Hyperprolactinemia

Background: Hyperprolactinemia is a condition of elevated serum prolactin. Prolactin is a 198 amino acid protein (23-kD) produced in the lactotroph cells of the anterior pituitary gland. Its primary function is to enhance breast development during pregnancy and to induce lactation. However, prolactin also binds to specific receptors in the gonads, lymphoid cells, and liver. Secretion is pulsatile; it increases with sleep, stress, pregnancy, and chest wall stimulation or trauma, and therefore must be drawn after fasting. Normal fasting values generally are less than 30 ng/mL depending on the individual laboratory.

Pathophysiology: The primary action of prolactin is to stimulate breast epithelial cell proliferation and induce milk production. Estrogen stimulates the proliferation of pituitary lactotroph cells, resulting in an increased quantity of these cells in premenopausal women, especially during pregnancy. However, lactation is inhibited by the high levels of estrogen and progesterone during pregnancy. The rapid decline of estrogen and progesterone in the postpartum period allows lactation to occur. During lactation and breastfeeding, ovulation may be suppressed due to the suppression of gonadotropins by prolactin.

Dopamine has the dominant influence over prolactin secretion. Secretion of prolactin is under tonic inhibitory control by dopamine, which acts via D2-type receptors located on lactotrophs. Prolactin production can be stimulated by the hypothalamic peptides, thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP). Thus, primary hypothyroidism (a high TRH state) can cause hyperprolactinemia. VIP increases prolactin in response to suckling, probably because of its action on receptors that increase adenosine 3,5-cyclic phosphate (cAMP).

Frequency:

In the US: This condition occurs in less than 1% of the general population and in 10-40% of patients presenting with secondary amenorrhea. Approximately 75% of patients presenting with galactorrhea and amenorrhea have hyperprolactinemia. Of these patients, approximately 30% have prolactin-secreting

• tumors.

Mortality/Morbidity:

• Mortality is unlikely; however, in cases where the condition is due to a large prolactin-secreting tumor, local mass effect can lead to significant morbidity.

• The condition causes systemic complaints that often resolve when the prolactin level returns to normal or once the tumor shrinks.

Sex:

• Clinical presentation in women is more obvious and occurs earlier than in men. They typically present with oligomenorrhea, amenorrhea, galactorrhea, or infertility. Galactorrhea is less common in postmenopausal women due to lack of estrogen. If a pituitary tumor is present, it is a microadenoma (<10 mm) approximately 90% of the time.

• Prolactinoma is less common in men than in women, typically presenting as an incidental finding on a brain CT scan or MRI, or with symptoms of tumor mass effect. This is most evident as a complaint of visual disturbances or headache. By the time of diagnosis in men, approximately 60% have macroprolactinomas.

History:

• Women typically present with a history of oligomenorrhea, amenorrhea, or infertility, which generally result from prolactin suppression of gonadotropin-releasing hormone (GnRH). Galactorrhea is due to the direct physiologic effect of prolactin on breast epithelial cells.

• Men typically present with complaints of sexual dysfunction, visual problems, or headache and are subsequently diagnosed with hyperprolactinemia in the evaluation process. Prolactin suppresses GnRH, causing a decrease in luteinizing hormone and follicle-stimulating hormone, ultimately leading to decreased serum testosterone levels and hypogonadism. Prolactinoma in men also may cause neurological symptoms, particularly visual-field defects.

• In both sexes, the presence of a pituitary tumor may cause visual-field defects or headache. Most patients with a prolactinoma (the most common type of pituitary adenoma) are women.

Physical: Physical findings most commonly encountered in patients with hyperprolactinemia are galactorrhea and, occasionally, visual-field defects. Typically, the diagnosis is made via the aid of laboratory studies.

Causes: The diagnosis of hyperprolactinemia should be included in the differential for female patients presenting with oligomenorrhea, amenorrhea, galactorrhea, or infertility or for male patients presenting with sexual dysfunction. The condition is discovered in the course of evaluating the patients problem. Once discovered, hyperprolactinemia has a broad differential that includes many normal physiologic conditions.

• Pregnancy always should be excluded unless the patient is postmenopausal or has had a hysterectomy. In addition, hyperprolactinemia is a normal finding in the postpartum period.

• Other common conditions to exclude include a nonfasting sample, excessive exercise, a history of chest wall surgery or trauma, renal failure, and cirrhosis. Postictal patients also develop hyperprolactinemia within 1-2 hours after a seizure. These conditions usually produce a prolactin level of less than 50 ng/mL.

• Hypothyroidism, an easily treated disorder, also may produce a similar prolactin level.

• Detailed drug history should be obtained because many common medications cause hyperprolactinemia, usually with prolactin levels of less than 100 ng/mL. Drugs that may cause the condition include the following:

• Dopamine receptor antagonists (eg, phenothiazines, butyrophenones, thioxanthenes, risperidone, metoclopramide, sulpiride, pimozide)

• Dopamine-depleting agents (eg, methyldopa, reserpine)

• Others (eg, isoniazid, danazol, tricyclic antidepressants, monoamine antihypertensives, verapamil, estrogens, antiandrogens, cyproheptadine, opiates, H2-blockers [cimetidine], cocaine)

• If no obvious cause is identified or if a tumor is suspected, MRI should be performed.

• Although no single test can help determine the etiology of hyperprolactinemia, a prolactinoma is likely if the prolactin level is greater than 250 ng/mL and less likely if the level is less than 100 ng/mL.

• Prolactin-secreting adenomas are divided into 2 groups: (1) microadenomas (more common in premenopausal women), which are smaller than 10 mm and (2) macroadenomas (more common in men and postmenopausal women), which are 10 mm or larger.

• If the prolactin level is greater than 100 ng/mL or less than 250 ng/mL, the evaluating physician must decide whether a radiographic study is indicated. In many cases, with the availability of MRI scanners, imaging is performed earlier and at lower prolactin levels to rule out a nonprolactin-producing tumor.

• When the underlying cause (physiologic, medical, pharmacologic) cannot be determined and an MRI does not identify an adenoma, idiopathic hyperprolactinemia is diagnosed.

Lab Studies:

• Generally, hyperprolactinemia is discovered in the course of evaluating a patient's presenting complaint, ie, amenorrhea, galactorrhea, erectile dysfunction. Occasionally, several fasting measurements of prolactin must be obtained.

• Current thyroid-stimulating hormone assays are very sensitive for detecting hypothyroid conditions.

• Measuring blood urea nitrogen and creatinine is important for detecting renal failure.

• History of alcohol abuse and abdominal examination may give clues for cirrhosis as a possible etiology.

• Pregnancy testing is required unless the patient is postmenopausal or has had a hysterectomy.

• Patients with macroadenoma should be evaluated for possible hypopituitarism. Male patients should have testosterone levels checked.

• Many patients with acromegaly have prolactin cosecreted with growth hormone. Anyone thought to have acromegaly should be evaluated with an insulin-like growth factor-1 (IGF-1) level measurement and a glucose tolerance test for nonsuppressible growth hormone levels if needed.

Imaging Studies:

• Although modern high-speed helical CT scanners produce very detailed images, MRI is the imaging study of choice. MRI can detect adenomas that are as small as 3-5 mm.

Other Tests:

• These would be determined by any identified cause, eg, visual-field testing especially if a pituitary macroadenoma is found or if optic nerve involvement is noted on imaging studies.

Medical Care: Direct treatment is geared toward resolving hyperprolactinemic symptoms or reducing tumor size. Patients on medications causing hyperprolactinemia should have them withdrawn if possible. Patients with hypothyroidism should be given thyroid hormone replacement therapy.

• When symptoms are present, medical therapy is the treatment of choice. Patients with hyperprolactinemia and no symptoms (idiopathic or microprolactinoma) can be monitored without treatment. Consider treatment for women with amenorrhea. In addition, duel-energy x-ray absorptiometry (DEXA) scanning should be considered to evaluate bone density.

• The persistent hypogonadism associated with hyperprolactinemia can lead to osteoporosis. Treatment significantly improves the patient's quality of life. If the goal is to treat hypogonadism only, patients with idiopathic hyperprolactinemia or microadenoma can be treated with estrogen replacement and prolactin levels can be monitored.

• Radiation treatment is another option. However, the risk of hypopituitarism makes this a poor choice. It may be rapidly growing tumors, but its benefits in routine treatment have not been shown to outweigh the risks.

• Medication

• The dopamine agonist, bromocriptine mesylate, is the initial drug of choice. It lowers the prolactin level in 70-100% of patients. Agents other than bromocriptine have been used (eg, cabergoline, quinagolide). Cabergoline and pergolide are available in the United States. Cabergoline, in particular, probably is more effective and causes fewer adverse effects than bromocriptine. However, it is much more expensive. Cabergoline often is used in patients who cannot tolerate the adverse effects of bromocriptine or in those who do not respond to bromocriptine. Pergolide has not been approved by the US Food and Drug Administration (FDA) for use in patients with this condition.

• Response to therapy should be monitored by checking fasting serum prolactin levels and checking tumor size with MRI. Most women (approximately 90%) regain cyclic menstruation and achieve resolution of galactorrhea. Testosterone levels in men increase but may remain below normal.
• Therapy should be continued for approximately 12-24 months (depending on the degree of symptoms or tumor size) and then withdrawn if prolactin levels have returned to the normal range. After withdrawal, approximately one sixth of patients maintain normal prolactin levels.
• Bromocriptine also is used to shrink macroadenomas. Normalization of visual fields is observed in as many as 90% of patients. A failure to improve within 1-3 months is an indication for surgery. Tumors usually shrink to 50% of their original size in approximately 90% of patients treated for macroadenomas for 1 year. In patients with nonprolactinoma tumors (masses that are compressing the pituitary stalk), medical treatment reduces serum prolactin levels but does not reduce tumor size. Cabergoline is somewhat more effective than bromocriptine in terms of tumor shrinkage.

Surgical Care: General indications for pituitary surgery include patient drug intolerance, tumors resistant to medical therapy, patients who have persistent visual-field defects in spite of medical treatment, and patients with large cystic or hemorrhagic tumors.

Consultations: Physicians who are comfortable with the initial evaluation of a patient (without evidence of tumor mass effect) can easily initiate therapy and provide follow-up. However, given the time constraints of modern ambulatory medicine, consultation with an en The goal of pharmacotherapy is to reduce morbidity and prevent complications.

Drug Category: Dopamine agonists -- These agents directly stimulate postsynaptic dopamine receptors. Dopaminergic neurons in tuberoinfundibular processes modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor, believed to be dopamine.

Drug Name		Bromocriptine (Parlodel) -- Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist; partial dopamine D1-receptor agonist. Inhibits prolactin secretion with no effect on other pituitary hormones. May be given with food to minimize possibility of GI irritation.
Adult Dose		1.25-2.5 mg PO initially; increase gradually every few days to approximately 5-10 mg daily in divided doses.
Pediatric Dose		Not recommended
Contraindications		Documented hypersensitivity; ischemic heart disease, uncontrolled hypertension, peripheral vascular disorders; breastfeeding
Interactions		Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease effects
Pregnancy		B - Usually safe but benefits must outweigh the risks.
Precautions		Caution in renal or hepatic disease; generally stopped during pregnancy but can be restarted if symptoms recur; perform regular visual-field testing during pregnancy to monitor for tumor growth; should be given hs to minimize postural hypotension or nausea
	Drug Name		Cabergoline (Dostinex) -- Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist with low affinity for D1 receptors.
	Adult Dose		0.25-1 mg twice/wk; start with a low dose and increase q4wk based on prolactin levels
	Pediatric Dose		Not recommended
	Contraindications		Documented hypersensitivity; ischemic heart disease, uncontrolled hypertension, peripheral vascular disorders; breastfeeding
	Interactions		Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease effects
	Pregnancy		B - Usually safe but benefits must outweigh the risks.
	Precautions		Caution in renal or hepatic disease; generally stopped during pregnancy but can be restarted if symptoms recur; perform regular visual-field testing during pregnancy to monitor for tumor growth; can be given hs to minimize postural hypotension or nausea

Further Outpatient Care:

• Once the diagnosis has been established and therapy initiated, fasting prolactin levels should be monitored monthly. Later, prolactin levels can be monitored every 3-6 months. Shrinkage of the tumor should be followed by formal visual-field testing and MRI.

Complications:

• Potential complications of hyperprolactinemia are primarily related to tumor size and the physiologic effects of the condition. These include blindness, hemorrhage, osteoporosis, and infertility.

• Prognosis: When followed for longer than 7 years, 90-95% of microadenomas remained stable or gradually decreased prolactin secretion.

• One third of patients with idiopathic hyperprolactinemia may experience resolution without treatment. This number increases to two thirds if the patient's basal prolactin level is less than 40 ng/mL.

• Surgery often is not curative for macroprolactinomas, with a recurrence rate of as high as 40% within 5 years.

• Recurrence rates of hyperprolactinemia are as high as 80%, and, subsequently, patients require long-term medical therapy.

Patient Education:

• A decrease in prolactin levels may restore ovulation. Advice about birth control methods should be given when prolactin levels approach the normal range.

Medical/Legal Pitfalls:

The primary reason physicians are sued is for failure to diagnose, regardless of the diagnosis. The diagnosis of hyperprolactinemia often is made during the evaluation of the patient's complaints. This condition is easily diagnosed unless the physician fails to consider it in his or her differential.