• Generalized condition caused by partial or total failure of pituitary gland's hormones: Adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and prolactin.
• System(s) affected: Endocrine/Metabolic; GI; Musculoskeletal; Nervous; Reproductive; Skin/Exocrine
• Synonym(s): Pituitary cachexia; Hypopituitarism syndrome; Simmonds syndrome; Panhypopituitarism
• Shortages of ACTH, TSH, and antidiuretic hormone (ADH) can be life-threatening.

• Predominant age: Occurs in adults and children. In children it may cause short stature and pubertal delay.
• Predominant sex: Male = Female

Incidence
12–42 new cases per million per year (1)

Prevalence
300–455 per million (1)

• Trauma
• Pregnancy and delivery

Genetics
Syndromic and nonsyndromic; isolated and multiple pituitary hormone deficiencies attributed to single-gene defects

Prevention of head trauma

• Childhood:
  • Genetic disorders
  • Perinatal asphyxia
  • Developmental disorders/pituitary hypoplasia, aplasia
  • Craniopharyngioma, other tumors
  • Cranial irradiation
  • Head trauma
• Adult:
  • Pituitary tumors; most common etiology
  • Other intrasellar or extrasellar tumors: Meningiomas, gliomas, metastases, craniopharyngiomas, chordomas, ependymomas
  • Surgery on pituitary or adjacent structures
  • Cranial irradiation
  • Pituitary infarction, apoplexy
  • Lymphocytic hypophysitis
  • Postpartum hemorrhage with hypotension (Sheehan syndrome)
  • Vascular: Internal carotid artery aneurysm, subarachnoid hemorrhage
  • Head trauma (2)
  • Infection:
    • Abscess, hypophysitis, meningitis, encephalitis
    • Tuberculosis, pneumocystis, histoplasmosis, toxoplasmosis, aspergillosis, cytomegalovirus
  • Infiltrative conditions: Hemochromatosis, granulomatous disease, histiocytosis X
  • Hypothalamic disease (secondary hypopituitarism)
  • Autoimmune disease: Lymphocytic hypophysitis
  • Chronic debilitating disease, nonspecific
  • Other: Hemochromatosis, granulomatous diseases, histiocytosis
  • Empty sella

• Childhood hypopituitarism
• Sheehan syndrome
• Hypothyroidism
• Kallmann syndrome

History
Assessment of pituitary function, history of:

• Pituitary or hypothalamic lesions
• Cranial radiation
• Head trauma or head surgery
• Gonadal dysfunction
• Craniofacial abnormalities
• Empty sella
• Inflammatory or granulomatous disease
• Pregnancy-related hemorrhage or hypotension
• 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 are related to specific hormone deficiency:
  • Corticotropin (ACTH): Hypotension, hypoglycemia, nausea, vomiting, extreme fatigue, asthenia, anorexia, pallor, weight loss:
    • In children: Failure to thrive, hypoglycemia
  • Thyrotropin: Tiredness, cold intolerance, constipation, weight gain, hair loss, dry skin, bradycardia, hoarseness, mental lethargy
  • Gonadotropin: Sexual dysfunction, loss of libido, infertility:
    • In men: Impotence, decreased muscle and bone mass
    • In women: Amenorrhea, dyspareunia
    • In children: Delayed puberty
  • Growth hormone: Commonly deficient when other hormones are deficient. Fatigue, decreased muscle mass and strength, increased visceral fat, general malaise:
    • In children: Growth retardation
  • Prolactin: Inability to lactate

Physical Exam

• Hypotension
• Pituitary failure secondary to tumors: Visual impairment:
  • Corticotropin (ACTH): Hypotension, anorexia, pallor, weight loss
  • Thyrotropin: Weight gain, hair loss, dry skin, bradycardia, hoarseness
  • Gonadotropin: Delayed puberty
  • Growth hormone: Decreased muscle mass and strength, increased visceral fat, growth retardation

• Stigmata specific to hormone deficiencies
• 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.
• Deficiencies may be single or multiple
• Laboratory measurement of basal and stimulated hormone levels, and levels of their target hormones.
• Corticotropin:
  • Basal ACTH at 8–9 AM, low level is positive test
  • Metapyrone test: Induced reduction in serum cortisol should cause increase in ACTH secretion.
  • Corticotropin stimulation test: Administration of synthetic ACTH should stimulate adrenal cortisol production, unless adrenal atrophy is present.
• Thyrotropin:
  • Secondary hypothyroidism, rare in absence of other pituitary hormone deficiencies
  • Low free T4 with inappropriately normal or low TSH suggests TSH deficiency
  • TSH not a reliable screening test
  • Thyroid-releasing hormone (TRH) stimulation: Blunted response in secondary hypothyroidism
• Gonadotropins:
  • Men: Serum testosterone is surrogate for LH deficiency in patients with known hypothalamic or pituitary disease. LH is elevated in primary hypogonadism, and normal or low in secondary hypogonadism.
  • Women: In women with known pituitary disease, LH and FSH testing not necessary in the presence of normal menses.
  • In the presence of oligomenorrhea or amenorrhea, measure FSH and LH levels.
  • Serum estradiol is low in hypogonadotropic hypogonadism.
  • Vaginal cytology for estrogenization index
  • 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.
• Growth hormone:
  • Growth hormone deficiency highly likely if >2 other pituitary hormones deficient.
  • Low serum IGF-1.
  • Provocative tests include insulin-induced hypoglycemia, and arginine plus arginine-growth hormone-releasing hormone. Positive tests show deficient serum growth hormone response.
• Genetic testing if indicated

Imaging

• MRI of hypothalamic-pituitary region
• Radiographs: Chest, skull, hands, wrists (for bone age)
• Gonadotropin deficiency may result in osteoporosis

Pathological Findings

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

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

ALERT
Geriatric Considerations
More difficult to diagnose in elderly

Pediatric Considerations

• Congenital malformations, genetic conditions may warrant screening for hypopituitarism.
• Growth hormone deficiency may result in growth retardation.
• Hypogonadism in prenatal pituitary failure
• Delayed puberty

Pregnancy Considerations

• Pregnancy-associated hemorrhage or hypotension may result in pituitary hypoperfusion and subsequent partial or complete pituitary failure (Sheehan syndrome)
• Lymphocytic hypophysitis may be triggered by pregnancy.

• Replacement of hormones secreted by target glands
• Treatment of ACTH, TSH, LH, and FSH deficiencies similar to the treatment of primary hormone deficiencies of their respective target organ:
  • ACTH deficiency results in cortisol deficiency: Treatment consists of administration of glucocorticoid hormones (hydrocortisone, dexamethasone, or prednisone) to mimic normal pattern of cortisol secretion; mineralocorticoid replacement rarely necessary.
  • TSH deficiency: Goal of treatment is normal T4 value. Treat with -thyroxine.
  • LH and FSH deficiency: Treatment depends on gender and whether fertility is desired:
    • Men: Testosterone replacement if fertility not desired, gonadotropins for fertility.
    • Women: Estrogen–progesterone (and possibly testosterone) replacement, or for fertility, pulsatile gonadotropins.
  • Recombinant human growth hormone (for treating short stature in children and for treating selected adult patients)
  • Hypoprolactinemia has no treatment.
  • Dosages and administration schedule vary according to age and sex
• Infectious disease: Antibiotics as appropriate
• Inflammatory or granulomatous disease: Specific treatment

General Measures

• Outpatient
• Inpatient for surgery when hypopituitarism is a result of pituitary tumor
• Hormonal replacement

For pituitary tumor

Exercise as tolerated, no specific limitations.

Patient Monitoring

• 3- and 12-month evaluations for post-treatment hormonal status.
• Patients with pituitary tumors: Include visual fields, thyroid and adrenal function, and sellar computerized imaging.

Wear medical identification bracelet or necklace.

• Variable, but guardedly favorable with replacement therapy
• If a result of postpartum necrosis, may have complete or partial recovery

• Adrenal crisis
• Infertility, sexual dysfunction
• Blindness
• Short stature, failure to thrive, developmental delay, delayed puberty
• Premature atherosclerosis
• Obesity

• Ascoli P, Cavagnini F. Hypopituitarism. Pituitary 2006;9:335–342.
• VanAken MO, Lamberts SW. Diagnosis and treatment of hypopituitarism. Pituitary 2006;8:183–191.
• Vance ML. Hypopituitarism. N Engl J Med 1994;330:1651–1662.

253.2 Panhypopituitarism

74728003 hypopituitarism (disorder)

In patient with documented ACTH deficiency, emphasize the need for additional cortisone at the time of any major physical stress [e.g., fever above 101°F (38.3°C); acute illness].

Michele Roberts, MD, PhD

1. Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, et al. Hypopituitarism. Lancet 2007;369:1461–1470.  [PMID:17467517]
2. Behan LA, Agha A. Endocrine consequences of adult traumatic brain injury. Horm Res 2007;68 Suppl 5:18–21.  [PMID:18174698]