Hypopituitarism

Although the onset of hypopituitarism is sometimes rapid, in most patients the onset is insidious. It may take years for the pituitary to cease functioning completely. The patient's age, overall physical and mental condition and the underlying etiology of hypopituitarism influence the clinical manifestations. Because of the vague symptoms and the length of time that it takes for symptoms to develop, patients may have visited several physicians and may have undergone several diagnostic tests without receiving a diagnosis.

Illustrative Case

A 31-year-old woman initially came to the family practice office because of malaise and intermittent vomiting of three years'duration. She also noted constipation, galactorrhea and amenorrhea for the previous two years. She had been divorced for several months and was finding that she could no longer care for her two young children because of progressive symptoms. She had recently been dismissed from her job as a store manager and reluctantly had accepted welfare.

She had been treated for a seizure disorder since childhood. She continued to require anticonvulsant therapy following a craniotomy for an arteriovenous malformation when she was 20 years old. She had been hospitalized on multiple occasions for persistent vomiting, dehydration and electrolyte disturbances.

Sarcoidosis had been diagnosed one year previously by means of a gastric biopsy and had been treated intermittently with steroids, which improved her symptoms. A surgeon had performed a biopsy of a mass in the right breast. Galactorrhea was also present. The mass was benign. Another physician performed cervical dilatation and uterine curettage because of the amenorrhea.

On physical examination, the patient appeared chronically ill. Her skin was pale and dry, and she had decreased body hair. Milk could be expressed from both breasts. Laboratory testing revealed hyponatremia, hypochloremia and hyperprolactinemia. Serum thyroid-stimulating hormone (TSH) and thyroxine (T.sub.4) levels were normal. Computed tomography (CT) of the sella turcica was consistent with neurosarcoidosis affecting the pituitary stalk. Subsequent testing confirmed hypopituitarism, which was treated with glucocorticoids, sex hormones and bromocriptine. The sarcoidosis has remained inactive. The patient has returned to work part time and is able to care for her children. Anatomy and Physiology

Knowledge of anatomy and pathophysiology aid in determining the etiology of hypopituitarism, understanding the clinical course and instituting appropriate therapy.

PITUITARY GLAND

The pituitary has been aptly named "the master gland." It influences the function of most of the other endocrine glands and acts to link the central nervous system with the endocrine system.

The pituitary is a small gland (approximately 0. 75 cc) located in a saddle-shaped depression of the sphenoid bone, the sella turcica. In close proximity are the optic chiasm, the cavernous sinus and the internal carotid arteries Figure 1). The pituitary consists of an anterior lobe and a posterior lobe.

The anterior pituitary, or adenohypophysis, releases numerous hormones that regulate the function of different target sites (Table 1). The posterior pituitary, or neurohypophysis, is responsible for the release of two similar 9-amino acid peptides, vasopressin and oxytocin. Vasopressin, or antidiuretic hormone (ADH), influences cardiovascular homeostasis and urine osmolality. Oxytocin, although used pharmacologically for the induction of labor, plays an uncertain physiologic role in normal labor.(1) Oxytocin also plays a role in the milk let-down reflex and is used pharmacologically for this purpose.

HYPOTHALAMUS

The pituitary is regulated by the hypothalamus (Table 2). The hypothalamic neuropeptides are secreted into either the long or short portal vessels Figure 1). The cells of the anterior pituitary are in turn stimulated or inhibited by these regulatory hormones.

Long, short and ultrashort feedback loops regulate the hypothalamic-pituitary axis. In long feedback loops, the output of the target gland governs the activity of the hypothalamus. For example, testosterone inhibits hypothalamic release of gonadotropin-releasing hormone (GnRH). In short feedback loops, the output of the target gland regulates pituitary activity. For example, thyroid hormones inhibit pituitary production of thyrotropin (or TSH). Ultrashort feedback loops exist between the pituitary and the hypothalamus. For example, pituitary TSH release inhibits hypothalamic production of thyrotropin releasing hormone (TRH). Although these examples are negative feedback loops, positive feedback loops also exist. For example, ovarian production of estradiol causes the pituitary to release more luteinizing hormone (LH) during the LH surge of the menstrual cycle.

The posterior pituitary does not produce its own hormones. Instead, vasopressin and oxytocin are produced by large neurons in the hypothalamus and released into the capillary beds of the posterior pituitary.

Etiology

Hypopituitarism is caused by a wide variety of disorders that disturb the gland itself, called primary hypopituitarism, or the hypothalamus, called secondary hypopituitarism (Table 3).

Neoplasms may cause hypopituitarism. Adenomas may gradually compress the contents of the sella, causing primary hypopituitarism. Adenomas may also cause pituitary apoplexy, a rapidly progressive opituitarism that results from hemorrhage, rapid swelling and necrosis. Craniopharyngiomas, usually considered childhood tumors, can also develop in young adults.(2) Cancer of the breast, lung or gastrointestinal tract may metastasize to the pituitary or the hypothalamus and cause hypopituitarism.(3,4)

Sheehan's syndrome, or postpartum pituitary necrosis, is classically associated with postpartum amenorrhea and failure of lactation. However, the syndrome may be subclinical in some patients, with symptoms surfacing only when these patients are stressed.(5)

Sarcoidosis may cause hypopituitarism by compressing or replacing normal tissue in the hypothalamus or, less commonly, the pituitary gland.(6,7) A similar process may occur in granulomatous hypophysitis,(8) hemochromatosis(9,10) or the autoimmune disorder lymphocytic hypophysitis.(11)

Head trauma may disrupt hypothalamic function, sever the pituitary stalk or damage the gland directly or indirectly secondary to intracranial bleeding. However, if the patient recovers from the trauma, the pituitary will usually recover some function. Patients with substantial pituitary destruction typically either do not survive or are left in a vegetative state.(12)

In the empty sella syndrome, the arachnoid space, which does not normally extend into the sella, herniates into the sella turcica through an incompetent sellar diaphragm and flattens the pituitary against the unyielding bone.(13) Because the gland is not destroyed, the degree of hypopituitarism may be less than one would expect, given the radiographic appearance.

Symptoms and Signs

Clinical manifestations of hypopituitarism, summarized in Table 4, are similar to those observed with target organ hypofunction. Patients may complain of a vague sense of poor health. They may appear depressed and chronically ill as a result of the hypometabolic state from anterior pituitary dysfunction. Often the symptoms contribute to family dysfunction. The patient's nutritional status is usually good, although weight loss of ten occurs when adrenocorticotropic hormone (ACTH) deficiency predominates.

ACTH deficiency produces an addisonian-like picture, except that skin pigmentation is decreased rather than increased. This is due to a deficiency in Beta -lipotropin, which is closely related to ACTH production. The skin takes on a dry, waxy, wrinkled appearance, suggesting premature aging. Anemia of chronic disease and decreased body hair are also common. The underlying condition may produce additional associated features, such as visual field defects with pituitary tumors or pulmonary symptoms with sarcoidosis.

The features of secondary hypothyroidism are similar to those of the primary disease, except that true myxedema is uncommon. The thyroid gland is shrunken and nonpalpable due to the lack of pituitary drive. Decreased pubic hair, libido and menses are often associated with primary hypothyroidism and thus do not necessarily indicate pituitary dysfunction.

Prolactin deficiency is only clinically significant in the postpartum setting, when failure to lactate is observed. Paradoxically, galactorrhea from hyperprolactinemia may be seen in secondary hypopituitarism because of a lack of hypothalamic inhibition of prolactin release.(14) Women with oxytocin deficiency typically experience normal labor and delivery.

The development of hypopituitarism before puberty results in delayed sexual maturation. Growth retardation is also noted, even if growth hormone secretion is unaltered.

Differential Diagnosis

Pituitary failure may be confused with target-organ failure or with illnesses that mimic the symptoms and signs of hypopituitarism.

Addison's disease and primary hypothyroidism both resemble hypopituitarism. Hyperkalemia, salt craving and hyperpigmentation are associated with primary adrenal insufficiency. Primary hypothyroidism is often associated with an enlarged thyroid gland. Loss of sexual characteristics may mimic menopause, but vasomotor symptoms are absent.

Patients with hypopituitarism may present with multiple vague complaints, which may be confused with psychologic disorders, such as hypochondriasis. Patients with anorexia nervosa are usually identifiable by their distorted body image and unusual patterns of food intake. They typically have dramatic weight loss, evidence of malnutrition and abnormalities in hypothalamic-pituitary-adrenal axis function.(1-5) Similarly, patients with malnutrition, vitamin deficiency and multiple chronic diseases share some of the clinical features of hypopituitarism.

Evaluation

A thorough clinical history and a detailed physical examination can suggest both the diagnosis and the etiology of hypopituitarism. The duration of symptoms can be brief, suggesting a mass lesion, or prolonged, suggesting a slowly progressive infiltrative process. A past history of head trauma, neurosurgery, obstetric complications or cancer may be an important clue. Since loss of sexual characteristics occurs early, examination of the genitalia is important.

Biochemical and anatomic diagnostic testing can be used to confirm the clinical diagnosis and determine the etiology of hypopituitarism. Biochemical evaluation can be performed by simultaneous evaluation of the target-gland hormone and its related trophic pituitary counterpart. The diagnosis of hypopituitarism is not difficult in a patient with subnormal serum levels of cortisol, thyroid hormones, sex hormone (estradiol in women, testosterone in men), TSH and follicle-stimulating hormone (FSH). When the results of these tests are equivocal, pituitary reserve should be assessed with provocative testing.(16) Measurement of serum ACTH levels is generally not useful. Because of the complex feedback systems, recent administration of target-organ hormones can confound the test results.

Since mass lesions are frequent causes of hypopituitarism, sella and pituitary anatomy should be evaluated radiographically with plain films, standard tomograms or CT scanning.(17) Although early magnetic resonance imaging (MRI) did not appear to be superior to CT, newer high-resolution MRI techniques appear to be more sensitive than CT in detecting pituitary microadenomas.(18) Treatment

Treatment of hypopituitarism is aimed at replacing the target-organ hormonal deficiencies and eliminating the primary disease, if possible. Glucocorticoid deficiency should be corrected first. Administration of 20 mg of oral hydrocortisone in the morning and 10 mg in the afternoon will replicate the normal circadian pattern. Nighttime doses should be avoided since they produce insomnia. Additional doses are required during times of physical stress, such as illness or surgery. A medical warning necklace or bracelet should be worn. Since aldosterone secretion is not affected, mineralocorticoid replacement is not necessary.

Thyroid replacement should not be instituted until the glucocorticoid deficiency has been corrected, because an adrenal crisis may result. Replacement therapy is started with a small dose (0.025 mg) of L-thyroxine. The dose is increased gradually, to a maintenance dose of 0. 1 to 0.2 mg, as determined by laboratory testing. Because of its short half-life, triiodothyronine should not be used.

Sex hormone replacement can be started when the patient is euthyroid. In women, sex hormones are replaced in the same manner as after surgical menopause. Men may be given testosterone replacement in the form of oral methyltestosterone, 20 to 30 mg daily, or intramuscular injections of testosterone enanthate or cypionate, 200 to 300 mg every three to four weeks. Restoration of secondary sexual characteristics, the therapeutic end point, may take months. Excessive doses will result in mood changes and emotional lability.

Synthetic analogs of vasopressin, either short-acting (lypressin [Diapidl) or long-acting (desmopressin; DDAVP), are available for the treatment of diabetes insipidus. These agents are administered by nasal spray.

In children, hormone replacement may not produce complete sexual development.

Surgery and radiation are used to treat pituitary neoplasms. Classically, the surgical approach has been through the frontal or temporal bone, a technique still used for large tumors. Currently, a less traumatic transsphenoidal approach is favored for both total hypophysectomy and microsurgical adenomectomy.(19) Since lifelong treatment is required for patients treated medically or surgically, and because hypopituitarism can be progressive, patients must be monitored for the rest of their lives.

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