormone-inhibiting hormone cause the anterior pituitary to release or inhibit growth hormone. This also acts on the liver to produce somatomedins as well as other cells throughout the body. 5. GnRH a. Gonadotropin-releasing hormone acts on the pituitary to release LH and FHS, which act on the gonads to produce androgens, estrogens and progesterone. They feed back to the anterior pituitary gland to regulate the hormones released as well as on the hypothalamus. 6. The whole point is that releasing and inhibiting hormones from the hypothalamus must pass through the anterior pituitary gland in order to control the release of hormones that it produces. Negative Feedback Loops Regulate Hypothalamic And Anterior Pituitary Hormones (Fig 6.6) 1. Negative feedback can occur at both the hypothalamus (to stop the releasing hormone) and the anterior pituitary gland (to stop the produced hormones). This can be caused by the releasing hormone as well as the pituitary’s hormone. Growth Hormone Secretion And Metabolic Effects (Fig 7.10) 1. Sleep, exercise, stress, Circadian rhythms, low plasma glucose levels, low plasma fatty acids and high plasma amino acids act on the hypothalamus. 2. This increases the secretion of GHRH and lowers the secretion of GHIH. 3. The GHRH acts on the anterior pituitary and increases the secretion of GH. 4. GH acts on four different aspects: a. Liver – GH increases the secretion of somatomedins, which act on many other tissues to increase cell division and have other growth-promoting effects. b. Many tissues – GH increases protein synthesis and somatomedin production. c. Adipose tissue – GH increases lipolysis and decreases glucose uptake. d. Muscle – GH increases amino acid uptake and decreases glucose uptake. 5. Actions in the tissues and muscles provide energy and substrates for growth. 6. The increase in GH secretion creates a short negative feedback loop on the hypothalamus. The secretion of somatomedins, protein synthesis, lipolysis, amino acid uptake and decrease in glucose uptake create a long negative feedback loop on the hypothalamus.