Preprohormone synthesis occurs on the RER and is directed by a specific mRNA.

Signal peptides are cleaved producing a prohormone, which is transported tot he Golgi.

Additional peptide sequences are cleaved to form the hormone, which is packaged in secretory granules for later release.

Derivatives of cholesterol.

Usually not stored.

Lipid soluble.

Thyroid, epi, norepi are derivatives of tyrosine.

Dissolved in plasma, transported to target tissues where they diffuse out of capillaries and into interstitial fluid and ultimately to target cells.

Circulate in blood mainly bound to plasma (>90% bound to albumin).

Bound proteins serve as storage reservoirs.

Hormone Secretion

Negative Feedback

Most commonly applied principle for regulating hormone secretion.

Self-limiting.

Hormone has biologic actions that, directly or indirectly inhibit further secretion of the same hormone.

Controlled variable is not the secretory rate of the hormone but the activity of the target tissue.

Hormone Secretion

Positive Feedback

Rare, explosive and self-reinforcing.

Hormone has biologic actions that, directly or indirectly, cause more secretion of the hormone.

Cyclical variations are superimposed on the negative/positive feedback control.

Influenced by seasonal changes, aging, diurnal cycles and sleep.

Increased/decreased by rate of secretion and rate of removal (metabolic clearance rate).

Hormones cleared through plasma by:

metabolic destruction by tissues

binding with tissues

excretion by liver into bile

excretion by kidneys

Water soluble and circulate freely in the blood.

Degraded by enzymes and rapidly excreted through the kidney or liver.

Too much hormone can have significant consequences.

Located on/in the target cell.

Large proteins, each cell to be stimulated has 2K-100K receptors, quantity not constant due to inactivation, destruction, and down regulation.

Hormones are highly specific.

Hormone decreases the number or affinity of receptors for itself or for another hormone.

Hormone increases the number or affinity of receptors for itself or another hormone.

Most all NT substances (ACh and norepi) combine with receptors in the postsynaptic membrane.

This causes a change in the receptor usually opening or closing a channel for more ions.

This altered movement of ions causes subsequent effect on postsynaptic cells.

Many hormones activate receptors that indirectly regulate the activity of target proteins by coupling with groups of cell membrane proteins called GTP-binding proteins (G-proteins).

More than 1000 known G-protein receptors.

guanosine triposphate (GTP) binding proteins that couple hormone receptors to adjacent effector molecules.

Diffuse across the cell membrane of target cells and bind to a cytosolic receptor and then to a nuclear receptor.  Causing a conformational change in the receptor which exposes a DNA-binding domain.  In the nucleus, the DNA-binding domain on the receptor interacts with the hormone-regulatory elements of specific DNA.  Transcription is initiated and results in new mRNA, which is translated in the cytoplasm and results in the production of specific proteins.

Measuring Hormones

Radioimmunoassays

First an antibody that is specific to the hormone to be measured is produced.

A small amount of the antibody is mixed with fluid from the subject to be measured.

Mixed with hormone that has been tagged with radioactive isotope.  Must be too little antibody to bind with all the hormone, making the natural hormone and the RA compete for binding.

The quantity of each is proportional to the concentration in the assay fluid.  If more RA binds, then low natural hormone.

Enzyme linked immunosorbant assays

Used to measure any protein.

Uses excess antibodies so all hormone molecules are captured in antibody/hormone complexes.

The amount of hormone captured is proportional to the hormone formed.

Widely used in clinical practice.

No RA isotopes.

Cost effective and automated.

Anterior lobe linked to the hypothalamus by the hypothalamic-hypophysial portal system.  Blood from the hypothalamus is delivered directly to the anteror pituitary.

Posterior lobe is derived from neural tissue.  nerve cell bodies are located in hypothalamic nuclei.  Hormones are synthesized in the nerve cell bodies, packaged in secretory granules, and transported down the axons to the posterior pituitary for release into circulation.

Growth hormone

Prolactin

TSH

LH

FSH

ACTH

Growth Hormone

Most important hormone for normal growth.

Single-chain polypeptide, homologous with prolactin and human placental lactogen.

Released in pulsatile fashion.

Secretion is increased by sleep, stress, hormones related to puberty, starvation, exercise, and hypoglycemia.

Secretion decreased by somatostatin, somatomedins, obesity, hyperglycemia, and pregnancy.

Growth hormone

Regulation

Hypothalamic control - GHRH and somatostatin

GHRH stimulates the synthesis and secretion of growth hormone.

Somatostatin inhibits secretion of growth hormone by blocking the response of the anterior pituitary to GHRH.

Negative feedback by somatomedins, which are produced when growth hormone acts on target tissues.

Somatomedins inhibit the secretion of growth hormone by acting directly on the anterior pituitary and by stimulating the secretion of somatostatin from the hypothalamus.

Negative feedback by GHRH and growth hormone.

GHRH inhibits its own secretion from the hypothalamus.

Growth hormone also inhibits its own secretion by stimulating the secretion of somatostatin from the hypothalamus.

Growth Hormone

Direct Actions

In the liver, growth hormone generates the production of somatomedins (IGF)

Decrease glucose uptake into cells

Increase lipolysis

Increase Protein Synthesis in muscle

Increase lean body mass

Increase production of IGF

Growth Hormone

Actions via IGF

Increase protein synthesis in chondrocytes

Increase linear growth

Increase protein synthesis in muscle

Increase lean body mass

Increase protein synthesis in most organs.

Increase organ size.

Growth Hormone

Deficiency

In children causes failure to grow, short stature, mild obesity, and delayed puberty.

Can be caused by:

Lack of anterior pituitary growth hormone

Hypothalamic dysfunction (decreases GHRH)

Failure to generate IGF in the liver

Growth hormone receptor deficiency

Growth Hormone

Excess

Treated with somatostatin analogs (octreotide), which inhibit growth hormone secretion.

Hypersecretion causes acromegaly.

Before puberty, causes increased linear growth (gigantism)

After puberty, causes increased periosteal bone growth, increased organ size, and glucose intolerance.

Major hormone responsible for lactogenesis.

Participates with estrogen for breast development.

Structurally homologous to growth hormone.

Prolactin

Regulation of secretion

Hypothalamic control by dopamine and thyrotropin releasing hormone (TRH)

Tonically inhibited by dopamine (PIF) so interruption of the hypothalamic-pituitary tract causes increased secretion of prolactin and sustained lactation.

TRH increases prolactin secretion.

Negative feedback by stimulating the hypothalamic release of dopamine.

Prolactin

Actions

Stimulates milk production.

Stimulates breast development.

Inhibits ovulation by decreasing synthesis and release of GnRH

Inhibits spermatogenesis

Prolactin

Physiology

Prolactin deficiency (destruction of the anterior pituitary), results in failure to lactate.

Prolactin excess results from hypothalamic destruction (due to loss of the tonic inhibitory control by dopamine) or from prolactin-secreting tumors (prolactinomas).

Causes galactorrhea and decreased libido.

Causes failure to ovulate and amenorrhea because it inhibits GnRH secretion.

Treated by bromocriptine, which reduces prolactin secretion by decreasing prolactin release by the anterior pituitary.

Females - blockage of the action of gonadotropins on the ovaries (20% secondary amenorrhea, infertility, risk of OP due to estrogen deficiency.

Male - impotence and hypogonadism.

70% patients with chromophobe adenomas of the anterior pituitary (prolactinoma).

Homologous nonapeptides.

Synthesized in hypothalamic nuclei and are packaged in secretory granules with their respective neurophysins.

Travel down the nerve axons for secretion by the posterior pituitary.

ADH

Actions

Regulates serum osmolarity by increasing the H2O permeability of the late distal tubules and collecting ducts.

Increased H2O permeability of the principal cells of the late disal tubules and collecting duct (via a V2 receptor and an adenylate cyclase cAMP mechanism.

Constriction of vascular smooth muscle (via V1 receptor and an IP3/Ca2 mechanism)

ADH

Physiology

Increases the urea permeability of the inner medullary collecting ducts.

Urea reabsorption from inner medullary collecting ducts contributes to urea recycling in the inner medulla and to the development of the cortico-papillary osmotic gradient.

Production of concentrated urine is also called hyperosmotic urine, produced when circulating ADH levels are high (water deprivation, hemorrhage, SIADH).

Oxytocin

Regulation

Causes ejection of milk from the breast when stimulated by suckling.

Suckling is the major stimulus for secretion.

Afferent fibers carry impulses from the nipple to the spinal cord.  Relays in the hypothalamus trigger release from the posterior pituitary.

Sight or sound of the infant may stimulate even in the absence of suckling.

Dilation of the cervix and orgasm increase the secretion of oxytocin.

Oxytocin

Action

Contraction of myopithelial cells in the breast.

Contraction of the uterus.

Can be used to induce labor and reduc post partum bleeding.

Present in the thyroid follicular epithelial cells.

Actively transports I- into the thyroid follicular cells for subsequent incorporation into thyroid hormones.

Thyroid Gland

Oxidation

Catalyzed by a peroxidase enzye in the follicular cell membrane.

Is the reactive form, which will be organified by combination with tyrosine on thyroglobulin.

Peroxidase enzyme inhibited by propyithiouracil, which is used to reduce thyroid hormone synthesis for the treatment of hyperthyroid.

The same enzyme catalyzes the remaining organification and coupling reactions involved in the synthesis of thyroid hormones.

Thyroid Gland

Organification

Tyrosine is incorporated into thyroglobulin on the ribosomes of the thyroid follicular cells.

Thyroglobulin is then packaged in secretory vesicles on the Golgi and extruded into the follicular lumen.

At the junction of the follicular cells and the follicular lumen, tyrosine residues of thyroglobuline react with I2 to form MIT and DIT.

Thyroid Gland

Coupling of MIT and DIT

While attached to thyroglobulin, two coupling reactions occur.

DIT + DIT = T4

DIT + MIT = T3

More T4 than T3 is synthesized, although T3 is more active.

Thyroid Gland

Iodinated Thyroglobulin

Stored in the follicular lumen until the thyroid gland is stimulated to secrete thyroid hormones.

Thyroid Gland

Stimulation of Thyroid Cells by TSH

When the thyroid cells are stimulated, iodinated thyroglobulin must be taken into the follicular cells.  Lysosomal enzymes then digest thyroglobulin, releasing T4 and T3 into circulation.

Leftover MIT and DIT are deiodinated by thyroid deiodinase.  The I2 released is reutilized to synthesize more thyroid hormones, therefore deficiency mimics B-12 deficiency.

Thyroid Gland

Binding of T3 and T4

Most of the T3 and T4 is bound to thyroxine-binding globulin (TBG).

In hepatic failure, TBG levels decrease, leading to a decrease in total thyroid hormone levels, but normal levels of free hormone.

In pregnancy, TBG levels increase, leading to an increase in total thyroid hormone levels, but normal levels of free hormone.

Thyroid Gland

Conversion of T4 to T3 and reverse T3 (rT3)

In the peripheral tissues, T4 is converted to T3 or rT3.

T3 is more biologically active than T4

rT3 is inactive.

Thyroid hormone

Secretion

Hypothalamic-Pituitary control TRH and TSH

TRH is secreted by the hypothalamus and stimulates the secretion of TSH by the anterior pituitary.

TSH increases both the synthesis and the secretion of thyroid hormones by the follicular cells via an adenylate cyclase-cAMP mechanism.

Chronic elevation of TSH causes hypertrophy of the thyroid gland.

T3 down-regulates TRH receptors in the anterior pituitary and thereby inhibits TSH secretion.

Thyroid Hormone

Secretion

Thyroid-stimulating immunoglobulins

Components of IgG fraction of plasma proteins and are antibodies to TSH receptors on the thyroid gland.

They bind to TSH receptors and stimulate the thyroid gland to secrete T3 and T4.

Circulate in high concentrations in patients with Graves' disease, which is characterized by high circulating levels of thryoid hormones and low concentrations of TSH (caused by feedback inhibition of thyroid hormones on the anterior pituitary)

Thyroid hormone

Actions

Growth

Attainment of adult stature requires thyroid hormone.

Thyroid hormones act synergistically with growth hormone and somatomedins to promote bone formation.

Thyroid hormones stimulate bone maturation as a result of ossification and fusion of the growth plates.

in thyroid hormone deficiency, bone age is less than chronologic age.

Thyroid Hormone

Actions

CNS - perinatal

Maturation of the CNS is absolutely dependent on thyroid hormone in the perinatal period.

Thyroid hormone deficiency causes irreversible mental retardation.  There is only a brief perinatal period when thyroid hormone replacement therapy is helpful, screening is mandatory.

Thyroid Hormone

Actions

CNS -adulthood

Hyperthyroidism causes hyperexcitability and irritability.

Hypothyroidism causes listlessness, slowed speech, somnolence, impaired memory, and decreased mental capacity.

Thyroid Hormone

Action

ANS

Many of the same actions as the Sympathetic NS because it up-regulates B1-adrenergic receptors in the heart.

Useful adjunct therapy for hyperthyroidism is treatment with a 3-adrenergic blocking agent, such as propanolol.

Thyroid Hormone

Actions

Basal Metabolic Rate (BMR)

O2 consumption and BMR are increased by thyroid hormone in all tissues except the brain, gonads, and spleen.  The resulting increase in heat production underlies the role of thyroid hormone in temperature regulation.

Increases the synthesis of Na, K-ATPase and consequently increases O2 consumption related to Na-K pump activity.

Thyroid Hormone

Actions

Cardio/Resp

Effects of thyroid hormone on cardiac output and ventilation rate combine to ensure that more O2 is delivered to the tissues.

Heart rate and stroke volume are increased.  These effects combine to produce increased cardiac output.

Ventilation rate is increased.

Thyroid Hormone

Metabolic Effects

Metabolism is increased to meet the demand for substrate associated with the increased rate of O2 consumption.

Glucose absorption from the GI tract is increased.

Glycogenolysis, gluconeogenesis, and glucose oxidation are increased.

Lipolysis is increased.

Protein synthesis and degradation are increased.  The overall effect of thryoid hormone is catabolic.

Zona Glomerulosa - produces aldosterone.

Zona fasciculata - produces mostly glucocorticoids (cortisol)

Zona reticularis - produces mostly androgens.

Progesterone, deoxycorticosterone, aldosterone, and cortisol

Progesterone is the precursor.

(19)Androgenic activity and precursors to the estrogens.

(18) have estrogenic activity

Glucocorticoid

Secretion

Oscillates with a 24-hour periodicity or circadian rhythm.  Levels are highest just before waking and lowest in the evening.

Synthesize POMC and secrete ACTH.

Second messenger is cAMP.

Increases steroid hormone synthesis in all zones of the adrenal cortex by stimulating cholesterol desmolase and increasing the conversion of cholesterol to pregnenolone.

Up-regulates its own receptor so that the sensitivity of the adrenal cortex to ACTH is increased.

Chronically increased levels cause hypertrophy of the adrenal cortex.

Second messenger is cAMP.

Cortisol

Negative Feedback

Inhibits secretion of CRH from the hypothalamus and the secretion of ACTH from the anterior pituitary.

When chronically elevated, the secretion of CRH and ACTH is inhibited by negative feedback.

Based on the ability of dexamethasone to inhibit ACTH secretion.

In normal persons, low-dose dexameth inhibits or suppresses ACTH secretion and cortisol secretion.

In persons with ACTH-secreting tumors, low-dose dexameth does not inhibit cortisol but high-dose dexameth does.

In persons with adrenal cortical tumors, neither low or high dose dexameth inhibits cortisol secretion.

Decreases in blood volume, cause a decrease in renal perfusion pressure, which increases renin secretion.  Renin catalyzes angiotensinogen to angiotensin 1, which is converted to angiotensin II by ACE.

Angiotensin II acts on the zona glomerulosa of the adrenal cortex to increase the conversion of corticosterone to aldosterone.

Aldosterone increases the renal Na reabsorption, restoring ECF volume and blood volume to normal.

Increases aldosterone secretion.

Aldosterone increases renal K secretion, restoring blood K to normal.

Glucocorticoids increase gluconeogenesis by increasing protein catabolism in muscle and decreasing protein synthesis, thereby providing more amino acids to the liver and gluconeogenesis.

Decrease glucose utilization and insulin sensitivity of adipose tissue.

Increase lipolysis, which provides more glycerol to the liver for gluconeogenesis.

Glucocorticoids

Anti-inflammatory Effects

Induce the synthesis of lipocortin, an inhibitor of phospholipase A2, which liberates arachidonate from membrane phospholipids, providing the precursor for prostaglandin and leukotriene synthesis.

Prostaglandins and leukotrienes are involved in the inflammatory response, glucocorticoids have anti-inflammatory properties by inhibiting arachidonate.

Inhibit the production of interleukin-2 and inhibit proliferation of T lymphocytes.

Inhibit the release of histamine and serotonin from mast cells and platelets.

Most commonly caused by autoimmune destruction of the adrenal cortex, causing acute adrenal crisis:

Decreased adrenal glucocorticoid, androgen, and mineralcorticoid.

Increased ACTH

Hypoglycemia

Weight loss, weakness, N/V

Hyperpigmentation

Decreased pubic and axillary hair in women.

ECF volume contraction, hypotension, hyperkalemia, and metabolic acidosis.

Glucocorticoids inhibit the production of IL-2 and T lymphocytes, which are critical for immunity.

Glucocorticoids are used to prevent rejection of transplanted organs.

Cortisol up-regulates alpha1 receptors on arterioles, increasing the vasoconstrictor effect of norepi.

Cortisol excess, arterial pressure increases.

Cortisol deficiency, arterial pressure decreases.

Aldosterone

Actions

Increased renal Na reabsorption

Increased Renal K secretion

Increased Renal H secretion

Caused by primary deficiency of ACTH.

Does not exhibit hyperpigmentation.

Does not exhibit volume contraction, hyperkalemia, or metabolic acidosis.

Symptoms similar to Addison's

Most commonly caused by the administration of pharmacologic doses of glucocorticoids.

Less commonly caused by bilateral hyperplasia of the adrenal glands.

Called Cushing's when it is caused by overproduction of ACTH.

Cushing's

Increased Cortisol and androgen

Increased ACTH

Hyperglycemia

Increased protein catabolism and muscle wasting

Central obesity

Poor wound healing

Virilization of women

HTN

OP

Striae

Ketoconazole, an inhibitor of steroid hormone synthesis, can be used for treatment.

Caused by an aldosterone-secreting tumor.

HTN

Hypokalemia

Metabolic alkalosis

Decreased renin secretion

Tumor of the adrenal medulla that secretes excessive amounts of catecholamines and is associated with increased excretion of VMA

Glucagon

Actions

Acts on the liver and adipose tissue, second messenger is cAMP.

Increases blood glucose by increasing glycogenolysis and prevents the recycling of glucose into glycogen, increases gluconeogenesis.

Increases blood fatty acid and ketoacid concentration, increases lipolysis.

Increases urea production.

Insulin

Regulation

Glucose binds to the receptor on beta cells.

Inside the beta cells, glucose is oxidized to ATP, which closes K channels in the cell membrane and leads to depolarization of the beta cells.  Sulfonyurea drugs stimulate insulin secretion by closing these K channels.

Depolarization opens Ca channels, which leads to an increase in intracellular Ca and then to secretion of insulin.

Insulin

Actions

Decreases blood glucose by:

Increases uptake of glucose into target cells

Promotes formation of glycogen from glucose in the muscle and liver, inhibiting glycogenolysis.

Decreases gluconeogenesis.

Decreases fatty acids/ketoacid concentrations in the blood.

Stimulates fat deposition and inhibits lipolysis and ketoacid formation.

Decreases blood amino acid concentration by stimulating the amino acid uptake into cells, increasing protein synthesis, and inhibiting protein degradation (anabolic).

Decreases blood K concentration by increasing K uptake into cells.

Produced by delta cells found in the stomach, intestine, and Islets of Langerhans in the pancreas.

Inhibitory hormone which inhibits the release of GH and TSH.

Suppresses the release of GI hormones.

Lowers the rate of gastric emptying, reduces smooth muscle contractions and blood flow within the intestine.

Inhibits release of insulin and glucagon.

Suppress the exocrine secretory action of pancreas.

40% of total Ca in blood is bound to plasma proteins.

60% is ultrafilterable, including Ca that is complexed to anions such as phosphate and free Ca++, which is biologically active.

Serum Ca is determined by the interplay of intestinal absorption, renal excretion, and bone remodeling. Hormonally regulated.

Seen in growing children

Intestinal Ca absorption exceeds urinary excretion, excess is deposited in the growing bones.

Seen in women during pregnancy or lactation

Intestinal Ca absorption is less than Ca excretion, and the deficit comes from maternal bones.

PTH

Secretion

Major hormone for regulation of serum Ca.

Synthesized and secreted by chief cells.

Controlled by serum Ca through negative feedback.  Decreased serum Ca increases PTH.

Mild decreases stimulate PTH secretion.

Severe decreases inhibit PTH secretion and produce symptoms of hypoparathyroidism (hypocalcemia)

Second messenger is cAMP

PTH

Action

Produce an increase in serum CA and decrease in serum Phosphate.

Second messenger is cAMP

Increases bone resorption, which brings both Ca and phosphate from bone mineral into ECF.

Inhibits renal phosphate reabsorption in the proximal tubal and increases phosphate excretion.

Increases renal Ca reabsorption.

Increases Intestinal Ca absorption.

Primary Hyperparathyroidism

Parathyroid adenoma

Increases serum Ca

Decreased serum phosphate

Increases urinary phosphate excretion

Increases urinary Ca excretion

Increased urinary cAMP

Increased bone resorption

Caused by PTH-related peptide (PTH-rp)

Secreted by some malignant tumors.

Has all the physiologic actions of PTH

Increased serum Ca

Decreased serum phosphate

Incrased urinary phosphate excretion

Decreased serum PTH levels

Most commonly a result of thryoid surgery or congenital.

Decreased serum Ca and tetany

Increased serum phosphate

Decreased urinary phosphate excretion

Pseudohypoparathyroidism

Type Ia-Albright's hereditary osteodystrophy

Defective G5 protein in kidney and bone, which causes end-organ resistance to PTH.

Hypocalcemia and hyperphosphatemia occur which are not correctable by the administration of exogenous PTH.

Circulating PTH levels are elevated.

Decreased GFR leads to decreased filtration of phosphate, phosphate retention, and increased serum phosphate, which complexes Ca and leads to decreased ionized Ca.

Decreased production of 1,25-dihydroxycholecalciferol by the diseased renal tissue, also contributes to decreased ionized Ca

Decreased Ca causes secondary hyperparathyroidism.

Combination of increased PTH and decreased 1,25 produces renal osteodystrophy, in which there is increased bone resorption and osteomalacia.

Provides Ca and phosphate to ECF for bone mineralization.

In children, deficiency causes rickets.

In adults, deficiency causes osteomalacia.

Secretion by increase in serum Ca.

Inhibits bone resorption.

Participates in Ca and phosphorus metabolism.  In many way, counter effects PTH.

Reduces blood Ca by:

Decreasing Ca absorption by the intestines.

Decreasing osteoclast activity in bones.

Decreasing Ca and phosphate reabsorption by the kidney tubules.