The most common cause of primary hypopituitarism in adults is a tumor. Other causes include congenital defects (hypoplasia or aplasia of the pituitary gland); pituitary infarction (most often from postpartum hemorrhage); or partial or total hypophysectomy by surgery, irradiation, or chemical agents; and, rarely, granulomatous disease (e.g., tuberculosis). Occasionally, hypopituitarism may have no identifiable cause, or it may be related to autoimmune destruction of the gland. Secondary hypopituitarism stems from a deficiency of releasing hormones produced by the hypothalamus—either idiopathic or possibly resulting from infection, trauma, or a tumor.

Primary hypopituitarism usually develops in a predictable pattern of hormonal failures. It generally starts with hypogonadism from gonadotropin failure (decreased FSH and LH levels). In adults, it causes cessation of menses in females and impotence in men. Growth hormone (GH) deficiency follows; in children, this causes short stature, delayed growth, and delayed puberty. In adults, it causes osteoporosis, decreased leanto-fat body mass index, adverse lipid changes, and subtle emotional dysphoria and lethargy. Subsequent failure of thyrotropin (decreased TSH levels) causes hypothyroidism; finally, adrenocorticotropic failure (decreased corticotropin levels) results in adrenal insufficiency. However,
when hypopituitarism follows surgical ablation or trauma, the pattern of hormonal events may not necessarily follow this sequence. Sometimes, damage to the hypothalamus or neurohypophysis from one of the above leads to diabetes insipidus. Hypopituitarism may develop years after pituitary radiation treatment.

Clinical features of hypopituitarism develop slowly and vary with the severity of the disorder and the number of deficient hormones. Signs and symptoms of hypopituitarism in adults may include gonadal failure (secondary amenorrhea, impotence, infertility, decreased libido), diabetes insipidus, hypothyroidism (fatigue, lethargy, sensitivity to cold, menstrual disturbances), and adrenocortical insufficiency (hypoglycemia, anorexia, nausea, abdominal pain, orthostatic hypotension).

Postpartum necrosis of the pituitary (Sheehan’s syndrome) characteristically causes failure of lactation, menstruation, and growth of pubic and axillary hair; and symptoms of thyroid and adrenocortical failure.

In children, hypopituitarism causes retarded growth or delayed puberty. Dwarfism usually isn’t apparent at birth but early signs begin to appear during the first few months of life; by age 6 months, growth retardation is obvious. Although these children generally enjoy good health, pituitary dwarfism may cause chubbiness due to fat deposits in the lower trunk, delayed secondary tooth eruption and, possibly, hypoglycemia. Growth continues at less than half the normal rate—sometimes extending into the patient’s 20s or 30s—to an average height of 4′ (122 cm), with normal proportions.

When hypopituitarism strikes before puberty, it prevents development of secondary sex characteristics (including facial and body hair). In males, it produces undersized testes, penis, and prostate gland; absent or minimal libido; and the inability to initiate and maintain an erection. In females, it usually causes immature development of the breasts, sparse or absent pubic and axillary hair, and primary amenorrhea.

Panhypopituitarism may induce a host of mental and physiologic abnormalities, including lethargy, psychosis, orthostatic hypotension, bradycardia, anemia, and anorexia. However, clinical manifestations of hormonal deficiencies resulting from pituitary destruction don’t become apparent until 75% of the gland is destroyed. Total loss of all hormones released by the anterior pituitary is fatal unless treated.

Neurologic signs associated with hypopituitarism and produced by pituitary tumors include headache, bilateral temporal hemianopia, loss of visual acuity and, possibly, blindness. Acute hypopituitarism resulting from surgery or infection is often associated with fever, hypotension, vomiting, and hypoglycemia—all characteristic of adrenal insufficiency.

Typically, oversecretion of human growth hormone (hGH) produces changes throughout the body, resulting in acromegaly and, when oversecretion occurs before puberty, gigantism. Eosinophilic or mixed-cell adenomas of the anterior pituitary gland may cause this oversecretion but the etiology of the tumors themselves remains unclear. Occasionally, hGH levels are elevated in more than one family member, which suggests the possibility of a genetic cause.

The earliest clinical manifestations of acromegaly include soft-tissue swelling of the extremities and coarsening of facial features. This rare form of hyperpituitarism occurs equally among males and females, usually between ages 30 and 50. Annually, it affects 3 to 4 people per every million.

In gigantism, proportional overgrowth of all body tissues causes remarkable height increases of as much as 6” (15 cm) per year. Gigantism affects infants and children, causing them to attain as much as three times the normal height for their age. As adults, they may ultimately reach a height of more than 80” (203 cm). Gigantism is rare; there have only been 100 reported cases.

Acromegaly develops slowly and typically produces diaphoresis, oily skin, hypermetabolism, and hypertrichosis. Severe headache, central nervous system impairment, bitemporal hemianopia, loss of visual acuity, and blindness may result from the intrasellar tumor compressing the optic chiasm or nerves.

Hypersecretion of hGH produces cartilaginous and connective tissue overgrowth, resulting in a characteristic hulking appearance, with an enlarged supraorbital ridge and thickened ears and nose. Prognathism, projection of the jaw, becomes marked and may interfere with chewing. Laryngeal hypertrophy, paranasal sinus enlargement, and thickening of the tongue cause the voice to sound deep and hollow. Distal phalanges display an arrowhead appearance on X-rays, and the fingers are thickened. Irritability, hostility, and various psychological disturbances may occur.

Prolonged effects of excessive hGH secretion include bowlegs, barrel chest, arthritis, osteoporosis, kyphosis, hypertension, and arteriosclerosis. Both gigantism and acromegaly may also cause signs of glucose intolerance and clinically apparent diabetes mellitus because of the insulin-antagonistic character of hGH. If acromegaly is left untreated, the patient is at risk for premature cardiovascular disease, colon polyps, and colon cancer.

Gigantism develops abruptly, producing some of the same skeletal abnormalities seen in acromegaly. As the disease progresses, the pituitary tumor enlarges and invades normal tissue, resulting in the loss of other trophic hormones, such as thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and corticotropin, thus causing the target organ to stop functioning.

Diabetes insipidus results centrally from intracranial neoplastic or metastatic lesions,
hypophysectomy or other neurosurgery, a skull fracture, or head trauma that damages the neurohypophyseal structures. It can also result nephrogenically from infection, granulomatous disease, and vascular lesions; it may be idiopathic and, rarely, familial. (Note: Pituitary diabetes insipidus shouldn’t be confused with nephrogenic diabetes insipidus, a rare congenital disturbance of water metabolism that results from renal tubular resistance to vasopressin.)

Normally, the hypothalamus synthesizes vasopressin. The posterior pituitary gland (or neurohypophysis) stores vasopressin and releases it into general circulation, where it causes the kidneys to reabsorb water by making the distal tubules and collecting duct cells water-permeable. The absence of vasopressin in diabetes insipidus allows the filtered water to be excreted in the urine instead of being reabsorbed.

Nephrogenic diabetes insipidus involves a defect in the parts of the kidneys that reabsorb water back into the bloodstream. It occurs less commonly than central diabetes insipidus. Nephrogenic diabetes insipidus may occur as an inherited disorder in which boys receive the abnormal gene that causes the disease on the X chromosome from their mothers. Nephrogenic diabetes insipidus may also be caused by diseases of the kidney (such as polycystic kidney disease) and the effects of certain drugs (such as lithium and amphotericin B) and as a result of hypercalcemia and hypokalemia.

Gestational diabetes insipidus occurs during pregnancy when an enzyme made by the placenta destroys antidiuretic hormone in the mother.

Diabetes insipidus is rare, affecting 1 in 25,000 people. Males and females are affected equally.

The patient’s history typically shows an abrupt onset of extreme polyuria (usually 4 to 16 L/day of dilute urine but sometimes as much as 30 L/day). As a result, the patient is extremely thirsty and drinks great quantities of water to compensate for the body’s water loss. This disorder may also result in nocturia. In severe cases, it may lead to extreme fatigue from inadequate rest caused by frequent voiding and excessive thirst. Other characteristic features of diabetes insipidus include signs and symptoms of dehydration (poor tissue turgor, dry mucous membranes, constipation, muscle weakness, dizziness, and hypotension). These symptoms usually begin abruptly, commonly appearing within 1 to 2 days after a basal skull fracture, a stroke, or surgery. Relieving cerebral edema or increased intracranial pressure may cause all of these symptoms to subside just as rapidly as they began.

Hypothyroidism results from inadequate production of thyroid hormone—usually because of dysfunction of the thyroid gland due to surgery (thyroidectomy), irradiation therapy (particularly with¹³¹I), inflammation, chronic autoimmune thyroiditis (Hashimoto’s disease) or, rarely, conditions such as amyloidosis and sarcoidosis. It may also result from pituitary failure to produce thyroid-stimulating hormone (TSH), hypothalamic failure to produce thyrotropin-releasing hormone, inborn errors of thyroid hormone synthesis, the inability to synthesize thyroid hormone because of iodine deficiency (usually dietary), or the use of antithyroid medications such as propylthiouracil. In patients with hypothyroidism, infection, exposure to cold, and sedatives may precipitate myxedema coma.

Hypothyroidism is more prevalent in females than males, and frequency increases with age; in the United States, incidence is rising significantly in people ages 40 to 50.

Typically, the early clinical features of hypothyroidism are vague: fatigue, menstrual changes, hypercholesterolemia, forgetfulness, sensitivity to cold, unexplained weight gain, and constipation. As the disorder progresses, characteristic myxedematous signs and symptoms appear: decreasing mental stability; dry, flaky, inelastic skin; puffy face, hands, and feet; hoarseness; periorbital edema; upper eyelid droop; dry, sparse hair; and thick, brittle nails. (See Facial signs of myxedema.)

Cardiovascular involvement leads to decreased cardiac output, slow pulse rate, signs of poor peripheral circulation and, occasionally, an enlarged heart. Other common effects include anorexia, abdominal distention, menorrhagia, decreased libido, infertility, ataxia, intention tremor, and nystagmus. Reflexes show delayed relaxation time (especially in the Achilles tendon).

In infants, cretinism usually results from defective embryonic development that causes congenital absence or underdevelopment of the thyroid gland. The next most common cause can be traced to an inherited enzymatic defect in the synthesis of thyroxine (T₄) caused by an autosomal recessive gene. Less frequently, antithyroid drugs taken during pregnancy produce cretinism in infants. In children older than age 2, cretinism usually results from chronic autoimmune thyroiditis.

The weight and length of an infant with infantile cretinism appear normal at birth, but characteristic signs of hypothyroidism develop by the time he’s 3 to 6 months old. In a breastfed infant the onset of most symptoms may be delayed until weaning because breast milk contains small amounts of thyroid hormone.

Typically, an infant with cretinism sleeps excessively, seldom cries (except for occasional hoarse crying), and is inactive. Because of this, his parents may describe him as a “good baby— no trouble at all.” However, such behavior actually results from lowered metabolism and progressive mental impairment. The infant with cretinism also exhibits abnormal deep tendon reflexes, hypotonic abdominal muscles, a protruding abdomen, and slow, awkward movements. He has feeding difficulties, develops constipation and, because his immature liver can’t conjugate bilirubin, becomes jaundiced.

His large, protruding tongue obstructs respiration, making breathing loud and noisy and forcing him to open his mouth to breathe. He may have dyspnea on exertion, anemia, abnormal facial features—such as a short forehead; puffy, wide-set eyes (periorbital edema); wrinkled eyelids; and a broad, short, upturned nose—and a dull expression, resulting from mental retardation. His skin is cold and mottled because of poor circulation, and his hair is dry, brittle, and dull. Teeth erupt late and tend to decay early; body temperature is below normal; and pulse rate is slow.

In the child who acquires hypothyroidism after age 2, appropriate treatment can prevent mental retardation. However, growth retardation becomes apparent in short stature (due to delayed epiphyseal maturation, particularly
in the legs), obesity, and a head that appears abnormally large because the arms and legs are stunted. An older child may show delayed or accelerated sexual development.

Autoimmune thyroiditis is due to anti-thyroid antibodies in the blood. It may cause inflammation and lymphocytic infiltration (Hashimoto’s thyroiditis). Glandular atrophy (myxedema) and Graves’ disease are linked to autoimmune thyroiditis.

Subacute granulomatous thyroiditis usually follows mumps, influenza, coxsackievirus, or adenovirus infection. Riedel’s thyroiditis is a rare condition of unknown etiology.

Miscellaneous thyroiditis results from bacterial invasion of the gland in acute suppurative thyroiditis; tuberculosis, syphilis, actinomycosis, or other infectious agents in the chronic infective form; and sarcoidosis and amyloidosis in chronic noninfective thyroiditis. Postpartum thyroiditis (silent thyroiditis) is another autoimmune disorder associated with transient thyroiditis in females within 1 year after delivery.

Thyroiditis is most prevalent among people ages 30 to 50 and is more common in women
than in men. Incidence is highest in the Appalachian region of the United States.

Autoimmune thyroiditis is usually asymptomatic and commonly occurs in females, with peak incidence in middle age. It’s the most prevalent cause of spontaneous hypothyroidism.

In subacute granulomatous thyroiditis, moderate thyroid enlargement may follow an upper respiratory tract infection or a sore throat. The thyroid may be painful and tender, and dysphagia may occur.

In Riedel’s thyroiditis, the gland enlarges slowly as it’s replaced by hard, fibrous tissues. This fibrosis may compress the trachea or the esophagus. The thyroid feels firm.

Clinical effects of miscellaneous thyroiditis are characteristic of pyogenic infection: fever, pain, tenderness, and reddened skin over the gland.