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Generalized Hypopituitarism


John D. Carmichael

, MD, Keck School of Medicine of the University of Southern California

Reviewed/Revised Apr 2023
Topic Resources

Generalized hypopituitarism refers to endocrine deficiency syndromes due to partial or complete loss of anterior lobe pituitary function. Various clinical features occur depending on the specific hormones that are deficient. Diagnosis involves imaging tests and measurement of pituitary hormone levels basally and after various provocative stimuli. Treatment depends on cause but generally includes removal of any tumor and administration of replacement hormones.

Hypopituitarism is divided into

  • Primary: Caused by disorders that affect the pituitary gland

  • Secondary: Caused by disorders of the hypothalamus

The different causes of primary and secondary hypopituitarism are listed in the table .


Symptoms and Signs of Generalized Hypopituitarism

Symptoms and signs relate to the underlying disorder and to the specific pituitary hormones that are deficient or absent. Onset is usually insidious and may not be recognized by the patient; occasionally, onset is sudden or dramatic.

Most commonly, growth hormone (GH) is lost first, then gonadotropins, and finally thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH). Vasopressin deficiency (causing arginine vasopressin deficiency ArginineVasopressin Deficiency (Central Diabetes Insipidus) Arginine vasopressin deficiency (central diabetes insipidus) results from a deficiency of vasopressin (antidiuretic hormone [ADH]) due to a hypothalamic-pituitary disorder. Polyuria and polydipsia... read more ) is rare in primary pituitary disorders but is common with lesions of the pituitary stalk and hypothalamus. Function of all target glands decreases when all hormones are deficient (panhypopituitarism).

Lack of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in children leads to delayed puberty Delayed Puberty Delayed puberty is absence of sexual maturation at the expected time. Diagnosis is by measurement of gonadal hormones (testosterone and/or estradiol), luteinizing hormone, and follicle-stimulating... read more . Premenopausal women develop amenorrhea, reduced libido, regression of secondary sexual characteristics, and infertility. Men develop erectile dysfunction, testicular atrophy, reduced libido, regression of secondary sexual characteristics, and decreased spermatogenesis with consequent infertility.

GH deficiency may contribute to decreased energy, abnormal body composition, and dyslipidemia but is usually asymptomatic and clinically undetectable in adults. Effects of GH deficiency in children Growth Hormone Deficiency in Children Growth hormone deficiency is the most common pituitary hormone deficiency in children and can be isolated or accompanied by deficiency of other pituitary hormones. Growth hormone deficiency... read more are discussed elsewhere.

ACTH deficiency results in hypoadrenalism Secondary Adrenal Insufficiency Secondary adrenal insufficiency is adrenal hypofunction due to a lack of adrenocorticotropic hormone (ACTH). Symptoms are the same as for Addison disease and include fatigue, weakness, weight... read more with attendant fatigue, hypotension, and intolerance to stress and infection. ACTH deficiency does not result in the hyperpigmentation characteristic of primary adrenal failure. ACTH deficiency does not result in hyponatremia or hyperkalemia as occurs in primary adrenal insufficiency Addison Disease Addison disease is an insidious, usually progressive hypofunctioning of the adrenal cortex. It causes various symptoms, including hypotension and hyperpigmentation, and can lead to adrenal crisis... read more Addison Disease because the renin-angiotensin-aldosterone pathway remains intact.

Hypothalamic lesions, which can result in hypopituitarism, can also disturb the centers that control appetite, causing a syndrome resembling anorexia nervosa, or sometimes hyperphagia with massive obesity.

Sheehan syndrome, which affects postpartum women, is pituitary necrosis due to hypovolemia and shock occurring in the immediate peripartum period. Lactation does not start after childbirth, and the patient may complain of fatigue and loss of pubic and axillary hair.

Pituitary apoplexy is a symptom complex caused by hemorrhagic infarction of either a normal pituitary gland or, more commonly, a pituitary tumor. Acute symptoms include severe headache, stiff neck, fever, visual field defects, and oculomotor palsies. The resulting edema may compress the hypothalamus, resulting in somnolence or coma. Varying degrees of hypopituitarism may develop suddenly, and the patient may present with vascular collapse because of deficient ACTH and cortisol. The cerebrospinal fluid often contains blood, and MRI documents hemorrhage.

Diagnosis of Generalized Hypopituitarism

  • MRI or CT

  • Pituitary hormone levels: TSH, prolactin, LH, FSH,

  • Target organ hormone levels: Free thyroxine (T4), testosterone (in men) or estradiol (in women), and cortisol levels plus provocative testing of pituitary-adrenal axis

  • Sometimes other provocative testing

Clinical features are often nonspecific, and the diagnosis must be established with certainty before committing the patient to a lifetime of hormone replacement therapy. Pituitary dysfunction must be distinguished from anorexia nervosa Anorexia Nervosa Anorexia nervosa is characterized by a relentless pursuit of thinness, a morbid fear of obesity, a distorted body image, and restriction of intake relative to requirements, leading to a significantly... read more , chronic liver disease, myotonia dystrophica, polyglandular autoimmune disease , and disorders of the other endocrine glands (see table ). The clinical picture may be particularly confusing when the function of more than one gland decreases at the same time. Evidence of structural pituitary abnormalities and of hormonal deficiencies should be sought with imaging and laboratory tests.


Imaging tests

Patients should undergo high-resolution CT or MRI, with contrast agent as required (to rule out structural abnormalities, such as pituitary adenomas). Positron emission tomography (PET) is a research tool used in a few specialized centers and therefore is rarely done. When no modern neuroradiologic facilities are available, a simple cone-down lateral x-ray of the sella turcica can identify pituitary macroadenomas with a diameter > 10 mm. Cerebral angiography is indicated only when other imaging tests suggest perisellar vascular anomalies or aneurysms.

Laboratory testing

Initial evaluation should include testing for TSH and ACTH deficiencies, because both conditions are potentially life threatening. Testing for deficiencies of other hormones Selective Pituitary Hormone Deficiencies Selective deficiencies of pituitary hormones may represent an early stage in the development of more generalized hypopituitarism. Patients must be observed for signs of other pituitary hormone... read more is also discussed elsewhere. Dynamic or provocative testing of pituitary function is seldom done except in the evaluation of adrenal insufficiency with the short ACTH stimulation test, and with testing to diagnose GH deficiency. Agents used in many tests, including thyrotropin-releasing hormone, growth hormone–releasing hormone, corticotropin-releasing hormone, and gonadotrophin-releasing hormone, are not available or are in limited supply. The insulin tolerance test for investigating adrenal and GH deficiency has been used less due to contraindications, requirements for close supervision, and favorable replacements with other agents. Tests used historically are included here for reference.

Free T4 and TSH levels should be determined. TSH is typically inappropriately low or normal in relation to low levels of circulating T4. The most common manifestation of central hypothyroidism is a pattern of normal TSH level with low free T4. In contrast, elevated TSH levels with low free T4 indicates a primary abnormality of the thyroid gland.

Synthetic thyrotropin-releasing hormone (TRH), 200 to 500 mcg IV given over 15 to 30 seconds, may help identify patients with hypothalamic as opposed to pituitary dysfunction, although this test is not often done due to lack of commercial availability. Serum TSH levels are generally measured at 0, 20, and 60 minutes after injection. If pituitary function is intact, TSH should rise by > 5 mIU/L, peaking by 30 minutes after injection. A delayed rise in serum TSH levels may occur in patients with hypothalamic disease. However, some patients with primary pituitary disease also show a delayed rise.

Serum ACTH levels are not helpful in the diagnosis of ACTH deficiency. Similarly, serum cortisol levels alone are not reliable indicators of ACTH-adrenal axis function, although a very low morning serum cortisol level (< 3.5 mcg/dL [96.6 nmol/L] between 7:30 and 9:00 AM) strongly suggests cortisol deficiency. One of several provocative tests should be done unless a morning level > 18 mcg/dL [500 nmol/L] obtained using polyclonal radioimmunoassays or a morning level > 15 mcg/dL (415 nmol/L) using monoclonal antibodies or liquid chromatography with tandem mass spectrometry (LC-MS/MS) rules out adrenal insufficiency.

The short ACTH stimulation test is a safer and less labor-intensive test for cortisol deficiency than the insulin tolerance test. In the short ACTH stimulation test, synthetic ACTH 250 mcg IV or IM (standard-dose test) or 1 mcg IV (low-dose test) is given, and the blood cortisol level is measured immediately before and 30 and 60 minutes after administration of the synthetic ACTH. Cortisol should rise significantly; a peak of < 18 mcg/dL (500 nmol/L) using polyclonal assays or < 15 mcg/dL (414 nmol/L) using monoclonal antibody assays or LC-MS/MS is abnormal. However, the short ACTH stimulation test is abnormal in secondary cortisol deficiency only when the test done at least 2 to 4 weeks after onset of the deficiency; before this time, the adrenal glands have not atrophied and remain responsive to exogenous ACTH.

The insulin tolerance test is considered the most accurate way of evaluating ACTH (as well as GH) reserve, but because of its demands, it is probably best reserved for patients in whom cortisol does not rise significantly during the short ACTH stimulation test (if confirmation is needed) or when a test must be done within 2 to 4 weeks of a possible pituitary injury. Regular insulin at a dosage of 0.1 units/kg body weight IV is given over 15 to 30 seconds, and venous blood samples are obtained to determine GH, cortisol, and glucose levels at baseline (before insulin administration) and 20, 30, 45, 60, and 90 minutes after it is given. If glucose drops to < 40 mg/dL (< 2.22 mmol/L) or symptoms of hypoglycemia develop, cortisol should increase by > 7 mcg/dL (> 193 nmol/L) or to > 18 mcg/dL (> 500 nmol/L). CAUTION: This test is hazardous in patients with severe documented panhypopituitarism or diabetes mellitus and in older people and is contraindicated in patients with coronary artery disease or epilepsy. A health care practitioner should be present during the test. Usually, only transient perspiration, tachycardia, and nervousness occur. If the patient complains of palpitations, loses consciousness, or has a seizure, the test should be stopped promptly and presumed hypoglycemia should be treated Treatment Hypoglycemia, or low plasma glucose level can result in sympathetic nervous system stimulation and central nervous system dysfunction. In patients with diabetes who take insulin or antihyperglycemic... read more by giving IV glucose.

Neither the short ACTH stimulation test nor the insulin tolerance test alone will differentiate between primary (Addison disease) and secondary (hypopituitary) adrenal insufficiency. Tests to make this distinction and to evaluate the hypothalamic-pituitary-adrenal axis are described under Addison disease Addison Disease Addison disease is an insidious, usually progressive hypofunctioning of the adrenal cortex. It causes various symptoms, including hypotension and hyperpigmentation, and can lead to adrenal crisis... read more Addison Disease .

The corticotropin-releasing hormone (CRH) test is done to distinguish between primary, secondary (pituitary), and tertiary (hypothalamic) causes of adrenal insufficiency. CRH 1 mcg/kg IV is given by rapid injection. Serum ACTH and cortisol levels are measured 15 minutes before, then at baseline, and 15, 30, 60, 90, and 120 minutes after the injection. Adverse effects include temporary flushing, a metallic taste in the mouth, and slight and transient hypotension. Use of this test is limited by cost and availability of CRH. Ease of administration of the short ACTH stimulation test has largely replaced this test.

Prolactin levels are routinely measured. These levels are often elevated up to 5 times normal values when a large pituitary tumor is present, even if it does not produce prolactin. The tumor compresses the pituitary stalk, preventing dopamine, which inhibits pituitary prolactin production and release, from reaching the pituitary. Patients with such hyperprolactinemia often have hypogonadotropism and secondary hypogonadism.

Measurement of basal levels of LH and FSH is most helpful in evaluating hypopituitarism in postmenopausal women not taking exogenous estrogens in whom circulating gonadotropin concentrations are normally high (> 30 mIU/mL [> 30 IU/L]). In premenopausal women, menstrual history is superior to measurement of gonadotropins in determining pituitary function. Although gonadotropin levels tend to be low in other patients with panhypopituitarism, overlap exists with the normal range. Levels of both hormones should increase in response to synthetic gonadotropin-releasing hormone (GnRH) at a dose of 100 mcg IV, with LH peaking about 30 minutes and FSH peaking 40 minutes after GnRH administration, but normal increases in LH and FSH in response to GnRH vary. However, normal, diminished, or absent responses to GnRH may occur in hypothalamic-pituitary dysfunction. Administration of exogenous GnRH is not helpful in distinguishing primary hypothalamic disorders from primary pituitary disorders. Dynamic testing of the gonadal axis is rarely indicated in adults and is rarely helpful in distinguishing gonadal axis deficiencies and delayed puberty in adolescents. GnRH is also not widely commercially available.

Screening for GH deficiency in adults is not recommended unless there is suspicion of pituitary damage due to trauma, surgery, or radiation and GH treatment is contemplated (eg, for unexplained reduced energy and quality of life in patients with hypopituitarism in which other hormones have been fully replaced). GH deficiency is suspected if 2 other pituitary hormones are deficient but may be present in isolation in patients treated for pituitary masses. GH deficiency is a near certainty in patients with 3 other pituitary deficiencies and a low serum insulin-like growth factor 1 (IGF-1) level. Because GH levels vary by time of day and other factors and are difficult to interpret, levels of IGF-1, which reflect GH, are used; low levels suggest GH deficiency, but normal levels do not rule it out. A provocative test of GH release Diagnosis Growth hormone deficiency is the most common pituitary hormone deficiency in children and can be isolated or accompanied by deficiency of other pituitary hormones. Growth hormone deficiency... read more may be necessary.

Treatment of Generalized Hypopituitarism

  • Hormone replacement

  • Treatment of cause (eg, tumor)

Treatment is replacement of the hormones of the hypofunctioning target glands, as discussed in the pertinent chapters in this section and elsewhere in THE MANUAL.

Treatment of adults with GH deficiency is begun with a low, once daily dose of GH (0.3 mg subcutaneously for women, 0.2 mg for men, and 0.1 mg for older patients) and titrated to achieve a mid-normal serum IGF-I level. Benefits of treatment include improved energy and quality of life, improved lipid profile, decreased cardiovascular risk factors, increased body muscle mass, and decreased body fat mass. In men with panhypopituitarism treated with GH, mortality decreases to rates for age-matched individuals without hypopituitarism. In women with panhypopituitarism treated with GH, mortality declines but does not reach normal levels.

In pituitary apoplexy, immediate surgery is warranted if visual field disturbances or oculomotor palsies develop suddenly or if somnolence progresses to coma because of hypothalamic compression. Although management with high-dose corticosteroids and general support may suffice in a few cases, transsphenoidal decompression of the tumor should generally be undertaken promptly.

In patients who have had surgery or radiation therapy to treat a pituitary tumor, treatment may be followed by the loss of other pituitary hormone functions. Patients treated with radiation may lose endocrine function slowly over years. Therefore, posttreatment hormonal status should be evaluated frequently, preferably at 3 and 6 months and yearly thereafter for at least 10 years and preferably up to 15 years after radiation therapy. Such evaluation should include at least assessment of thyroid and adrenal function. Patients may also develop visual difficulties related to fibrosis of the optic chiasm. Sellar imaging and visual field assessment should be done at least every 2 years initially for about 10 years, particularly if residual tumor tissue is present.

Drugs Mentioned In This Article

Drug Name Select Trade
Arginine, Nutricia SHS L-Arginine, R-Gene
Pitressin, Vasostrict
Humulin R, Iletin II Regular, Myxredlin, Novolin R, Velosulin BR
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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