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Flashcards in hypothalamic pituitary dysfunction Deck (80):

List factors which stimulate release of GH

sleep, stress, ghrelin, arginine, hypoglycemia


List factors which inhibit release of GH

Obesity/FFA, glucocorticoids, leptin, hyperglycemia


clinical signs of GH excess and deficiency. How do you assess?

excess: acromegaly (large body tissues). Deficiency: GH deficiency. Check GH and IGF( liver)


clinical signs of PRL excess and deficiency. How do you assess?

excess: hypogonadism. Deficiency: failed lactation. Check PRL and breast


clinical signs of FSH/LH excess and deficiency. How do you assess?

excess; rare. Deficiency: hypogonadism. Check LHFSH and testosterone or estradiol (gonads)


clinical signs of ACTH excess and deficiency. How do you assess?

excess: cushings. Deficiency: adrenal insufficiency. Check ACTH and cortisol/ DHEA-S (adrenal gland)


clinical signs of TSH excess and deficiency. How do you assess?

excess: hyperthyroidism. Deficiency: hypothyroidism. Check TSH and T4/T3 (thyroid)


clinical signs of ADH excess and deficiency

excess: SIADH. Deficiency: diabetes insipidus


Levels of Hypothalamic-Pituitary- Target Organ Defect

Tertiary disorders: hypothalamus. Secondary: pituitary. Primary: target organ


what is dynamic pituitary testing and give examples for GH and ACTH

Utilizes Known Physiologic Stimulators and Suppressors of Pituitary Hormone Release. Hormone Excess is assessed by a Suppression Test (e.g., Oral glucose tolerance test for GH suppression to confirm acromegaly). Hormone Deficiency is assessed by a Stimulation Test (e.g., insulin tolerance test to evaluate pituitary (ACTH and GH) reserves.


Dynamic test for ACTH deficiency

cosyntropin stimulating test- hypoglycemia using insulin, metryapone


dynamic test for GH deficiency

Stimulating tests: glucagon or Arginine, ITT


GH regulation

GH stimulates release of IGF-1 from liver, which inhibits pituitary release of GH and hypothalamus release of GHRH. Also, GH directly inhibits pituitary and hypothalamus


List actions of GH

1. increases blood glucose (via IGF-1). 2. increases bone and cartilage mass/growth. 3. increases protein synthesis and muscle mass. 4. increases fat breakdown and TGA levels. 5. increases salt/H20


compare GH excess before and after puberty

GIGANTISM-Growth hormone excess before puberty (before closure of the growth plates) results in very tall stature. ACROMEGALY-GH excess after puberty (after completion of linear growth) results in large body tissues but not height.


clinical presentation of acromegaly

facial changes, headaches, hyperhidrosis, amenorrhea, sleep apnea, HTN, dyslipidemia, parasthesias, carpal tunnl, impaired glucose tolerance/diabetes


Diagnosis of GH excess

Elevated IGF-1 is best screening test due to long half life and integrated 24 hr secretion. Note that GH levels fluctuate widely over 24 hrs and normal values can overlap with GH-secreting tumors. Check OGTT/GH for equivocal cases. Pituitary MRI. Also clinical features


primary cause of GH excess

pituitary macroademonas- 80%


acromegaly treatment

surgery, somatostatin analogs, GH receptor antagonists, radiation therapy


clinical presentation of GH deficiency

1. body composition: increased fat, decreased muscle mass and strength. 2. bone strength: bone loss and fracture risk. 3. Metabolic/cardiovascular: increased cholesterol and C-RP. 4. psychological: impaired energy and modd, decreased quality of life


GH deficiency treatment

GH replacement therapy is controversial in adult onset. Modest benefits in body comp, metabolic parameters and QoL


diagnosis of adult onset GH deficiency

1. insulin induced hypoglycemia (gold standard). 2. GHRH-arginine (second best) no longer available in US. 3. arginine and glucagon stimulation tests. 4. IGF-1 level is low


causes of hyperprolactinemia

1. Physiological :Pregnancy, suckling, sleep, stress. 2. Pharmacological: Estrogens (OCPs), Antipsychotics, antidepressants (TCAs), antiemetics (reglan), Opiates. 3. Pathological: Pituitary Stalk Interruption, Hypothyroidism, chronic renal/liver failure, seizure
Prolactinoma1. Physiological :Pregnancy, suckling, sleep, stress. 2. Pharmacological: Estrogens (OCPs), Antipsychotics, antidepressants (TCAs), antiemetics (reglan), Opiates. 3. Pathological: Pituitary Stalk Interruption, Hypothyroidism, chronic renal/liver failure, seizure
Prolactinoma1. Physiological :Pregnancy, suckling, sleep, stress. 2. Pharmacological: Estrogens (OCPs), Antipsychotics, antidepressants (TCAs), antiemetics (reglan), Opiates. 3. Pathological: Pituitary Stalk Interruption, Hypothyroidism, chronic renal/liver failure, seizure
Prolactinoma1. Physiological :Pregnancy, suckling, sleep, stress. 2. Pharmacological: Estrogens (OCPs), Antipsychotics, antidepressants (TCAs), antiemetics (reglan), Opiates. 3. Pathological: Pituitary Stalk Interruption, Hypothyroidism, chronic renal/liver failure, seizure


Compare prolactinomas in women vs men

10:1 female to male. Females: microadenomas- galactorrhoea in 30-80%, menstrual irregularity, infertility, impairs GnRH pulse generator. Males: macroadenomas- galactorrhoea in <30%, visual field abnormalities, headache, impotence, EOM paralysis, antieror pituitary malfunction


prolactinoma diagnosis

1. random PRL level. 100-150ng/dl correlates with microadenoma. 200-250ng/dl correlates with macroadenoma. 2. pituitary MRI


Prolactin deficiency causes, presentation and diagnosis

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


Cortisol functions

Gluconeogenesis, Breakdown of Fat and Protein for Glucose Production, Control Inflammatory Reactions


Clinical presentation of chronic cortisol excess

1. changes in carb, protein and fat metabolism: wasting of fat/muscle, central obesity, osteoporosis, diabetes, elevated TG. 2. Changes in sex hormones: amenorrhea, excess hair, impotence. 3. salt and water retention: HTN, edema. 4. impaired immunity. 5. neurocognitive changes


ACTH dependent and independent causes of hypercortisolism

Dependent (75%): Corticotrope Adenoma (Cushing’s Disease), Ectopic Cushing’s (ACTH/CRH tumors). Independent (30%): Adrenal Adenomas, Adrenal Carcinoma, Nodular Hyperplasia (micro or macro)


screening guidlelines for Cushings syndrome

Screening indicated in patients with multiple and progressive “high-discriminatory” features of Cushing’s Syndrome


Clinical signs of Cushing syndrome

Plethoric/moon facies, wide violaceous striae (abdominal, axillary), Spontaneous Ecchymoses (bruising), Proximal Muscle Weakness, early osteoporosis


cortisol rhythms

Episodic- Major ACTH/cortisol burst in the early morning (before awakening). Cortisol drops lowest at 11-12pm


Cortisol binding

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


Screening tests for Cushings

1. Disrupted Circadian Rhythm- Midnight Salivary or Serum Cortisol. 2. Increased Filtered Cortisol Load - 24 hr Urine Free Cortisol. 3. Attenuated Negative Feedback- Low Dose (1 mg) Dexamethasone Suppression test (11-12 p.m.)



Overactivation of the HPA axis without tumorous cortisol hypersecretion. Severe Depression/ Anxiety/OCD, Severe Obstructive Sleep Apnea, Alcoholism, Poorly-controlled DM, Physical Stress (acute illness, surgery, pain)


Cushings workup

1. Midly elevated plasma ACTH. 2. MRI of pituitary: ~80% microadenomas, 50% identified on MRI). 3. Sampling of inferior petrosal sinus if MRI negative


Etiology of central adrenal insufficiency

secondary causes: Tumor resection for Cushings (pituitary, ectopic or adrenal), Supraphysiologic exogenous glucocorticoid use (most common), opioids and megace


Clinical Presentation of secondary/tertiary adrenal insufficiency (AI)

Fatigue, Anorexia, nausea/vomiting and weight loss , Generalized malaise/aches, Scant Axillary/Pubic hair (DHEA-S dependent in females), Hyponatremia and Hypoglycemia


Diagnosis of central adrenal insufficiency

1. basal testing: random am cortisol18, excludes AI). 2. stimulation: Insulin-induced hypoglycemia (gold standard)–assesses entire hypothalamic-pituitary-adrenal axis. 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.


Hypogonadism differential dx

1. Hypergonadotropic (High FSH/LH): Congenital, Klinefelters, testicular injury, autoimmune testicular dz, glycoprotein tumor. 2. Hypogonadotropic (Low FSH/LH): Hypothalamic/pituitary dz (macroadenomas, prolactinomas, XRT, GnRH deficiency, hemochromatosis) or functional deficiency (critical illness, OSA, starvation, meds)


compare clinical features of hypogonadism in females vs males

females: amenorrhea, infertility, vagina dryness, hot flashes, decreased libido, breast atrophy, reduced bone mineral density. Males: reduced libido, ED, oligospermia, infertility, decreased muscle mass, testicular atrophy, hot flashes with acute/severe onset


Clinical presentation of gonadotropin excess

Most FSH/LH tumors are silent. Rare presentation include: ovarian hyper-stimulation syndrome (females) or macro-orchidism (males). Middle-aged patients (males >females) with macroadenomas and related mass effects (i.e., headaches, vision loss, cranial nerve palsies, and/or pituitary hormone deficiencies).


gonadotropinoma diagnosis

Low serum FSH/LH, low serum testosterone or estrogen, pituitary MRI, immunohistochemical staining of tumor for FSH, LH or ASU


Secondary Etiologies of thyrotropin (TSH) elevation

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


Clinical presentation of thyrotropinoma

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.


Thyrotropinoma diagnosis

Elevated Free T4 and a non-suppressed TSH. Pituitary MRI (>80% macroadenomas)


Secondary causes of TSH deficiency

Pituitary/Hypothalamic Diseases and/or their treatments, Critical Illness/Starvation-Euthyroid Sick Syndrome, Congenital defects (TSH-beta mutations, PROP1, POUF1 mutations), Drug induced-supraphysiologic steroids, dopamine, rexinoids.


TSH deficiency presentation

Similar to primary hypothyroidism (e.g., fatigue, weight gain, cold intolerance, constipation, hair loss, irregular menses). Possible mass effects


TSH deficiency diagnosis

Low Free T4 levels in the setting of a low or normal TSH.



Deficiency of 1 or more pituitary hormones



loss of all pituitary hormones


Etiologies of hypopituitarism

Congenital (trxn factor mutations) Or acquired -75% (macroadenomas/pituitary surgery or radiation, infiltrative/infectious/granulomatous, TBI, subarachnoid hemorrhage, apoplexy)


define apoplexy

Clinical syndrome of headache, vision changes, ophthalmoplegia and altered mental status caused by the sudden hemorrhage or infarction of the pituitary gland. Occurs in ~10-15% of pituitary adenomas; sub-clinical disease is more common


Diagnosis of apoplexy

pituitary MRI or CT


apoplexy treatment

Emergent surgery is indicated for evidence of severe vision loss, rapid clinical deterioration, or mental status changes. Stress dose steroids for adrenal insufficiency


Causes of ADH deficiency

common with metastatic tumors (i.e., breast, lung or GI) or craniopharyngiomas, but not pituitary adenomas


describe the progression of loss of anterior pituitary hormones in hypopituitarism



Diagnosis of hypopituitarism

basal and dynamic testing of hormones


Treatment of hypopituitarism

Replace end organ hormone: 1. thyroid: L-thyroxine. 2. adrenal: hydrocortisone or prednisone. 3. gonadal: estrogen, test, gonadotropin or GnRH. 4. GH: subQ shots. 5. PRL: SQ formulation, research only


What are bio-identical hormones

hormones made by pharmacies that are supposedly individually tailored based on saliva. Exaggerated and unproven claims of safety and efficacy relative to other FDA-approved products


clinical syndromes of posterior pituitary

primarily associated with disorders of AVP (aka arginine vasopressin aka ADH)


Regulation of ADH release

Hyperosmolar state and hypovolemia (baroreceptors)



vascular vasoconstriction and water reabsorption in kidneys (via aquaporin channels)



A syndrome of inappropriate AVP release/action in the absence of physiologic osmotic or hypovolemic stimulus


SIADH presentation

Hallmark is the excretion of inappropriately concentrated urine in the setting of hypo-osmolality and hyponatremia. SIADH is one of the most frequent causes of hyponatremia. Neurological sx from osmotic fluid shifts and brain edema


SIADH etiologies

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 Narcotics, Nicotine, Anti-psychotics, Carbamazepine, Vincristine. 5. Misc.-Nausea, Stress and Pain


SIADH criteria

1. Hyponatremia (Na+ 100 mOSm/kg) with normal renal function. 3. Euvolemic Status (no orthostatics hypotension)


SIADH treatment

Mild-moderate hyponatremia (120-124mmol/L): Water restriction (500-1000ml/24hrs), V2 receptor antagonists, salt tablets, lasix, urea (europe). Severe hyponatremia (<120mmol/L): hypertonic saline (3%) if pt is symptomatic (delirium, seizure,coma)


consequence of correcting hyponatremia too fast

osmotic demyelination syndrome


Features of osmotic demyelination syndrome

mutism/dyarthria, lethargy, behavioral changes, confusion, movmement difficulty, muscle contraction, dysphagia


How to reduce risk of demyelination syndrome

If chronic hyponatremia: limit correction to <48hrs): no limitations


Diabetes insipidus

DI is a syndrome of hypotonic polyuria as a result of either: Inadequate ADH secretion OR Inadequate renal response to ADH


main Causes of diabetes insipidus

Central diabetes insipidus, nephrogenic DI, pregnancy (increased ADH metabolism from placental vasopressinase), psychogenic polydipsia.


significance of DI

§Can lead to severe dehydration if thirst mechanisms are impaired, or if the patient has limited access to water.


compare nephrogenic vs neurogenic causes of DI

nephrogenic: congenital mutation in aquaporin, drugs (lithium, amphotericin B), electrolyte abnormalities, infiltrative kidney dz, vascular dz. Neurogenic: neoplasms, idiopathic (AVP Ab), congential mutation in AVP, inflammatory/infectious, trauma


Post operative DI

Triphase 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. Can also have an isolated second SIADH phase which is more common


DI diagnosis

1. 24 hr urine volume collection (normalized to creatinine). 2. urine and plasma osmolalities. 3. water deprivation test. 4. pituitary imaging


What is a water deprivation test

Restrict fluids to stimulate ADH release, then measure urine and plasma osmolality, serum Na and urine output.


compare water deprivation test results for neurogenic, nephrogenic and psychogenic DI

neurogenic: no change in urine osmolarity or plasma ADH. Nephrogenic: no change in urine osmolarity and increase in plasma ADH. Psychogenic: increased urine osmolarity and plasma ADH


DI treatment

First line: dDAVP - no vasopressor effect second line: ADH