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Pituitary and Hypothalamic Diseases

Pituitary and Parasellar Tumors

Pituitary adenomas are the most common cause of hypopituitarism in the adult. Hypopituitarism results from compression of the normal pituitary cells by the adenoma. Pituitary microadenomas (less than 10 mm in diameter) usually do not cause hypopituitarism but rather cause symptoms from pituitary hormone hypersecretion. Small nonfunctioning pituitary tumors are usually asymptomatic. When pituitary glands were examined at autopsy in patients who had died without known pituitary disease, small microadenomas were frequently identified. In two large series small microadenomas were found in 22% and 27% of cases. Nonfunctioning pituitary tumors often present clinically when the tumors are large enough to cause compressive symptoms including headache, visual symptoms and cranial nerve palsies as well as hypopituitarism. Most nonsecreting microadenomas are at low risk for significant tumor enlargement. Surgery does not seem to be indicated for these tumors unless they enlarge or cause symptoms. Asymptomatic macroadenomas are more likely to cause clinical symptoms and should be either surgically removed or carefully followed with frequent scans and visual field testing.

Pituitary tumors are almost always benign and appear to be monoclonal in origin. The cause of most of these tumors is at present unclear. Approximately 40% of growth hormone secreting tumors have been reported to have missense activating point mutations in the alpha subunit of Gs, the stimulatory regulator of adenylyl cyclase. Recently, the MEN1 gene has been cloned and mutations in this gene have been reported in the majority of patients with this familial syndrome characterized by pituitary, parathyroid and pancreatic endocrine tumors. The MEN1 gene codes for a 610 amino acid protein product which has been termed menin. Screening for MEN1 gene mutations should facilitate early diagnosis and treatment.

Granulomatous and Infiltrative Disorders

A variety of granulomatous diseases including sarcoidosis and histiocytosis can occasionally cause hypopituitarism. Sarcoidosis can involve the hypothalamus but the pituitary may be involved as well. Diabetes insipidus is frequently reported in patients with hypothalamic-pituitary sarcoidosis. A variety of anterior pituitary deficits may occur as well. Isolated giant cell granulomas have also been found in the pituitary of patients (primarily middle-aged or older women) without other systemic evidence of sarcoidosis.

Vascular Lesions

Vascular causes of hypopituitarism include aneurysms, pituitary infarction and hemorrhage into the pituitary gland. Intrasellar aneurysms can simulate pituitary tumors and it may be difficult to distinguish between the two without the use of angiography or MRI. Acute hemorrhage into the pituitary.

Ischemic necrosis of the pituitary has been a frequently reported cause of hypopituitarism following severe postpartum hemorrhage (Sheehan's syndrome). The current incidence of this disorder however appears to have decreased as a result of  increased intracranial pressure.

Lymphocytic Hypophysitis

Lymphocytic hypophysitis is being recognized with increasing frequency as a cause of hypopituitarism primarily in women during pregnancy and in the postpartum period. It is considered to be a form of autoimmune endocrine disease and is associated with other endocrine autoimmune disorders.

Trauma

Head trauma can be associated with both diabetes insipidus and anterior pituitary insufficiency. Although the pathological consequences of head.

Radiation

Hypopituitarism has been reported in patients after irradiation for head and neck neoplasia. The hypothalamic-pituitary region is often included in the field of radiotherapy for nasopharyngeal cancer. In one study 14 out of 15 patients that received between 5000 - 8000 rads to the hypothalamic region.

Infection

A variety of infections have been reported to involve the pituitary. The most common are acute bacterial infections. These infections may result either from direct extension of a bacterial process in the sphenoid sinus, cavernous sinus or meninges or from hematogenous seeding associated.

Congenital Abnormalities and Idiopathic Deficiencies

Congenital abnormalities of the pituitary and hypothalamus are often associated with developmental abnormalities of other midline structures including optic nerve hypoplasia, absence of the septum pellucidum and a variety of associated facial abnormalities. Basal encephaloceles, congenital defects in the base of the skull through which meninges and brain tissue have herniated, are associated with hypothalamic-pituitary dysfunction. Isolated anterior pituitary hormone deficiencies may be congenital or acquired and are often on a hypothalamic basis. The most common isolated deficiencies are growth hormone and gonadotropins. Patients with isolated gonadotropin deficiency associated with hyposmia or anosmia and other midline defects are considered to have Kallman's syndrome. Recently, mutations of the gene encoding the transcription factor pit-l.

Diagnosis of Hypopituitarism

Hypopituitarism can result from a variety of etiologies, as discussed above, which can either compromise the pituitary directly or the hypothalamic nuclei which regulate pituitary function. The signs and symptoms of hypopituitarism result from specific anterior pituitary hormonal deficiencies.

When evaluating ACTH and cortisol secretion however, it is usually necessary in addition to baseline measurements to make an assessment.

Hyperprolactinemia and Prolactin Secreting Pituitary Tumors

Hyperprolactinemia is encountered commonly in clinical medicine. Aside from the physiologic elevations of prolactin normally seen during pregnancy and lactation as well as during sleep and stress, there are numerous pharmacologic and pathologic causes of hyperprolactinemia. A variety of drugs, most notably dopamine receptor antagonists such as the neuroleptics and metoclopramide, often cause hyperprolactinemia and elevated prolactin levels.

Hyperprolactinemia causes hypogonadotropic hypogonadism in women and men primarily due to the inhibitory effect of high prolactin levels on hypothalamic GnRH release. The most common symptoms of hyperprolactinemia are amenorrhea and galactorrhea in women and decreased libido and impotence in men. Objectives in the therapeutic approach to hyperprolactinemia vary with the symptoms and the presentation of the patient.

Cabergoline can be taken less frequently than the other drugs and appears to be advantageous for patients who experience side effects on the other drugs. Transsphenoidal surgery is also very effective if the drugs are not tolerated or if they do not work. Rarely radiotherapy may be required depending on the response to surgery and dopamine agonist treatment.

Growth Hormone Secreting Pituitary Tumors

More than 99% of the cases of acromegaly are caused by pituitary adenomas. Rarely acromegaly may be caused by ectopic GHRH production. The clinical manifestation include soft tissue changes with coarsening of the facial features and enlargement of the hands and feet. Excessive sweating and arthritic complaints axe common. Gigantism can occur if GH is hypersecreted prior to puberty.

The somatostatin analog octreotide however has recently proved to be successful in the long-term treatment of acromegaly. Reduction of growth hormone and IGF-1 levels and tumor shrinkage have been reported in many cases. Side effects include nausea, diarrhea, and gallstones. However because of the expense and side effects as well as the need for multiple daily injections octreotide has not replaced transsphenoidal surgery as the first line of treatment for most patients with acromegaly. It has however proved to be an important alternative for patients not cured by surgery. A depot, long acting preparation of octreotide (Sandostatin-LAR) has just been approved for use in the United States this year and should improve patient convenience and compliance. A growth hormone receptor antagonist is also being evaluated in clinical trials and preliminary reports indicate that this new class of drugs may be both well-tolerated and effective.

ACTH Secreting Pituitary Tumors

Clinical Manifestations of Cushing's Syndrome

The clinical features of Cushing's syndrome result from prolonged overproduction of glucocorticoids. These include central obesity, cutaneous atrophy and easy bruisability, muscle wasting, osteoporosis, hypertension, diabetes mellitus and personality changes. In addition excess production of adrenal androgens in women is associated with hirsutism, ache and amenorrhea. Cushing's disease occurs five times more frequently in women than in men with the peak incidence occurring between 20-50 years of age.

Pituitary ACTH hypersecretion (Cushing's disease) is the most frequent cause of Cushing's syndrome aside from exogenous glucocorticoid administration. Other causes of Cushing's syndrome which include adrenal adenomas and carcinomas and ectopic secretion of ACTH by a non-pituitary tumor must be considered in the differential diagnosis of hypercortisolism. When initially evaluating a patient suspected of having Cushing's syndrome the overnight 1 mg dexamethasone suppression test can be used as a reliable and convenient screening test.

Treatment of Cushing's Disease

Transsphenoidal surgery is currently the treatment of choice for patients with Cushing's disease. Microadenomas are usually found in most patients at the time of surgery and can be selectively removed with eventual resumption of normal hypothalamic-pituitary-adrenal function. If no adenoma is found either a partial or total hypophysectomy may be elected because of the morbidity and mortality associated with this disease.

FSH/LH/TSH Secreting Pituitary Tumors and Nonsecreting Pituitary Tumors

Long-standing primary hypogonadism and hypothyroidism are normally associated with hypersecretion of FSH and LH or TSH. In some cases this loss of feedback suppression on the hypothalamic-pituitary axis can lead to pituitary hyperplasia with sella enlargement. This has been reported most commonly with primary hypothyroidism and can be accompanied by visual field defects which are reversible with thyroid hormone replacement.

Treatment of Hypopituitarism

Hydrocortisone administered orally in two divided doses is often used for basal glucocorticoid replacement. Although a commonly recommended replacement regimen is 20 mg in the morning and 10 mg in the evening, it should be emphasized that the exact replacement regimen needs to be individualized for each patient. Some patients will feel well on as little as 10-15 mg of hydrocortisone per day. Patients should be monitored clinically.