Chapter 11

Endocrine Glands Secretion & Action of Hormones

11-1

Endocrine Glands

Are ductless & secrete hormones into bloodstream Hormones go to target cells that contain receptor proteins for it Neurohormones are secreted into blood by specialized neurons Hormones affect metabolism of targets

Fig 11.1

11-4

Chemical Classification of Hormones

Amine hormones are derived from tyrosine or tryptophan Include NE, Epi, thyroxine, melatonin Polypeptide/protein hormones are chains of amino acids Include ADH, GH, insulin, oxytocin, glucagon, ACTH, PTH Glycoproteins Long polypeptide bound to a carbohydrate group Include LH, FSH, TSH Steroids are lipids derived from cholesterol Include testosterone, estrogen, progesterone & cortisol

11-7

Common Aspects of Neural & Endocrine Regulation

Both NS & endocrine system use chemicals to communicate Difference between NTs & hormones is transport in blood & more diversity of effects in hormone targets Some chemicals are used as hormones & NTs Targets for both NTs & hormones must have specific receptor proteins Must be way to rapidly inactivate both
11-12

Hormone Interactions
A tissue usually responds to # of hormones 2 hormones are synergistic if work together to produce an effect
Produce a larger effect together than individual effects added together Effects of Epi and NE on heart rate

A hormone has permissive effect if it enhances responsiveness of a target organ to 2nd hormone If action of 1 hormone inhibits effect of another, it is antagonistic
11-13

Hormone Levels & Tissue Responses

Half-life is time required for blood level to be reduced by half
Ranges from mins to hrs for most (days for thyroid hormones)

Normal tissue responses are produced only when hormones are in physiological range High (pharmacological) doses can cause # of side effects
Probably by binding to receptors of other hormones
11-14

Hormone Levels & Tissue Responses continued

Priming effect (upregulation) occurs when a hormone induces more of its own receptors in target cells
Results in greater response in target cell

Desensitization (downregulation) occurs after long exposure to high levels of polypeptide hormone
Subsequent exposure to this hormone produces a lesser response Due to decrease in # of receptors on targets Most peptide hormones have pulsatile secretion which prevents downregulation

11-15

Mechanisms of Hormone Action

11-16

Mechanisms of Hormone Action

Target cell receptors show specificity, high affinity, & low capacity for a hormone Lipid hormones have receptors in target's cytoplasm &/or nucleus because can diffuse thru plasma membrane Receptors for water-solubles are on surface of target cell

11-17

Hormones That Bind to Nuclear Receptor Proteins

Lipid hormones travel in blood attached to carrier proteins
They dissociate from carriers to pass thru plasma membrane of target
Receptors are called nuclear hormone receptors

Fig 11.4
11-18

Nuclear Hormone Receptors

Serve as transcription factors when bound to hormone ligands
Activate transcription

Constitute a "superfamily" composed of steroid family & thyroid hormone family (which includes vitamin D & retinoic acid)

11-19

Nuclear Hormone Receptors

Have ligand (hormone)-binding & DNA-binding domains
Binds hormone & translocates to nucleus Binds to hormone-response element (HRE) on DNA located adjacent to target gene

Fig 11.5

11-20

Fig. 11.6

Mechanism of Thyroid Hormone Action

continued

T3 & receptor bind to 1 half-site Other half-site binds retinoic acid

Two partners form heterodimer that activates HRE
Stimulates transcription of target gene

Fig 11.7
11-23

Hormones That Use 2nd Messengers

Water soluble hormones use cell surface receptors because cannot pass through plasma membrane
Actions are mediated by 2nd messengers Hormone is extracellular signal; 2nd messenger carries signal from receptor to inside of cell

11-24

Adenylate Cyclase-cAMP
Mediates effects of many polypeptide & glycoprotein hormones Hormone binds to receptor causing dissociation of a G-protein subunit

Fig 11.8
11-25

Adenylate Cyclase-cAMP continued

G-protein subunit binds to & activates adenylate cyclase
Which converts ATP into cAMP
cAMP attaches to inhibitory subunit of protein kinase

Fig 11.8
11-26

Adenylate Cyclase-cAMP continued

Inhibitory subunit dissociates, activating protein kinase Which phosphorylates enzymes that produce hormones effects cAMP inactivated by phosphodiesterase

Fig 11.8
11-27

Pituitary Gland

11-34

Pituitary Gland

Pituitary gland is located beneath hypothalamus at base of forebrain

Fig 8.16
11-35

Pituitary Gland continued

Is structurally & functionally divided into anterior & posterior lobes Hangs below hypothalamus by infundibulum Anterior produces own hormones
Controlled by hypothalamus

Posterior stores & releases hormones made in hypothalamus

Fig 11.12
11-36

Anterior Pituitary

Secretes 6 trophic hormones that maintain size of targets

High blood levels cause target to hypertrophy
Low levels cause atrophy

11-37

Anterior Pituitary continued

Growth hormone (GH) promotes growth, protein synthesis, & movement of amino acids into cells Thyroid stimulating hormone (TSH) stimulates thyroid to produce & secrete T4 & T3

Adrenocorticotrophic hormone (ACTH) stimulates adrenal cortex to secrete cortisol, aldosterone Follicle stimulating hormone (FSH) stimulates growth of ovarian follicles & sperm production Luteinizing hormone (LH) causes ovulation & secretion of testosterone in testes Prolactin (PRL) stimulates milk production by mammary glands
11-38

Anterior Pituitary continued

Release of Anterior Pituitary hormones is controlled by hypothalamic releasing & inhibiting factors & by feedback from levels of target gland hormones

11-39

Anterior Pituitary continued

Releasing & inhibiting hormones from hypothalamus are released from axon endings into capillary bed in median eminence
Carried by hypothalamohypophyseal portal system directly to another capillary bed in A. Pit.
Diffuse into A. Pit. & regulate secretion of its hormones

Fig 11.15

11-40

 Involves short feedback loop in which retrograde flow of blood & hormones from A. Pit. to hypothalamus inhibits secretion of releasing hormone Involves negative feedback of target gland hormones & during menstrual cycle, estrogen stimulates LH surge by positive feedback

Feedback Control of Anterior Pituitary

Fig 11.17

11-41

Higher Brain Function & Anterior Pituitary Secretion

Hypothalamus receives input from higher brain centers that can affect A. Pit. secretion
E.g. psychological stress affects circadian rhythms, menstrual cycle, & adrenal hormones

11-42

Growth Hormone Secretion

Is from anterior pituitary; stimulated by GHRH, & inhibited by somatostatin, from hypothalamus Follows a circadian pattern--is greater during sleep & lower during waking hours Stimulates growth in children & adolescents Has important metabolic effects in adults
Is stimulated by increased blood amino acids & decreased blood glucose Is increased during fasting Stimulates protein synthesis, fat breakdown, & decreases glucose use by most tissues
19-61

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 (diabetogenic) Promotes bone and cartilage growth Regulates blood levels of nutrients after a meal and during periods of fasting Stimulates glucose synthesis by liver

Insulin-like Growth Factors (IGFs)

Are similar to pro-insulin; produced by many tissues Are called somatomedins because mediate many of GH's effects Liver produces & secretes IGF-1 in response to GH
IGF-1 in turn stimulates cell division & growth of cartilage
These actions are supported by IGF-2 which has more insulinlike actions

Do not mediate effects of GH on lipolysis & glucose sparing (i.e. metabolic effects)
19-62

Metabolic Action of Growth Hormone

Figure 16.6

Growth Hormone & Body Growth

Growth of skeleton occurs first as growth of cartilage at epiphyseal discs which then become converted to bone
Mediated by IGF-1 & 2 which stimulate chondrocytes to divide & secrete more cartilaginous matrix Growth stops when epiphyseal discs are ossified

Gigantism produced by excess GH secretion in children Dwarfism caused by inadequate secretion of GH during childhood
19-64

Growth Hormone & Body Growth

Excess GH secretion in adults, after epiphyseal discs are ossified, results in acromegaly
There is no increase in height However soft tissue still grows
Causing elongation of jaw, deformities in hands, feet, & bones of face

Fig 19.18

19-65

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 decreased release of GHIH. 2. GHRH and GHIN travel via the hypothalamo-hypophyseal 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

Posterior Pituitary
Stores & releases 2 hormones produced in hypothalamus:
Antidiuretic hormone (ADH/vasopressin) which promotes H20 conservation by kidneys Oxytocin which stimulates contractions of uterus during parturition
& contractions of mammary gland alveoli for milk-ejection reflex

11-43

Hypothalamic Control of Posterior Pituitary

Supraoptic nuclei of hypothalamus produce ADH Paraventricular nuclei produce oxytocin Both transported along hypothalamo-hypophyseal tract to posterior pituitary Release controlled in hypothalamus by neuroendocrine reflexes
Fig 11.13
11-44

Thyroid Gland

11-51

Thyroid Gland

Is located just below the larynx Secretes T4 & T3 which set BMR & are needed for growth, development
11-52

Thyroid Gland
Consists of microscopic thyroid follicles
Outer layer is follicle cells that synthesize T4 Interior filled with colloid, a protein-rich fluid

11-53

Production of Thyroid Hormones

Iodide (I-) in blood is actively transported into follicles & secreted into colloid
Where it is oxidized to iodine (I2) & attached to tyrosines of thyroglobulin
A large storage molecule for T4 & T3 TSH stimulates hydrolysis of T4 & T3s from thyroglobulin & then secretion

Fig 11.23
11-54

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 (calorigenic effect) 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

Diseases of the Thyroid - Goiter

In absence of sufficient dietary iodide, T4 & T3 cannot be made & levels are low
Low T4 & T3 dont provide negative feedback & TSH levels go up
Because TSH is a trophic hormone, thyroid gland grows Resulting in a goiter

Fig 11.25
11-55

Diseases of the Thyroid - Hypothyroidism

People with inadequate T4 & T3 levels are hypothyroid
Have low BMR, weight gain, lethargy, cold intolerance & myxedema = puffy face, hands, feet During fetal development hypothyroidism can cause cretenism (severe mental retardation)

11-56

Diseases of the Thyroid - Hyperthyroidism

Goiters are also produced by Grave's disease
Autoimmune disease where antibodies act like TSH & stimulate thyroid gland to grow & oversecrete = hyperthyroidism
Characterized by exopthalmos, weight loss, heat intolerance, irritability, high BMR

11-57

11-58

Calcitonin
Secreted by C cells of thyroid gland Works with PTH & 1,25 Vit D3 to regulate blood Ca2+ levels Stimulated by increased plasma Ca2+ Inhibits activity of osteoclasts Stimulates urinary excretion of Ca2+ & P043- by inhibiting reabsorption Physiological significance in adults is not understood
19-72

Parathyroid Glands
Are 4 glands embedded in lateral lobes of thyroid gland Secrete Parathyroid hormone (PTH)
Most important hormone for control of blood Ca2+ levels
Fig 11.28

11-59

Parathyroid Hormone (PTH)

Secreted by parathyroid glands Is most important hormone in control of Ca2+ levels Release is stimulated by low blood Ca2+ levels Stimulates osteoclasts to reabsorb bone Stimulates kidneys to reabsorb Ca2+ from filtrate, & inhibits reabsorption of P043 Promotes formation of 1,25 Vit D3 that stimulates Ca2+ absorption by intestines Many cancers secrete PTH-related protein that interacts with PTH receptors producing hypercalcemia
19-71

Parathyroid Hormone

Release stimulated by decreased blood Ca2+ Acts on bones, kidney, & intestines to increase blood Ca2+ levels

Fig 11.29
11-60

Effects of Parathyroid Hormone

Figure 16.11

1,25 Vitamin D3
Synthesis begins in skin when cholesterol derivative is converted to Vit D3 by sunlight

Fig 19.21

19-75

1,25 Vitamin D3 continued

Directly stimulates intestinal absorption of Ca2+ & P043 When Ca2+ intake is inadequate, directly stimulates bone reabsorption Stimulates kidney to reabsorb Ca2+ and P043
Simultaneously raising Ca2+ & P043- results in increased tendency of these to precipitate as hydroxyapatite

Stimulated by PTH Inadequate Vit D in diet & body causes osteomalacia & rickets (loss of bone calcification)
19-76

Overview of Hormonal Control of

Fig 19.23 Fig 19.24

2+ Ca

19-77

Adrenal Gland

11-45

Adrenal Glands

Sit on top of kidneys Each consists of outer cortex & inner medulla
2 arise differently during development

Fig 11.18
11-46

Adrenal Glands
Medulla synthesizes & secretes 80% Epi & 20% NE
Controlled by sympathetic

Cortex is controlled by ACTH & secretes:

Cortisol which inhibits glucose utilization & stimulates gluconeogenesis Aldosterone which stimulate kidneys to reabsorb Na+ and secrete K+ & some supplementary sex steroids

11-47

Adrenal Medulla
Hormonal effects of Epi last 10X longer than NE Innervated by preganglionic Symp fibers Activated during "fight or flight" response
Causes:
Increased respiratory rate Increased HR & cardiac output General vasoconstriction which increases venous return Glycogenolysis & lipolysis

11-49

Effects of Epinephrine Secretion from Adrenal Medulla

Metabolic Effects of Epi & Norepi

Are similar to glucagon, stimulating glycogenolysis & lipolysis

Fig 19.15
19-57

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

Metabolic Effects of Cortisol

Cortisol is secreted in response to ACTH
Which is often released in response to stress, including fasting & exercise
Where it supports effects of glucagon Promotes lipolysis, ketogenesis, & protein breakdown
Protein breakdown increases amino acid levels for use in gluconeogenesis in liver

19-58

Metabolic Effects of Cortisol continued

Fig 19.16

19-59

Stress and the Adrenal Gland

Figure 16.15

Stress & the Adrenal Gland

Stress induces a non-specific response called general adaptation syndrome (GAS)
Causes ACTH & cortisol release Often affects physiology negatively

Fig 11.20
11-50

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

Islets of Langerhans continued

Betas secrete insulin in response to low blood glucose
Promotes entry of glucose into cells & conversion of glucose into glycogen & fat Decreases blood glucose

Fig 11.31
11-64

Insulin & Glucagon Secretion

Normal fasting glucose level is 65 105 mg/dl
Insulin & glucagon normally prevent levels from rising above 170mg/dl after meals or falling below 50mg/dl between meals

Fig 19.7

19-40

Regulation of Blood Glucose Levels

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

Regulation of Insulin Secretion

Fig 19.10
19-44

Effects of ANS on Insulin & Glucagon

ANS innervates islets Activation of Parasymp NS stimulates insulin secretion Activation of Symp NS stimulates glucagon & inhibits insulin
This can cause "stress hyperglycemia"

19-45

Diabetes Mellitus
Characterized by chronic high blood glucose levels (hyperglycemia) Type I (insulin dependent or IDDM) is due to insufficient insulin secretion Type II (insulin independent or NIDDM) is due to lack of effect of insulin

19-49

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

Type I Diabetes
b cells of islets are destroyed by autoimmune attack Glucose is unable to enter resting muscle or adipose cells
Rate of fat synthesis lags behind rate of lipolysis Fatty acids are converted to ketone bodies, producing ketoacidosis

Increased glucagon levels stimulate glycogenolysis in liver

19-51

Effects of Uncontrolled Type I Diabetes

Fig 19.12
19-52

Hypoglycemia
Reactive hypoglycemia is oversecretion of insulin due to an exaggerated response of b cells to a rise in glucose
Occurs in people who are genetically predisposed to type II diabetes Symptoms include tremors, hunger, weakness, blurred vision, & confusion

Fig 19.14
19-54

Miscellaneous Glands & Hormones

11-65

Pineal Gland

Is located in basal forebrain near thalamus Secretes melatonin in response to activity of suprachiasmatic nucleus (SCN) of hypothalamus

Fig 11.32

11-66

Pineal Gland continued

SCN is primary timing center for circadian rhythms

Reset by daily light/dark changes

Melatonin is involved in aligning physiology with sleep/wake cycle & seasons

Secreted at night & is inhibited by light Inhibits GnRH (antigonadotropic) in many animals

11-67

Thymus

Is located around trachea below thyroid Produces T cells of immune system & hormones that stimulate them

Fig 11.33
11-68

Sex & Reproductive Hormones

Gonads (testes & ovaries) secrete steroid hormones testosterone, estrogen, & progesterone Placenta secretes estrogen, progesterone, hCG, and somatomammotropin

11-69

Estrogen
Causes epiphyseal discs (cartilaginous growth plates) to seal (ossify) which stops growth Is necessary for proper bone mineralization & prevention of osteoporosis Stimulates osteoblast activity & suppresses formation of osteoclasts

19-73

Autocrine & Paracrine Regulation

Autocrine regulators are produced & act within same tissue of an organ
All autocrines control gene expression in target cells Paracrine regulators are autocrines that are produced within one tissue & act on different tissue in same organ. Autocrines & paracrines include:
Cytokines (lymphokines, interleukins) Growth factors (promote growth & cell division) Neutrophins (provides trophic support for normal & regenerating neurons)

11-71

Table 11.2

Table 11.6

Table 11.7

Table 11.8