A. Symptoms and Signs

Hyperprolactinemia may cause hypogonadotropic hypogonadism and reduced fertility. Men usually have diminished libido and erectile dysfunction that may not respond to testosterone replacement; gynecomastia sometimes occurs. Prolactinomas are pituitary neuroendocrine tumors whose diagnosis is often delayed in men, such that pituitary prolactinomas may grow and present with late manifestations of a pituitary macroprolactinoma (1 cm or larger).

About 90% of premenopausal women with prolactinomas experience amenorrhea, oligomenorrhea, or infertility. Estrogen deficiency can cause decreased vaginal lubrication, irritability, anxiety, and depression. Galactorrhea (lactation in the absence of nursing) is common. During pregnancy, clinically significant enlargement of a microprolactinoma (smaller than 10 mm) occurs in less than 3%; clinically significant enlargement of a macroprolactinoma occurs in about 30%.

Pituitary prolactinomas may cosecrete GH and cause acromegaly (see Acromegaly). Large tumors may cause headaches, visual symptoms, and pituitary insufficiency.

Aside from pituitary tumors, some women secrete an abnormal form of PRL that appears to cause peripartum cardiomyopathy (see Part 11). Suppression of PRL secretion with dopamine agonists can reverse the cardiomyopathy.

B. Laboratory Findings

An elevated serum prolactin level should be verified with a repeat determination, ideally in a different laboratory. Biotin supplements can cause falsely low serum PRL measurements; patients should not take a biotin supplement for at least 8 hours before the blood draw. Evaluate for conditions known to cause hyperprolactinemia, particularly pregnancy (serum hCG), hypothyroidism (serum FT₄ and TSH), kidney disease (BUN and serum creatinine), cirrhosis (liver tests), and hyperparathyroidism (serum calcium). Screen for acromegaly with a random serum IGF-1 level. Men are evaluated for hypogonadism with serum total and free testosterone, LH, and FSH. Women who have amenorrhea are assessed for hypogonadism with serum estradiol, LH, and FSH. In the presence of an extremely high serum prolactin, certain immunoradiometric assays report falsely low PRL levels, the "high-dose hook effect." The electrochemiluminescent (ECLIA) assay that is used in most major laboratories in the United States is more accurate. If an immunoradiometric assay is being used, patients with pituitary macroadenomas larger than 3 cm should have PRL measured on serial dilutions. Patients with macroprolactinomas or manifestations of possible hypopituitarism should be evaluated for hypopituitarism. Patients with hyperprolactinemia who are relatively asymptomatic and have no apparent cause for hyperprolactinemia should have an assay for macroprolactinemia, which is an increased circulating level of a high molecular weight PRL that is biologically inactive but is detected on assays.

C. Imaging

Patients with hyperprolactinemia not induced by drugs, hypothyroidism, or pregnancy should be examined by pituitary MRI. Small prolactinomas may be demonstrated (eFigure 28-3), but clear differentiation from normal variants is not always possible. The normal pituitary grows during pregnancy. MRI is therefore generally not performed during pregnancy unless there are visual-field defects or other neurologic symptoms, in which case a limited MRI study without gadolinium should be done.

eFigure 28-3. Coronal MRI Showing Large Pituitary Adenoma Elevating and Distorting the Optic Chiasm

Coronal MRI showing large pituitary adenoma elevating and distorting the optic chiasm. (Reproduced, with permission, from Riordan-Eva P, Augsburger JJ. Vaughan & Asbury's General Ophthalmology, 19th ed. McGraw-Hill, 2018.)

A. Dopamine Agonists

Dopamine agonists (cabergoline, bromocriptine, or quinagolide) are the initial treatment of choice for patients with giant prolactinomas and those with hyperprolactinemia desiring restoration of normal sexual function and fertility. Even cystic prolactinomas respond to dopamine agonists; in one report, median cyst volume was reduced by 83% and chiasmal compression resolved in four of five cases. Cabergoline is the most effective and usually best-tolerated ergot-derived dopamine agonist. Begin with 0.25 mg orally once weekly for 1 week, then 0.25 mg twice weekly for the next week, then 0.5 mg twice weekly. Further dosage increases may be required monthly, based on serum PRL levels, up to a maximum of 1.5 mg twice weekly. Bromocriptine (1.25-20 mg/day orally) is an alternative. Women who experience nausea with oral preparations may find relief with deep vaginal insertion of cabergoline or bromocriptine tablets; vaginal irritation sometimes occurs. Quinagolide (Norprolac; not available in the United States) is a non-ergot-derived dopamine agonist for patients intolerant or resistant to ergot-derived medications; the starting dosage is 0.075 mg/day orally, increasing as needed and tolerated to a maximum of 0.6 mg/day. Patients whose tumor is resistant to one dopamine agonist may be switched to another in an effort to induce a remission.

Dopamine agonists are given at bedtime to minimize side effects of fatigue, nausea, dizziness, and orthostatic hypotension, which occur in up to 50% of patients. These symptoms usually improve with dosage reduction and continued use. Dopamine agonists can cause a variety of psychiatric side effects (particularly depression, impulse control disorder, and hypersexuality) that are not dose related and may take weeks to resolve once the drug is discontinued. If antipsychotic drugs are required, one should be chosen that has less blocking of the D₂-receptor, such as aripiprazole. In doses used for prolactinomas, dopamine agonists have not caused cardiac valvulopathy.

Dopamine agonists do not increase the risk of miscarriage or teratogenicity. Pregnant women with microprolactinomas may safely stop treatment during pregnancy and breastfeeding. However, over 20% of macroadenomas enlarge significantly during pregnancy; if therapy is withdrawn, patients must be monitored with serum PRL determinations and computer-assisted visual fields. Women with macroprolactinomas who have responded to dopamine agonists may safely receive oral contraceptives as long as they continue receiving dopamine agonist therapy.

Men with cabergoline-resistant macroprolactinomas may have high serum estradiol levels, especially if they receive hCG or testosterone replacement therapy. Estradiol stimulates prolactin secretion and tumor growth. In these cases, cabergoline therapy can be supplemented with anastrozole, an aromatase inhibitor that reduces serum estradiol levels. Anastrozole is given orally in doses ranging from 0.5 mg three times weekly to 1 mg daily, with dosage adjustments to keep serum estradiol levels in the normal range for males.

B. Surgical Treatment

Transsphenoidal pituitary surgery may be urgently required for large tumors undergoing apoplexy or those severely compromising visual fields. It is also used electively for patients who do not tolerate or respond to dopamine agonists. Transsphenoidal pituitary surgery is generally well tolerated, with a mortality rate of less than 0.5%. For pituitary microprolactinomas, skilled neurosurgeons are successful in normalizing PRL in 87% of patients and some patients prefer surgery to long-term therapy with dopamine agonists.

Complications, such as CSF leakage, meningitis, stroke, or visual loss, occur in about 3% of cases; sinusitis, nasal septal perforation, or infection complicates about 6.5% of transsphenoidal surgeries. Diabetes insipidus can occur within 2 days postoperatively but is usually mild and self-correcting. Hyponatremia can occur abruptly 4-14 days postoperatively in 21% of patients; symptoms may include nausea, vomiting, headache, malaise, or seizure. Mild hyponatremia (Na greater than or equal to 125 mmol/L) can usually be managed as an outpatient restriction of free water plus tolvaptan, if necessary. Symptomatic or severe hyponatremia (Na less than 125 mmol/L) usually requires inpatient management and gradual correction with intravenous 3% saline plus tolvaptan if necessary.

C. Stereotactic Radiosurgery

Stereotactic radiosurgery is seldom required for prolactinomas since they usually respond to cabergoline or surgery. It is reserved for patients with macroadenomas that are growing despite treatment with dopamine agonists or patients who are intolerant to dopamine agonists. (See Acromegaly.)

D. Chemotherapy

Some patients with aggressive pituitary macroadenomas or carcinomas are not surgical candidates and do not respond to dopamine agonists or radiation therapy. A small percentage of patients with aggressive tumors respond to cabergoline with the addition of either temozolomide (150-200 mg/m² orally daily for 5 days of each 28-day cycle) or everolimus. Treatment efficacy is determined by PRL measurement and MRI scanning.