Prolactin is unique among the pituitary hormones in that the predominant central control mechanism is inhibitory, reflecting dopamine-mediated suppression of PRL release. Prolactin acts to induce and maintain lactation and decrease reproductive function and drive (via suppression of gonadotropin-releasing hormone [GnRH], gonadotropins, and gonadal steroidogenesis).
Physiologic elevation of PRL occurs in pregnancy and lactation. Otherwise, PRL-secreting pituitary adenomas (prolactinomas) are the most common cause of PRL levels >100 μg/L. Less pronounced hyperprolactinemia is commonly caused by medications (risperidone, chlorpromazine, perphenazine, haloperidol, metoclopramide, opiates, H2 antagonists, amitriptyline, selective serotonin reuptake inhibitors [SSRIs], verapamil, estrogens), pituitary stalk damage (tumors, lymphocytic hypophysitis, granulomas, trauma, irradiation), primary hypothyroidism, or renal failure. Nipple stimulation may also cause acute PRL increases.
In women, amenorrhea, galactorrhea, and infertility are the hallmarks of hyperprolactinemia. In men, symptoms of hypogonadism (Chap. 174) or mass effects are the usual presenting symptoms, and galactorrhea is rare.
Fasting, morning PRL levels should be measured; when clinical suspicion is high, measurement of levels on several different occasions may be required. If hyperprolactinemia is present, nonneoplastic causes should be excluded (e.g., pregnancy test, hypothyroidism, medications).
If the pt is taking a medication that is known to cause hyperprolactinemia, the drug should be withdrawn, if possible. A pituitary MRI should be performed if the underlying cause of PRL elevation is unknown. Resection of hypothalamic or sellar mass lesions can reverse hyperprolactinemia due to stalk compression. Medical therapy with a dopamine agonist is indicated in microprolactinomas for control of symptomatic galactorrhea, for restoration of gonadal function, or when fertility is desired. Alternatively, estrogen replacement may be indicated if fertility is not desired, but tumor size should be carefully monitored. Dopamine agonist therapy for macroprolactinomas generally results in both adenoma shrinkage and reduction of PRL levels. Cabergoline (initial dose 0.5 mg a week, usual dose 0.5–1 mg twice a week) and bromocriptine (initial dose 0.625–1.25 mg qhs, usual dose 2.5 PO three times a day) are the two most frequently used dopamine agonists. Cabergoline is the more effective and better-tolerated drug. These medications should initially be taken at bedtime with food, followed by gradual dose increases, to reduce the side effects of nausea and postural hypotension. Other side effects include constipation, nasal stuffiness, dry mouth, nightmares, insomnia, or vertigo; decreasing the dose usually alleviates these symptoms. Dopamine agonists may also precipitate or worsen underlying psychiatric conditions. Cardiac echocardiography is prudent before starting cabergoline therapy as there has been concern about an association with valvular heart disease. In pts with microadenomas successfully treated (normal PRL, full tumors shrinkage), therapy may be withdrawn after 2 years, followed by careful monitoring for tumor recurrence. Spontaneous remission of microadenomas, presumably caused by infarction, occurs in some pts. Surgical debulking may be required for macroprolactinomas that do not adequately respond to medical therapy.
Women with microprolactinomas who become pregnant should discontinue dopaminergic therapy, as the risk for significant tumor growth during pregnancy is low. In those with macroprolactinomas, visual field testing should be performed at each trimester. A pituitary MRI should be performed if severe headache and/or visual defects occur.
GH hypersecretion is primarily the result of pituitary somatotrope adenomas, mostly sporadic, but also in conjunction with MEN 1, Carney syndrome, McCune-Albright syndrome, and familial AIP mutations. Extrapituitary causes of acromegaly (ectopic growth hormone–releasing hormone [GHRH] production) are very rare.
The peak occurrence of acromegaly is at age 40–45. In children, GH hypersecretion prior to long bone epiphyseal closure results in gigantism. The presentation of acromegaly in adults is usually indolent, and diagnosis is typically delayed by up to a decade. Pts may note a change in facial features, widened teeth spacing, deepening of the voice, snoring, increased shoe or glove size, ring tightening, hyperhidrosis, oily skin, arthropathy, and carpal tunnel syndrome. Frontal bossing, mandibular enlargement with prognathism, macroglossia, an enlarged thyroid, skin tags, thick heel pads, and hypertension may be present on examination. Associated conditions include cardiomyopathy, left ventricular hypertrophy, diastolic dysfunction, sleep apnea, glucose intolerance, diabetes mellitus, colon polyps, and colonic malignancy. Overall mortality is increased approximately threefold.
Insulin-like growth factor type I (IGF-I) levels are a useful screening measure, with elevation suggesting acromegaly. Due to the pulsatility of GH, measurement of a single random GH level is not useful for screening. The diagnosis of acromegaly is confirmed by demonstrating the failure of GH suppression to <0.4 μg/L within 1–2 h of a 75-g oral glucose load. MRI of the pituitary usually reveals a macroadenoma.
The primary treatment modality for acromegaly is transsphenoidal surgery. GH levels are not normalized by surgery alone in many pts with macroadenomas; in those, somatostatin analogues provide adjunctive medical therapy that suppresses GH secretion with modest to no effect on tumor size. Octreotide (50 μg SC three times a day) is used for initial therapy to determine response. Once a positive response and tolerance of side effects (nausea, abdominal discomfort, diarrhea, flatulence) are established, pts are changed to long-acting depot formulations (octreotide LAR 20–30 mg IM every 2–4 weeks or lanreotide autogel 90–120 mg IM once a month). Dopamine agonists (bromocriptine, cabergoline) can be used as adjunctive therapy but are generally not very effective. The GH receptor antagonist pegvisomant (10–30 mg SC daily) can be added in pts who do not respond to somatostatin analogues. Pegvisomant is highly effective in lowering IGF-I levels but does not lower GH levels or decrease tumor size. Pituitary irradiation may also be required as adjuvant therapy but has a slow therapeutic onset and a high rate of late hypopituitarism.
NONFUNCTIONING AND GONADOTROPIN-PRODUCING ADENOMAS
These tumors are the most common type of pituitary neoplasm and usually present with symptoms of one or more hormonal deficiencies or mass effect (See Chap. 171). They typically produce small amounts of intact gonadotropins (usually FSH) as well as uncombined α-subunit and LHβ and FSHβ subunits. Surgery is indicated for mass effects or hypopituitarism; asymptomatic small adenomas may be followed with regular MRI and visual field testing. Diagnosis is based on immunohistochemical analysis of resected tumor tissue. Medical therapy is usually ineffective in shrinking these tumors.
TSH-producing adenomas are rare but often large and locally invasive when they occur. Pts present with goiter and hyperthyroidism, and/or sella mass effects. Diagnosis is based on elevated serum free T4 levels in the setting of inappropriately normal or high TSH secretion and MRI evidence of a pituitary adenoma. Surgery is indicated and is usually followed by somatostatin analogue therapy to treat residual tumor. Somatostatin analogue therapy (see above) leads to normalization of TSH and euthyroidism in most and tumor shrinkage in 50–75% of pts. If necessary, thyroid ablation or antithyroid drugs can be used to reduce thyroid hormone levels.