Hyperprolactinemia

Essentials of Diagnosis

• Women

  • Oligomenorrhea, amenorrhea

  • Galactorrhea

  • Infertility

• Men

  • Hypogonadism

  • Decreased libido and erectile dysfunction

  • Infertility

• Elevated serum prolactin levels

• CT or MRI may show pituitary adenoma

General Considerations

• Table 26–1 lists causes of hyperprolactinemia

• Augmentation or reduction mammoplasty, and mastectomy may stimulate PRL secretion

• In acromegaly, there may be cosecretion of GH and PRL

• Most are microadenomas (< 1 cm in diameter) that do not grow even with pregnancy or oral contraceptives

• Some giant prolactinomas (> 3 cm in diameter) can spread into the cavernous sinuses and suprasellar areas; rarely, they may erode the floor of the sella to invade the paranasal sinuses

Demographics

• Prolactin-secreting pituitary tumors more common in women

• Usually sporadic but rarely familial as part of multiple endocrine neoplasia type 1 (MEN-1)

Symptoms and Signs

• Hypogonadotropic hypogonadism

  • Men

    • Erectile dysfunction

    • Diminished libido

    • Gynecomastia (sometimes)

  • Women

    • Amenorrhea, oligomenorrhea, or infertility

    • Estrogen deficiency can cause decreased vaginal lubrication, irritability, anxiety, and depression

    • Galactorrhea

    • During pregnancy, clinically significant enlargement of a microprolactinoma (diameter < 10 mm) occurs in < 3%; clinically significant enlargement of a macroprolactinoma (diameter ≥ 10 mm) occurs in about 30%

• Pituitary prolactinomas

  • May co-secrete growth hormone and cause acromegaly

  • Large tumors may cause

    • Headaches

    • Visual symptoms

    • Pituitary insufficiency (hypogonadism)

Differential Diagnosis

• Increased pituitary size is a normal variant in young women

• 10–25% of patients with hyperprolactinemia have macroprolactinemia, an increased circulating level of a high molecular weight PRL that is biologically inactive

• See Table 26–1

Laboratory Tests

• The following tests should be done to rule out conditions that cause hyperprolactinemia:

  • Serum human chorionic gonadotropin (to rule out pregnancy)

  • Serum free thyroxine (FT₄) and thyroid-stimulating hormone (TSH) (to rule out hypothyroidism)

  • Blood urea nitrogen and serum creatinine (to rule out kidney disease)

  • Liver biochemical tests (to rule out cirrhosis)

  • Serum calcium (to rule out hyperparathyroidism)

• To evaluate men for hypogonadism, obtain

  • Serum total and free testosterone

  • Luteinizing hormone (LH)

  • Follicle-stimulating hormone (FSH)

• To assess women with amenorrhea for hypogonadism, obtain

  • Serum estradiol

  • LH

  • FSH

• Consider assay for macroprolactinemia if patient is asymptomatic with no apparent cause for hyperprolactinemia

• Electrochemiluminescent (ECLIA) assay is more accurate than immunoradiometric assay

• If an immunoradiometric assay is being used, patients with pituitary macroadenomas > 3 cm should have PRL measured on serial dilutions

Imaging Studies

• MRI of pituitary and hypothalamus indicated when hyperprolactinemia persists without obvious cause

• MRI is not usually performed in pregnant women with macroprolactinoma

• However, MRI of the pituitary should be done if visual-field defects or other neurologic symptoms develop

• Small prolactinomas may be demonstrated, but clear differentiation from normal variants is not always possible

Medications

• Dopamine agonists are initial treatment of choice for

  • Patients with giant prolactinomas

  • Patients with hyperprolactinemia desiring restoration of normal sexual function and fertility

• Cabergoline

  • 0.25 mg once weekly orally for 1 week

  • Then, 0.25 mg twice weekly for 1 week

  • Then, 0.5 mg twice weekly

  • Further increases may be required monthly, up to 1.5 mg twice weekly, based on serum prolactin

• Bromocriptine, 1.25–20.0 mg/day orally, is an alternative

• Quinagolide is a dopamine agonist for patients intolerant of or resistant to other agents

  • Not available in the United States

  • Dose: start at 0.075 mg/day orally, up to 0.6 mg/day

• Give dopamine agonists at bedtime to minimize side effects (fatigue, nausea, dizziness, and orthostatic hypotension), which usually improve with dosage reduction and continued use

  • Psychiatric side effects occur, are not dose related, and may take weeks to resolve after dopamine agonist is discontinued

• Treat hypothyroidism with levothyroxine

• Estrogen replacement or oral contraceptives

  • Safe for women with microprolactinomas who have amenorrhea or wish contraception

  • Minimal risk of stimulating adenoma enlargement

• Estrogens and testosterone

  • Can stimulate macroprolactinomas

  • Should not be used unless in full remission with medication or surgery

Surgery

• Transsphenoidal resection may be urgently required for large tumors severely compromising visual fields or undergoing apoplexy

• Transsphenoidal selective resection of the pituitary adenoma is done electively for patients who fail dopamine agonists

Therapeutic Procedures

• Stereotactic radiosurgery

  • Seldom required for prolactinomas, since they usually respond to cabergoline or surgery

  • Reserved for patients with macroadenomas that are growing despite treatment with dopamine agonists

• For patients with aggressive pituitary macroadenomas or carcinomas who do not respond to dopamine agonists or radiation therapy

  • Temozolomide (150–200 mg/m² orally daily for 5 days of each 28-day cycle) or everolimus may be added to cabergoline

  • Treatment efficacy is determined by prolactin measurement and MRI scanning

Follow-Up

• Women with microadenomas may have dopamine agonists safely withdrawn during pregnancy

• Macroadenomas may enlarge during pregnancy; if therapy is withdrawn, they must be followed up clinically and with computer-assisted visual field perimetry

• After pituitary surgery or radiation, monitor serum prolactin every 3 months

Complications

• Macroadenomas can impair visual fields and cause hypopituitarism

• Untreated hypogonadism increases risk of osteoporosis

• Fluid and electrolyte disturbances occur in most patients postoperatively

• Diabetes insipidus can occur within 2 days postoperatively but is usually mild and self-correcting

• Hyponatremia can occur abruptly 4–13 days postoperatively in 21% of patients; symptoms may include nausea, vomiting, headache, malaise, or seizure

Prognosis

• Pituitary prolactinomas generally respond well to dopamine agonist therapy

• During pregnancy, growth of a pituitary prolactinoma occurs in

  • 3% of women with a microprolactinoma

  • 23% of those with a macroprolactinoma (> 1 cm diameter)

• If cabergoline is stopped after 2 years therapy, hyperprolactinemia recurs in

  • 68% of patients with idiopathic hyperprolactinemia

  • 79% of patients with microprolactinomas

  • 84% of patients with macroprolactinomas