• Presentation depends on acuity of onset and severity of hypopituitarism. Initial symptoms may be nonspecific and of insidious onset, depending on severity of hormone deficiency: Fatigue, hypotension, cold intolerance:
  • Pituitary failure secondary to tumors may present with symptoms related to mass effect: Headache, visual impairment, hypothalamic dysfunction.
  • Symptoms per specific hormone deficiency:
    • ACTH: Hypotension, hypoglycemia, nausea, vomiting, extreme fatigue, asthenia, anorexia, pallor, weight loss; in children, failure to thrive, hypoglycemia
    • TSH: In adults, fatigue, cold intolerance, constipation, weight gain, hair loss, dry skin, bradycardia, hoarseness, mental confusion or increased forgetfulness; in children, childhood growth failure
    • Gonadotropins: Sexual dysfunction, loss of libido, infertility; in men, impotence, decreased facial and body hair, decreased muscle and bone mass; in women, menstrual disturbance, dyspareunia; in children, delayed puberty can present with eunuchoid habitus
    • GH: Commonly deficient when other hormones are deficient. In adults, fatigue, decreased muscle mass and strength, increased visceral fat, general malaise; in children, growth retardation
    • Prolactin: Inability to lactate
    • ADH: Polyuria, polydipsia, orthostasis, hypotension
• Assessment of pituitary function is indicated in individuals with history of the following:
  • Head trauma, pituitary surgery or cranial radiation
  • Pituitary or hypothalamic lesions
  • Craniofacial abnormalities
  • Empty sella
  • Gonadal dysfunction
  • Inflammatory or granulomatous disease
  • Postpartum hemorrhage or hypotension

• Pituitary failure secondary to tumors:
  • ACTH: Hypotension, tachycardia, orthostasis, pallor, weight loss
  • TSH: Weight gain, hair loss, dry skin, bradycardia, hoarseness, hypotension, edema
  • Gonadotropins: Loss of secondary sexual characteristics (loss of pubic and axillary hair, decreased gonadal size and muscle mass)
  • GH: Decreased muscle mass and strength, increased visceral fat, growth retardation
• Visual field defects
• Children:
  • Congenital malformations and syndromes, especially malformations of the head and genitalia
  • Growth retardation and delayed puberty

Lab

• Documentation of ≥1 deficiencies of pituitary hormones: Hormones are tested individually.
• Laboratory measurement of basal and stimulated hormone levels and levels of their target hormones.
• Corticotropin (ACTH):
  • Basal cortisol at 8–9 a.m.; low level (<3 mcg/dL) is positive test while >18 mcg/dL rules out ACTH deficiency. For levels between 3 and 18 mcg/dL one of the following tests should be performed:
    • Metyrapone test: Induced reduction in serum cortisol should increase ACTH secretion and 11-DOC levels.
    • ACTH stimulation test: Administration of synthetic ACTH should stimulate adrenal cortisol production unless adrenal atrophy is present due to decreased ACTH production. A peak cortisol level >18 mcg/dL is an adequate response.
    • Insulin-induced hypoglycemia: Should increase ACTH and cortisol secretion. Test is contraindicated in coronary artery disease (CAD), seizure disorder, or cerebrovascular disease.
• TSH (not a reliable screening test):
  • Secondary hypothyroidism is rare in absence of other pituitary hormone deficiencies.
  • Low free T₄ with inappropriately normal or low TSH suggests TSH deficiency.
  • Thyrotropin-releasing hormone (TRH) stimulation: Blunted response in secondary hypothyroidism
• Gonadotropins:
  • Men: Low serum testosterone is surrogate for LH deficiency in patients with known hypothalamic or pituitary disease. Free testosterone levels are more accurate in obesity. LH is elevated in primary hypogonadism and normal or low in secondary hypogonadism.
  • Women: In women with known pituitary disease, LH and FSH testing is not necessary in the presence of normal menses.
  • In the presence of oligomenorrhea or amenorrhea, measure LH and FSH levels.
  • Serum estradiol is low in hypogonadotropic hypogonadism.
  • Exclude hyperprolactinemia.
• Prolactin:
  • Isolated hypoprolactinemia is rare.
  • Prolactin deficiency prevents lactation.
  • In prolactin deficiency, basal plasma levels are low and fail to rise after injection of TRH.
  • Elevated prolactin may accompany hypopituitarism due to the disruption of hypothalamic inhibitory influences; this is the stalk effect.
• GH:
  • GH deficiency highly likely if ≥2 other pituitary hormones deficient
  • Low serum IGF-1 (in older adults with GH deficiency, IGF-1 levels may be in lower part of normal range)
  • Provocative tests include insulin-induced hypoglycemia (insulin tolerance test), glucagon stimulation and arginine–GH-releasing hormone. Positive tests show deficient serum GH response. Again, insulin-induced hypoglycemia is contraindicated in CAD, seizure disorder, or cerebrovascular disease.

Initial Labs

• Initial tests should be based on clinical suspicion; test both the trophic pituitary hormone and the hormone produced by the targeted gland (e.g., TSH and free T₄). The testing should be ideally at 8 a.m. because many hormone levels are affected by circadian rhythm.
• ACTH: cortisol; LH, FSH: estradiol, testosterone; GH: IGF-1; TSH/free T₄: prolactin.
• Biochemical tests should precede imaging studies.

Imaging

• MRI of hypothalamic–pituitary region
• If MRI is contraindicated, then high-resolution CT with pituitary/sella focus
• Radiographs: Skull, hands (for bone age)
• Dual-energy x-ray absorptiometry: Gonadotropin and GH deficiency may result in osteoporosis.

Follow-Up and Special Considerations Patients should be followed closely for symptoms and signs of under-/overreplacement of hormones, as laboratory measurements of hormones may not be enough to determine adequacy of hormone replacement. Hypopituitary patients are at increased risk of CVD and osteoporosis.

Pathological Findings

• Destruction of anterior pituitary
• Atrophy of adrenal cortex, thyroid, gonads

• Primary hypothyroidism or hypogonadism
• Addison disease, primary adrenal insufficiency
• Hypothalamic insufficiency
• Kallmann syndrome
• Chronic liver disease
• Constitutional short stature