Endocrine Physiology

Suresh VenuGobal Senior Lecturer in Anaesthesia and Intensive Care University Malaya Medical Centre 16th September 2011

Chapter 17

Functional Organization of Endocrine System

General Characteristics
Glands that secrete chemical signals (hormones) into circulatory system Hormone characteristics Produced in small quantities Secreted into intercellular space Transported some distance in circulatory system Acts on target tissues elsewhere in body Regulate activities of body structures Ligands: more general term for chemical signals

Regulation of Activities: Comparison of Endocrine and Nervous Systems

Endocrine: amplitude modulated signals. Amount of hormone determines strength of signal Onset within minutes of secretion of hormone Nervous: frequency-modulated signals. Frequency of action potentials produced by neurons determines strength of signal. Onset within milliseconds Two systems actually inseparable Nervous system secretes neurohormones into circulatory system Nervous system uses neurotransmitters and neuromodulators as ligands Some parts of endocrine system innervated directly by nervous system

Intercellular Chemical Signals

Hormones: type of intercellular signal. Produced by cells of endocrine glands, enter circulatory system, and affect distant cells; e.g., estrogen Autocrine: released by cells and have a local effect on same cell type from which chemical signals released; e.g., prostaglandin Paracrine: released by cells and affect other cell types locally without being transported in blood; e.g., somatostatin Pheromones: secreted into environment and modify behavior and physiology; e.g., sex pheromones Neurohormone: produced by neurons and function like hormones; e.g., oxytocin Neurotransmitter or neuromodulator: produced by neurons and secreted into extracellular spaces by presynaptic nerve terminals; travels short distances; influences postsynaptic cells; e.g., acetylcholine.

Control of Secretion Rate

Most hormones controlled by negative feedback systems Most hormones are not secreted at constant rate, but their secretion is regulated by three different methods
1. The action of a substance other than a hormone on an endocrine gland. 2. Neural control of endocrine gland. 3. Control of secretory activity of one endocrine gland by hormone or neurohormone secreted by another endocrine gland

1.

Humoral stimulus: Action of Substance

Other Than Hormone

An increased blood glucose concentration stimulates increased insulin secretion from the pancreas Insulin increases glucose uptake by tissues, which decreases blood glucose levels. Autonomic nervous system also influences insulin secretion Hypocalcemia stimulates PTH secretion from parathyroids Hypersecretion stimulates calcitonin from parafollicular cells

2. Nervous System Regulation

Stimuli such as stress or exercise activate the sympathetic division of the autonomic nervous system Sympathetic neurons stimulate the release of epinephrine and smaller amounts of norepinephrine from the adrenal medulla. Epinephrine and norepinephrine prepare the body to respond to stressful conditions. Once the stressful stimuli are removed, less epinephrine is released as a result of decreased stimulation from the autonomic nervous system.

3. Hormonal Regulation
Secretion of tropic homones from hypothalamus stimulates secretion of anterior pituitary homrones. Example shows TRH (thyrotropic releasing hormone) from hypothalamus stimulating secretion of TSH from anterior pituitary. Note: TSH itself is a tropic hormone in that it stimulates T3/T4 secretion.

Positive and Negative Feedback

POSITIVE During the menstrual cycle, before ovulation, small amounts of estrogen are secreted from the ovary. Estrogen stimulates the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and luteinizing hormone (LH) from the anterior pituitary GnRH also stimulates the release of LH from the anterior pituitary LH causes the release of additional estrogen from the ovary. The GnRH and LH levels in the blood increase because of this positivefeedback effect.

Positive and Negative Feedback

NEGATIVE During the menstrual cycle, after ovulation, the ovary begins to secrete progesterone in response to LH. Progesterone inhibits the release of GnRH from the hypothalamus and LH from the anterior pituitary. Decreased GnRH release from the hypothalamus reduces LH secretion from the anterior pituitary. GnRH and LH levels in the blood decrease because of this negative-feedback effect.

Changes in Hormone Secretion Through Time

a) Chronic hormone regulation. Maintenance of relatively constant concentration of hormone. Thyroid hormone. b) Acute hormone regulation. Epinephrine in response to stress. c) Cyclic hormone regulation. Female reproductive hormones.

 Hormones dissolve in blood plasma and are transported in free form or are reversibly bound to plasma proteins Free form can diffuse from plasma into interstitial fluid and affect cells As concentration of free hormone molecules increase, more hormones molecules diffuse from capillaries into interstitial spaces to bind to target cells Lipid soluble hormones diffuse through capillary cells. Water soluble hormones diffuse through pores in capillaries called fenestrae. A large decrease in plasma protein concentration can result in loss of a hormone from the blood because free hormones are rapidly eliminated from circulation through kidney or liver Hormones are distributed quickly because they circulate in the blood

Transport and Distribution

Metabolism and Excretion

Half-life: The length of time it takes for half a dose of substance to be eliminated from circulatory system Long half-life: regulate activities that remain at a constant rate through time. Usually lipid soluble and travel in plasma attached to proteins Short half-life: watersoluble hormones as proteins, epinephrine, norepinephrine. Have a rapid onset and short duration

Hormone (Ligand) Interaction with Target Tissues

Portion of molecule where ligand binds is called binding site. If the molecule is a receptor (like in a cell membrane) the binding site is called a receptor site Ligand/receptor site is specific; e.g., epinephrine cannot bind to the receptor site for insulin. The purpose of binding to target tissue is to elicit a response by the target cell.

DownRegulation

Normally, receptor molecules are degraded and replaced on a regular basis. Down-regulation
Rate at which receptors are synthesized decreases in some cells after the cells are exposed to a ligand. Combination of ligands and receptors can increase the rate at which receptor molecules are degraded. This combined form is taken into the cell by phagocytosis and then broken down.

Tissues that exhibit downregulation are adapted to shortterm increases in hormone concentration. Tissues that respond to hormones maintained at constant levels normally do not exhibit downregulation.

Up-Regulation
Some stimulus causes increase in synthesis of receptors for a hormone, thus increases sensitivity to that hormone For example, FSH stimulation of the ovary causes an increase of LH receptors. Ovarian cells are now more sensitive to LH, even if the concentration of LH does not change. This causes ovulation.

Membrane-Bound Receptors
Receptor: integral proteins with receptor site at extracellular surface. Interact with ligands that cannot pass through the plasma membrane. Ligands Water-soluble or large-molecularweight hormones. Attachment of ligand causes intracellular reaction. Large proteins, glycoproteins, polypeptides; smaller molecules like epinephrine and norepinephrine

Intracellular Receptors
Receptors: in the cytoplasm or in the nucleus Ligands Lipid soluble and relatively small molecules; pass through the plasma membrane. React either with enzymes in the cytoplasm or with DNA to cause transcription and translation Thyroid hormones, testosterone, estrogen, progesterone, aldosterone, and cortisol

Membrane-Bound Receptors

Proteins or glycoproteins that have polypeptide chains folded to cross cell membrane several times Ligand binds reversibly to receptor site on receptor protein Three different results of ligand binding 1. Alteration of membrane permeability. Example: acetylcholine 2. Activation of G proteins associated with the membrane, causes production of intracellular mediator such as cyclicAMP, leads to activation of intracellular enzymes. Example: LH 3. Receptors linked to intracellular enzymes through intracellular mediators. Mediators alter activity of intracellular enzymes. Examples: nitric oxide, cyclicGMP, Ca ions.

Intracellular Receptors
Proteins in cytoplasm or nucleus Hormones bind with intracellular receptor and receptor-hormone complex activate certain genes, causes transcription of mRNA and translation. These proteins (enzymes) produce the response of the target cell to the hormone Latent period of several hours because time is required to produce mRNA and protein Processes limited by breakdown of receptorhormone complex Estrogen and testosterone produce different proteins in cells that cause the differing secondary sexual characteristics of females and males.

Endocrine System Functions

Metabolism and tissue maturation Ion regulation Water balance Immune system regulation Heart rate and blood pressure regulation Control of blood glucose and other nutrients Control of reproductive functions Uterine contractions and milk release

Pituitary Gland and Hypothalamus

Where nervous and endocrine systems interact Hypothalamus regulates secretions of anterior pituitary Posterior pituitary is an extension of the hypothalamus Anterior pituitary produces nine major hormones that
Regulate body functions Regulate the secretions of other endocrine glands

Pituitary Gland Structure

Posterior pituitary (neurohypophysis): extension of the nervous system via the infundibulum
Secretes neurohormones

Anterior pituitary (adenohypophysis)

Consists of three areas with indistinct boundaries: pars distalis, pars intermedia, pars tuberalis

Hypothalamus, Anterior Pituitary, and Target Tissues

Releasing and Inhibiting Hormones

Tropins or tropic hormones: hormones that regulate the hormone secretions of target endocrine tissues. All anterior pituitary hormones are tropins. Releasing hormones secreted by the hypothalamus: GHRH. Growth hormone-releasing hormone. Causes the anterior pituitary to release growth hormone. TRH. Thyroid-releasing hormone. Causes the anterior pituitary to release thyroid-stimulating hormone (TSH). CRH. Corticotropin-releasing hormone. Causes anterior pituitary to produce adrenocorticotropic hormone (ACTH) GnRH. Gonadotropin-releasing hormone. Causes anterior pituitary to produce FSH (follicle stimulating hormone) and LH (luteinizing hormone). PRH. Prolactin-releasing hormone. Causes the anterior pituitary to release prolactin. Inhibiting hormones: GHIH. Growth hormone-inhibiting hormone, somatostatin. Causes the anterior pituitary to decrease release of growth hormone. PIH. Prolactin-inhibiting hormone. Causes the anterior pituitary to decrease release of prolactin.

Hypothalamus, Posterior Pituitary and Target Tissues

Hypothalamic neurons syntheisze ADH and oxytocin. Latter hormones travel to post. pituitary via axons of hypothalamic neurons. ADH and oxytocin enter circulation in post. pituitary.

Hormones of Posterior Pituitary: ADH

Antidiuretic hormone (ADH). Also called vasopressin. A. Osmoreceptors (specialized neurons of hypothalamus monitor changes in intercellular osmolality (relative concentrations of electrolytes and water). If the concentration of electrolytes increases or if the concentration of water decreases, then ADH secretion is stimulated. B. Baroreceptors (specialized neurons found in walls of atria of heart, large veins, carotid arteries, aortic arch) sense changes in blood pressure (BP). If BP decreases, then ADH secretion is stimulated.

Control of ADH Secretion

Control of Oxytocin Secretion

Anterior Pituitary Hormones

Growth hormone (GH) or somatotropin Thyroid-stimulating hormone (TSH) Adrenocorticotropic hormone (ACTH) Melanocyte-stimulating hormone (MSH) Beta endorphins Lipotropins Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Prolactin

Growth Hormone (GH or somatotropin) Stimulates uptake of amino acids; protein synthesis; growth in most tissues. Stimulates breakdown of fats to be used as an energy source but stimulates synthesis of glycogen: glucose sparing Promotes bone and cartilage growth Regulates blood levels of nutrients after a meal and during periods of fasting Stimulates glucose synthesis by liver

Metabolic Action of Growth Hormone

Figure 16.6

Growth Hormone Stimulation: functions in

regulating growth, tissue maintenance, metabolism
GHRH from hypothalamus causes release of Growth hormone from anterior pituitary effects Target tissues: most tissues of the body Direct effect: GH binds to receptors on cells and causes changes within the cells. Increased lipolysis and decreased use of glucose for energy Indirect effect: causes liver and skeletal muscle to produce somatomedins; e.g., insulinlike growth factors (IGFs) Insulinlike growth factors: bind to receptors on membranes of target cells. Stimulate growth in cartilage, bone; increased synthesis of proteins in skeletal muscle.

Regulation of GH Secretion
1. Stress and decreased glucose levels increase release of GHRH

and decrease release of GHIH. 2. GHRH and GHIN travel via thehypothalamohypophyseal portal system to ant. pituitary 3. Increased GHRH and reduced GHIH act on AP and result in increased GH secretion. 4. GH acts on target tissues. 5. Increasing GH levels have neg feedback effect on hypothala.

Growth Hormone: Inhibition

Hypothalamus produces growth hormone inhibiting hormone (GHIH = somatostatin) Inhibits production of GH by anterior pituitary. GHRH secretion in response to low blood glucose, stress, increase in certain a.a. GHIH secretions in response to high blood glucose. Peak GH levels during deep sleep; levels lower at other times of day. Hyposecretion of GH may result in dwarfism Hypersecretion may result in giantism or acromegaly depending on ossification of epiphyseal plates

TSH and Thyroid Hormones

TRH from hypothalamus causes the release of TSH from anterior pituitary which causes secretion and storage of hormones T3 and T4 from and within the thyroid gland TSH increases activity of phospholipase that opens Ca2+ channels, increasing Ca2+ concentration in cells of the thyroid gland T3 and T4 inhibit TRH and TSH secretion

Adrenocorticotrophic Hormone (ACTH)

CRH from hypothalamus causes release of ACTH from anterior pituitary which Causes cortisol secretion from the adrenal cortex (a glucocorticoid from the zona fasciculata) Causes aldosterone secretion from the adrenal cortex (a mineralocorticoid from the zona glomerulosa) Binds directly to melanocytes of the skin; causes increase in production of melanin.

Melanocyte Stimulating Hormone, Endorphins, and Lipotropins

ACTH, MSH, endorphins and lipotropins all derived from the same large precursor molecule when stimulated by CRH MSH causes melanocytes to produce more melanin Endorphins act as an analgesic; produced during times of stress. Lipotropins cause adipose cells to catabolize fat

LH, FSH, Prolactin

Gonadotrophs: glycoprotein hormones that promote growth and function of the gonads LH and FSH
Both hormones regulate production of gametes and reproductive hormones Testosterone in males Estrogen and progesterone in females

GnRH from hypothalamus stimulates LH and FSH secretion Prolactin: role in milk production
Regulation of secretion: prolactin-releasing hormone (PRH) and prolactin-inhibiting hormones (PIH)

Thyroid Gland

One of largest endocrine glands; Highly vascular. Iodine enters follicular cells by active transport. Only gland that stores hormone. Histology Composed of follicles: follicular cells surrounding thyroglobulin/thyroid hormones Parafollicular cells: between follicles Physiology Follicular cells secrete thyroglobulin into lumen of follicle. Iodine and a.a. tyrosine necessary for production of T3 and T4. Hormones stored here attached to the thyroglobulin then absorbed into follicular cells; hormones disattached from thyroglobulin and released into circulation. Parafollicular cells. Secrete calcitonin which reduces [Ca2+] in body fluids when Ca levels are elevated.

Biosynthesis of Thyroid Hormones

Thyroid Hormones
Produced by follicular cells Triiodothyronine or T3 -less produced Tetraiodothyronine or T4 or thyroxine-more
99.6% of thyroxine in the blood is bound to thyroxinebinding globulin (TBG) from the liver. Rest is free. TBG has a higher affinity for T4 than for T3; amt of free unbound T3 in plasma is 10xs greater than free T4. Only free thyroxine and T3 can enter cells; boundthyroxine serves as a reservoir of this hormone 33-40% of T4 converted to T3 in cells: T3 more potent Bind with intracellular receptor molecules and initiate new protein synthesis Increase rate of glucose, fat, protein metabolism in many tissues thus increasing body temperature Normal growth of many tissues dependent on presence of thyroid hormones.

Effects of T3 and T4
1. Maintain normal rate of metabolism. 2. Increase the rate at which glucose, fat, and protein are metabolized. 3. Increase the activity of Na+-K+ pump which increases body temperature. 4. Can alter the number and activity of mitochondria resulting in greater ATP synthesis and heat production. 5. Normal growth and maturation of bone, hair, teeth, c.t., and nervous tissue require thyroid hormone. 6. Both T3 and T4 play a permissive role for GH and GH does not have its normal effect on tissues if T3 and T4 are lacking. 7. See Table 18.4 for effects of hypo- and hypersecretion

Regulation of T3 and T4 Secretion

Regulation of Calcitonin Secretion

Produced by parafollicular cells Secretion triggered by high Ca2+ concentration in blood; acts to decrease Ca2+ concentration Primary target tissue: bone. Decreases osteoclast activity, lengthens life span of osteoblasts.

Parathyroid Glands
Embedded in thyroid Two glands on each side Secrete PTH: target tissues are bone, kidneys and intestines.
Increases blood calcium and phosphate levels Stimulates osteoclasts Promotes calcium reabsorption by kidneys and PO4 excretion Increases synthesis of vitamin D which, in turn, increases absorption of Ca and PO4 by intestines. Net loss of PO4 under influence of PTH.

Regulation depends on calcium levels.

Effects of Parathyroid Hormone

Figure 16.11

Adrenal Glands
Near superior poles of kidneys; retroperitoneal Inner medulla; outer cortex Medulla: formed from neural crest; sympathetic. Secretes epinephrine and norepinephrine Cortex: three zones from superficial to deep Zona glomerulosa Zona fasciculata Zona reticularis

Adrenal Medulla
Secretory products are neurohormones: epinephrine and norepinephrine Combine with adrenergic membrane-bound receptors All function through G protein mechanisms Secretion of hormones prepares body for physical activity Effects are short-lived; hormones rapidly metabolized Epinephrine Increases blood levels of glucose Increases fat breakdown in adipose tissue Causes dilation of blood vessels in skeletal muscles and cardiac muscles. Epinephrine and norepinephrine increase heart rate and force of contraction; cause blood vessels to constrict in skin, kidneys, gastrointestinal tract, and other viscera

Hormones of Adrenal Cortex

Mineralocorticoids: Zona glomerulosa Aldosterone produced in greatest amounts. Increases rate of sodium reabsorption by kidneys increasing sodium blood levels Glucocorticoids: Zona fasciculata Cortisol is major hormone. Increases fat and protein breakdown, increases glucose synthesis, decreases inflammatory response Androgens: Zona reticularis Weak androgens secreted then converted to testosterone by peripheral tissues. Stimulate pubic and axillary hair growth and sexual drive in females

Regulation of Cortisol Secretion

Glucocorticoids (Cortisol)
Help the body resist stress by:
Keeping blood sugar levels relatively constant Maintaining blood volume and preventing water shift into tissue

Cortisol provokes:
Gluconeogenesis (formation of glucose from noncarbohydrates) Rises in blood glucose, fatty acids, and amino acids

Stress and the Adrenal Gland

Figure 16.15

Pancreas
Located along small intestine and stomach; retroperitoneal Exocrine gland
Produces pancreatic digestive juices

Endocrine gland
Consists of pancreatic islets Composed of
Alpha cells; secrete glucagon Beta cells; secrete insulin Delta cells; secrete somatostatin

Glucagon
A 29-amino-acid polypeptide hormone that is a potent hyperglycemic agent Its major target is the liver, where it promotes:
Glycogenolysis the breakdown of glycogen to glucose Gluconeogenesis synthesis of glucose from lactic acid and noncarbohydrates Release of glucose to the blood from liver cells

Insulin
Target tissue is the liver, adipose tissue, muscle, and satiety center of hypothalamus A 51-amino-acid protein consisting of two amino acid chains linked by disulfide bonds Synthesized as part of proinsulin and then excised by enzymes, releasing functional insulin Insulin:
Lowers blood glucose levels Enhances transport of glucose into body cells Counters metabolic activity that would enhance blood glucose levels

Regulation of Blood Glucose Levels

The hyperglycemic effects of glucagon and the hypoglycemic effects of insulin
Figure 16.17

Diabetes Mellitus (DM)

Results from hyposecretion or hypoactivity of insulin The three cardinal signs of DM are:
Polyuria huge urine output Polydipsia excessive thirst Polyphagia excessive hunger and food consumption

Hyperinsulinism excessive insulin secretion, resulting in hypoglycemia

Diabetes Mellitus (DM)

Figure 16.18

Regulation of Insulin Secretion

Regulation of Blood Nutrient Levels

Regulation of Blood Nutrient Levels During Exercise

Hormones of the Reproductive System

Male: Testes Testosterone
Regulates production of sperm cells and development and maintenance of male reproductive organs and secondary sex characteristics

Female: Ovaries Estrogen and Progesterone

Uterine and mammary gland development and function, external genitalia structure, secondary sex characteristics, menstrual cycle

Inhibin
Inhibits FSH secretion

Inhibin
Inhibits FSH secretion

Relaxin
Increases flexibility of symphysis pubis

Pineal Body
In epithalamus; produces melatonin and arginine vasotocin

Thymus Gland, GI Tract, Kidneys

Thymosin. Development of the immune system. GI tract: several hormones regulate digestion and enzyme secretion. Studied with digestive system. Kidneys secrete erythropoietin, which signals the production of red blood cells Adipose tissue releases leptin, which is involved in the sensation of satiety, and stimulates increased energy expenditure

Hormone-like Substances
Autocrines: chemical signals released by a cell and the substance affects that same cell. Chemical mediators of inflammation which are modified fatty acids: eicosanoids such as prostaglandins, thromboxanes, prostacyclins, and leukotrienes Paracrines: chemical signals released into intercellular fluid and affecting nearby cells. Endorphins and enkephalins modulate sensation of pain Several growth factors

Effects of Aging on Endocrine System

Gradual decrease in secretory activity of some glands
GH as people age except in people who exercise regularly Melatonin Thyroid hormones Kidneys secrete less renin

Familial tendency to develop type II diabetes