Hypothalamic & Pituitary Dysfunction

Question 1

Clinical features of GH excess

Answer 1

• Gigantism → before epiphyseal plate closure
• Acromegaly → after epiphyseal plate closure
  
  • acral/facial changes
  • heachaches
  • hyperhydrosis (increased sweating),
  • oligo/amenorrhea
  • obstructive sleep apnea
  • hypertention
  • dyslipidemia
  • paresthesias/carpal tunnel syndrome
  • impaired glucose tolerance/diabetes mellitus

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Question 2

Dx of GH excess

Answer 2

• Clinical Features of GH excess AND
• Elevated IGF-1 level (age and gender matched)-best screening test
  
  • GH levels fluctuate widely over 24 hrs and normal values can overlap with GH-secreting tumors
• Confirmatory testing for equivocal IGF-1 level → Oral glucose tolerance test
• Pituitary MRI-macroadenomas are detected in most cases of acromegaly (>80%).

Question 3

Clinical Presentation of GH deficiency

Answer 3

• altered body composition (e.g., ↑ central obesity, ↓ lean body mass)
• ↓ bone mineral density
• pro-atherogenic lipid profile / ↑ inflammatory markers (e.g., CRP, hypertriglycerides, IL-6)
• impaired psychological well-being (e.g., fatigue and depression).

Question 4

Dx of GH Deficiency

Answer 4

• Low IGF-1 in the setting of multiple other pituitary hormone deficiencies
• Provocative testing for GH reserve:
  
  • Insulin induced hypoglycemia is gold standard
  • Contraindications: elderly, h/o seizure disorder, coronary artery disease or cerebrovascular disease.
• GHRH-Arginine is second best test but no longer available in U.S
• Arginine and glucagon test, but problematic.

Question 5

Tx of GH deficiency

Answer 5

Tx → controversial in adults b/c cost/benefit; thus limit to severe GH deficiencies

Question 6

Clinical presentation of hyperrolactinemia

Answer 6

• Hormone Effects-Galactorrhea;
  
  • causes irregular menses and amenorrhea (♀)
  • erectile dysfunction (♂)
  • infertility, osteoporosis, ↓ libido
• Female usually microadenoma, male macro (Female:Male = 10:1)
• Mass Effects if macroadenoma-related (♂ > ♀) and includes:
  
  • headaches
  • vision disturbances
  • cranial nerve palsies
  • pituitary hormone deficiencies

Question 7

Dx of hyperprolactinemia

Answer 7

• Random PRL level should use gender-based normative ranges
• Levels usually >100-150 ng/mL with prolactinomas
• Pituitary MRI

Question 8

Clinical presentation fo prolactin deficiency

Answer 8

• Usually caused by severe lactotrope destruction from any cause
• Failed lactation in post-partum females, no effect in males.

Question 9

Dx of prolactin deficiency

Answer 9

• Low random basal PRL level

Question 10

Clinical presentation of hypercortisolism

Answer 10

• Specific features of Cushing’s include:
  
  • facial plethora
  • easy bruising
  • wide (>1 cm) violaceous striae
  • proximal muscle weakness
• General signs/symptoms (poor specificity):
  
  • weight gain/obesity, diabetes, hypertension, irregular menses, dorsocervical hump, acne, low libido, depression or hirsutism
• Most Often iatrogenic, i.e. chronic steroid use
• Rare → 3 / 1 million

Question 11

Screening for hypercortisolism

Answer 11

• Disrupted Circadian Rhythm → midnight salivary or serum cortisol
• Increased Filtered Cortisol Load → 24 hour urinary cortisol
• Attenuated Negative Feedback → 1 mg dexamethasone suppression test (1 mg dexamethasone given at 11-12 p.m., followed by ~8 am cortisol level. Normal cortisol suppression <1.8 ug/dl)

Question 12

Dx of hypercortisolism

Answer 12

• plasma ACTH level
• imaging
• inferior petrosal sinus sampling
• Caveat: “Pseudo-Cushing’s” disease:
  
  • non-tumoral activation of hypothalamic-pituitary-adrenal (HPA) axis (e.g., severe depression, alcoholism, marked stressors) ==> false-positive screening

Question 13

Clinical presentation of cortisol deficiency

Answer 13

• Fatigue, pallor
• anorexia, weight loss
• nausea, vomiting, abdominal pain,
• hyponatremia
• hypoglycemia
• orthostatic dizziness
• scant axillary/pubic hair which is DHEA-S dependent.

Question 14

Dx of cortisol deficiency

Answer 14

• Random a.m. cortisol level
  
  • <3 ug/dl = confirmatory
  • >18 = excludes
• Stimulation tests to assess HPA axis
  
  • Insulin-induced hypoglycemia (gold standard)
    
    • hard to administer = ↑ resources
  • Cosyntropin (synthetic ACTH 1-24) stimulation test
    
    • valid for assessing HPA axis only if prolonged (several weeks-months) interruption of pituitary signaling.

Question 15

Clinical presentation of LH/FSH Tumor in Females

Answer 15

• Hypogonadotropic Hypogonadism
• Most often clinically silent.
• Females:
  
  • anovulatory cycles
  • oligo/amenorrhea
  • infertility
  • hot flashes
  • vaginal dryness/atrophy
  • dyspareunia
  • reduced bone mineral density (BMD)

Question 16

Clinical presentation of LH/FSH Tumor in Males

Answer 16

• Hypogonadotropic Hypogonadism
• Most often clinically silent.
• Males: Reduced libido, erectile dysfunction, oligospermia or azoospermia, testicular atrophy, infertility, decreased muscle mass and low BMD.

Question 17

Rare presentation of LH/FSH tumor

Answer 17

• Rare presentation (from functionally-intact FSH/LH molecules) include:
  
  • ovarian hyperstimulation syndrome (females)
  • macro-orchidism (males).

Question 18

Dx of LH/FSH tumor

Answer 18

1. Clinical
2. Blood work: FSH/LH, T and E2, alpha-subunit
3. Imaging: Pituitary MRI
4. Immunohistochemical analyses (+FSH or LH staining of the resected tumor) establishes the diagnosis

Question 19

Clinical presentation of Thyrotropinoma

Answer 19

• Thyrotropinoma (TSHoma)-similar clinical presentation to primary hyperthyroidism
• hyperthyroid sx = goitre, tremor, weight loss, heat intolerance, hair loss, diarrhea, irregular menses AND
• mass effects (i.e., headaches, vision loss) from macroadenoma

Question 20

Dx of Thyrotropinoma

Answer 20

• Elevations of free thyroxine (T4) and triiodothyronine (T3) concentrations
• non-suppressed (inappropriately normal or frankly elevated) TSH level.
• Pituitary MRI

Question 21

Clinical presentation of Central hypothyroidism

Answer 21

• Central Hypothyroidism-similar clinical presentation to primary hypothyroidism
• fatigue
• weight gain
• cold intolerance
• constipation
• hair loss
• irregular menses

Question 22

Dx of central hypothyroidism

Answer 22

• Central hypothyroidism: Low Free T4 levels in the setting of a low or normal TSH.
• Pituitary MRI

Question 23

Clinical presentation of SIADH

Answer 23

• 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

Question 24

Dx of SIADH

Answer 24

• Hyponatremia → Na+ < 135 mEq/L (very common) and hypotonic plasma → osmolality < 275 mOsm/kg
• Inappropriate urine concentration (Urine Osm >100 mOSm/kg) with normal renal function
• Euvolemic Status → No pitting edema, no JVD
• Elevated urinary sodium excretion (with normal salt and water intake)

Question 25

Clinical presentation of Diabetes Insipidus (central or nephrogenic)

Answer 25

* Polyuria/Nocturia, Polydipsia * 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).

Question 26

Dx of Diabetes Insipidus (central or nephrogenic)

Answer 26

* Confirm polyuria with a 24 hr urine volume collection (normalize to a 24 hr creatinine) * Assess plasma osmolality and urine osmolality * Water Deprivation Test * Pituitary Imaging (for suspected neurogenic DI)

Question 27

Conditions necc. to exclude with polyuria for dx of DI

Answer 27

* Exclude: Primary polydipsia (psychogenic), Pregnancy (increased ADH metabolism) * Exclude hyperglycemia, renal insufficiency and electrolyte disturbances (K+, Ca2+).

Question 28

Clinical Presentation of hypopituitarism

Answer 28

* Depends on the severity of the pituitary hormone deficiencies and their rate of development. * Represents a continuum from partial to complete pituitary hormone deficiency. * 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)

Question 29

Dx of hypopituitarism

Answer 29

* Assessment of pituitary hormones and target hormones as previously detailed for basal and provocative testing. * Treat with end organ hormone replacement.

Question 30

Major fxns of posterior pituitary

Answer 30

* Neurohypophysis-20% of the pituitary gland - makes ADH and Oxytocin * AVP = arginine vasopressin = ADH = antidiuretic hormone * Oxytocin-mediates milk let-down and uterine contractions

Question 31

Stimulation leading to AVP/ADH release + downstream effects

Answer 31

* AVP release is stimulated by: * High osmolar states (via hypothalamic osmoreceptors) * Hypovolemia (via baroreceptors) * AVP causes free water retention (via V2 receptors in the kidney) and vasoconstriction (via V1 receptors of blood vessels)

Question 32

Most common posterior pituitary disorders

Answer 32

* SIADH = sydrome of inappropriate ADH * → inappropriate concentration of urine excreted in the setting of hypo-osmolality and hyponatremia * Diabetes insipidus ==\> a syndrome of hypotonic polyuria as a result of either

Question 33

General characteristics of SIADH

Answer 33

* SIADH → inappropriate concentration of urine excreted in the setting of hypo-osmolality and hyponatremia. * One of the most common causes of hyponatremia * Etiologies → Malignancy, pulmonary disorder, CNS disorder, Drugs, Other (nausea, stress, pain) * Clinical presentation (see separate card) * Diagnosis (see separate card)

Question 34

General characteristics of Diabetes Insipidus

Answer 34

* a syndrome of hypotonic polyuria as a result of either: * Inadequate ADH secretion * Inadequate renal response to ADH * Hallmark → Voluminous (Urine output \> 40 ml/kg/day) dilute urine * Causes → Central diabetes insipidus, nephrogenic diabetes insipidus, pregnancy-increased ADH metabolism from placental vasopressinase, psychogenic polydipsia

Question 35

Etiology of hypopituitarism

Answer 35

* 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 * genetic defects

Question 36

Order of pituitary hormone deficiencies in hypopituitarism

Answer 36

* Generally predictable order of pituitary hormones deficiencies: * GH≈FSH/LH \> TSH ≈ACTH \> PRL * ADH deficiency- infrequent with pituitary adenomas, but common with metastatic diseases to the pituitary gland (e.g., lung, breast or colon) and craniopharyngiomas.

Question 37

Tx of hypopituitarism

Answer 37

* Glucocorticoids- Prednisone or hydrocortisone–first line therapies. * Thyroid hormone-multiple T4 formulations available. * 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). * dDAVP-oral or nasal formulations * PRL- SQ formulation, research use only.