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 are generally less than 25-30 ng/mL, depending on the individual laboratory, but can also vary for a number of reasons. Normal levels are also generally higher in women.
Nonpuerperal hyperprolactinemia is a state in which pituitary lactotroph adenomas produce prolactin. These lactotroph adenomas are called prolactinomas and account for approximately 40% of all pituitary tumors. However, hyperprolactinemia can also be from a pharmacologic cause or some other pathologic problem of the hypothalamic-pituitary dopaminergic pathways. Idiopathic hyperprolactinemia is possible though a diagnosis of exclusion.
The primary action of prolactin is to stimulate breast epithelial cell proliferation, thereby inducing and maintaining 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 commence. During lactation and breastfeeding, ovulation may be suppressed due to the suppression of gonadotropins by prolactin, but may return before menstruation resumes. Therefore, this cannot be considered a reliable form of birth control.
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), vasoactive intestinal peptide (VIP), epidermal growth factor, and dopamine receptor agonists. 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).
This condition occurs in less than 1% of the general population and in 5-14% 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 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.
Rare cases of metastatic malignant prolactinoma have been described in the literature, but they number less than 50.
Bone resorption can be seen due to sex steroid attenuation mediated by the hyperprolactinemic state. A 25% decrease in spinal bone density can be seen in women with hyperprolactinemia and may be irreversible, even with normalization of prolactin levels.
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.
Women typically present with a history of oligomenorrhea, amenorrhea, or infertility, which generally results 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 findings most commonly encountered in patients with hyperprolactinemia are galactorrhea and, in the case of prolactinomas, visual-field defects. Typically, the diagnosis is made via the aid of laboratory studies.
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 patient's problem. Once discovered, hyperprolactinemia has a broad differential that includes many normal physiologic conditions.
Pregnancy should always 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 can include the following :
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. Although medications can cause significant elevation of prolactin, a level of 500 ng/mL or greater is diagnostic of a macroprolactinoma.
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 non–prolactin-producing tumor.
When the underlying cause (physiologic, medical, pharmacologic) cannot be determined and an MRI does not identify an adenoma, idiopathic hyperprolactinemia is diagnosed.
Another potential cause of hyperprolactinemia is macroprolactinemia. The majority of prolactin in the bloodstream is monomeric (approximately 85%). However, dimeric and polymeric forms may also coexist. Macroprolactinemia is the apparent increase in serum prolactin without typical symptoms. In this condition, serum prolactin molecules can polymerize and subsequently bind to immunoglobulin G (IgG). This form of prolactin is unable to bind to prolactin receptors and exhibits no systemic response. In the asymptomatic patient with hyperprolactinemia, this condition should be considered. The discovery of macroprolactinemia could save the patient the inconvenience and cost of an in-depth evaluation for a microadenoma. Consult laboratory personnel for any special collecting requirements. Women with macroprolactinemia are able to conceive. This condition generally requires no treatment.
Generally, hyperprolactinemia is discovered in the course of evaluating a patient's presenting complaint, for instance amenorrhea, galactorrhea, or 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 co-secreted 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.
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.
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).
Direct treatment is geared toward resolving hyperprolactinemic symptoms or reducing tumor size. Patients on medications that cause 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 radiographic absorptiometry scanning should be considered to evaluate bone density.
In cases of pharmacologic-induced hyperprolactinemia, an evaluation of the risk-benefit profile of the causative agent is imperative. Stopping the drug is ideal, but this may not be feasible. A good example would be in the schizophrenic patient in whom a single antipsychotic agent is the cause, but is keeping the patient’s psychoses under control. The cautious addition of a dopamine agonist may be considered.
The persistent hypogonadism associated with hyperprolactinemia can lead to osteoporosis. Baseline dual-energy x-ray absortiometry (DEXA) scanning is appropriate. 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 necessary for rapidly growing tumors, but its benefits in routine treatment have not been shown to outweigh the risks.
The dopamine agonist, bromocriptine mesylate, is often the initial drug of choice and may require high doses to achieve clinical improvement and shrinkage of prolactinomas. It can lower the prolactin level in 70-100% of patients. While the evidence supporting the use of medication therapy first is largely based on uncontrolled observational studies, they do strongly support the use of these medications. Agents other than bromocriptine have been used (eg, cabergoline, quinagolide). Cabergoline, in particular, probably is more effective and causes fewer adverse effects than bromocriptine. However, it is much more expensive. Cabergoline is often used in patients who cannot tolerate the adverse effects of bromocriptine or in those who do not respond to bromocriptine.[9, 10, 11, 12]
Pergolide, a drug previously used for the treatment of hyperprolactinemia was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to stop pergolide abruptly. Health care professionals should assess patients’ need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.
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.
Kharlip et al looked at the recurrence of hyperprolactinemia after withdrawal of cabergoline therapy in 46 patients who had undergone long-term treatment with the drug. At the beginning of the investigation, the study's patients were normoprolactinemic and had experienced tumor volume reduction after at least 2 years of treatment with cabergoline. The overall recurrence rate of hyperprolactinemia following cabergoline withdrawal was 54%; it was estimated that the recurrence risk by 18 months after the drug's discontinuation was 63%.
Kharlip et al also found that recurrence risk was related to the size of the tumor remnant remaining before therapy was discontinued, with an 18% risk increase for each millimeter of remnant. They concluded that withdrawal of cabergoline is safe in patients meeting the criteria used in the study but that close follow-up with these patients is essential, particular in the first year after the drug's discontinuation.
Bromocriptine is also 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.
Dekkers et al also investigated the effects of dopamine agonist withdrawal on patients with hyperprolactinemia, either the idiopathic form or that caused by prolactinomas. In a meta-analysis of 19 studies, encompassing a total of 743 patients, the authors found, just as Kharlip et al did, a high rate of recurrence of hyperprolactinemia following medication withdrawal. According to a stratified analysis, the treatment success rate (maintenance of normoprolactinemia after drug withdrawal) for patients with idiopathic hyperprolactinemia (32%) was greater than it was for individuals with prolactinomas (21% of patients with microprolactinomas, 16% of patients with macroprolactinomas). It was also found that the administration of cabergoline for at least 2 years provided the greatest probability of treatment success.
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.
In patients with symptomatic prolactinomas who are either not responding to high doses of dopamine agonists or cannot tolerate the high doses necessary, transspenoidal surgery has been suggested as the best treatment. However, no controlled studies have evaluated the surgical outcomes in medically resistant tumors.
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 endocrinologist is often necessary.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Clinical Context: 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.
Clinical Context: Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist with low affinity for D1 receptors.
Clinical Context: Pituitary selective dopamine-2 receptor agonist used in cases of bromocriptine resistance or intolerance. Used in the UK, not available in US.
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.[15, 16]
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.
Potential complications of hyperprolactinemia are primarily related to tumor size and the physiologic effects of the condition. These include blindness, hemorrhage, osteoporosis, and infertility.
When monitored 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 is often 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.