Pituitary Dysfunction Flashcards

Question

Prolactin Deficiency

Answer 1

a. Etiology: Severe pituitary (lactotrope) destruction from any cause (e.g., pituitary tumors, infiltrative diseases, infectious diseases, infarction, neurosurgery or radiation). b. Clinical Presentation: Failed lactation in postpartum females, no known effect in males. c. Diagnosis: low basal PRL level

Answer 2

a. A Catabolic “Stress” Hormone i. Essential for Life b. Primary Functions: i. Gluconeogenesis ii. Metabolism of Fat and Protein iii. Control Inflammatory Reactions c. ACTH acts on adrenal cortex i. ZF, stimulates glucocorticoid production ii. ZG, usually inactivated by 11-beta HSD2 - but can activate mineralcorticoid receptor in marked excess (HTN, hypokalemia) iii. ZR, stimulates steroid hormone synthesis

Answer 3

a. Changes in Carbohydrate, Protein and Fat Metabolism i. Peripheral Wasting of Fat/Muscle ii. Central obesity, Moon facies, fat pads iii. Osteoporosis iv. Diabetes v. Hypertriglyceridemia b. Changes in Sex Hormones i. Amenorrhea/Infertility ii. Excess hair growth (♀) iii. Impotence c. Salt and Water Retention i. HTN and Edema d. Impaired Immunity e. Neurocognitive Changes

Answer 4

Causes: a. ACTH Dependent i. Corticotrope Adenoma (Cushing’s Disease) ii. Ectopic Cushing’s (ACTH/CRH tumors) b. ACTH Independent i. Adrenal Adenomas ii. Adrenal Carcinoma iii. Nodular Hyperplasia (micro or macro)

Answer 5

a. Incidence: 2-3 cases per 1 million/year. b. ~10-15% of Functional Pituitary adenomas c. Female, Middle-aged predominance

Answer 6

```  Obesity  Fatigue  Menstrual Irregularities  Hirsutism  HTN ``` ```  Glucose Intolerance/DM  Dyslipidemia  Acne  Anxiety/Depression  Peripheral Edema  Metabolic Syndrome ```

Answer 7

Screening indicated in patients with multiple and progressive “high discriminatory” features of Cushing’s Syndrome. ``` Specific Signs of Cushing’s Syndrome 1. Plethoric/moon facies 2. Wide (>1 cm), violaceous striae (abdominal, axillary) 3. Spontaneous Ecchymoses 4. Proximal Muscle Weakness 5. Early/Atypical Osteoporosis (atraumatic rib fx) ```

Answer 8

1. Plethoric/moon facies 2. Wide (>1 cm), violaceous striae (abdominal, axillary) 3. Spontaneous Ecchymoses 4. Proximal Muscle Weakness 5. Early/Atypical Osteoporosis (atraumatic rib fx)

Answer 9

a. Episodic ACTH/cortisol secretions daily b. Major ACTH/cortisol burst in the early morning (before awakening) . c. Cortisol Nadir 11-12 pm (assuming a normal sleep-wake cycle)

Answer 10

a. Most cortisol is bound to transcortin (cortisol binding globulin-CBG). b. 10-15% bound to albumin (less tightly) c. 5% Unbound (Free cortisol)

Answer 11

a. Disrupted Circadian Rhythm i. Midnight Salivary or Serum Cortisol b. Increased Filtered Cortisol Load i. 24 hr Urine Free Cortisol c. Attenuated Negative Feedback i. Low Dose (1 mg) Dexamethasone Suppression test (11-12 p.m.)

Answer 12

a. “Pseudo-Cushing’s Disease” overactivation of the HPA axis, without tumorous cortisol hypersecretion b. Conditions that can give false negatives for Cushing's (lead to high cortisol) i. Severe Depression/Anxiety/OCD ii. Severe Obesity iii. ?Obstructive Sleep Apnea iv. Alcoholism v. Poorly-controlled DM/hypoglycemia vi. Physical Stress (acute illness, surgery, pain)

Answer 13

1. ACTH LEVEL • Plasma ACTH levels are usually high-normal to mildly elevated in Cushing’s disease 2. IMAGING • Pituitary MRI (~80% microadenomas, 50% identified on MRI) 3. INFERIOR PETROSAL SINUS SAMPLING • For a negative/equivocal MRI

Answer 14

a. Etiologies of Primary AI-separate lecture b. Etiologies of Secondary/Tertiary AI---> Suppression of the HPA axis i. S/p tumor resection for Cushing’s Syndrome (pituitary, ectopic or adrenal) ii. Supraphysiologic exogenous glucocorticoid use (most common) > 5-7.5 mg prednisone (or equivalent glucocorticoid dose) for >1 month iii. Drugs: Opioids and megace c. Hypothalamus/Pituitary Diseases and/or their treatments. d. Other-Isolated ACTH deficiency (very rare)

Answer 15

Clinical Presentation of secondary/tertiary adrenal insufficiency (AI) 1. Fatigue 2. Anorexia, nausea/vomiting and weight loss 3. Generalized malaise/aches 4. Scant Axillary/Pubic hair (DHEA-S dependent in females) 5. Hyponatremia and Hypoglycemia

Answer 16

a. Basal Testing: Random a.m. cortisol level, <3 ug/dl (establishes AI diagnosis), >18 ug/dl (excludes AI diagnosis), additional provocative testing required for equivocal results. b. Stimulation Tests i. Insulin-induced hypoglycemia (gold standard)–assesses entire hypothalamic-pituitary-adrenal axis. ii. Cosyntropin (synthetic ACTH 1-24) stimulation test-valid for assessing HPA axis only if prolonged (several weeks-months) loss of pituitary signaling and resulting adrenal atrophy.

Answer 17

1. Hypergonadotropic Hypogonadism--> High FSH/LH i. Congenital Anorchia ii. Klinefelter’s Syndrome iii. Testicular Injury iv. Autoimmune Testicular Dz v. Glycoprotein Tumor (rarely) 2. Hypogonadotropic Hypogonadism i. Hypothalamic/Pituitarydiseases - Macroadenomas, prolactinomas, XRT - Isolated GnRH Deficiency (Kallman’s=anosmia vs. Idiopathic) - Hemochromatosis ii. “Functional” Deficiency-Critical Illness, OSA, starvation, Meds-opiates, glucocorticoids

Answer 18

``` FEMALES a. Anovulatory cycles i. oligo/amenorrhea, infertility b. Vagina dryness, dyspareunia c. Hot Flashes d. Decreased libido e. Breast atrophy f. Reduced bone mineral density (BMD) ``` ``` MALES a. Reduced libido, b. Erectile dysfunction c. Oligospermia or azoospermia, d. Infertility e. Decreased muscle mass, testicular atrophy and decreased BMD. f. Hot flashes with acute and severe onset of hypogonadism. ```

Answer 19

a. Clinical Presentation of Gonadotrope Adenomas i. The majority of FSH/LH tumors are clinically silent (?inefficient intact LH/FSH hormone synthesis or secretion). ii. Rare presentation (from functionally-intact FSH/LH molecules) include: ovarian hyper-stimulation syndrome (females) or macro-orchidism (males). b. Middle-aged patients (males >females) with macroadenomas and related mass effects (e.g., headaches, vision loss, cranial nerve palsies, and/or pituitary hormone deficiencies).

Answer 20

Etiologies a. Secondary i. Thyrotropin secreting pituitary tumor-very rare (<1% of pituitary tumors) ii. Thyroid hormone resistance (generalized or pituitary-specific, rare conditions)

Answer 21

Clinical Presentation a. Thyrotropinoma (TSHoma)-similar clinical presentation to primary hyperthyroidism (i.e., goitre, tremor, weight loss, heat intolerance, hair loss, diarrhea, irregular menses) but also with associated mass effects (i.e., headaches, vision loss, loss of pituitary gland function) from macroadenoma. b. Diagnosis i. Elevated Free T4 and a non-suppressed TSH ii. Pituitary MRI (>80% macroadenomas)

Answer 22

a. Etiologies 1. Pituitary/Hypothalamic Diseases and/or their treatments 2. Critical Illness/Starvation-Euthyroid Sick Syndrome 3. Congenital defects (TSH-beta mutations, PROP1, POUF1 mutations) 4. Drug induced-supraphysiologic steroids, dopamine, rexinoids. b. Clinical presentation: similar to primary hypothyroidism (e.g., fatigue, weight gain, cold intolerance, constipation, hair loss, irregular menses). i. Possible mass effects c. Diagnosis: Low Free T4 levels in the setting of a low or normal TSH.

Answer 23

a. Definition: Deficiency of 1 or more pituitary hormones. i. Panhypopituitarism=loss of all pituitary hormones b. Etiologies: i. Congenital-Genetic Diseases (transcription factor mutations) ii. Acquired-Pituitary Lesions and/or their treatments (75%) - Macroadenomas/Pituitary Surgery/Radiation Therapy - Infiltrative/Infectious/Granulomatous diseases - Traumatic Brain Injury/Subarchnoid Hemorrhage - Apoplexy - Autoimmune Hypophysitis-Immune-tolerance disruptors (Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4, Ipilimumab)

Answer 24

a. Apoplexy Definition: Clinical syndrome of headache, vision changes, ophthalmoplegia and altered mental status caused by the sudden hemorrhage or infarction of the pituitary gland. b. Occurs in ~10-15% of pituitary adenomas; subclinical disease is more common c. Diagnosis: Pituitary MRI or CT d. Treatment i. Emergent surgery is indicated for evidence of severe vision loss, rapid clinical deterioration, or mental status changes. ii. Stress dose steroids for adrenal insufficiency.

Answer 25

a. Predictable Loss of Anterior Pituitary Hormones b. Anti-diuretic Hormone (ADH)-deficiency-common with metastatic tumors (i.e., breast, lung or GI) or craniopharyngiomas, but not pituitary adenomas.

Answer 26

a. Clinical Presentation: i. Depends on the severity of the pituitary hormone deficiencies and their rate of development. ii. Generally similar presentation to target gland hormone deficiency, with some exceptions: - Primary adrenal insufficiency also presents w/ hyperkalemia from mineralcorticoid deficiency and hyperpigmentation from ACTH excess) . b. Diagnosis: Basal and Dynamic Testing

Answer 27

Treatment of Anterior Pit. Hormone Deficiencies (End Organ Hormone Replacement): 1. Thyroid – Multiple L-thyroxine formulations available. 2. Adrenal – Physiologic hydrocortisone or prednisone i. Medic Alert Bracelet, Sick day rules for glucocorticoid replacement ii. No mineralcorticoid replacement needed 3. Gonadal – i. Various formulations-oral/transdermal E2, transdermal/IM Testosterone ii. Gonadotropin or pulsatile GnRH therapy 4. Growth Hormone i. Various Formulations of subcutaneous shots (not orally active). Prolactin – SQ formulation, research purposes only.

Answer 28

a. Media Misinformation b. “Chemically-Identical” Hormones c. “Custom-made, by compounding pharmacies, and individually-tailored based on saliva tests.” d. Exaggerated and unproven claims of safety and efficacy relative to other FDA-approved products.

Answer 29

a. Clinical syndromes are primaril associated with disorders of AVP i. AVP (arginine vasopressin) = ADH (antidiuretic hormone). b. Release Controlled Primarily By-High osmolar states i. via hypothalamic osmoreceptors

Answer 30

a. Release Controlled Primarily by--> High osmolar states i. via hypothalamic osmoreceptors b. Release Also Controlled By: i. Hypovolemia via baroreceptors

Answer 31

V1 – Vascular Vasoconstriction, Platelet aggregation V2 - Antidiuretic effects in kidney Adenylate cyclase activation movement of Aquaporin water channels to the cell membrane water reabsorption

Answer 32

a. Vasopressin is secreted from the posterior pituitary gland in response to reductions in plasma volume, in response to increases in the plasma osmolality, and in response to cholecystokinin (CCK) secreted by the small intestine: b. Secretion in response to reduced plasma volume is activated by pressure receptors (baroreceptors) in the veins, atria, and carotid sinuses i. Secretion in response to increases in plasma osmotic pressure is mediated by osmoreceptors in the hypothalamus. c. Secretion in response to increases in plasma CCK is mediated by an unknown pathway. d. The neurons that make AVP, in the hypothalamic supraoptic nuclei (SON) and paraventricular nuclei (PVN), are themselves osmoreceptors, but they also receive synaptic input from other osmoreceptors located in regions adjacent to the anterior wall of the third ventricle. These regions include the organum vasculosum of the lamina terminalis and the subfornical organ.

Answer 33

a. SIADH Definition: A syndrome of inappropriate AVP release/action in the absence of physiologic osmotic or hypovolemic stimulus. b. Hallmark is the excretion of inappropriately concentrated urine in the setting of hypo-osmolality and hyponatremia. c. SIADH is one of the most frequent causes of hyponatremia, and occurs in an estimated: i. 15-22% of hospitalized patients ii. 5-7% of ambulatory patients

Answer 34

Major Categories 1. Malignant Disease- Carcinoma, Lymphoma, Sarcomas 2. Pulmonary Disorders-Infections, Asthma, Cystic Fibrosis, Positive Pressure Ventilation 3. CNS Disorders-Infection, Tumors, Trauma, Bleeds 4. Drugs-Stimulate/Potentiate AVP release/actions i. Narcotics, Nicotine, Anti-psychotics, Carbamazepine, Vincristine Misc.-Nausea, Stress and Pain

Answer 35

Clinical Presentation a. Depends on the severity of hyponatremia and the rapidity of development (acute, <48 hr) b. Manifests with neurological symptoms from osmotic fluid shifts and brain edema c. Plasma Na+ Signs/Symptoms 130-135 mmol/L Usually Asymptomatic 125-130 mmol/L Anorexia, N/V, Headaches, Irritable 115-125 mmol/L Altered Sensorium, Gait disturbance <115 mmol/L Seizure, Coma, Death

Answer 36

Criteria a. Hyponatremia (Na+ <135 mmol/L) and hypotonic plasma (osmolality <275 mOsm/kg) b. Inappropriate urine concentration (Urine Osm >100 mOSm/kg) with normal renal function c. Euvolemic Status (no orthostatics hypotension) d. Exclusion of other potential causes of euvolemic hypoosmolality i. Hypothyroidism ii. Hypocortisolism

Answer 37

a. Identify and Reverse Underlying Disorder (when possible) b. Treatment depends on the severity of hyponatremia, the rate of development and the patient’s symptomatology 1. Mild-to-Moderate Hyponatremia (Na+ ~120-134 mmol/L) i. Water Restriction (500-1000L/24hrs) ii. V2 Receptor Antagonists ($$$) iii. Salt tablets, Lasix, Urea (Europe) 2. Severe Hyponatremia (usually Na+ <120 mmol/L) i. Hypertonic (3%) Saline-if patient is symptomatic (delirium/seizure/coma)

Answer 38

a. Limit Correction of Chronic Hyponatremia: i. < 12 mmol in the first 24 hrs. ii. Slower correction with other risk factors associated with osmotic demyelination syndrome - Hypokalemia, alcoholism, poor nutritional status b. NO LIMITATIONS with acute onset hyponatremia i. (e.g., <48 hr onset, marathon runners)

Answer 39

a. Definition-DI is a syndrome of hypotonic polyuria as a result of either: i. Inadequate ADH secretion ii. Inadequate renal response to ADH b. Hallmark-Voluminous (Urine output > 40ml/kg/d) dilute urine c. Main Causes: i. Central Diabetes Insipidus ii. Nephrogenic Diabetes Insipidus iii. Pregnancy-increased ADH metabolism from placental vasopressinase, but is generally not clinically relevant. iv. Primary Polydipsia d. Clinical Significance: Can lead to severe dehydration if thirst mechanisms are impaired, or if the patient has limited access to water

Answer 40

a. Nephrogenic DI i. Congenital: X-linked recessive AVP V2 receptor gene mutation; autosomal recessive aquaporin-2 water channel gene mutation ii. Drugs: demeclocycline, lithium, amphotericin B iii. Electrolyte abnormalities: hypokalemia and hypercalcemia iv. Infiltrative kidney diseases: sarcoidosis and amyloidosis v. Vascular disease: sickle cell anemia b. Neurogenic DI i. Neoplasms: craniopharyngioma, metastatic pituitary disease (e.g., colon, breast, lung) ii. Idiopathic:+AVP Ab iiii. Congenital defects: autosomal dominant AVP neurophysin gene mutation iv. Inflammatory/Infectious/granuloma pituitary diseases: lymphocytic hypophysitis,histiocytosis, sarcoidosis v. Trauma/Vascular event: neurosurgery, TBI/deceleration injury

Answer 41

a. Classic Triphasic Response: 1° phase– DI-polyuric phase due to axonal shock/decreased AVP release (days 1-5) 2° phase – SIADH from degenerating neurons/excessive AVP release (days 6-11) 3° phase-Permanent DI after depleted ADH stores and if >80% AVP neuronal cell death b. Permanent DI-uncommon complication with an experienced neurosurgeon (<1%) c. Isolated Second (SIADH) Phase-More Common (~25%)

Answer 42

a. Confirm polyuria with 24 hr urine volume collection (normalized to creatinine) b. Exclude hyperglycemia (osmotic diuresis), renal insufficiency and electrolyte disturbances (K+/Ca 2+) c. Assess Urine and Plasma Osmolalities d. Consider Water Deprivation Test e. Pituitary Imaging (for suspected neurogenic DI)

Answer 43

a. Fluid restriction to stimulate ADH release b. Measure Uosm , Posm Serum Na+ and Urine output c. Urine concentration Response to dDAVP d. +/- ADH Level after mild dehydration

Answer 44

a. Anti-Diuretic Hormone Replacements 1. First Line-dDAVP (nasal, oral or parenteral routes of administration) i. Longer half-life than ADH ii. No Vasopressor Effect 2. Second-Line-ADH (IV, SQ or IM routes of administration). b. Goals: i. Resolution of Polyuria/Polydipsia ii. Minimal disruption of sleep/daily routine iii. Normal Serum Sodium

Answer 45

Anterior Pituitary-80% of the whole pituitary gland o Five differentiated cell types that secrete six major hormones o Complex integration of signals: Positive and negative influences on pituitary hormone secretion from the CNS, hypothalamus, target hormones and physiologic factors.

Answer 46

a. The loss of a target (peripheral) organ hormone may be due to a defect at the level of the target organ, the pituitary gland, or the hypothalamus, which are referred to as primary, secondary and tertiary endocrine disorders, respectively. b. Secondary and tertiary disorders may be difficult to distinguish and are referred to as central disorders.

Answer 47

a. Basal Testing- TSH/Free T4, ACTH/a.m. cortisol, PRL, GH/IGF-1, LH, FSH, Testosterone (in males), estradiol (in females)-and timed within 5-7 days of starting menses (follicular phase). i. Pituitary hormone deficiency is established by a low target hormone level in the setting of a low, or an inappropriately normal, pituitary hormone level. ii. Pituitary hormone excess is established by a high target hormone level in the setting of an inappropriately normal or high pituitary hormone level. b. Dynamic Testing is done if indicated by an equivocal basal test. It utilizes known physiologic stimulators and suppressors of pituitary hormone release. i. Hormone deficiency is assessed by a stimulation test (e.g., insulin tolerance test for adrenal insufficiency). ii. Hormone Excess is assessed by a suppression test (e.g., oral glucose tolerance test for GH suppression in acromegaly).

Answer 48

a. GH Excess 1. Gigantism (before epiphyseal plate closure) 2. Acromegaly (after epiphyseal plate closure) o Etiologies: Pituitary tumors (95%), ectopic GH/GHRH tumors (5%) b. Diagnosis i. Clinical Features of GH excess (old pictures are helpful), AND ii. Elevated IGF-1 level (age and gender matched)-best screening test iii. GH levels fluctuate widely over 24 hrs and normal values can overlap with GH-secreting tumors iv. Confirmatory testing (for equivocal IGF-1 level) -Oral glucose tolerance test-75 gm oral glucose load, followed by growth hormone testing q 30 minutes for 2 hrs (abnormal GH response >1 ug/L or >0.40 ng/ml with ultrasensitive GH assays). v. Pituitary MRI-macroadenomas are detected in most cases of acromegaly (>80%).

Answer 49

a. Clinical Features of GH excess (old pictures are helpful), AND b. Elevated IGF-1 level (age and gender matched)-best screening test i. best screen c. GH levels fluctuate widely over 24 hrs and normal values can overlap with GH-secreting tumors d. Confirmatory testing (for equivocal IGF-1 level) - Oral glucose tolerance test-75 gm oral glucose load, followed by growth hormone testing q 30 minutes for 2 hrs (abnormal GH response >1 ug/L or >0.40 ng/ml with ultrasensitive GH assays). e. Pituitary MRI-macroadenomas are detected in most cases of acromegaly (>80%).

Answer 50

a. Etiologies: Pituitary/hypothalamic diseases and/or their treatments (e.g., surgery, radiation therapy), childhood onset GHD and traumatic brain injury. b. Clinical Presentation: i. altered body composition (e.g., increased central obesity, reduced lean body mass) ii. decreased bone mineral density iii. increased insulin resistance/glucose intolerance, pro-atherogenic lipid profile/increased inflammatory markers (e.g., CRP, hypertriglycerides, IL-6) iv. and impaired psychological well-being (e.g., fatigue and depression). c. Diagnosis: Adult GH Deficiency is best established by i. Low IGF-1 (in the setting of multiple other pituitary hormone deficiencies) ii. Provocative testing for GH reserve 1. Insulin induced hypoglycemia (gold standard). Insulin (0.1U/kg) to induce hypoglycemia (blood sugar <40 mg/dl). Normal GH response: > 3-5 ug/dl. Contraindications: elderly, h/o seizure disorder, coronary artery disease or cerebrovascular disease. 2. GHRH-Arginine (second best test), although no longer available in U.S 3. Arginine and glucagon-currently available tests, but problematic.

Answer 51

Clinical Presentation: a. altered body composition (e.g., increased central obesity, reduced lean body mass) b. decreased bone mineral density c. increased insulin resistance/glucose intolerance, pro-atherogenic lipid profile/increased inflammatory markers (e.g., CRP, hypertriglycerides, IL-6) d. and impaired psychological well-being (e.g., fatigue and depression). Diagnosis: Adult GH Deficiency is best established by a. Low IGF-1 (in the setting of multiple other pituitary hormone deficiencies) i. Must be age/gender-matched b. Provocative testing for GH reserve 1. Insulin induced hypoglycemia (gold standard). Insulin (0.1U/kg) to induce hypoglycemia (blood sugar <40 mg/dl). Normal GH response: > 3-5 ug/dl. i. Contraindications: elderly, h/o seizure disorder, coronary artery disease or cerebrovascular disease. 2. GHRH-Arginine (second best test), although no longer available in U.S 3. Arginine and glucagon-currently available tests, but problematic.

Answer 52

a. Physiological i. Pregnancy, suckling, sleep, stress b. Pharmacological i. Estrogens ii. Antipsychotics , antidepressants (tricyclics, MAO-I), anti-emetics (reglan), anti-HTN (verapamil) iii. Opiates c. Pathological i. Prolactinoma ii. Pituitary Stalk Interruption (from any cause) iii. Hypothyroidism, chronic renal/liver failure, seizure d. Idiopathic; macroprolactin (PRL:IgG complex)

Answer 53

a. Clinical Presentation i. Hormone Effects-Galactorrhea (rarely in males), irregular menses/amenorrhea (♀), erectile dysfunction (♂), infertility, osteoporosis, decreased libido ii. Mass Effects-Macroadenoma-related (♂ > ♀) and includes: headaches, vision disturbances, cranial nerve palsies and pituitary hormone deficiencies b. Diagnosis i. Random PRL level (use gender-based normative ranges) ii. Levels usually >100-150 ng/mL with prolactinomas iii. Pituitary MRI

Answer 54

a. Etiology: Severe lactotrope destruction from any cause (e.g., pituitary tumors, infiltrative diseases, infectious diseases, infarction, neurosurgery or radiation) b. Clinical Presentation: Failed lactation in post-partum females, no effect in males. c. Diagnosis: low random PRL level

Answer 55

For treating Hyperprolactinemia a. Bromocriptine (Parlodel) 2.5 mg tab. “Start low and go slow” i. Common Side Effects: GI upset, Nasal Congestion, Orthostatic Dizzyness. ii. Preferred only if planned pregnancy

Answer 56

a. Etiologies of Cortisol Excess (hypercortisolism) • ACTH –Dependent (70-75%)-Corticotrope adenomas/Cushing’s Disease (CD), ectopic ACTH/CRH tumors • ACTH-Independent (25-30%)-adrenal adenomas, adrenal carcinomas, nodular (micro or macro) adrenal hyperplasia b. Clinical Presentation of Hypercortisolism • Specific features of Cushing’s include: facial plethora, easy bruising, wide (>1 cm) violaceous striae and proximal muscle weakness • General signs/symptoms (poor specificity): weight gain/obesity, diabetes, hypertension, irregular menses, dorsocervical hump, acne, low libido, depression or hirsutism

Answer 57

a. Initial Screening Tests: 1) 24 hour urinary cortisol, 2) 11-12 p.m. salivary cortisol test, or 3) 1 mg dexamethasone suppression test (1 mg dexamethasone given at 11-12 p.m., followed by ~8 am serum cortisol level. Normal cortisol suppression <1.8 ug/dl). i. Caveat: “Pseudo-Cushing’s” disease: non-tumoral activation of hypothalamic-pituitary-adrenal (HPA) axis (e.g., severe depression, alcoholism, marked stressors) can give a false-positive screening test. b. Plasma ACTH level is normal to mildly elevated in Cushing’s disease c. Pituitary MRI (~80% microadenomas, 50% identified) d. Inferior petrosal sinus sampling (IPSS) for a negative or equivocal MRI. e. Positive test for Cushing’s disease: basal central/peripheral ACTH gradient (> 2), or >3 after CRH stimulation

Answer 58

a. Primary (adrenal gland failure) (Will be covered in the Adrenal lecture) b. Secondary/Tertiary i. Suppression of the HPA axis • Supraphysiologic exogenous glucocorticoid use (most common) • S/p tumor resection for Cushing’s Syndrome (pituitary, ectopic or adrenal) • Drugs: Opioids and megace ii. Diseases of the Hypothalamus/Pituitary and/or their treatments iii. Other-Isolated ACTH deficiency (congenital TPIT mutations). Very rare c. Presentation of secondary/tertiary adrenal insufficiency (AI) i. Fatigue, pallor, anorexia, weight loss, nausea, vomiting, abdominal pain, hyponatremia, hypoglycemia, orthostatic dizziness and scant axillary/pubic hair (DHEA-S dependent). d. Diagnosis i. Random a.m. cortisol level, <3 ug/dl (establishes AI diagnosis), >18 ug/dl (excludes AI diagnosis), 3-18 ug/dl equivocal result; requires additional provocative testing ii. Stimulation tests to assess HPA axis -Insulin-induced hypoglycemia (gold standard)–assesses entire axis. -Cosyntropin (synthetic ACTH 1-24) stimulation test-valid for assessing HPA axis only if prolonged (several weeks-months) interruption of pituitary signaling. ACTH-250 ug IV, check serum cortisol level at 30 & 60 minutes. Normal cortisol response >18 mg/dl

Answer 59

a. Blood tests: usually low FSH/LH, T/E2 b. Pituitary MRI c. Immunohistochemical analyses (+FSH, LH, or ASU staining) of the resected tumor

Answer 60

a. Presentation of secondary/tertiary adrenal insufficiency (AI) i. Fatigue, pallor, anorexia, weight loss, nausea, vomiting, abdominal pain, hyponatremia, hypoglycemia, orthostatic dizziness and scant axillary/pubic hair (DHEA-S dependent). b. Diagnosis i. Random a.m. cortisol level, <3 ug/dl (establishes AI diagnosis), >18 ug/dl (excludes AI diagnosis), 3-18 ug/dl equivocal result; requires additional provocative testing ii. Stimulation tests to assess HPA axis -Insulin-induced hypoglycemia (gold standard)–assesses entire axis. -Cosyntropin (synthetic ACTH 1-24) stimulation test-valid for assessing HPA axis only if prolonged (several weeks-months) interruption of pituitary signaling. ACTH-250 ug IV, check serum cortisol level at 30 & 60 minutes. Normal cortisol response >18 mg/dl

Answer 61

a. The vast majority of FSH/LH tumors are clinically silent macroadenomas and present in middle-aged patients with mass effects (i.e., headaches, vision loss, cranial nerve palsies, or pituitary hormone deficiencies) b. Hypogonadotropic Hypogonadism i. Females: anovulatory cycles, oligo/amenorrhea, infertility, hot flashes, vaginal dryness/atrophy, dyspareunia, reduced bone mineral density (BMD) ii. Males: Reduced libido, erectile dysfunction, oligospermia or azoospermia, testicular atrophy, infertility, decreased muscle mass and low BMD. Hot flashes with acute and severe onset of hypogonadism. c. Rare presentation (from functionally-intact FSH/LH molecules) include: ovarian hyperstimulation syndrome (females) or macro-orchidism (males). d. Diagnosis • FSH/LH, T and E2, alpha-subunit • Pituitary MRI • Immunohistochemical analyses (+FSH or LH staining of the resected tumor) establishes the diagnosis

Answer 62

a. TSH Elevation (Will also be covered in a separate lecture) 1. Primary hypothyroidism from thyroid gland failure (Hashimoto’s disease most common) 2. Thyrotropin secreting pituitary tumor-very rare (<1% of pituitary tumors) 3. Other-Thyroid hormone resistance and recovery phase of euthyroid sick syndrome. b. TSH Deficiency 1. Pituitary/Hypothalamic Diseases and/or their treatments 2. Congenital defects (TSH-beta mutations, PROP1, POU1F1 mutations) 3. Drug induced-supraphysiologic steroids, dopamine, rexinoids.

Answer 63

a. Clinical Presentation i. Thyrotropinoma (TSHoma)-similar clinical presentation to primary hyperthyroidism (i.e., goitre, tremor, weight loss, heat intolerance, hair loss, diarrhea, irregular menses) but also with associated mass effects (i.e., headaches, vision loss) from macroadenoma. ii. Central Hypothyroidism-similar clinical presentation to primary hypothyroidism (e.g., fatigue, weight gain, cold intolerance, constipation, hair loss, irregular menses). b. Diagnosis o Thyrotropinoma: elevations of circulating thyroxine (T4) and triiodothyronine (T3) concentrations, and a non-suppressed (inappropriately normal or frankly elevated) TSH level. o Central hypothyroidism: Low Free T4 levels in the setting of a low or normal TSH. o Pituitary MRI

Answer 64

a. Definition: Deficiency of >1 pituitary hormone(s). Panhypopituitarism=deficiencies of all pituitary hormones. b. Etiologies: Pituitary tumors and/or their treatment (75% of cases), parasellar tumors (e.g., craniopharyngiomas, meningiomas), pituitary infarction/apoplexy/Sheehan’s syndrome, infiltrative diseases (sarcoidosis, lymphocytic hypophysitis, hemochromatosis, Langerhan’s cell histiocytosis), infection (TB, abscess), traumatic brain injury/subarachnoid hemorrhage, or genetic defects. c. Generally predictable order of pituitary hormones deficiencies: i. GH≈FSH/LH > TSH ≈ACTH > PRL ii. ADH deficiency- infrequent with pituitary adenomas, but common with metastatic diseases to the pituitary gland (e.g., lung, breast or colon) and craniopharyngiomas.

Answer 65

o Apoplexy a. Definition: Clinical syndrome of headache, vision changes, ophthalmoplegia and altered mental status caused by the sudden hemorrhage or infarction of the pituitary gland. b. Occurs in ~10-15% of pituitary adenomas; sub-clinical disease is more common c. Diagnosis: Pituitary MRI or CT d. Treatment • Emergent surgery is indicated for evidence of severe vision loss, rapid clinical deterioration, or mental status changes. • Stress dose steroids are indicated for presumptive adrenal insufficiency. Expectant management is indicated for thyroid hormone and sex steroids. i. Residual pituitary hormone deficiencies are common.

Answer 66

Empty Sella Syndrome (ESS) a. Primary ESS-due to arachnoid herniation through a congenital diaghragmatic defect. i. Hyperprolactinemia in ~10% of cases, but hypopituitarism is uncommon. b. Secondary ESS- due to pituitary/parasellar disease and/or their treatment. Pituitary deficiencies are more common than in primary ESS.

Answer 67

a. Clinical Presentation of Hypopituitarism o Depends on the severity of the pituitary hormone deficiencies and their rate of development. o Represents a continuum from partial to complete pituitary hormone deficiency. o Similar presentation to target gland hormone deficiency as detailed above with some exceptions (e.g., primary adrenal insufficiency also presents w/hyperkalemia from mineralcorticoid deficiency and hyperpigmentation from ACTH excess). b. Diagnosis o Assessment of pituitary hormones and target hormones with basal and dynamic testing. c. Treatment: Replacement of hormones as indicated by deficiencies i. Glucocorticoids- Prednisone or hydrocortisone–first line therapies. ii. Thyroid hormone-multiple T4 formulations available. iii. Testosterone or estrogen • Various formulations-oral/transdermal E2, transdermal/IM Testosterone • Gonadotropin therapy is sometimes required for fertility treatment. • Growth hormone-subcutaneous shots (controversial use in adults regarding cost-to- benefit ratio). iv. dDAVP-oral or nasal formulations

Answer 68

Neurohypophysis-20% of the pituitary gland i. other name for posterior pituitary a. AVP = arginine vasopressin = ADH = antidiuretic hormone i. AVP release is stimulated by: • High osmolar states (via hypothalamic osmoreceptors) • Hypovolemia (via baroreceptors) b. AVP causes free water retention (via V2 receptors in the kidney) and vasoconstriction (via V1 receptors of blood vessels) c. Oxytocin-mediates milk let-down and uterine contractions

Answer 69

A syndrome of inappropriate AVP release in the absence of hyperosmotic or hypovolemic stimulus. The hallmark of SIADH is excretion of concentrated urine in the setting of serum hypoosmolality and hyponatremia. Etiology of SIADH • CNS disturbances (e.g., mass lesion, inflammatory diseases, degenerative/ demyelinative diseases, head injury, subarachnoid hemorrhage, hydrocephalus). • Drugs: o Stimulate AVP release: morphine, nicotine, phenothiazine, tricyclic antidepressants o Direct renal effects and/or potentiates AVP effects- prostaglandin synthesis inhibitor o Mixed or uncertain actions: carbamazepine, clofibrate, vincristine, cyclophosphamide, haloperidol. • Pulmonary disease (e.g., infections, mechanical ventilation) • Tumors (e.g., bronchogenic carcinoma, thymoma, leukemia, sarcoma, mesothelioma). • Other: idiopathic, AIDS, prolonged physical exercise, nausea, pain Clinical Presentation of SIADH • Presentation depends on the severity and rate of hyponatremia development • Manifests with neurological symptoms from osmotic fluid shifts and brain edema • Symptoms range from mild → severe, and include: headaches, fatigue, anorexia, nausea, vomiting, altered sensorium, seizure, coma and death Criteria for Diagnosis • Hyponatremia (Na+ <135 mEq/L) and hypotonic plasma (osmolality <275 mOsm/kg) • Inappropriate urine concentration (Urine Osm >100 mOSm/kg) with normal renal function • Euvolemic Status • Elevated urinary sodium excretion (with normal salt and water intake) • Exclude other potential causes of euvolemic hypo-osmolality: o Hypothyroidism o Hypocortisolism Treatment of SIADH • Treat underlying etiology • Water restriction to 500-1000 mL/24 h • Vasopressin (V2) Receptor Antagonists (e.g., Conivaptan, Tonivaptan) • Hypertonic saline (3%) infusion for severe, symptomatic hyponatremia Important to limit rate of sodium correction to avoid central pontine myelinolysis

Answer 70

a. Etiology of SIADH i. CNS disturbances (e.g., mass lesion, inflammatory diseases, degenerative/ demyelinative diseases, head injury, subarachnoid hemorrhage, hydrocephalus). ii. Drugs: o Stimulate AVP release: morphine, nicotine, phenothiazine, tricyclic antidepressants o Direct renal effects and/or potentiates AVP effects- prostaglandin synthesis inhibitor o Mixed or uncertain actions: carbamazepine, clofibrate, vincristine, cyclophosphamide, haloperidol. iii. Pulmonary disease (e.g., infections, mechanical ventilation) iv. Tumors (e.g., bronchogenic carcinoma, thymoma, leukemia, sarcoma, mesothelioma). v. Other: idiopathic, AIDS, prolonged physical exercise, nausea, pain b. Clinical Presentation of SIADH • Presentation depends on the severity and rate of hyponatremia development • Manifests with neurological symptoms from osmotic fluid shifts and brain edema • Symptoms range from mild → severe, and include: headaches, fatigue, anorexia, nausea, vomiting, altered sensorium, seizure, coma and death

Answer 71

a. Clinical Presentation of SIADH i. Presentation depends on the severity and rate of hyponatremia development ii. Manifests with neurological symptoms from osmotic fluid shifts and brain edema iii. Symptoms range from mild → severe, and include: headaches, fatigue, anorexia, nausea, vomiting, altered sensorium, seizure, coma and death b. Criteria for Diagnosis 1) Hyponatremia (Na+ <135 mEq/L) and hypotonic plasma (osmolality <275 mOsm/kg) 2) Inappropriate urine concentration (Urine Osm >100 mOSm/kg) with normal renal function 3) Euvolemic Status 4) Elevated urinary sodium excretion (with normal salt and water intake) 5) Exclude other potential causes of euvolemic hypo-osmolality: o Hypothyroidism o Hypocortisolism

Answer 72

a. Criteria for Diagnosis 1) Hyponatremia (Na+ <135 mEq/L) and hypotonic plasma (osmolality <275 mOsm/kg) 2) Inappropriate urine concentration (Urine Osm >100 mOSm/kg) with normal renal function 3) Euvolemic Status 4) Elevated urinary sodium excretion (with normal salt and water intake) 5) Exclude other potential causes of euvolemic hypo-osmolality: o Hypothyroidism o Hypocortisolism b. Treatment of SIADH i. Treat underlying etiology ii. Water restriction to 500-1000 mL/24 h iii. Vasopressin (V2) Receptor Antagonists (e.g., Conivaptan, Tonivaptan) iv. Hypertonic saline (3%) infusion for severe, symptomatic hyponatremia Important to limit rate of sodium correction to avoid central pontine myelinolysis

Answer 73

a. Diabetes Insipidus (DI) is a syndrome of hypotonic polyuria from either inadequate AVP secretion (central or neurogenic DI) or inadequate renal response to AVP (nephrogenic DI). b. The hallmark of DI is the excretion of voluminous amounts of dilute urine. c. Presentation i. Polyuria/Nocturia ii. Polydipsia iii. Hypernatremia quickly develops if the patient does not have an intact thirst mechanism (e.g., adipsia from hypothalamic injury), or has limited access to water (such as in the elderly).

Answer 74

1. Neurogenic (Central) DI • Neoplasms-Craniopharyngioma, metastatic pituitary disease (e.g., colon, breast and lung), Rathke’s cleft cysts. • Idiopathic: +AVP antibodies • Congenital-autosomal dominant AVP neurophysin gene mutation • Inflammatory/Infectious/granulomatous pituitary diseases-lymphocytic hypophysitis, meningitis, encephalitis, histiocytosis, sarcoidosis • Trauma/Vascular event-neurosurgery injury, deceleration injury/traumatic brain injury • Trauma-neurosurgery injury, deceleration injury o Classic ‘triphasic’ response: 1) Axonal shock/decreased AVP release (DI), 2) Degenerating neurons/excessive AVP release (SIADH), 3) Depleted AVP stores (permanent DI). Requires loss of >80 of SON/PVN nuclei o Transient DI and isolated secondary SIADH are more common than permanent DI. 2. Nephrogenic DI • Congenital-X-linked recessive AVP V2 receptor gene mutation; autosomal recessive aquaporin-2 water channel gene mutation • Drugs-demeclocycline, lithium, cisplatin, amphotericin B • Electrolyte abnormalities-hypokalemia and hypercalcemia • Infiltrative kidney diseases-sarcoidosis an

Answer 75

a. Confirm polyuria with a 24 hr urine volume collection (normalize to a 24 hr creatinine) b. Exclude hyperglycemia, renal insufficiency and electrolyte disturbances (K+, Ca2+). c. Assess plasma osmolality and urine osmolality d. Water Deprivation Test e. Pituitary Imaging (for suspected neurogenic DI).