Endocrine System

I. Background:

A. There are two types of glands:

1. Endocrine

a. Ductless

b. Secrete hormones into surrounding tissue fluid

c. Vascular or lymphatic drainage receive hormones

d. Examples of endocrine glands:

i. Pituitary

ii. Thyroid

iii. Parathyroid

iv. Adrenal

v. Pineal

vi. Thymus

e. Some organs also have discrete areas of endocrine tissue as well as exocrine tissue

i. Pancreas

ii. Gonads

iii. Hypothalamus

2. Exocrine

a. Have ducts

b. Nonhormonal products are directed to membrane surfaces

II. Hormones—chemical substances secreted by cells into extracellular fluids, that regulate metabolic function of other cells in the body

A. Chemistry

1. Classification

a. Amino acid-based hormones

i. Most hormones

b. Steroid hormones

i. Gonadal and adrenocortical hormones

B. Mechanism of action—increase or decrease rates of normal cellular activity

1. Hormonal effects

a. Alter plasma membrane permeability

b. Alter protein or regulatory molecule synthesis

c. Activate or inactivate enzyme

d. Induction of secretory activity

e. Stimulate mitosis

2. Mechanisms that transduce hormonal signal into an intracellular change

a. G-protein linked receptor activation of intracellular second messengers

i. Amino acid-based hormones

b. Direct gene activation

i. Steroid hormones

3. Overview of second-messenger systems

a. Hormone binds plasma membrane receptor

b. G-protein signals effector to produce an intracellular message (i.e., second messenger)

c. Second messenger mediates cellular response to hormone

i. Signaling cascades

ii. Protein kinases

4. Examples of signaling mechanisms

a. cAMP (slide)

b. PIP-Calcium signal mechanism (slide)

5. Direct gene activation

a. Steroid hormones are lipid soluble

i. Pass through plasma membrane

b. Once inside, hormone binds to intracellular receptor

i. Activated complex is formed

c. Activated complex passes into nucleus and binds to specific DNA sequences

d. Association with DNA sequence turns on gene

i. Gene sequence is transcribed

C. Target cell specificity

1. Mediated by specific protein receptors

a. Receptors are localized to cells that are influenced by a given hormone

b. Hormones act as molecular triggers

2. Factors affecting target cell activation

a. Hormonal levels

b. Number of receptors on target cell

c. Receptor affinity

i. Can be up or down regulated based on microenvironmental conditions

D. Hormonal activity—half-life, onset and duration

1. Half-life—measure of hormonal persistence in blood stream

a. Depends on rate of synthesis and release

b. Speed of removal or degradation

2. Onset of effect is dependent on hormone type

a. Steroid

i. Hours to days

3. Duration is generally short (e.g., 20 minutes) although depends on hormone type

E. Control of hormone release

1. Typically negative feedback

a. Hormone secretion is triggered in response to a stimulus

b. As hormone level increases, target organ is affectedc. Further hormone release is inhibits

2. Types of stimuli

a. Humoral

i. Endocrine glands release hormones in direct response to changing levels of ions or nutrients

ii. E.g., PTH release in response to changes in calcium levels

b. Neural

i. Nerve fibers stimulate hormonal release

ii. E.g., sympathetic activated release of catecholamines from adrenal medulla

c. Hormonal

i. Glands release hormones in response to other hormones

ii. E.g., hypothalamic releasing and inhibiting factors

III. Major Endocrine Organs

A. Pituitary (hypophysis)

1. General characteristics

a. Connected to the superiorly lying hypothalamus

i. Infundibulum—stalk-like connection

ii. Hypothalamus is part of the brain

iia. Connection between brain and endocrine system

b. Two major lobes

i. Posterior

ii. Anterior

c. Posterior lobe + infundibulum = neurohypophysis

d. Anterior lobe (adenohyophysis) is comprised of glandular tissue

e. Highly vascular

2. Connections between posterior pituitary and hypothalamus

a. Posterior is an outgrowth of the brain and maintains its neural connections

b. Neurons in the supraoptic and paraventricular nuclei of the hypothalamus give rise to the hypothalamic-hypophyseal tract

i. Hormones are synthesized in the secretory cells of the hypothalamus

ii. Oxytocin and antidiuretic hormone

c. When neurons fire, hormones are released into capillary bed in post. pituitary

3. Connections between anterior pituitary and hypothalamus

a. Anterior lobe is derived from epithelial tissue

b. No direct connection between post. pituitary or hypothalamus

c. Vascular connection

i. Hypophyseal portal veins

d. Releasing and inhibiting hormones secreted by hypothalamus are carried by portal system to anterior pituitary

i. Regulate the activity of secretory cells in ant. pituitary

B. Anterior pituitary hormones

1. Anterior pituitary is referred to as the Master gland

2. 6 hormones as well as a number of other active molecules

3. Tropic hormones (4/6)

a. Regulate secretory activity of other endocrine glands

b. TSH—thyroid-stimulating hormone

c. ACTH—adrenocorticotropic hormone

d. FSH—follicle-stimulating hormone

e. LH—lutenizing hormone

4. Other hormones (2/6)

a. Have neuroendocrine targets

b. PRL—Prolactin

c. GH—growth hormone

5. Growth hormone

a. Produced by somatotropic cells

b. Stimulates most cells in the body to grow and divide

c. Major targets are bones and muscles

d. Anabolic hormone

i. Promotes metabolism

e. Growth-promoting effects are mediated indirectly

i. IGF’s—insulin-like growth factors

ii. Produced by liver and other tissues

f. Effects of growth hormone

i. Stimulates uptake of amino acids from blood and their incorporation into proteins

ii. Stimulates sulfur uptake

iii. Mobilizes fats from fat deposits

iv. Decreases rate of glucose uptake and metabolism

iva. Diabetogenic effect—elevation of blood glucose

g. Regulation by hypothalamic hormones (negative feedback)

i. GHRH—growth hormone releasing hormone (somatocrinin)

ii. GHIH—growth hormone inhibiting hormone (somatostatin)

h. Abnormalities

i. Adolescent hypersecretion—gigantism

ii. Adult hypersecretion—acromegaly

iia. Tissues still sensitive to GH grow disproportionately

iii. Adult hyposecretion—little effect

iiia. Progeria—occurs when deficit is severe

iv. Adolescent hyposecretion—pituitary dwarfism

6. Thyroid-stimulating hormone (TSH)

a. Stimulates normal growth and activity of the thyroid gland

b. Tropic hormone

c. Controlled by hypothalamus

i. TRH—thyroid releasing hormone

ii. Feedback inhibition

iii. GHIH also inhibits

7. Adrenocorticotropic hormone (ACTH)

a. ACTH stimulates adrenal cortex to release corticosteroid hormones

i. Glucocorticoids—offset effects of stress

b. ACTH release is controlled by CRH

i. Corticotropin-releasing hormone (CRH) is a hypothalamic hormone

ii. CRH has a diurnal rhythm

c. Feedback inhibition: rising glucocorticoids inhibit CRH secretion

8. Gonadotropins: FSH and LH

a. Regulate gonads

b. FSH stimulates gamete production

c. LH promotes production of gonadal hormones

d. FSH and LH work in concert to cause follicle to mature

i. LH causes egg to be extruded from follicle

e. In males, LH stimulates interstitial cells of the testes to produce testosterone

f. LH and FSH release is controlled by the hypothalamus

i. GnRH—gonadotropin-releasing hormone

g. Negative feedback inhibition regulates FSH and LH release

9. Prolaction

a. Stimulates milk production

b. PRH and PIH

i. Serotonin and dopamine

c. Levels parallel those of estrogen

C. Posterior pituitary hormones

1. General characteristics

a. ADH and oxytocin are comprised of 9 amino acids

i. Differ only in the identity of 2 residues

b. Released in response to neural signals from hypothalamus

2. Oxytocin

a. Stimulates smooth muscle contraction

b. Muscle response depends on number of oxytocin receptors

i. Uterus and breast

ii. Number of receptors increases during pregnancy

iii. Afferent impulses as uterus stretches during pregnancy signals release of oxytocin during late stages of pregnancy

c. Hormonal trigger for milk ejection

d. Positive feedback mechanism

3. ADH—antidiuretic hormone

a. Inhibits or prevents urine production

b. In response to increases in solute concentration, ADH is released from hypothalamus

i. Hypothalamus has osmoreceptors

c. ADH causes kidney tubules to reabsorb more water

d. At high doses, ADH causes vasoconstriction

i. Causes increases systolic BP

e. Diabetes insipidus (tasteless)

i. Deficiency in ADH secretion

ii. Output of huge amounts of urine and thirst

C. Thyroid gland

1. Structure

a. Two lobes connected by isthmus

b. Follicles

i. Follicle cells produce thyroglobin

ii. Lumen stores colloid—thyroglobin in association with iodine

c. Thyroid hormone is derived from iodinated thyroglobin

d. Parafollicular cells produce calcitonin

2. Thyroid hormone (TH)

a. Two metabolically active iodine-containing hormones

i. Thyroxine (T₄)

ii. Triiodothyronine (T₃)

b. Thyroxine (T₄) is produced by thyroid gland

c. Triiodothyronine (T₃) is formed at target tissue

i. T₄ is converted into T₃

d. Increases metabolism in most tissues by stimulating glucose oxidation

e. Increases adrenergic receptors in blood vessels

f. Regulates tissue growth and development

g. T₄ is bound to plasma proteins (TBG—thyroxine-binding globulin) and transported to target tissues

i. Bind target tissue receptors

ii. T₃ is bound more readily

h. Regulation

i. Falling levels trigger TSH release

ii. Rising levels of thyroxine inhibits TSH release

iii. Conditions in which there is increased energy requirements causes TRH release from hypothalamus

3. Metabolic disturbances associated with thyroid gland activity

a. Myxsedema—hypothyroid disorder

i. If from lack of iodine, condition is called endemic (colloidal) goiter

ii. Colloid is made but cannot be iodinated to make functional hormone

iii. TSH secretion increase to stimulate TH production

iv. Follicles accumulate more unuseable colloid

b. Cretinism—hypothyroidism in infants

i. Thyroid hormone replacement therapy prevents but cannot reverse effects

c. Graves’ disease—hyperthyroid pathology

i. Autoimmune disease

ii. Abnormal antibodies that mimic TSH

iii. Exopthalmus

4. Calcitonin

a. Lowers blood calcium levels

b. Antagonist to the effect of parathyroid hormone

i. Inhibits calcium release from bones by osteoclast activity

ii. Stimulates calcium uptake and incorporation

iii. Calcium acts as a humoral signal for calcitonin release

D. Parathyroid glands

1. Two pairs of glands in the posterior aspect of the thyroid gland

2. Chief cells (principal cells) secrete PTH—parathyroid hormone

3. Parathyroid hormone

a. Controls calcium balance

b. Released in response to falling blood calcium levels

c. PTH stimulates osteoclast activity

i. Digest bone matrix and releases calcium

d. Enhances reabsorption by kidney tubules

e. Increases calcium absorption by intestine

i. Stimulates conversion of vitamin D into active form

f. Hyperparathyroidism

i. Rare

ii. Calcium is leached from bones and replaced by connective tissue

iii. Elevated blood calcium asversely affects NS and contributes to formation of kidney stones as excess calcium is deposited in kidney tubules

g. Hypoparathyroidism—PTH deficiency following injury or surgical removal

i. Increased NS excitability

E. Adrenal glands

1. Two endocrine glands

a. Adrenal medulla

i. Acts as part of the sympathetic NS

b. Adrenal cortex

2. Involved in response to stressful conditions

3. Adrenal cortex

a. Corticosteroids

i. Steroids

ii. More than two dozen

iii. Synthesized from cholesterol

b. Mineralocorticoids (type of corticosteroid)

i. Regulate electrolyte concentrations in extracellular fluid

ii. Aldosterone is most abundant

iii. Aldosterone reduces excretion of sodium from the body

iv. Stimulates reabsortion of sodium in the distal tubule of kidney

c. Mechanisms controlling aldosterone secretion (4)

i. Renin-angiotensin mechanism: JGA releases renin in response to blood pressure decrease, initiates cascade forming angiotensin II formation, angiotensin II stimulates aldosterone release from adrenal cortex

ii. Direct stimulation by plasma sodium and potastium ions

iii. ACTH: at very high levels of ACTH, aldosterone secretion is increased

iv. ANP—atrial natriuretic peptide: when blood pressure is high, heart release ANP to inhibit renin and aldosterone secretion

d. Glucocorticoids (type of corticosteroid)

i. Influence metabolism and mediate response to stress

ii. Cortisol, cortisone, corticosterone

iii. Only cortisol is secreted in significant amounts

iv. Non-stress: CRH, ACTH, cortisol release, negative feedback

v. Stress: Sympathetic NS overrides inhibitory effects of elevated cortisol levels and triggers CRH release

vi. Gluconeogenesis: primary effect of cortisol; conversion of fats into glucose

e. Cushing’s disease: excess cortisone

i. Characterized by persistent hyperglycemia (steroid diabetes)

ii. Loss of muscle and bone protein

iii. Water and salt retention

iv. “moon” face

v. Redistribution of body fat (e.g., buffalo hump)

vi. Anti-inflammatory effects mask infection

f. Addison’s disease: hyposecretory disorder of adrenal cortex

i. Weight loss

ii. Reduced plasma glucose and sodium levels

iii. Severe dehydration and hypotension

g. Gonadocorticoids (Sex hormones): primarily androgens

i. Androstenedione converted to testosterone and dihydrotestosterone

ii. Small amounts of estrogens

iii. Adrenal cortex secretion of sex hormones is only a fraction of gonadal sources

iv. Possible role in onset of puberty (levels rise during years preceding onset)

4. Adrenal medulla

a. Chromaffin cells

i. Modified postganglionic sympathetic neurons

ii. Secrete epinephrine and norepinephrine

b. Initial response to stress is mediated by sympathetic NS

c. Activation of adrenal medulla and associated release of EPI and NE prolong sympathetic response

i. Elevated BP and heart rate

ii. Mobilization of glucose

iii. Shunt blood from GI

F. Pancreas

1. Contains both exocrine (GI enzymes) and endocrine cells

2. Pancreatic islets (islets of Langerhans)

a. Two populations

i. Alpha cells—produce glucagons

ii. Beta cells—produce insulin

3. Effects

a. Insulin: hypoglycemic hormone

b. Glucagon: hyperglycemic hormone

4. Glucagon effects

a. Breakdown of glycogen to glucose (glyconeogenesis)

b. Synthesis of glucose from lactic acid, fatty acids and amino acids

c. Release of glucose from liver

5. Regulation of glycogen

a. Humoral response to decreased circulating glucose

6. Insulin effects

a. Lower blood glucose

i. Enhances membrane transport of glucose into body cells

b. Alter protein and fat metabolism

c. Inhibits breakdown of glycogen

d. Triggers enzymatic activity

i. Oxidation of glucose for ATP production

ii. Synthesis and storage of glycogen

iii. Conversion of glucose to fat and its storage

7. Regulation of insulin

a. Humoral response to increased circulating glucose

8. Diabetes mellitus (DM)—hyposecretion or hypoactivity of insulin

a. Excessive hyperglycemia triggers sympathetic response

i. Activates systems associated with hypoglycemia

b. Lipidemia

i. Fats are mobilized to use as cellular food

ii. Fatty acid metabolites (ketones) accumulate as ketone bodies

iii. Blood pH drops—ketoacidosis

c. Signs of diabetes mellitus

i. Polyuria

ii. Polydipsia

iii. Polyphagia

d. Polyuria

i. Excessive glucose in kidney filtrate acts as a diuretic (i.e., inhibits water reabsortion)

ii. Increased urine output causes dehydration and decreased blood volume

iii. Electrolyte loss in association with excretion of excess ketones (- charged)

e. Polydipsia

i. Dehydration stimulates thirst centers in brain

f. Polyfagia

i. Glucose cannot be used because it cannot be absorbed by cells

ii. Results in hunger

9. Types of DM

a. Type I

i. IDDM—insulin dependent DM

ii. Autoimmume destruction of beta cells

iii. Juvenile onset

iv. Lack insulin activity

v. Long term cardiovascular and neural problems

b. Type II

i. NIDDM—non-insulin dependent DM

ii. Usually after the age of 40

iii. 90% of DM cases

iv. Most patients are overweight

v. Genetic link

vi. Insulin is produced in inadequate quantities or with faulty receptors

G. Gonads

1. Same sex hormones as those produced by adrenal cortex

2. Ovaries produce estrogens and progesterone

a. Sexual maturation and menstrual cycle

3. Testes produce testosterone

a. Sexual maturation

b. Sex drive

4. Release of gonadal hormones is regulated by gonadotropins

H. Pineal gland

1. Floor of third ventricle within diencephalons

2. Primary secretory product is melatonin

3. Pineal gland receives indirect inputs from visual system

4. SCN has melatonin receptors

I. Thymus

1. Large in children, decreases with age

2. Hormonal products important for T cell maturation

a. Thymopoietins

b. Thymosins