HYPOthalamic-pituitary dysfunction Chapter 17 & 18

Hypothalamic-pituitary system Neuroendocrine System Contains the hypothalamus and Pituitary Gland Controls thyroid, adrenal and reproductive function

Anterior pituitary TROPIC HORMONES MSH: secretion of melanin (melanocyte stimulating hormone) FSH: estrogen production and spermatogenesis (follicle stimulating hormone) LH: ovulation, progesterone and testosterone production (luteinizing hormone) ACTH: cortisol production and maintenance of adrenal gland (adrenocorticotropic hormone) TSH: thyroid hormone production (thyroid stimulating hormone) GH: skeletal muscle growth, regulates metabolism, necessary for stress adaptation (growth hormone) Regulated by GHRH and Somatostatin IGF-1 and IGF-2 (insulin-like growth factor) Prolactin: milk production (lactation)

Posterior pituitary POLYPEPTIDE HORMONES ADH (vasopressin): controls plasma osmolality (antidiuretic hormone) Regulated by glutamate and GABA Increased release with stress, trauma, decreased intravascular volume Decreased release with decreased plasma osmolality and increased intravascular volume Oxytocin: uterine contraction and milk ejection Also has some antidiuretic effects

Adrenal glands

Adrenal Medulla Catecholamine secretion Epinephrine and norepinephrine

Adrenal Cortex Glucocorticoids Carbohydrate metabolism, immune suppression, anti-inflammatory effects, suppress bone formation, suppress ADH secretion, stimulate gastric acid secretion In high levels cause: Increased appetite, fat deposits in face, abdomen, upper back, hypocalcemia, decreased ACTH synthesis

Cortisol CRH  ACTH  cortisol secretion Potent naturally occurring glucocorticoid Necessary for maintenance of life Diurnal release of ACTH Negative feedback loop associated with ACTH release Increased release: low levels of circulating cortisol; stress reactions Decreased release: high levels of circulating cortisol; synthetic glucocorticoid use

Mineralcorticoids Aldosterone Natural occurring mineralcorticoid Promotes sodium retention and potassium excretion Regulated by the renin-angiotensin system (primarily angiotensin II) Sodium and water depletion Hyperkalemia Decreased blood volume

Hormonal alterations 1. Inadequate Synthesis Precursor dysfunction 2. Failure of Feedback Systems Too much or too little hormone synthesis 3. Inactive Hormones Directly inhibited or degraded 4. Ineffective Hormone Delivery Decreased blood supply Inadequate carriers 5. Decreased Target-Cell Sensitivity Too little receptors Presence of antibodies on receptors

SIADH Increased ADH release regardless of plasma osmolality Causes: Neoplasms Pulmonary disorders CNS disorders Medications

Manifestations: HYPONATREMIA Thirst Dyspnea Fatigue Vomiting Confusion (late) Lethargy (late) Convulsions (late) Irreversible neurological damage (late)

Diagnostics: Treatment: Serum hypoosmolality Serum hyponatremia Urine hyperosmolality Normal adrenal, thyroid, and renal function Resistant hyponatremia Treatment: Fluid restriction Hypertonic solutions Use of demeclocycline

demeclocycline Tetracycline drug class Has unique side effect of stimulating urine flow Used for SIADH

Diabetes insipidus Decreased ADH release Causes: Neurogenic Insufficient secretion of ADH Interference of ADH synthesis (brain tumors, aneurysm, infection, thrombosis) Nephrogenic Renal tubules do not respond appropriately to ADH Acquired Pyelonephritis, polycystic kidney disease, anesthetics, medications Genetic

Manifestations: Polyuria Nocturia Thirst Polydipsia Dilute urine Urine hypoosmolality Serum hypernatremia Serum hyperosmolality

Treatment: Desmopressin Treatment of underlying cause

desmopressin Vasopressin Antidiuretic hormone Promotes renal conservation of water, increasing permeability of renal tubules Used for Diabetes Insipidus Given intranasally, SQ, IV, or PO Adverse effects: Excessive water retention Limited side effects

Hypopituitarism Causes: Inadequate Hypothalamic Releasing Hormones Inadequate anterior pituitary gland Infarction Adenoma Damage to pituitary stalk Meningitis Tuberculosis Autoimmune disorders

Manifestations: Deficient ACTH : anorexia, fatigue, hypoglycemia Deficient TSH : cold intolerance, lethargy, decreased metabolism Deficient FSH and LH : amenorrhea, testicular atrophy, decreased libido Deficient GH : hypopituitary dwarfism (children) Feeling of poor well-being, osteoporosis, fatigue (adult) generalized complaints Panhypopituitarism (all anterior pituitary hormones are deficient)

HYperpituitarism Acromegaly Prolonged exposure to increased GH and IGF-1 Middle aged adults Rare Slowly progressive Cause: Pituitary adenoma

Manifestations: Enlarged tongue Enlarged sweat glands Coarse skin Excessive body hair Enlargement of facial bones (protrusion of forehead and jaw) Enlargement of hands and feet

Treatment: Surgical removal of GH secreting adenoma Radiation Octreotide Lanreotide Pegvisomant

Somatostatin analogs Ocreotide Lanreotide IM injection Indicated for acromegaly Adverse effects: GI symptoms gallstones Lanreotide Prefilled SQ syringe Diarrhea

Growth hormone receptor antagonist Pegvisomant Most effective drug option for acromegaly SQ injection Expensive Adverse effects: GI upset Chest pain Flu-like symptoms Monitor hepatic function

Prolactinoma Sustained, elevated release of prolactin Manifestations: Galactorrhea Amenorrhea Treatment: Bromocriptine Cabergoline Causes: Pituitary tumor

Dopamine agonists Ergot derivatives Cabergoline -PO with or without food -can be used to correct amenorrhea, infertility and galactorrhea associated with a prolactinoma -can also cause tumor regression -immediate effects of decreased prolactin secretion -should monitor prolactin monthly until normal, treatment can stop after 6 months of normal levels -adverse effects: nausea, headache, dizziness Bromocriptine Similar, except is not tolerated as well as cabergoline

Alterations of adrenal function HYPERCORTISOLISM Cushing Syndrome Chronic exposure to excessive cortisol Cushing Disease Excessive secretion of ACTH Cushing-Like Syndrome Administration of synthetic glucocorticoids

Manifestations: Weight gain Fat deposits in face, trunk and cervical area (moon face, buffalo hump) Glucose intolerance (hyperglycemia) Protein wasting (thin extremities) Osteoporosis Collagen loss (thin, weak skin, striae, bruising) Increased catecholamine activity (hypertension) Increased mineralcorticoid activity (edema, potassium loss) Cushing Disease in Females (increased androgen levels) Increased hair growth Acne amenorrhea

Diagnostics: Urine cortisol Dexamethasone suppression test Measurement of ACTH and cortisol levels

Treatment: treat underlying cause tumor removal radiation therapy Ketoconazole antifungal, but also blocks glucocorticoid synthesis 600-800 mg/day (high doses) must monitor liver enzymes at this high dose

Secondary Adrenal Insufficiency : decreased ACTH HYPOCORTISOLISM Addison’s Disease (Primary Adrenal Insufficiency) : increased ACTH, decreased cortisol and aldosterone Secondary Adrenal Insufficiency : decreased ACTH Causes: Autoimmune attack of the adrenal cortex (Primary Adrenal Insufficiency) Prolonged administration of glucocorticoids (Secondary Adrenal Insufficiency) Pituitary tumors (Secondary Adrenal Insufficiency) Infections (tuberculosis)

Manifestations: Weakness Fatigue Hyperpigmentation of the skin (only in Addison’s disease) Weight loss Hypotension Hypoglycemia Syncope

Diagnostics: Hyperkalemia Hyponatremia Hypoglycemia Decreased serum and urine cortisol Increased ACTH (Addison’s Disease)

Treatment: Lifelong glucocorticoid supplementations (higher doses during acute stressors) Hydrocortisone Mineralcorticoid supplementation Fludrocortisone

Hydrocortisone For use in Addison’s Disease Take entire dose in am or 2/3 in am and remainder in afternoon Lifelong supplementation Increased dose at times of stress Excessive doses can produce symptoms of Cushing’s Syndrome

Mineralcorticoid replacement 0.1 mg PO daily Fludricortisone Mineralcorticoid replacement 0.1 mg PO daily Used in combination with glucocorticoid Adverse effects: With high doses Hypertension Hypokalemia Weight gain Edema

Hypersecretion of androgens and estrogens Caused by adrenal adenomas or carcinomas Feminization: development of female secondary sex characteristics Gynecomastia, testicular atrophy, decreased libido, early development of sex characteristics Virilization: development of male secondary sex characteristics Excessive face/body hair growth, clitoral enlargement, amenorrhea, acne, breast atrophy

Tumor of adrenal medulla PHEOCHROMOCYTOMA Causes continuous, excessive secretion of catecholamines Rare and can be malignant Manifestations: Hypertension, tachycardia, diaphoresis, palpitations, headaches, hypermetabolism Treatment: Check for excessive catecholamines in blood and urine Surgical removal of tumor Alpha and beta blockers