BASICS
DESCRIPTION
- Generalized condition caused by deficiency of anterior pituitary hormones: adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and prolactin. Less commonly, the posterior pituitary gland's hormones can be affected: vasopressin (AVP) (antidiuretic hormone [ADH]) and oxytocin (1)[A]
- Generally, the order that hormone deficiencies develop is predictable, with decreased secretion of hormones least essential for life (GH, LH, and FSH) occurring earlier and more frequently than TSH and ACTH.
- System(s) affected: cardiovascular, endocrine/metabolic, gastrointestinal, musculoskeletal, nervous, reproductive, skin/exocrine
- Synonym(s): empty sella syndrome; Simmonds syndrome; panhypopituitarism; Sheehan syndrome (postpartum); pituitary apoplexy
EPIDEMIOLOGY
Incidence
- 40 new cases/million/year
- Adults and children. In children, it may cause short stature and pubertal delay.
- Predominant sex: male = female
Prevalence
- 46/100,000
- 61% due to pituitary tumors, 9% parapituitary lesions, 19% other causes, 11% idiopathic
ETIOLOGY AND PATHOPHYSIOLOGY
- 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 parasellar tumors: meningiomas, gliomas, metastases, craniopharyngiomas, chordomas, ependymomas, suprasellar dysgerminomas, infundibulomas, astrocytomas, hamartomas
- Surgery on pituitary or adjacent structures, cranial irradiation
- Vascular: internal carotid artery aneurysm, subarachnoid hemorrhage, pituitary infarction, apoplexy, postpartum hemorrhage with hypotension (Sheehan syndrome)
- Head trauma
- Infection: abscess, hypophysitis, meningitis, encephalitis, tuberculosis, pneumocystic pneumonia, histoplasmosis, toxoplasmosis, aspergillosis, cytomegalovirus
- Infiltrative conditions: hemochromatosis, granulomatous disease, histiocytosis X, sarcoidosis
- Hypothalamic disease (secondary hypopituitarism)
- Autoimmune disease: lymphocytic hypophysitis
- Pituitary hemorrhage (apoplexy)
- Empty sella
Genetics
- Pituitary and hypothalamic hormone transcription factor defects cause the following congenital hormone deficiencies:
- AVP, diabetes insipidus
- DAX-1, congenital adrenal hypoplasia, hypogonadotropic hypogonadism
- GnRH-R and GPR54, loss-of-function mutations
- HESX-1, associated with septo-optic dysplasia
- KAL1 and FGFR1, Kallmann syndrome
- PROP1, LHX3, LHX4, combined pituitary hormone deficiency
- POMC, ACTH deficiency, obesity, red hair
- POU1F1 (Pit-1), combined pituitary hormone deficiency
- SF1, adrenal failure, 46,XY gonadal dysgenesis
- Genetic defects in pituitary hormone receptors
- ACTH receptor defects: congenital insensitivity to ACTH
- GH receptor defects: Laron dwarfism
- LH/FSH receptor mutations
- TSH receptor loss-of-function mutation
RISK FACTORS
- Pituitary or parapituitary tumors
- Pregnancy and delivery
- Head trauma
- Pituitary or cranial radiation
- Pituitary surgery
- Vascular aneurysms and cerebrovascular accidents
- Lymphocytic hypophysitis
- Infiltrative diseases
- Infections
GENERAL PREVENTION
Prevention of head trauma, experienced neurosurgeon, early detection of pituitary tumors, improved obstetric care (2)[B]
COMMONLY ASSOCIATED CONDITIONS
- Diabetes insipidus
- Kallmann syndrome
- Delayed puberty with growth delay
DIAGNOSIS
HISTORY
- Initial symptoms are nonspecific and insidious, 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 (3)[B].
- 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 (2)[A]:
- 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
PHYSICAL EXAM
- 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
DIFFERENTIAL DIAGNOSIS
- Primary hypothyroidism or hypogonadism
- Addison disease, primary adrenal insufficiency
- Hypothalamic insufficiency
- Kallmann syndrome
- Chronic liver disease
- Constitutional short stature
DIAGNOSTIC TESTS & INTERPRETATION
- 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 to 9 am; low level (<3 μg/dL) is positive test, whereas >18 μg/dL rules out ACTH deficiency. For levels between 3 and 18 μg/dL, one of the following tests should be performed:
- Metyrapone test: Induced reduction in serum cortisol should increase ACTH secretion and 11-DOC levels (4)[A].
- 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 μg/dL is an adequate response (4)[B].
- Insulin-induced hypoglycemia: should increase ACTH and cortisol secretion. Test is contraindicated in coronary artery disease (CAD), seizure disorder, or cerebrovascular disease (4)[B].
- 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 are deficient.
- Low serum insulin-like growth factor-1 (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 (5)[A].
Initial Tests (lab, imaging)
- 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). Test at 8 am as many hormone levels are affected by circadian rhythm.
- ACTH (cortisol); LH, FSH (estradiol, testosterone); GH (IGF-1); TSH (free T4); prolactin (1)[B]
- Biochemical tests should precede imaging studies.
- MRI of hypothalamic-pituitary region
- If MRI is contraindicated, then high-resolution CT with pituitary/sella focus
- Radiographs: skull; in children-hands (for bone age)
- Dual-energy x-ray absorptiometry: Gonadotropin and GH deficiency may result in osteoporosis.
Follow-Up Tests & Special Considerations
Patients should be followed closely for symptoms and signs of under- or 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 cardiovascular disease (CVD) and osteoporosis (3)[B].
Test Interpretation
- Destruction of anterior pituitary
- Atrophy of adrenal cortex, thyroid, gonads
TREATMENT
GENERAL MEASURES
If admitted for pituitary surgery, supplement with all deficient hormones, especially stress-dose glucocorticoids.
MEDICATION
- Adrenal insufficiency should be excluded before thyroid hormone replacement; otherwise, thyroid hormone replacement could precipitate adrenal crisis.
- Treatment of ACTH, TSH, LH, and FSH deficiencies are similar to the treatment of primary hormone deficiencies of their respective target organs.
- 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 is rarely necessary (4)[A].
- TSH deficiency: Goal of treatment is normal free T4 value. Treat with levothyroxine.
- LH and FSH deficiencies: 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 pulsatile gonadotropins for fertility
- Recombinant human GH (for treating short stature in children and for treating selected adult patients) (5)[B]
- 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
SURGERY/OTHER PROCEDURES
Ideally, transsphenoidal/translabial hypophysectomy for a pituitary macroadenoma causing hypopituitarism or mass effects; if unresectable by this method, then craniotomy may be an option if visual impairment has manifested (1)[A].
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- 1-, 3-, and 12-month evaluations for postsurgical or posttraumatic hormonal status and annual evaluation for those with hormone deficiencies (3)[B]
- Patients with pituitary tumors: include visual fields, thyroid and adrenal function, and sellar MRI
PATIENT EDUCATION
Wear a medical alert identification bracelet or necklace identifying the deficiency.
PROGNOSIS
- Variable but guardedly favorable with replacement therapy. Studies show modest increase in CVD morbidity and mortality.
- Hormone deficiencies are generally permanent but, in specific circumstances, may have complete or partial recovery.
COMPLICATIONS
Adrenal crisis; infertility, sexual dysfunction; blindness; short stature, failure to thrive, developmental delay, delayed puberty; premature atherosclerosis, obesity, osteoporosis
REFERENCES
11 Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, et al. Hypopituitarism. Lancet. 2007;369(9571):1461-1470.22 Fernandez-Rodriguez E, Bernabeu I, Castro AI, et al. Hypopituitarism after traumatic brain injury. Endocrinol Metab Clin North Am. 2015;44(1):151-159.33 Toogood AA, Stewart PM. Hypopituitarism: clinical features, diagnosis, and management. Endocrinol Metab Clin North Am. 2008;37(1):235-261.44 Darzy KH. Radiation-induced hypopituitarism. Curr Opin Endocrinol Diabetes Obes. 2013;20(4):342-353.55 Kargi AY, Merriam GR. Diagnosis and treatment of growth hormone deficiency in adults. Nat Rev Endocrinol. 2013;9(6):335-345.
CODES
ICD10
- E23.0 Hypopituitarism
- E89.3 Postprocedural hypopituitarism
ICD9
- 253.2 Panhypopituitarism
- 253.7 Iatrogenic pituitary disorders
SNOMED
- Hypopituitarism (disorder)
- hypopituitarism due to pituitary tumor (disorder)
- Radiotherapy-induced hypopituitarism (disorder)
- Panhypopituitarism (disorder)
- Sheehans syndrome (disorder)
- Empty sella syndrome
CLINICAL PEARLS
- In patients with documented ACTH deficiency, emphasize the need for additional glucocorticoids at the time of any major physical stress or illness. The glucocorticoid dose can be doubled for 3 to 5 days.
- In pediatric cases-congenital malformations and genetic conditions-may warrant screening for hypopituitarism; GH deficiency may result in growth retardation; delayed puberty may be a manifestation of hypopituitarism.
- 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.