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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
The different causes of primary and secondary hypopituitarism are listed in the table below (see Table: Causes of Hypopituitarism).
Causes of 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 ACTH. Vasopressin deficiency 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. 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 but is usually asymptomatic and clinically undetectable in adults. Suggestions that GH deficiency accelerates atherosclerosis are unproved. Effects of GH deficiency in children are discussed elsewhere.
TSH deficiency leads to hypothyroidism, with such symptoms as facial puffiness, hoarse voice, bradycardia, and cold intolerance.
ACTH deficiency results in hypoadrenalism with attendant fatigue, hypotension, and intolerance to stress and infection. ACTH deficiency does not result in the hyperpigmentation characteristic of primary adrenal failure.
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 CSF often contains blood, and MRI documents hemorrhage.
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, chronic liver disease, myotonia dystrophica, polyglandular autoimmune disease (see Table: Differentiation of Generalized Hypopituitarism from Other Selected Disorders), and disorders of the other endocrine glands. 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.
Differentiation of Generalized Hypopituitarism from Other Selected Disorders
Patients should undergo high-resolution CT or MRI, with contrast media as required (to rule out structural abnormalities, such as pituitary adenomas). 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.
Initial evaluation should include testing for TSH and ACTH deficiencies, because both conditions are potentially life threatening. Testing for deficiencies of other hormones is also discussed elsewhere.
Free T4 and TSH levels should be determined. Levels of both are usually low in generalized hypopituitarism; a pattern of normal TSH level with low free T4 may also occur. In contrast, elevated TSH levels with low free T4 indicate a primary abnormality of the thyroid gland.
Synthetic thyrotropin-releasing hormone (TRH), 200 to 500 mcg IV given over 15 to 30 sec, may help identify patients with hypothalamic as opposed to pituitary dysfunction, although this test is not often done. Serum TSH levels are generally measured at 0, 20, and 60 min after injection. If pituitary function is intact, TSH should rise by > 5 mU/L, peaking by 30 min 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 cortisol levels alone are not reliable indicators of ACTH-adrenal axis function, although a very low morning serum cortisol level (< 3.5 μg/dL between 7:30 and 9:00 am) almost certainly indicates cortisol deficiency. One of several provocative tests should be done. 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 min after administration of synthetic ACTH. Cortisol should rise significantly; a peak of < 20 µg/dL is abnormal. However, the short ACTH stimulation test is abnormal in secondary cortisol deficiency only when the test done at least 2 to 4 wk 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 and prolactin) reserve, but because of its demands, it is probably best reserved for patients who fail the short ACTH stimulation test (if confirmation is needed) or when a test must be done within 2 to 4 wk of a possible pituitary injury. Regular insulin at a dosage of 0.1 units/kg body weight IV is given over 15 to 30 sec, 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 min later. If glucose drops to < 40 mg/dL (< 2.22 mmol/L) or symptoms of hypoglycemia develop, cortisol should increase by > 7 μg/dL or to >20 μg/dL. (Caution: This test is hazardous in patients with severe documented panhypopituitarism or diabetes mellitus and in the elderly 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 by giving 50 mL of 50% glucose solution IV.
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.
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 min before, then at baseline, and 15, 30, 60, 90, and 120 min after the injection. Adverse effects include temporary flushing, a metallic taste in the mouth, and slight and transient hypotension.
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). 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 min and FSH peaking 40 min after GnRH administration. However, normal, diminished, or absent responses to GnRH may occur in hypothalamic-pituitary dysfunction. Normal increases in LH and FSH in response to GnRH vary. Administration of exogenous GnRH is not helpful in distinguishing primary hypothalamic disorders from primary pituitary disorders.
Screening for GH deficiency in adults is not recommended unless 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. Because GH levels vary by time of day and other factors and are difficult to interpret, levels of insulin -like growth factor 1 (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 (see Growth Hormone Deficiency in Children : Diagnosis) may be necessary.
Although the usefulness of provocative testing of pituitary function using releasing hormones remains to be established, if such testing is elected, it is most efficient to evaluate multiple hormones simultaneously. Growth hormone–releasing hormone (1 mcg/kg), CRH (1 mcg/kg), TRH (200 mcg), and GnRH (100 mcg) are given together IV over 15 to 30 sec. Glucose, cortisol, GH, TSH, prolactin, LH, FSH, and ACTH are measured at frequent intervals for the ensuing 180 min. The normal responses are the same as those delineated earlier for individual testing.
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. Adults ≤ 50 yr deficient in GH are now sometimes treated with GH doses of 0.002 to 0.012 mg/kg sc once/day. Benefits of treatment include improved energy and quality of life, increased body muscle mass, and decreased body fat mass. Suggestions that GH replacement can prevent an acceleration of atherosclerosis induced by GH deficiency are unproved.
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.
Surgery and radiation therapy may be followed by the loss of other pituitary hormone functions. Irradiated patients may lose endocrine function slowly over years. Therefore, posttreatment hormonal status should be evaluated frequently, preferably at 3 and 6 mo and yearly thereafter for at least 10 yr and preferably up to 15 yr 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 yr initially for about 10 yr, particularly if residual tumor tissue is present.
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