Ch 21- Mechanisms of hormonal regulation

• Hormones can be water-soluble or lipid-soluble.

Water-Soluble Hormones

• These include peptides (growth hormone, insulin, leptin, parathyroid hormone, prolactin), glycoproteins (follicle-stimulating, luteinizing, thyroid-stimulating hormones.
• Polypeptides (adrenocorticotropic, antidiuretic hormone, calcitonin, endorphins, glucagon, hypothalamic hormones, lipotropins, melanocyte-stimulating hormone, oxytocin, somatostatin, thymosin, thyrotropin-releasing hormone).
• Amines (epinephrine, norepinephrine)

Lipid-Soluble Hormones

• Thyroxine is an amine but is lipid-soluble (both thyroxine [T4] and triiodothyronine [T3]).
• Steroids (cholesterol is a precursor)
• Estrogens, glucocorticoids (cortisol), mineralocorticoids (aldosterone), progestins (progesterone), and testosterone are all steroids
• Derivatives of arachidonic acid (autocrine or paracrine action).
• Includes leukotrienes, prostacyclins, prostaglandins, and thromboxanes.

Transmission of Protein Hormones in Blood

• Once released, hormones distribute throughout the body.
• Peptide or protein hormones are water-soluble, circulating in free (unbound) forms, and have a short half-life due to being catabolized by circulating enzymes.
• Insulin has a half-life of 3-5 minutes and is catabolized by insulinases.
• Lipid-soluble hormones (cortisol and adrenal androgens) are transported bound to a carrier protein and can remain in the blood for hours to days.
• Only free hormones can initiate changes within a target cell, a significant change in binding proteins can affect free hormone concentrations.
• Released hormones affect only cells with appropriate receptors, which recognize and bind with high affinity and initiate a signal to intracellular effectors.

Oxytocin

• It is a polypeptide hormone synthesized in the supraoptic and paraventricular nuclei of the hypothalamus.
• Oxytocin is implicated in behavior responses, especially in women; and plays a role in brain responsiveness to stressful stimuli, especially in pregnant and postpartum states.
• The posterior pituitary secretes and stores it.
• Once synthesized, it is packaged with neurophysin in secretory vesicles and moved down the pituitary stalk to the pars nervosa for storage.
• Cholinergic and adrenergic neurotransmitters mediate its release and the major stimulus for release is glutamate.
• Oxytocin causes uterus contraction and milk ejection in lactating women; and may affect sperm motility in men.
• It is secreted due to suckling and mechanical distention of the female reproductive tract.
• Suckling causes oxytocin to bind to receptors on myoepithelial cells in mammary tissues, increases intramammary pressure and milk expression (“let down” reflex).
• Uterus distention causes oxytocin to stimulate contractions (positive feedback), enhance effectiveness of contractions near the end of labor, promote placenta delivery, and stimulate postpartum uterine contractions (preventing excessive bleeding).

ADH (Antidiuretic Hormone)

• ADH controls osmolality and is a major homeostatic function of the posterior pituitary.
• It acts on vasopressin 2 (V2) receptors of renal tubular cells to increase their permeability, increasing water absorption into the blood, concentrating urine, and reducing serum osmolality.
• Its effects may be inhibited by hypercalcemia, prostaglandin E, and hypokalemia.
• The hypothalamus, located near or in the supraoptic nuclei, regulates the secretion of ADH (a polypeptide hormone) via osmoreceptors.
• ADH secretion:
• Increases when plasma osmolality increases, stimulating osmoceptors, increasing water absorption from the kidney, and diluting plasma to its set-point osmolality (approx. 280 mOsm/kg).
• Has no direct effect on electrolytes, but with increased water absorption serum electrolytes may decrease due to a dilutional effect.
• Is affected by changes in intravascular volume, monitored by baroreceptors in the left atrium, carotid arteries, and aortic arch; volume loss of 7-25% stimulates receptors.
• Increases in response to stress, trauma, pain, exercise, nausea, nicotine, heat exposure, and drugs (morphine).
• ADH secretion decreases with decreased plasma osmolality, increased intravascular volume, hypertension, increased estrogen, progesterone, and angiotensin II levels, and alcohol ingestion.
• ADH does not affect vessel tone; high serum levels act on vasopressin I (V1) receptors, causing vasoconstriction and increased arterial blood pressure.
• Vasopressin may be given during hemorrhage to achieve homeostasis and raise blood pressure in shock states.

Location of Hormone Target Cells

• The Hypothalamus at the base of the brain contains connections vital to the hypothalamic-pituitary system.
• The infundibulum connects to the pituitary gland.
• Hypophysial portal blood vessels connect to the anterior pituitary.
• The hypothalamohypophysial tract (nerve tract) connects to the posterior pituitary, where ADH/oxytocin travels.
• Hypothalamus:
• Neurosecretory cells synthesize and secrete hypothalamic-releasing hormones to regulate hormone release on the anterior pituitary
• Synthesizes ADH and oxytocin, which are stored and released from the posterior pituitary gland.
• Also synthesizes releasing/inhibitory hormones: PIH, PRH, TRH, GnRH, hypothalamic somatostatin, GHRH, CRH, and substance P.

Anterior Pituitary Hormones

• Thyrotropin-releasing hormone (TRH) stimulates release of thyroid-stimulating hormone (TSH) and modulates prolactin secretion.
• Gonadotropin-releasing hormone (GnRH) stimulates release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
• Somatostatin inhibits release of growth hormone (GH) and TSH.
• Growth hormone-releasing hormone (GHRH) stimulates release of GH.
• Corticotropin-releasing hormone (CRH) stimulates release of adrenocorticotropic hormone (ACTH) and β-endorphin.
• Substance P inhibits synthesis/release of ACTH; stimulates secretion of GH, FSH, LH, and prolactin.
• Prolactin-inhibiting hormone (PIH, dopamine) inhibits synthesis and secretion of prolactin.
• Prolactin-releasing hormone (PRH) stimulates secretion of prolactin.

Posterior Pituitary Hormones

• Antidiuretic hormone (ADH) increases water reabsorption through renal collecting ducts to reduce plasma osmolarity.
• Oxytocin stimulates contraction of the uterus and milk ejection in lactating women.

Tropic Hormones

• Adrenocorticotropic hormone (ACTH)
• Target organ: Adrenal gland (cortex)
• Function: Increases steroidogenesis (cortisol and androgenic hormones); synthesis of adrenal proteins contributing to maintenance of the gland
• Melanocyte-stimulating hormone (MSH)
• Target Organ: Anterior Pituitary
• Function: Promotes secretion of melanin and lipotropin by anterior pituitary, makes skin darker
• Growth hormone (GH)
• Target Organs: Muscle, bone, liver
• Function: Regulates metabolic processes related to growth and adaptation to physical and emotional stressors, muscle growth, increased protein synthesis, increased liver glycogenolysis, increased fat mobilization
• Affects Liver: Induces formation of somatomedins, or insulin-like growth factors (IGFs) that have actions like insulin
• Prolactin Target Organ: Breast
• Function: Milk production
• Thyroid-stimulating hormone (TSH)
• Target Organ: Thyroid gland
• Function: Increase production and secretion of hormones, increases iodide uptake and promotes hypertrophy and hyperplasia of thymocytes
• Luteinizing hormone (LH)
• Target Organ in Women: Granulosa Cells
• Function in Women: Ovulation, progesterone production
• Target Organ in Men: Leydig Cells
• Function in Men: Testicular growth, testosterone production
• Follicle-stimulating hormone (FSH)
• Target Organ in Women: Granulosa Cells
• Function in Women: Follicle maturation, estrogen production
• Target Organ in Men: Sertoli Cells
• Function in Men: Spermatogenesis
• β-Lipotropin
• Target Organ: Adipose cells
• Function: Fat breakdown and release of fatty acids
• β-Endorphins
• Target Organs: Adipose cells, brain opioid receptors
• Function: Analgesia, may regulate body temperature, food and water intake

Calcitonin

• It is controlled by the thyroid gland (secreted by C cells); also called thyrocalcitonin, it acts to lower serum calcium levels by inhibition of bone-resorbing osteoclasts.
• High levels are required for these effects, and deficiencies do not lead to hypocalcemia.
• The metabolic consequences of calcitonin deficiency or excess do not appear to be significant in humans.
• Calcitonin is used to treat osteoporosis, osteoarthritis, Paget bone disease, hypercalcemia, osteogenesis imperfecta, and metastatic cancer of the bone.
• Procalcitonin:
• Is a precursor molecule to calcitonin; a stress hormone elevated in infectious and inflammatory disorders.
• Its measurement aids in diagnosing serious diseases.
• Produced by parafollicular cells of the thyroid.
• Elevated serum calcium and gastrin stimulate calcitonin. Decreased calcium suppresses calcitonin release.
• CalcitonIN brings calcium back INTO the bone and opposes PTH.
• OsteoBLASTS: Take calcium from the bloodstream and put it back in the bone.
• OsteoCLASTS: Calcitonin receptors are on osteoCLASTS, stopping osteoclasts to prevent calcium from entering into bloodstream and ceasing bone breakdown.
• Elevated serum calcium- major stimulant for calcitonin

Calcitonin Functions

• Lowers serum calcium by opposing bone-resorbing effects of PTH, prostaglandins, and calciferols by inhibiting osteoclastic activity.
• Gastrin and other stimulants: lowers serum phosphate levels.
• Calcium-rich foods (regardless of serum Ca++ levels): May also decrease calcium and phosphorus absorption in the GI tract.
• Pregnancy: Lowered serum calcium suppresses calcitonin release

TSH (Thyroid Stimulating Hormone)

• TSH is a glycoprotein hormone synthesized and stored within the anterior pituitary.
• The anterior pituitary secretes TSH (from thyrotrophs) that binds with TSH receptor sites on the plasma membrane of thyroid follicular cells.
• TSH's role on the thyroid gland includes an immediate increase in the release of stored thyroid hormones; an increase in iodide uptake and oxidation; increase in thyroid synthesis; an increase in the synthesis and secretion of prostaglandins by the thyroid; and increased growth of the thyroid gland by stimulating thymocyte hyperplasia, hypertrophy, and decreasing apoptosis.
• Anterior pituitary releases TSH, stimulates synthesis of TH, thyroid hormone rises, a negative-feedback effect on the HPA, causing inhibition of TRH, release of TSH, decreasing TH synthesis and secretion.

Parathyroid Hormone (PTH)

• PTH is the single most important factor regulating serum calcium concentration
• It is produced by the parathyroid glands.
• The role of PTH is to increase serum calcium concentration and decrease serum phosphate concentration.
• A decrease in serum ionized calcium levels stimulates PTH secretion.
• PTH enters the circulation in unbound form, attaches to plasma membrane receptors on target tissues, mediated by activating the adenylyl cyclase system, and acts directly on bones:
• Acute hypocalcemia stimulates osteoblasts to release receptor activator for nuclear factor (NF-kb), receptor activator (RANKL), and macrophage-colony stimulating factor (M-CSF), leading to osteoclast proliferation, maturation, and the release of acidic enzymes (capthepsin), mobilizing calcium from bone (bone resorption) and increasing serum calcium levels.
• Chronic stimulation by PTH results in bone remodeling.

PTH Action

• PTH acts directly on kidneys to increase calcium reabsorption, while phosphate reabsorption is decreased.
• PTH acts on plasma membrane receptors in distal tubules of the nephron to increase the reabsorption of calcium, increasing serum calcium, which inhibits PTH secretion.
• PTH acts on the proximal tubules to decrease reabsorption of phosphorus and bicarbonate.
• Mineral containing from foods combines with calcium to form the hard structure of bones and teeth
• Phosphate:
• Phosphate comes from food.
• Phosphate is found in all cells
• Phosphate is absorbed with help from Vitamin D
• Calcium stored in bones is used when calcium levels are too low:
• Extra calcium it is taken from the bones when low and calcium levels regulated.
• Hyperphosphatemia: leads to hypocalcemia because of calcium phosphate precipitation in soft tissue and bone. Alterations in serum phosphate levels may indirectly influence secretion by affecting serum calcium levels.

Insulin

• Insulin is an anabolic hormone that promotes glucose uptake primarily in the liver, muscle, and adipose tissue. It increases the synthesis of proteins, carbohydrates, lipids, and nucleic acids
• Beta cells of the pancreas synthesize insulin from the precursor proinsulin
• Secretion is regulated by chemical, hormonal, and neural control
• Increase in Insulin secretion:
• Beta cells are stimulated by the parasympathetic nervous system (usually before eating a meal)
• Increased blood levels of glucose, amino acids (leucine, argine, and lysine) and GI hormones (glucagon, gastrin, cholecystokinin, secretin)
• Decrease in Insulin secretion:
• Response to low blood levels of glucose (hypoglycemia)
• High levels of insulin (negative-feedback to the beta cells)
• Sympathetic stimulation of the beta cells in the islets
• Prostaglandins also inhibit insulin secretion
• Insulin action facilitates the intracellular transport of potassium (K+), phosphate, and magnesium

Insulin Actions

• Actions on the Liver Cells: increased glucose uptake and glycogenesis, decreased glucose use and glycogenolysis
• More Actions: increased fatty acid synthesis, decreased ketogenesis and the urea cycle activity
• Actions on the Muscle Cells: Insulin increases glucose uptake and glycogenesis, decreases glucose use and glycogenolysis
• Actions on the Muscle Cells: increased amino acid uptake and protein synthesis
• Actions on the Adipose Cells: Insulin increases glucose uptake and glycogenesis. decreases glucose use and glycogenolysis: increases glycerol phosphate, increased fat esterification and fat storage
• Actions on the Adipose Cells: decreases lipolysis

Aldosterone

• It is most potent naturally occurring mineralocorticoids which acts to conserve sodium by increasing the activity of the sodium pump of the epithelial cells in the nephron
• Initial stages of aldosterone synthesis occur in the adrenal zona fasciculata and zona reticularis → final conversion of corticosterone to aldosterone occurs in the zona glomerulosa
• Renin-angiotensin-aldosterone system regulates aldosterone – activated by sodium and water depletion, increased potassium levels, and diminished effective blood volume
• Angiotensin II (primary stimulant of aldosterone synthesis and secretion)
• serum potassium concentration directly stimulates aldosterone secretion and ACTH acutely stimulates aldosterone secretion (secondary to angiotensin II and potassium

Feedback Mechanisms

• When Na+ and K+ levels are WNL approximately 50-250 mg of aldosterone is secreted daily (50% to 75% binds to plasma proteins)
• Aldosterone:
• maintains extracellular volume by acting on distal nephron epithelial cells to increase sodium+ reabsorption, and potassium and hydrogen excretion (renal effect takes 90 minutes – 6 hours)reabsorbed and potassium and hydrogen excretion.
• is degraded in the liver and is excreted by the kidney
• Other effects of aldosterone include:
• enhancement of cardiac muscle contraction
• Elevated levels are implicated in myocardial changes associated with heart failure.

Epinephrine and Norepinephrine

• Adrenal medulla releases chromaffin cells, which store and secrete epinephrine and norepinephrine.
• Both are synthesized from the amino acid phenylalanine.
• 30% of circulating epinephrine comes from the adrenal medulla
• 70% is released from nerve terminals.
• The medulla is only a minor source of norepinephrine
• Both categorized as water soluble amines
• Under physiologic stress to the body:
• In traumatic injury, hypoxia or hypoglycemia Acetylcholine (from preganglionic sympathetic fibers)
• Stimulated to triggers release of adrenal catecholamines
• Depolarizes chromaffin cells, exocytosis of storage granules, and the release of both into the bloodstream
• ACTH and glucocorticoids increase secretion of catecholamines
• Catecholamines remain in plasma for seconds – minutes, exerts rapid biologic effects by activating adenylyl cyclase system.
• Neurons remove catecholamines from plasma, store them in new cytoplasmic granules, or they undergo deactivation and excretion in urin
• Catecholamines have diverse effects on the entire body

Catecholamines have diverse effects

• Release and body response have been characterized as the “fight or flight” response.
• These activate adrenergic receptors on cell membranes of ALL visceral organs and smooth muscles, and promote hyperglycemia
• Epinephrine increases heart rate, oxygen intake and blood flow
• Norepinephrine maintains blood pressure