Hypopituitarism– Causes, Symptoms, Diagnosis, Treatment and Ongoing care
- Generalized condition caused by partial or total failure of anterior pituitary gland’s 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: AVP/ADH and oxytocin.
- System(s) affected: Cardiovascular; Endocrine/Metabolic; Gastrointestinal; Musculoskeletal; Nervous; Reproductive; Skin/Exocrine
- Synonym(s): Empty sella syndrome; Hypopituitarism; Pituitary cachexia; Simmonds syndrome; Panhypopituitarism; as a consequence of blood loss during pregnancy, Sheehan syndrome
- Shortages of ACTH, TSH, and ADH can be life-threatening.
- First described by Dr. Morris Simmonds in 1914
- 12–42 new cases per million per year
- Predominant age: Occurs in adults and children. In children, it may cause short stature and pubertal delay.
- Predominant sex: Male = Female
- In a Northern Spain study, 45.5 per 100,000 were diagnosed with hypopituitarism with 4.2 new cases diagnosed per year.
- Of these patients 61% were due to pituitary tumors, 9% had other lesions, 19% had other causes, and 11% were idiopathic.
- Pregnancy and delivery
- Vascular aneurysms
- Lymphocytic hypophysitis
- Infiltrative diseases
- Pituitary and hypothalamic hormone transcription factor defects:
- AVP, diabetes insipidus
- DAX-1, adrenal hypoplasia congenital, hypogonadotropic hypogonadism
- GnRH-R and GPR54 loss-of-function mutations
- HESX-1, associated with septo-optic dysplasia
- KAL1 and FGFR1, Kallmann syndrome
- PROP1, 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
Prevention of head trauma, experienced neurosurgeon
- Genetic disorders
- Perinatal asphyxia
- Developmental disorders/pituitary hypoplasia, aplasia
- Craniopharyngioma, other tumors
- Cranial irradiation
- Head trauma
- Pituitary tumors: Most common etiology; other intrasellar or extrasellar 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, pneumocystis, histoplasmosis, toxoplasmosis, aspergillosis, cytomegalovirus
- Infiltrative conditions: Hemochromatosis, granulomatous disease, histiocytosis X, sarcoidosis
- Hypothalamic disease (secondary hypopituitarism)
- Autoimmune disease: Lymphocytic hypophysitis
- Chronic debilitating disease, nonspecific
- Empty sella
Commonly Associated Conditions
- Childhood hypopituitarism
- Sheehan syndrome
- Kallmann syndrome
- 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:
- ACTH: Hypotension, hypoglycemia, nausea, vomiting, extreme fatigue, asthenia, anorexia, pallor, weight loss; in children, failure to thrive, hypoglycemia
- TSH: In adults, tiredness, 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, nocturia, polydypsia, orthostasis, hypotension
- Assessment of pituitary function, history of:
- Cranial radiation
- Craniofacial abnormalities
- Empty sella
- Gonadal dysfunction
- Head trauma or head surgery
- Inflammatory or granulomatous disease
- Pituitary or hypothalamic lesions
- Pregnancy-related hemorrhage or hypotension
- Pituitary failure secondary to tumors:
- ACTH: Hypotension, anorexia, pallor, weight loss
- TSH: Weight gain, hair loss, dry skin, bradycardia, hoarseness, hypotension, constipation
- Gonadotropins: Delayed puberty
- GH: Decreased muscle mass and strength, increased visceral fat, growth retardation
- Visual field defects
- Congenital malformations and syndromes, especially malformations of the head and genitalia
- Growth retardation and delayed puberty
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.
- Basal ACTH at 8–9 a.m.; low level is positive test.
- Metapyrone test: Induced reduction in serum cortisol should cause increase in ACTH secretion.
- ACTH stimulation test: Administration of synthetic ACTH should stimulate adrenal cortisol production unless adrenal atrophy is present.
- Insulin-induced hypoglycemia: Should cause increase in ACTH and cortisol secretion. Test is contraindicated in coronary artery disease (CAD), seizure disorder, or feebleness.
- Secondary hypothyroidism; rare in absence of other pituitary hormone deficiencies
- Low free T4 with inappropriately normal or low TSH suggests TSH deficiency.
- TSH is not a reliable screening test.
- Thyrotropin-releasing hormone (TRH) stimulation: Blunted response in secondary hypothyroidism
- 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 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.
- Vaginal cytology for estrogenization index
- Exclude hyperprolactinemia.
- 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 termed stalk effect.
- GH deficiency highly likely if ≥2 other pituitary hormones deficient
- Low serum IGF-1
- Provocative tests include insulin-induced hypoglycemia and arginine plus arginine–GH-releasing hormone. Positive tests show deficient serum GH response. Again, insulin-induced hypoglycemia is contraindicated in CAD, seizure disorder, or feebleness.
- Genetic testing, if indicated
Initial lab tests
- Initial tests should be based on clinical suspicion; test both the trophic hormone and the hormone produced by the targeted gland. The testing should be paired and ideally at 8 a.m. because most of these hormones are affected by circadian rhythm.
- ACTH: Cortisol; LH, FSH: estradiol, testosterone; GH: IGF-1; TSH: free T4; prolactin; pituitary α subunit
- Biochemical tests should precede imaging studies.
- Magnetic resonance imaging (MRI) of hypothalamic–pituitary region
- If MRI is contraindicated, then high-resolution computed tomography (CT) with pituitary/sella focus
- Radiographs: Chest, skull, hands, wrists (for bone age)
- Dual energy x-ray absorptiometry: Gonadotropin deficiency may result in osteoporosis.
- 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
- More difficult to diagnose in elderly
- Adrenal insufficiency should be excluded before thyroid hormone replacement is initiated; otherwise, thyroid hormone replacement could precipitate adrenal crisis (1).
- 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 is rarely necessary.
- TSH deficiency: Goal of treatment is normal free T4 value. Treat with levothyroxine.
- 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 pulsatile gonadotropins for fertility
- Recombinant human GH (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
If patient is admitted for pituitary surgery, patient should be supplemented with all deficient hormones, especially with stress-dose glucocorticoids.
Ideally, transsphenoidal/translabial hypophysectomy for a pituitary adenoma; if unresectable by this method, then craniotomy may be an option if visual impairment has manifested. Patient could be discharged home on physiologic glucocorticoid replacement and have an ACTH stimulation test 4–6 weeks after discharge from the hospital to assess the hypothalamic–pituitary–adrenal axis.
Exercise as tolerated; no specific limitations
- 3- and 12-month evaluations for post-treatment hormonal status
- Patients with pituitary tumors: Include visual fields, thyroid and adrenal function, and sellar CT imaging.
Specifically but not limited to adrenal insufficiency; the patient should wear a medical alert identification bracelet or necklace identifying the deficiency.
- Variable but guardedly favorable with replacement therapy
- If a result of postpartum necrosis, may have complete or partial recovery
- Adrenal crisis
- Infertility, sexual dysfunction
- Short stature, failure to thrive, developmental delay, delayed puberty
- Premature atherosclerosis
1. Osman IA, Leslie P. Addison’s disease. Adrenal insufficiency should be excluded before thyroxine replacement is started. BMJ. 1996;313:427.
Ascoli P, Cavagnini F. Hypopituitarism. Pituitary. 2006;9:335–42.
Behan LA, Agha A. Endocrine consequences of adult traumatic brain injury. Horm Res. 2007;68(Suppl 5):18–21.
Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, et al. Hypopituitarism. Lancet. 2007;369:1461–70.
VanAken MO, Lamberts SW. Diagnosis and treatment of hypopituitarism. Pituitary. 2006;8:183–91.
74728003 hypopituitarism (disorder)
In patient with documented ACTH deficiency, emphasize the need for additional cortisone at the time of any major physical stress or illness. The glucocorticoid dose can be doubled for 3–5 days.
- Congenital malformations; genetic conditions may warrant screening for hypopituitarism.
- GH deficiency may result in growth retardation.
- Hypogonadism in prenatal pituitary failure
- Delayed puberty
- 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.