Hyperprolactinemia and Prolactinomas

Diagnosis

Prolactin is a polypeptide secreted from the lactotrophs of the anterior pituitary (Leung and Pacaud, 2004; Mancini et al., 2008). The main function of prolactin is the development of breast tissue in preparation for milk production and maintenance of lactation postpartum. Unlike other pituitary hormone regulation, prolactin release is predominantly under inhibitory control. Dopamine is the principal inhibitor, and prolactin stimulators such as TRH and estrogen have minor roles.

Hypersecretion of prolactin may be physiologic or pathologic in origin. Physiologic stimulators include exercise, pain, breast stimulation, sexual intercourse, general anesthesia, and pregnancy. Pathologic causes of hyperprolactinemia include prolactinomas, decreased dopaminergic inhibition of prolactin secretion through pharmacologic agents, and decreased clearance of prolactin. Early manifestation of prolactin hypersecretion is galactorrhea and menstrual irregularities, notably amenorrhea, in women and erectile dysfunction or loss of libido in men. Rarely, galactorrhea with gynecomastia can occur in men. These patients are at risk of developing osteoporosis secondary to hypogo-nadism as well as a result of the direct inhibitory effect of prolactin on bone formation. Galactorrhea is rarely found in postmenopausal women with hyperprolactinemia, in whom mass effect of prolactinomas may cause the principal presenting symptom, such as headache or visual disturbance (Mancini et al., 2008). Similarly, the diagnosis of prolactino-mas in men is often delayed because the clinical signs and symptoms of hyperprolactinemia are less obvious.

Clinical evaluation of patients with suspected prolactino-mas should include a thorough evaluation of medication history and presence of comorbidities. Many drugs are known to cause hyperprolactinemia, including phenothiazines, haloperidol, metoclopramide, H2 antagonists, imipramines, selective serotonin reuptake inhibitors (SSRIs), calcium channel blockers, and hormones. The physical examination may reveal galactorrhea and visual field defects. Women may have mild hirsutism and men decreased facial hair growth.

Laboratory tests include serum prolactin and thyroid function. Primary hypothyroidism is associated with hyperpro-lactinemia secondary to elevated TRH that induces prolactin secretion. Testing should also seek systemic illnesses with increased prolactin levels, such as liver or renal failure. MRI is the imaging modality of choice for the anatomic evaluation of the hypothalamus and pituitary gland. Complete pituitary hormone evaluation should be performed when an adenomatous mass is noted in the region of the pituitary.

Features to distinguish hyperprolactinemia associated with pituitary tumors include (1) prolactin levels greater than 150 ng/mL, (2) loss of normal sleep-associated increases in prolactin levels, and (3) failure of prolactin levels to rise in response to exogenous TRH. No test is absolute, and diagnosis of prolactinoma depends on radiologic studies.

Clinicians should be aware of two prolactin assay-related conditions that may cause diagnostic confusion. In macro-prolactinemia, large-molecular-weight prolactin, aggregated with globulins, is recorded as elevated levels of prolactin in the absence of any physiologic or pathologic cause of hyperprolactinemia (Mancini et al., 2008). Macroprolactinemia is suspected in the patient with very high prolactin level and no galactorrhea or tumor on pituitary MRI. The second area of confusion occurs when extremely high concentrations of serum prolactin overwhelm the assay reagents such that the measurements underestimate the true concentration of pro-lactin. This is referred to as the "hook effect."

Treatment

The treatment of hyperprolactinemia depends on the etiology, presence or absence of mass effects (e.g., visual changes), presence of bothersome galactorrhea or associated pituitary hormone deficiencies, and whether fertility is desired (Leung and Pacaud, 2004; Mancini et al., 2008). If possible, drugs known to cause prolactin elevation should be discontinued and serum prolactin concentration remeasured. Persistent hyperprolactinemia requires pituitary-hypothalamus imaging.

Treatment of prolactinomas includes dopamine agonists as first-line treatment. In select subgroups, surgical excision is recommended, usually through the transsphenoidal approach. Rare patients with large, residual tumor mass after surgery not responsive to medical therapy may be offered radiation therapy. Associated hormone deficiency should also be targeted. Often, as the prolactin levels are normalized, symptoms of hypogonadism can be reversed.

Bromocriptine and cabergoline are U.S. Food and Drug Administration (FDA)-approved dopamine agonists used to treat hyperprolactinemia. Cabergoline has greater toler-ability than bromocriptine and is more effective in achieving normalization of prolactin levels in 90% of patients with prolactinomas. Because of long-standing experience, however, bromocriptine is the preferred agent in women who want to become pregnant. Bromocriptine should be discontinued once pregnancy has been confirmed, even though the risk of teratogenicity is small. Pregnant women with prolactinomas should be warned to report any visual disturbances or headaches, because up to 10% of microprolactinomas and 30% of macroprolactinomas increase in size sufficient to cause symptoms. During pregnancy, prolactin levels should be monitored periodically, but interpretation of the results may be difficult. Pregnant women with macroadenomas should receive similar advice and have serial visual field testing.

Pergolide is an alternative but non-FDA-approved medication for hyperprolactinemia. Caution should be exercised with all these ergot derivatives because of rare case reports of valvular heart damage in patients taking the drug at very high doses for prolonged periods.

Withdrawal of the drug may lead to recurrent prolactin hypersecretion and adenoma growth, although the microadenomas have resolved after a few years of treatment in some patients. The dosage of the dopamine agonist may be reduced when prolactin levels have been normalized for 1 year and tumor size has been significantly reduced. Medication withdrawal may be considered after 2 years in those with normal prolactin levels and an MRI scan showing no tumor, or tumor reduction more than 50% and more than 5 mm from the optic chiasm, with no invasion of the cavernous sinus. Pituitary MRI and serum prolactin levels should be monitored closely thereafter.

Indications for transsphenoidal surgery in patients with prolactinomas include medical treatment failure or medication intolerance, very large tumors threatening visual pathways, or hemorrhagic infarcts (apoplexy). Approximately 30% of macroadenomas can be successfully removed surgically.

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