Pituitary Adenomas and Hypopituitarism9,12

GENERAL PRINCIPLES

• The anterior pituitary gland secretes prolactin, growth hormone, and four trophic hormones, including corticotropin (ACTH), thyrotropin (TSH), and the gonadotropins, luteinizing hormone and follicle-stimulating hormone.

• Anterior pituitary function is regulated by hypothalamic hormones that reach the pituitary via portal veins in the pituitary stalk. The predominant effect of hypothalamic regulation is to stimulate secretion of pituitary hormones, except for prolactin, which is inhibited by hypothalamic dopamine secretion.

• Secretion of trophic hormones is also regulated by negative feedback by their target gland hormone,

and the normal pituitary response to target hormone deficiency is increased secretion of the appropriate trophic hormone.

• Anterior pituitary dysfunction can be caused by disorders of either the pituitary or hypothalamus.

• Pituitary adenomas are the most common pituitary disorder. They are classified by size and function.

î Microadenomas are lt;10 mm in diameter and cause clinical manifestations only if they produce excess hormone. They are too small to produce hypopituitarism or mass effects.

î Macroadenomas are gt;10 mm in diameter and may produce any combination of pituitary hormone excess, hypopituitarism, and mass effects (headache, visual field loss).

î Secretory adenomas produce prolactin, growth hormone, or ACTH.

î Nonsecretory macroadenomas may cause hypopituitarism or mass effects.

î Nonsecretory microadenomas are common incidental radiographic findings, seen in approximately 10%-20% of the normal population, and do not require therapy.

• Other pituitary or hypothalamic disorders, such as head trauma, pituitary surgery or radiation, and postpartum pituitary infarction (Sheehan syndrome), may cause hypopituitarism.

DIAGNOSIS

Clinical Presentation

• Hypopituitarism may be suspected in the presence of clinical signs of target hormone deficiency (e.g., hypothyroidism) or pituitary mass effects.

• In hypopituitarism (deficiency of one or more pituitary hormones), gonadotropin deficiency is most common, causing amenorrhea in women and androgen deficiency in men. Secondary hypothyroidism or adrenal failure rarely occurs alone. Secondary adrenal failure causes cortisol deficiency but does not affect aldosterone; hyperkalemia and hyperpigmentation do not occur, although life-threatening adrenal crisis may develop.

• Hormone excess most commonly results in hyperprolactinemia, which can be due to a secretory adenoma or due to nonsecretory lesions that damage the hypothalamus or pituitary stalk. Growth hormone excess (acromegaly) and ACTH and cortisol excess (Cushing disease) are caused by secretory adenomas. Hormone excess can be present concurrently with other hormone deficiencies.

• Mass effects because of pressure on adjacent structures, such as the optic chiasm, include headaches and loss of visual fields or acuity. Hyperprolactinemia may also be due to mass effect. Pituitary apoplexy is sudden enlargement of a pituitary tumor due to hemorrhagic necrosis.

• Asymptomatic pituitary adenomas are commonly incidentally discovered on imaging.

Diagnostic Testing

• Incidental adenoma

î If an incidental microadenoma is found on imaging done for another purpose, the patient should be evaluated for clinical evidence of hyperprolactinemia, Cushing disease, or acromegaly.

î Plasma prolactin and insulin-like growth factor 1 (IGF-I) should be measured, and tests for Cushing syndrome should be performed if symptoms or signs of this disorder are evident.

î If no pituitary hormone excess exists, therapy is not required. Whether such patients need repeat imaging is not established, but the risk of enlargement is clearly small.

î Incidental discovery of a macroadenoma is unusual. Patients should be evaluated for hormone excess and hypopituitarism. Most macroadenomas should be treated because they are likely to grow further.

• Hypopituitarism

î Laboratory evaluation begins with evaluation of target hormone function, including plasma-free T₄ and a Cortrosyn stimulation test (see “Adrenal Failure” section).

î If recent onset of secondary adrenal failure is suspected (within a few weeks of evaluation), the patient should be treated empirically with glucocorticoids and should be tested 4-8 weeks later because the Cortrosyn stimulation test cannot detect secondary adrenal failure of recent onset.

î In men, plasma testosterone should be measured. The best evaluation of gonadal function in women is the menstrual history.

î If a target hormone is deficient, its trophic hormone is measured to determine whether target gland dysfunction is secondary to hypopituitarism. An elevated trophic hormone level indicates primary target gland dysfunction. In hypopituitarism, trophic hormone levels are not elevated and are usually within (not below) the reference range. Thus, pituitary trophic hormone levels can be interpreted only with knowledge of target hormone levels, and measurement of trophic hormone levels alone is useless in the diagnosis of hypopituitarism. If pituitary disease is obvious, target hormone deficiencies may be assumed to be secondary, and trophic hormones need not be measured.

• Anatomic evaluation of the pituitary gland and hypothalamus is best done by MRI and should be performed to evaluate any pituitary hormone excess or deficiency. However, hyperprolactinemia and Cushing disease may be caused by microadenomas too small to be seen. The prevalence of incidental microadenomas should be kept in mind when interpreting MRIs.

TREATMENT

• Secondary adrenal failure should be treated immediately, especially if patients are to undergo surgery (see “Adrenal Failure” section).

• Treatment of secondary hypothyroidism should be monitored by measurement of plasma-free T₄ (see “Hypothyroidism” section).

• Infertility due to gonadotropin deficiency may be correctable, and patients who wish to conceive should be referred to an endocrinologist.

• Treatment of hypogonadism in premenopausal women requires replacement of estrogen and progesterone. This can be conveniently done with combination oral contraceptives.

• Treatment of hypogonadism in men requires testosterone replacement, with either topical testosterone gel, 40-50 mg applied daily, or by injection of testosterone enanthate or testosterone cypionate, 100­200 mg IM every 2 weeks. Testosterone replacement therapy disrupts spermatogenesis; men who are concerned about fertility should be seen by an endocrinologist.

• Treatment of growth hormone deficiency in adults has been advocated by some, but the long-term benefits, risks, and cost-effectiveness of this therapy are not established.

• Treatment of pituitary macroadenomas generally requires transsphenoidal surgical resection, except for prolactin-secreting tumors.