Hyperpituitarism and hypopituitarism Notes

Chapter 2 Acyanotic Defects NOTES HYPERPITUITARISM & HYPOPITUITARISM GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders caused by excess/insufficient pituitary hormones, disruption in hypothalamic-pituitary axis function CAUSES Hyperpituitarism ▪ Genetic inheritance ▪ Secreting tumors (intracranial, ectopic) Hypopituitarism ▪ Intracranial tumors, bleeding, infarction ▪ Neurosurgery, head trauma, infection ▪ Idiopathic SIGNS & SYMPTOMS ▪ Disruption in growth, regulation; depends on affected hormones ▪ If pituitary adenoma, sequence of loss: “Go Look For The Adenoma” (see mnemonic) MNEMONIC: Go Look For The Adenoma Pituitary adenoma sequence of loss Growth hormone (GH) Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Thyroid-stimulating hormone (TSH) Adrenocorticotropic hormone (ACTH) DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan, MRI ▪ Intracranial, ectopic tumors; bleeding, infarction LAB RESULTS ▪ Altered levels of pituitary, target tissue hormones OTHER DIAGNOSTICS ▪ History, physical examination TREATMENT MEDICATIONS Hyperpituitarism ▪ Somatostatin + dopamine agonists; GH receptor antagonists Hypopituitarism ▪ Hormone replacement (e.g. glucocorticoids, thyroid hormone) SURGERY ▪ Surgical excision of tumor OSMOSIS.ORG 107

ACROMEGALY osms.it/acromegaly PATHOLOGY & CAUSES ▪ GH hypersecretion in adulthood after epiphyseal closure → enlargement of extremities, face CAUSES ▪ Pituitary adenoma produces excess GH ▪ Nonpituitary tumors (pancreatic, lung, adrenal gland) produce ectopic GH COMPLICATIONS ▪ Glucose intolerance to Type II diabetes, high blood pressure, respiratory problems, carpal tunnel syndrome, heart/kidney failure SIGNS & SYMPTOMS ▪ Soft tissue, bone swelling ▫ Hands, feet ▫ Skull: jaw protrusion, enlargement (macrognathia), increased spacing of teeth; forehead, brow protrusion ▫ Organomegaly: heart, kidneys; vocal cords → slow, deep voice ▪ Joint pain, headache, vision problems, thickened skin ▪ Excess sweating, hair growth, pigmentation LAB RESULTS Blood tests ▪ Acromegaly ▫ ↑ insulin-like growth factor-1 (IGF-1) / somatomedin C ▪ Oral glucose tolerance test (OGTT) ▫ Hyperglycemia TREATMENT MEDICATIONS ▪ Somatostatin agonists ▫ Stop GH production ▪ Dopamine agonists, alternative to somatostatin agonists ▫ For tumors that affect prolactin levels ▪ GH receptor antagonists ▫ Blocks GH binding to receptors SURGERY ▪ Transsphenoidal tumor resection OTHER INTERVENTIONS ▪ Tumor radiation DIAGNOSIS DIAGNOSTIC IMAGING MRI of sella turcica with gadolinium ▪ Somatotroph adenoma; tumoral location CT scan of chest/abdomen ▪ Ectopic tumors 108 OSMOSIS.ORG Figure 18.1 The clinical appearance of acromegaly. The facial features are coarse and mandibular overgrowth has lead to prognathism.

Chapter 18 Hyperpituitarism & Hypopituitarism Figure 18.2 The appearance of the hands in the case of acromegaly. The acromegalic right hand is larger with expanded soft tissues and thickened, stubby fingers. CONSTITUTIONAL GROWTH DELAY osms.it/constitutional-growth-delay PATHOLOGY & CAUSES ▪ Normal variation in rate of growth → temporary delay during early childhood, puberty ▪ Eventual adult height within normal range CAUSES ▪ Alterations in hormones critical for growth, development ▪ GH axis: regulates bone, muscle growth ▪ ↓ GH → ↓ production of IGF-1/ somatomedin C (prevents cell death), ↑ cellular metabolism, cell division, differentiation throughout body ▪ Hypothalamic-pituitary-gonadal axis: regulates sexual maturation ▪ ↓ gonadotropin-releasing hormone (GnRH) → ↓ anterior pituitary production of gonadotropins (LH, FSH) → ↓ production of sex hormones by gonads (estrogen, progesterone in individuals who are biologically female, testosterone in individuals biologically male) → delayed development of sex organs, secondary sexual characteristics RISK FACTORS ▪ Family history of delayed growth COMPLICATIONS ▪ Psychosocial stress SIGNS & SYMPTOMS ▪ Normal size at birth ▪ Short preadolescent stature ▪ Delayed pubertal development, skeletal age DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Delayed bone development OTHER DIAGNOSTICS ▪ History, physical examination ▪ Height growth curve below, parallel to third percentile ▪ Delayed Tanner scale staging OSMOSIS.ORG 109

TREATMENT OTHER INTERVENTIONS ▪ Provide reassurance regarding eventual normal growth, development DIABETES INSIPIDUS (DI) osms.it/diabetes-insipidus PATHOLOGY & CAUSES ▪ Disorder of fluid balance characterized by defect in urine concentration → excretion of large volumes of dilute urine ▪ Diabetes = to pass through; insipidus = tasteless TYPES Neurogenic (central) DI ▪ DI caused by absence/↓ secretion/ production of antidiuretic hormone (ADH) by posterior pituitary Nephrogenic DI ▪ Kidneys unresponsive to ADH secreted by posterior pituitary ▪ Damage of renal tubules from systemic disease (e.g. polycystic kidney disease, pyelonephritis, amyloidosis) ▪ Lithium toxicity ▫ Interferes with aquaporin function SIGNS & SYMPTOMS ▪ Polyuria ▫ Neurogenic: urine amount varies depending on degree of ADH production/secretion ▫ Nephrogenic: daily output of > 3L in adults; > 2L/m2 in children ▪ Nocturia, polydipsia, dehydration, hypotension ▪ Neurogenic DI ▫ Lack of other pituitary hormones CAUSES Neurogenic DI ▪ Idiopathic (most common) ▪ Damage to hypothalamus/pituitary/ supraoptico-hypophyseal tract (e.g. head trauma, pituitary adenoma), neurosurgery, infection (e.g. tuberculosis), infiltrative disease (e.g. Langerhans cell histiocytosis), hypoxic encephalopathy, ischemia ▪ Familial (familial neurohypophyseal DI) ▫ Autosomal dominant gene mutation ▪ Congenital (e.g. septo-optic dysplasia) Nephrogenic DI ▪ Hereditary ▫ Defect in genes encoding for ADH receptor/aquaporin function 110 OSMOSIS.ORG DIAGNOSIS DIAGNOSTIC IMAGING Cranial MRI (neurogenic DI) ▪ Hyperintensities, pituitary stalk thickening identifies signs of hypothalamic/pituitary dysfunction LAB RESULTS ▪ ▪ ▪ ▪ ↓ ADH levels (neurogenic), urine osmolarity ↑ plasma osmolarity Hypernatremia Water deprivation test (ADH stimulation test): fluid deprivation → ADH (vasopressin) administered subcutaneously

Chapter 18 Hyperpituitarism & Hypopituitarism ▫ ↑ urine osmolality: confirms neurogenic DI ▫ Little/no ↑ urine osmolality: confirms nephrogenic DI TREATMENT MEDICATIONS Neurogenic DI ▪ Desmopressin (dDAVP) (synthetic vasopressin) ▪ Chlorpropamide ▫ Enhances renal response to low levels of ADH Neurogenic/nephrogenic DI ▪ Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g. indomethacin) ▫ ↑ renal concentration of urine ▪ Thiazide diuretics (e.g. hydrochlorothiazide) + low sodium diet ▫ ↓ polyuria (↑ water permeability to collecting tubules) OTHER INTERVENTIONS ▪ Fluid replacement ▪ Diet ▫ Low solute (low sodium, low protein) GIGANTISM osms.it/gigantism PATHOLOGY & CAUSES ▪ GH hypersecretion during childhood → rapid, excessive linear growth CAUSES ▪ ▪ ▪ ▪ Excessive secretion of GH, GHRH, IGF-1 Tumor in pituitary gland Tumors outside pituitary, secrete GH Hereditary ▫ Gene mutation (e.g. McCune Albright syndrome, multiple endocrine neoplasia Type I) COMPLICATIONS ▪ Cardiovascular conditions: hypertension in children ▪ Bone conditions: osteoarthritis ▪ Diabetes mellitus: insulin resistance SIGNS & SYMPTOMS ▪ Overgrowth of face, extremities ▪ Headaches ▪ Maxilla/mandible protrusion DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Pituitary tumors CT scan ▪ Tumors in other organs, might secrete GH/ GHRH X-ray ▪ Assess bones LAB RESULTS Blood tests ▪ OGTT ▫ Hyperglycemia ▫ Elevated IGF-1 ▪ Height significantly above standard deviations ▪ Obesity OSMOSIS.ORG 111

TREATMENT MEDICATIONS ▪ Somatostatin agonists ▫ Shrink pituitary tumors, stop GH production ▪ Dopamine agonists ▫ If somatostatin agonists not effective ▫ Effective in tumors producing hyperprolactinemia ▪ Somatostatin + dopamine agonists ▪ GH receptor antagonists SURGERY ▪ For small pituitary adenomas ▫ Transsphenoidal surgical approach OTHER INTERVENTIONS ▪ Radiation (not recommended for children) ▫ Can produce panhypopituitarism (decreased secretion in most pituitary hormones) → learning disabilities, obesity Figure 18.3 The worlds tallest ever recorded man, Robert Wadlow, was diagnosed with from gigantism as a consequence of pituitary hyperplasia. He stood at 2.27m/8ft 11in and wore a size 37 shoe. GROWTH HORMONE DEFICIENCY (GHD) osms.it/growth-hormone-deficiency PATHOLOGY & CAUSES ▪ Conditions caused by decreased production of GH (AKA somatotropin) ▪ Partial/complete, permanent/transient 112 OSMOSIS.ORG CAUSES ▪ Hypothalamic/pituitary dysfunction ▫ Tumors (e.g. pituitary/parasellar adenomas); radiation; traumatic injury; autoimmune disease; genetic mutations (e.g. PROP1); congenital structural defects of brain (e.g. Prader–Willi, Turner syndrome); idiopathic

Chapter 18 Hyperpituitarism & Hypopituitarism SIGNS & SYMPTOMS ▪ Newborns ▫ Hypoglycemia, micropenis, excessive jaundice ▪ Children ▫ Stunted growth/short stature, delayed puberty ▫ Nystagmus, hypoglycemia, retinal defects, midfacial defects (e.g. cleft lip) ▫ Severe cases: delayed basic motor skills (e.g. standing, walking) ▫ Moderately overweight (rare—severely obese) ▪ Adults ▫ Decreased muscle mass, decreased bone mineral density, high 5-alpha reductase, baldness, cardiac conditions ▫ Psychological issues (memory problems, social issues, depression) ▪ Serum IGF-1 ▫ More accurate assessment of GH secretion; not affected by external factors ▫ Less than standard gender-specific levels → confirms diagnosis ▪ Insulin tolerance test ▫ Regular insulin administered via intravenous (IV) → measure blood at 30 minute intervals ▫ Subnormal increase in serum GH confirms diagnosis TREATMENT MEDICATIONS ▪ Daily injections with recombinant growth hormone (rGH) ▫ Childhood: GH daily injections; stature monitoring throughout growth period ▫ Adulthood: 25% treatment for children DIAGNOSIS LAB RESULTS ▪ Serum GH levels < 1ng/mL ▫ Nonspecific test for GH deficiency: affected by circadian rhythms, food intake, stress HYPERPITUITARISM osms.it/hyperpituitarism PATHOLOGY & CAUSES ▪ Disorders caused by pituitary hormones hypersecretion CAUSES ▪ Pituitary adenoma (most common) ▪ Genetic mutation from single cell (monoclonal) → tumorigenesis → tumor secretes hormones ▫ Prolactin → prolactinoma ▫ ACTH → Cushing’s disease ▫ GH → acromegaly (occurs during adulthood after epiphyseal closure), gigantism (during childhood before epiphyseal closure) SIGNS & SYMPTOMS ▪ Diaphoresis; visual field problems; headaches; lethargy; excessive hair growth; larger organs, extremities, facial components OSMOSIS.ORG 113

DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Sella turcica, pituitary glands LAB RESULTS ▪ Elevated hormone levels in serum TREATMENT MEDICATIONS ▪ Dopamine agonists: gonadal dysfunctions ▫ Inhibit prolactin secretion ▫ Inhibitors of tumoral cells division SURGERY ▪ Total/partial removal of pituitary/tumor ▫ Endonasal transsphenoidal surgery (most common) HYPERPROLACTINEMIA osms.it/hyperprolactinemia PATHOLOGY & CAUSES ▪ Disorder caused by high blood levels of pituitary hormone prolactin ▪ Prolactin: secreted by lactotroph cells in anterior segment of pituitary CAUSES ▪ Prolactinoma/lactotroph adenoma (prolactin-secreting tumor) ▪ Pregnancy ▪ Damage to hypothalamic-pituitary stalk ▪ Disorders affecting hypothalamus ▪ Drugs, medication, heavy metal poisoning ▫ Inhibits dopamine production ▫ Dopamine receptor antagonists, synthesis inhibitors → pituitary overproduces prolactin ▪ Renal failure ▪ Primary hypothyroidism SIGNS & SYMPTOMS ▪ Individuals who are biologically male ▫ Impaired genital activity (hypogonadism) → infertility, impotence ▫ Decreased libido 114 OSMOSIS.ORG ▫ Overdevelopment of mammary glands (gynecomastia) ▫ Spontaneous secretion, flow of breast milk (galactorrhea) ▪ Individuals who are biologically female ▫ Irregular menstrual cycles: sometimes complete lack of menstruation (amenorrhoea); no ovulation → infertility ▫ Galactorrhea ▫ Painful breasts ▪ Visual impairment, headaches when pituitary adenoma presses on optic nerve DIAGNOSIS DIAGNOSTIC IMAGING Head MRI/CT scan ▪ Tumors/lesions in hypothalamic-pituitary area: if none + high serum levels: idiopathic hyperprolactinemia LAB RESULTS ▪ High serum prolactin levels OTHER DIAGNOSTICS ▪ Lower bone density ▪ Pregnancy/hypothyroidism

Chapter 18 Hyperpituitarism & Hypopituitarism TREATMENT MEDICATIONS SURGERY ▪ Surgical removal of tumor ▫ High rate recurrence ▪ Tumor: dopamine agonist (inhibit prolactin production, secretion) ▫ Bromocriptine/cabergoline HYPOPITUITARISM osms.it/hypopituitarism PATHOLOGY & CAUSES ▪ Disorders caused by complete/partial lack of pituitary hormone production, secretion CAUSES ▪ Tumors ▫ Pituitary adenomas → compression → intracranial pressure → destruction of pituitary ▫ Brain (e.g. metastatic cancer) ▫ Body ▪ Traumatic injury, shock, stroke → ischemia ▪ Vascular ▫ Hemorrhages (e.g. aneurysms, subarachnoid hemorrhage) ▪ Radiation ▪ Infections ▫ Brain (e.g. meningitis) ▫ Abnormal brain cells/substance infiltrations (e.g. hemochromatosis) ▫ Autoimmune disorders (e.g. autoimmune hypophysitis) ▪ Congenital (defect in transcription factors) ▫ PROP1 gene mutation → hormone deficiency (most common) ▫ Pituitary transcription factor 1 (PIT1) mutation → GH, prolactin, TSH deficiencies ▪ Hypothalamic dysfunction, decrease in releasing hormones SIGNS & SYMPTOMS ▪ Occur when ≥ 75% of anterior pituitary nonfunctional ▪ Vary depending on hormone affected ▪ Sequence of loss: “Go Look For The Adenoma” (see mnemonic) ▪ If tumor present ▫ Pressure on optic chiasm → visual disturbances ▫ Increased intracranial pressure → headache MNEMONIC: Go Look For The Adenoma Pituitary adenoma sequence of loss Growth hormone (GH) Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Thyroid-stimulating hormone (TSH) Adrenocorticotropic hormone (ACTH) DIAGNOSIS LAB RESULTS ▪ Blood tests ▫ Serum thyroid levels (T3/T4) ▫ ACTH secretion (measure serum cortisol in the morning) OSMOSIS.ORG 115

TREATMENT MEDICATIONS ▪ Hormone replacement ▫ ACTH deficiency: hydrocortisone ▫ TSH deficiency: levothyroxine ▫ FSH/LH deficiency: testosterone (for individuals who are biologically male); estrogen-progestin (for premenopausal individuals who are biologically female) SURGERY ▪ Surgical excision of tumors HYPOPROLACTINEMIA osms.it/hypoprolactinemia PATHOLOGY & CAUSES ▪ Low serum prolactin levels due to damaged lactotroph cells in anterior pituitary CAUSES ▪ Sheehan’s syndrome ▫ Postpartum hemorrhage → hypotension, decreased circulation to pituitary, ischemia, damaged lactotroph cells ▪ Medications ▫ Dopamine, dopamine agonists; inhibit prolactin release ▪ Tumors ▫ Pressure on pituitary/hypothalamus → damage lactotroph cells SIGNS & SYMPTOMS ▪ Individuals who are biologically female and breastfeeding ▫ Decreased lactation (agalactorrhea) 116 OSMOSIS.ORG DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Tumor confirmation LAB RESULTS ▪ Low prolactin levels despite receiving thyrotropin-releasing hormone (TRH) ▫ Individuals who are biologically female: < 3µg/L ▫ Individuals who are biologically male: < 5µg/L TREATMENT MEDICATIONS ▪ Dopamine antagonists ▫ Oppose dopamine in individuals who want to breastfeed SURGERY ▪ Surgical removal of tumor

Chapter 18 Hyperpituitarism & Hypopituitarism PITUITARY APOPLEXY osms.it/pituitary-apoplexy PATHOLOGY & CAUSES DIAGNOSIS ▪ Pituitary function impaired due to hemorrhage into gland ▪ Hemorrhage → blood collects within pituitary interstitium → swelling → infarction, loss of pituitary function → compression of surrounding structures DIAGNOSTIC IMAGING RISK FACTORS ▪ ↓ pituitary hormone levels, target tissue hormones ▪ Intracranial tumors, head trauma, neurosurgery, Sheehan’s syndrome (postpartum pituitary necrosis) COMPLICATIONS ▪ Hypopituitarism, neuronal damage SIGNS & SYMPTOMS ▪ Meningeal stretching ▫ Severe headache ▪ Optic chiasm compression ▫ Diplopia, bitemporal hemianopia ▪ Parenchymal compression ▫ Mental status changes ▪ Clinical manifestations of hypopituitarism (e.g. ↓ ACTH → ↓ cortisol → hypoglycemia, hypotension, adrenal crisis) CT scan/MRI ▪ Enlarged pituitary gland; hyperintense blood-filled center LAB RESULTS TREATMENT MEDICATIONS ▪ Hormone replacement ▫ Glucocorticoids (emergent), levothyroxine SURGERY ▪ Surgical decompression ▪ Transphenoidal resection of pituitary gland OSMOSIS.ORG 117

SHEEHAN'S SYNDROME osms.it/sheehans-syndrome PATHOLOGY & CAUSES DIAGNOSIS ▪ AKA postpartum pituitary gland necrosis ▪ Destruction of lactotroph cells of anterior pituitary in setting of postpartum hemorrhage DIAGNOSTIC IMAGING CAUSES LAB RESULTS ▪ Pituitary increases in size during gestation → metabolic activity of lactotrophs increase, blood supply does not → pituitary vulnerable to perfusion decrease → hypovolemia, hypotension, shock → pituitary infarction, necrosis SIGNS & SYMPTOMS MRI ▪ Pituitary ring sign (halo around empty sella) ▪ Pituitary hormone levels OTHER DIAGNOSTICS ▪ Obstetric history TREATMENT MEDICATIONS ▪ Glucocorticoid replacement (emergent) if adrenal insufficiency ▪ Ongoing hormone replacement as needed ▪ Pituitary dysfunction SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION (SIADH) osms.it/SIADH PATHOLOGY & CAUSES ▪ Inappropriate ADH secretion → ↓ water excretion ▫ ADH overproduced, secreted → highly concentrated urine, ↓ volume ▫ ↑ intake of fluids, ADH secretion → water retention → dilutes plasma sodium levels → hyponatremia 118 OSMOSIS.ORG CAUSES ▪ Central nervous system (CNS) disorders enhance ADH production, release ▫ Trauma, stroke, hemorrhage, infection ▫ Mental illness, though carbamazepine effects ▪ Ectopic production of ADH ▫ Lung malignancies: e.g. small cell carcinoma

Chapter 18 Hyperpituitarism & Hypopituitarism ▫ Nonmalignant lung disorders: pneumonia, tuberculosis, cystic fibrosis (CF) ▪ Medications ▫ Anticonvulsants, opioids, sulfonylureas ▪ Injury/surgical removal of pituitary SIGNS & SYMPTOMS ▪ Body weakness ▫ Fatigue, dizziness, confusion, nausea, lethargy; anorexia ▪ Muscle cramps ▫ Myoclonus,tremors ▪ Seizures TREATMENT MEDICATIONS ▪ ADH receptor antagonist (e.g. tolvaptan) OTHER INTERVENTIONS ▪ Water restriction ▫ < 800mL daily ▫ If SIADH associated with subarachnoid hemorrhage, fluid restriction not recommended ▪ IV hypertonic saline administration for severe cases, oral salt tablets, loop diuretics ▪ Urea administration ▫ Increases urine output DIAGNOSIS LAB RESULTS ▪ Urinalysis ▫ Highly concentrated urine ▪ Serum tests ▫ Hyponatremia, low plasma osmolarity OSMOSIS.ORG 119