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Endocrinology Randal C. Jaffe Department of Physiology 268 CME 996-4933 RCJaffe@uic.edu http://www.uic.edu/~rcjaffe/teaching/coursema.html

HORMONES Endocrine - substance produced by one cell or group of cells which passes into the blood stream in small amounts and which promotes a response in a second set of cells Paracrine - substance produced by one set of cells of a tissue and have effects on different cells of the same tissue Autocrine - substance produced by the same cells they have effects on

Endocrine Glands Ductless Rich vascular supply

General Aspects of Hormones and the Processes they Control Many hormones often act on the same physiological process Positive Negative Feedback control between hormone and process regulated

Hormone Functions Homeostasis Growth Development Maturation Reproduction Senescence

All tissues except those with barriers (e.g. brain and placenta) bathed by blood which contains hormone Allows various parts of the body to adjust to changing conditions (i.e. maintain homeostasis) Allows body to function synchronously

Response time Rapid like the nervous system Delayed Generally slower than nervous system - latent period Passage into the blood stream Effects synthetic processes

Hormone vs. neurotransmitter No sharp distinction Some function as either Hormones can be release in response to nerve stimulation

Radioimmunoassay Specificity of antibodies Recognize a single hormone Sensitivity Low variability

Receptors Specific proteins which bind a specific hormone Impart responsiveness on tissue Receptor is required for response Deficiency due to absence of hormone or receptor

Protein hormones Receptors at the cell membrane Second messengers cAMP Ca+2 Inositol triphosphate Tyrosine kinase Other

cAMP Activation of adenylyl cyclase Production of cAMP from ATP Activation of protein kinase A

Ca+2 Calmodulin and other calcium binding proteins

Inositol triphosphate Phospholipase C catalyzes the conversion of phosphatidylinositol 4,5-diphosphate to inositol 1,4,5-triphosphate and diacylglycerol IP3 triggers release of Ca+2 from the endoplasmic reticulum Diacylglycerol activates protein kinase C

Receptor Kinases Binding of the hormone causes receptor autophosphorylation Receptor now has tyrosine kinase activity

Steroids, Thyroid Hormones, 1,25 diOHVitD3, Retinoic Acid Nuclear

PITUITARY

3 Parts Adenohypophysis or anterior pituitary Neurohypophysis or posterior pituitary Pars intermedia or intermediate lobe

Anterior pituitary produces 6 hormones Growth hormone - somatotropin, GH Prolactin - PRL Adrenocorticotropic hormone - ACTH Follicle-stimulating hormone - FSH Luteinizing hormone - LH Thyroid-stimulating hormone - TSH

Release (in part at least) controlled by releasing hormones or release inhibiting hormones Produced in hypothalamus Pass through median eminence in portal vessels to anterior pituitary

GROWTH HORMONE Protein - MW 21,500 Great deal of species variability

Named GH because it promoted growth in animals whose pituitaries were removed (hypophysectomy) Increases activity of chondrocytes - cartilage forming cells As cartilaginous epiphyseal plates widen they lay down more matrix at the ends of the long bones Actually indirect effect of GH Stimulates IGF-I release from liver among other tissues

Release Controlled by 2 Hypothalamic factors GHRH promotes Somatostatin inhibits Also produced in pancreas and inhibits release of insulin and glucagon

Growth

Factors Genetic Extrinsic factors Hormonal factors

Genetic

Extrinsic factors nutrition protein vitamins minerals calories

Hormonal factors  GH via IGF-I Fails to promote growth in absence of insulin, thyroid hormones, and in starvation Thyroid hormones Androgens

Hormonal factors (cont.) Estrogens Small doses increase High doses decrease Glucocorticoids decrease Insulin

Three phases of growth - only prepubertal growth primarily due to GH In utero Birth to onset of puberty Puberty

In utero Classic endocrine glands of the fetus not involved IGF-I and IGF-II of fetal origin involved May be from placenta

Birth to onset of puberty GH and thyroid hormones critical

Puberty Rapid growth then stops Primary hormone involved testosterone In females adrenal androgens may be important Cessation of growth seems to be estrogen mediated

GH Plasma Levels Plasma levels high during first days of life and decline by about 2 weeks of age Levels not much different in pubertal child and adult (4 ng/ml) IGF-I peaks at 13-17 years of age Linear growth stops because of closure of the epiphyses of the long bones

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Daily variations Peak shortly after the onset of sleep (ca. 40 ng/ml) Decreased in REM sleep Elevated with exercise Eating due to amino acids Raised with fasting

Physiological effects of GH Proteins Fatty acids Carbohydrates

Proteins Increases amino acid transport into cells Increases mRNA synthesis Increases protein synthesis Results in positive nitrogen balance (more nitrogen taken in than excreted)

Fatty acids Increases release from adipose tissues Increases blood lipid levels Increases their usage as a source of energy Prolonged GH excess can lead to ketosis

Carbohydrates Decreases utilization - antiinsulin effect Inhibits glucose uptake into muscle Increases tissue glycogen stores Increases blood carbohydrate levels

Prolonged GH excess Can lead to "pituitary diabetes" Glucose utilization only moderately affected Insulin does not correct elevated blood glucose levels Prolonged elevation of blood glucose can lead to burn out of insulin producing cells of the pancreas and true diabetes

Physiological effects of IGF-I Produced in many tissues but liver portion regulated by GH Has direct effect on linear growth Has insulin like properties

Disease states

Excess Growing person gigantism After linear growth stops acromegaly Excess growth of soft tissues

Deficiency Dwarfism - shortened stature Laron dwarfism - deficiency in IGF-I

INTERMEDIATE LOBE

Melanocyte stimulating hormone (MSH) Causes dispersion of melanosomes in skin resulting in skin darkening Role in human skin color not clear First 13 aa of ACTH out of 39 same as aMSH Excess ACTH (Addisons and Cushings syndromes) can lead to skin darkening

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POSTERIOR LOBE Antidiuretic hormone (vasopressin, ADH) Oxytocin

Synthesized in hypothalamus ADH mainly in the supraoptic nuclei Oxytocin mainly in the paraventricular nuclei Transported to posterior pituitary via axons of the neurohypophyseal tract Release regulated by nervous impulses traveling down fibers of the neurohypophyseal tract

ADH Kidney - Increases permeability of collecting ducts resulting in increased water reabsorption. Lack of ADH - diabetes insipidus - excretion of large volumes of urine

Control of release Osmolarity of plasma As osmolarity increases increased ADH release Threshold about 280 mOsm and normal is 290 Increased ADH promotes greater water retention lowering the osmolarity

Control of release (cont.) Hemorrhage or circulatory shock Massive amounts of ADH cause contraction of the smooth muscles of the blood vessels Raises blood pressure Pressor effect of ADH

Control of release (cont.) Increased release with surgical stress, morphine, nicotine, barbiturates Decreased release with alcohol and opiate antagonists

Oxytocin

Effects Causes contraction of smooth muscles of uterus May be involved in normal parturition Milk letdown effect

Milk letdown effect Causes contraction of myoepithelial cells of breast  Contracts alveoli  Milk ejected into ducts  Events initiated by suckling breast