11-12: Endocrine System Hormones and Homostasis

11-12: Endocrine SystemHormones and Homostasis Canisius College Bio 112 Jason Mayberry

Hormones outside the Hypothalamic-Pituitary Axis The Pituitary has little or no control over Humoral responses of the Parathyroid, Parafolicular cells the Pancreas, and the Adrenal Medulla Hypothalamus in the Brain Pituitary Gland in the Brain Parafollicular Cells GH, TSH, Prolactin, ACTH, FSH, LH, Oxyt, ADH Parathyroids Adrenal medulla IGF T3, T4 Adrenal Cortex Steroids Sex Steroids Pancreas

Endocrine-Nervous Integration Molecules Hormonal Visceral Sensory Neurons Emotion Na+Cl– Thyroid Mammary Glands Adrenal Cortex Gonads Liver, Muscles, and Bones • Input into the Hypothalamus • Neural Input • Visceral Sensory • Emotional Input (Limbic System) • Blood Born Signals • Hormonal Input (molecules secreted into the blood stream by other organs) • Molecules in the blood not produced by the body; glucose, ions, etc) • Fast Responses • Signals through axons to nerve cells in the Brain stem • Stimulates Autonomic Nervous System • Slower but Long-lasting responses • Produces two hormones which work independently: Oxytocin and Antdiuretic Hormone • Sends trophic hormones to the Pituitary telling it to release other hormones of its own • The Parathyroid, Parafolicular cells, and the Pancreas act independent of the Hypothalams. Hypothalamus Pituitary Endocrine Responses mediated through Pituitary Autonomic Responses mediated through Brain Stem Sym-pathetic“Fight or Flight” Para-Sympathetic“Rest and Digest”

Long-Distance Signaling • Endocrine signaling (Glands): • A ductless gland releases hormones into the bloodstream. The blood stream caries the hormone throughout the body. Bloodvessel Response Synapse • Synaptic signaling (Neurons): • A neuron releases neurotransmitters on a cell with receptors for the transmitter (paracrine) Neuron Response • Neuroendocrine signaling: • A neuron releases neurohormones into the blood stream. • The blood stream caries the neurohormone to its target. Neurosecretorycell Bloodvessel Response

Hypothalamic-Pituitary Axis Infundibulum HYPOTHALAMUS • Hypothalamus: Comprised of discrete Neural and Neuroendocrine cell clusters called nuclei. • Infundibulum: Connects Hypothalamus to Pituitary • Posterior Pituitary (Neurohypophysis) • Axons from Supraoptic and Paraventricular Nucleus of the Hypothalamus end here • Hypothalamic neurohormones released directly into the general systemic circulation • Does not produce any of its own hormones • Neurohypophysis technically includes the Infundibulum • Anterior Pituitary (Adenohypophysis) • Functionally connected to Infundibulum through Hypophyseal Portal System (Capillary – vein – capillary) • Nerve endings from other Hypothalamic Neuroendocrine nuclei end in Infundibulum and release neurhormones into portal system • Different cell types in Anterior Pituitary have receptors for specific Hypothalamic hormones • Produce and release different hormones into the systemic circulation in response to Hypothalamic neuro hormones • Because the only effect of Hypothalamic hormones released into the Portal System is to caused or inhibit Anterior Pituitary hormone release, they are called “Releasing Hormones” or “Inhibiting Hormones” PITUITARY HYPOTHALAMUS Paraventricular Other Supraoptic Portal Vein ANTERIOR PITUITARY POSTERIOR PITUITARY General Circulation

Hypothalamic – Pituitary Axis Hypothalamus Pituitary Hypothalamus Hypothalamic nuclei Infundibular stalk Arterial blood supply Capillaries Portal veins Anterior pituitary gland Posterior pituitary gland To venous circulation

Summary of Hypothalamus Controlled Hormones HYPOTHALAMUS (Neurohormones) General Hormones (Non-Trophic) Releasing Hormones (Trophic) Growth HRH ThyrotropinRH Cortico-tropin RH Gonado-tropic RH ProlactinRH Anti-diuretic Oxy-tocin Hypothalamic-Pituitary Portal Vein ANTERIOR PITUITARY (Glandular Hormones) POSTERIOR PITUITARY GH TSH ACTH FSH & LH PRL Adrenal Cortex Cortisone (and other Steroids) Liver IGF Thyroid T3 T4 Gonads Release Energy Stores Breakdown of Fat and Muscle; Glycogen Storage Sex Steroids and Gamete Production Breasts: Milk Production in Breast Kidneys: Increase Water Reabsorption Uterine Contraction Milk let-down T3 Increase Metabolic Rate; Growth Growth

Summary of Hypothalamus Controlled Hormones HYPOTHALAMUS (Neurohormones) General Hormones (Non-Trophic) Releasing Hormones (Trophic) Growth HRH ThyrotropinRH Gonado-tropic RH Cortico-tropin RH ProlactinRH Anti-diuretic Oxy-tocin Hypothalamic-Pituitary Portal Vein ANTERIOR PITUITARY (Glandular Hormones) POSTERIOR PITUITARY GH TSH FSH & LH ACTH PRL Adrenal Cortex Cortisone (and other Steroids) Liver IGF Thyroid T3 T4 Gonads Release Energy Stores Sex Steroids and Gamete Production Breakdown of Fat and Muscle; Glycogen Storage Breasts: Milk Production in Breast Kidneys: Increase Water Reabsorption Uterine Contraction Milk let-down T3 Increase Metabolic Rate; Growth Growth

Thyroid Stimulating Hormone (TSH) α-subunit (92 a.a.) same for TSH, FSH, and LH β-subunit (unique for TSH, FSH and LH) GH=110 a.a. OH OH I I I I I I I O O CH2 CH2 H2N H2N COOH COOH Thyroxine (T4) Triiodothyronine (T3) • Composed of two protein subunits linked covalently • Alpha subunit is the same for FSH and LH • Beta subunit is unique for each • Binds to receptors on thyroid “Follicle Cells (see next slide) • Stimulates release of thyroid hormones • Stimulates production of more thyroid hormones TSH produced in the anterior pituitary Thyroid Gland

Thyroid Gland • Follicles • “Colloid” filled cavities within the thyroid gland • Storage of Iodine • Middle link in production of Thyroid Hormones (T3 and T4) • Follicle Cells • Contain Transmembrane receptors for TSH • Surround Follicles • First and last steps of thyroid hormone production • Parafollicular Cells • Sensitive to blood Ca2+ levels • Produce calcitonin as an antagonist to parathyroid hormone (discussed later in connection with Parathyroid) Follicles Follicle Cells Parafollicular Cells

A.C. α γ β ATP I I Production of Thyroid Hormones Blood Vessel Thyroglobulin is produced in Follicle Cells (140 tyrosine residues) and exocytosed into the Follicle I- TF I- Iodination of Tyrosine produces Mono- and Di-Iodotyrosines (MIT and DIT) I- I- I- Iodide trapping: Iodide (I-) is actively pumped into Follicle Cells Oxidation of iodide forms Iodine, which is then passes to the Follicle by facilitated diffusion Coupling of Iodotyrosines produces T3 and T4 precursors which are Endocytosed back into Follicle Cell. I- I- Hydrolysis by Lysosomes frees T4 and T3 (12:1 ratio) which then diffuses into the blood. I-

Steroid and Thyroid Hormone Receptors ADP ATP • Steroids and Thyroid Hormones are Trophic hormones (but not the only ones) • Entering the Cell • Steroid Hormones are Lipophilic and pass freely through the plasma membrane • Thyroid Hormones are actively brought across the cell by transport proteins at the expense of ATP. • Once in the cell both classes of hormones bind to and activate transcription factors resulting in Gene Transcription Steroid or Thyroid Hormone mRNA Gene

Action of Thyroid Hormones OH OH I I I I I I I O O CH2 CH2 H2N H2N COOH COOH Conversion in target tissues • Conversion to Active Form • Only T3 is biologically active (elicits a response from target cells) • T4 is converted to T3 inside target cells Active T3 Inactive T4 • Increases Metabolic Rate • Increase protein production and degradation (particularly Mitochondrial Proteins (i.e. greater turnover of proteins) • Uncoupling Protein (UCP) short-circuits ATP production, increasing heat output (brown fat in infants) • Increased the amount of free glucose in the blood • Fat breakdown • Growth • Stimulates production of GH and IGF • Independent synergistic effect on growth with GH and IGF • Critical in development of the brain and reproductive systems GH and IGF Tissue Growth UCP

Regulation of Thyroid Hormone TRH T3 inhibits TRH production TSH T3 and T4 inhibits TSH release Negative Feedback: when the effect of a stimulus (e.g. TSH) results in the inhibition of that stimulus. T3 and T4

Disorders relating to Thyroid Hormones Boy with Goiter Baby with Cretinism Antibody Exopthalmos • HYPOTHYROIDISM • Decrease in T3 and T4 levels; Slower metabolic rate, always cold, Slows mentation • Myxedema: Hypothyroidism in adults • Damage to Hypothalamus, Pituitary, or Thyroid • Iodine Deficiency • Thyroid is unable to make T3 and T4 • Low levels of T3 and T4 lead to high TSH levels because there is no negative feedback • Increased stimulation of the thyroid causes a Goiter (enlarged Thyroid) • Hashimoto's disease: autoimmune attack of Thyroid • Cretinism: results from Hypothyroidism prenatally or as an infant • Usually genetic or diet induced • Short, disproportionate of stature with thick tongue and neck (usually physically handicapped) • Causes permanent mental retardation • HYPERTHYROIDISM • Increased T3 and T4 levels; Increased metabolic rate, always hot, Exopthalamus • TRH, TSH, or T3/4 secreting tumors • Grave’s Disease • Autoimmune disease where antibodies bind TSH receptors stimulating Thyroid activity • Not subject to negative feedback • Continued stimulation causes Goiter (less severe than due to iodine deficiency) • Exopthalmos results from edema and scarring of tissue behind eyes. TRH TSH T3 and T4

Normal iodine intake Reduced iodine intake TRH Excess TRH Normal negative feedback Reduced negative feedback - TSH Excess TSH Enlarged thyroid Normal thyroid Low T4 and T3 due to lack of iodine Normal levels of T4 and T3 5.1 cm 5.1 cm In iodine deficiency, T4 and T3 levels decrease, allowing TSH to increase and overstimulate the thyroid. Normally,T4 and T3 Prevent overstimulation of the thyroid gland by TSH.

Adrenal Gland Adrenal Cortex Adrenal Steroids (e.g. Aldosterone and Cortisol) Adrenal Medulla Epinephrine Kidney

Adrenocorticotropic Hormone and Stress Responses Hypothalamus Short Term Stress Responses Prolonged Stress Responses Stress Nerve Impulses Through the Spinal Chord ACTH from the Anterior Pituitary Blood Stream Adrenal Cortex releases steroids Adrenal Medulla releases Epinephrine Effects of epinephrine and norepinephrine: Effects of mineralocorticoids: Effects of glucocorticoids: • Glycogen broken down to glucose;increased blood glucose • e.g. Cortisol • e.g. Aldosterone • Increased blood pressure • Proteins and fats broken down and converted to glucose, leading to increased blood glucose • Retention of sodium ions and water by kidneys • Increased breathing rate • Increased metabolic rate • Increased blood volume and blood pressure • Change in blood flow patterns, leading toincreased alertness and decreased digestive,excretory, and reproductive system activity • Partial suppression of immune system

Tropic effects only:FSHLHTSHACTH Neurosecretorycells of thehypothalamus Nontropic effects only:ProlactinMSH Nontropic and tropic effects:GH Hypothalamicreleasing andinhibitinghormones Portal vessels Endocrine cellsof the anteriorpituitary Pituitaryhormones Prolactin FSH and LH MSH ACTH GH HORMONE TSH TARGET Melanocytes Mammaryglands Liver, bones,other tissues Thyroid Adrenalcortex Testes orovaries

Hypothalamus and Neurohypophysis: Oxytocin • 9 amino acid hormone produced primarily in the Paraventricular nucleus (PV) • Breasts • Stimulation of the nipples triggers oxytocin release • Oxytocin causes smooth muscle cells surrounding the mammary glands to contract, forcing milk out the nipples • Hearing a baby cry can also trigger Oxytocin release and milk let down • Uterus • Causes Uterine smooth muscle contractions • Receptors for Oxytocin increase near the end of pregnancy • Afferent signals from stretching uterus and cervix to PV nucleus creates positive feedback loop • Pitocin is an oxytocin analogue which is often given to hasten delivery Paraventricular Nucleus Paraventricular Nucleus Positive Feedback: When the effect of a stimulus increase the stimulus Supraoptic Nucleus Supraoptic Nucleus Positive Feedback: Oxytocin causes uterine muscles to contract, increasing stretching on the cervix. Stimulation of receptors in the nipples sends afferent signals to the PVN Positive Feedback: Oxytocin causes smooth muscles in mammary gland to contract causing Milk Letdown and reinforcing the baby’s suckling. Stretching of Cervix causes signals to be sent to the PVN Positive feedback on Oxytocin release while suckling Positive feedback on Oxytocin release during parturition • Also thought to be involved in sexual arousal, orgasm, and sexual satisfaction in both males and females as well as promoting nurturing and affectionate behavior in non-sexual relationships (“cuddle hormone”). No known disorders.

Hypothalamus and Neurohypophysis: ADH Antidiuretic Hormone (Vasopressin) Paraventricular Nueclei • 9 amino Acids (only 2 different from Oxytocin) • Produced primarily in the SupraopticNucleus • Diuresis = urination so… • ADH causes the kidneys to reabsorb more water from the urine-concentrating tubules, thus increasing the blood volume. • At high levels it also causes vasoconstriction (increasing blood pressure), hence the name vasopressin. • Regulation of ADH • Blood brain barrier not present in Supraoptic Nucleus • Osmoreceptors (sensitive to blood osmolarity) in Hypothalamus detect Na+ concentration in blood • When Na+ concentration gets too high (indicating a low water concentration in the blood) Action Potentials increase the level of ADH release • When Na+ is low (indicating a high water concentration) ADH is still released but at much lower levels Supraoptic Nueclei

Hypothalamus Neurosecretorycells of thehypothalamus Figure 45.15 Neurohormone Axons Posteriorpituitary HORMONE ADH Oxytocin Mammary glands,uterine muscles Kidneytubules TARGET

Hormones outside the Hypothalamic-Pituitary Axis The Pituitary has little or no control over Humoral responses of the Parathyroid, Parafolicular cells the Pancreas, and the Adrenal Medulla Hypothalamus in the Brain Pituitary Gland in the Brain Parafollicular Cells GH, TSH, Prolactin, ACTH, FSH, LH, Oxyt, ADH Parathyroids Adrenal medulla IGF T3, T4 Adrenal Cortex Steroids Sex Steroids Pancreas

Functional Anatomy of the Pancreas Pancreatic Ducts Guide Pancreatic Juice to the Small Intestines Acinar Cells Produce Enzymes in a Basic solution to aid in digestion Islets of Langerhans Produce Hormones which are secreted into the extracellular space and picked up by the blood Stomach • α (alpha) cells: Secrete Glucagon • β (beta) cells: Secrete Insulinand Amylin • δ (delta) cells: Secrete Somatostatin (GHIH) • F cells: Secrete Pancreatic Polypeptide

Antagonistic Activity of Insulin and Glucagon • Antagonistic Hormones • Hormones that bring about opposite effects on the same variable. • The presence of one is NOT negative feedback on the other. • Each is regulated independently Liver, Skeletal Muscle take up Glucose ATP rises in β-cells Insulin Released Blood Glucose levels drop Food Intake Blood Glucose Concentration Fasting ADP rises in α-cells Glucagon Released Liver, releases Glucose Blood Glucose levels Rise

Antagonism of Insulin and Glucagon Insulin Body cells (Liver, Skeletal Muscle, and Adipose)take up moreglucose. Beta cells ofpancreasrelease insulininto the blood. Liver takesup glucose and stores itas glycogen. STIMULUS:Blood glucose level rises (for instance, after eating acarbohydrate-rich meal). Blood glucoselevel declines. Start with one of the stimuli Homeostasis:Blood glucose level(70–110 mg/m100mL) STIMULUS:Blood glucose level falls (for instance, afterskipping a meal). Blood glucoselevel rises. Liver breaksdown glycogenand releasesglucose intothe blood. Alpha cells of pancreasrelease glucagon intothe blood. Glucagon

Adrenal Medulla OH HO OH CH2 HO OH H2N CH2 H2N COOH CH2 H2N COOH OH HO OH HO OH H2N OH H2N • Catecholamine • Derived from the amino acid Tyrosine • A second ”OH” added to the phenyl group • Dopamine from the Hypothalamus • Norepinephrine and Epinephrine form the Adrenal medulla (and as neurotransmitters) • Hydrophilic so can travel free in the blood stream. Phenylethanolamine N-methyl transferase Tyrosine Hydroxylase DopaDecarboxylase Dopamine β-hydroxylase 1 2 3 4 Effects of epinephrine and norepinephrine: Norepinephrine Hypothalamus • Glycogen broken down to glucose;increased blood glucose Tyrosine • Increased blood pressure Epinephrine DOPA Dopamine • Increased breathing rate Adrenal Gland • Increased metabolic rate Cortex • Change in blood flow patterns, leading toincreased alertness and decreased digestive,excretory, and reproductive system activity Medullas Epinephrine (i.e. Adrenaline)

Epinephrine Skeletal muscle cell or Liver cell Activated adenylyl cyclase Activated GPCR GTP Activated G-protein  subunit ATP cAMP PKA (inactive) PKA (active) Phosphorylase kinase (inactive) Phosphorylase kinase (active) Glycogen synthase (active) Glycogen Synthase (inactive) P P ATP ATP ATP Glycogen phosphorylase (inactive) Glycogen phosphorylase (active) P Glycogen breakdown is stimulated. Glycogen synthesis is inhibited.

Summary of Hormonal Control of Blood Glucose Levels Hormones that DECREASE Glucose Levels Hormones that INCREASE Glucose Levels Insulin Glucagon Epinephrine Thyroid Hormones (T3) Growth Hormone Glucocorticoids (Cortisol)

Calcium Regulation Vitamin D Stimulates Calcium Absorption Calcium Stored in bones Calcium Reabsorbed or Lost in Urine Activates Production of Vitamin D • Parathyroid Glands on back of Thyroid • Secrete Parathyroid Hormone (PTH) in response to low blood Ca2+ (Ca2+ inhibits release) • Elevates Blood Calcium • Responsible for bone Resoprtion in individuals with anorexia. • Parafollicular Cells of Thyroid • Secrete Calcitonin in response to high Ca2+ • Lowers Blood Calcium • Only significant before adults, while the bone are still growing Promotes Osteoclast Activity (bone breakdown) Inhibits Osteoclast Activity Stimulates Ca2+ Reabsorption Calcium Reabsorbed or Lost in Urine

Blood Calcium Regulation • In adult humans, Blood calcium is regulated primarily through Increasing or Decreasing PTH. • Calcitonin is important in other species as an antagonistic hormone to PTH • In Humans, Calcitonin is primarily important in promoting Ca2+ deposition during periods of bone growth. Less PTH is secreted. Parathyroid glands are inhibited by Ca2+. Less Ca2+ is released from bone and decreased absorption & reabsorption Blood Ca2+ level exceeds normal limit. HOMEOSTASIS Normal blood Ca2+ level PTH stimulates release of Ca2+from bone, and Ca2+ absorption & reabsorption Ca2+ level in blood falls below normal limit. Parathyroid glands are stimulated by low blood Ca2+ level. More PTH is secreted.

Regulation of Blood Ca2+ NORMAL BLOOD Ca2+ LEVEL (about 10 mg/100 mL) Blood Ca2+ level rises. Blood Ca2+level falls. Active vitamin D increases Ca2+. PTH stimulates Ca2+ uptake and promotes activation of vitamin D. Parathyroid glands release PTH. PTH PTH stimulates Ca2+ release.

Skin Liver FYI: Vitamin D Production UV Light Heat 7-Dehydroxycholesterol Pre-Vitamin D Vitamin D3 (Cholecalciferol) HO HO 25 Hydroxylase HO OH OH 25-OH D3 HO HO OH Activates 1 Hydroxylase 1,25(OH)2D3 (Vitamin D) Kidneys Intestines PTH Calcium Absorption

Table 45.1

11-12: Endocrine System Hormones and Homostasis