Hyperplolactinemia is a common endocrine disorder, occurring in 15% to 20% of women with menstrual disturbances [1–3], 43% to 87% of women with both amenorrhea and galactorrhea [1,2], and 30% to 40% of infertile women [4,5]. Although hypogonadism is a prominent feature of hyperprolactinemia, only 1% to 2% of men reporting a loss of libido or sexual potency have some degree of hyperprolactinemia [6,7]. Men are also more likely than women to seek treatment for a prolactin-secreting macroadenoma. This sex disparity may be because of a true difference in the pathophysiologic characteristics of this condition, or it may be because of the more obvious manifestations of symptoms in women compared with men.
PHYSIOLOGY OF PROLACTIN SECRETION
Prolactin (PRL) secretion is pulsatile, with a sleepassociated increase in PRL concentrations. Daytime pulses may be triggered by meals, stress, or exercise or may occur spontaneously. Before puberty, PRL concentrations are similar in males and females. After the onset of puberty in females, PRL concentrations increase in response to estrogen secretion. Three predominant species of PRL of different molecular weights (23,000; 48,000; and 170,000) are detectable in the peripheral circulation. The primary roles of PRL in women are the stimulation of breast growth and the subsequent maintenance of milk production. The role of PRL in men is less clear. PRL stimulates adrenal androgen production, but it inhibits gonadal steroid synthesis via 5α-reductase, which is responsible for converting testosterone to dihydrotestosterone .
In contrast to the other pituitary hormones, PRL is predominantly under tonic inhibitory control. Dopamine, which is synthesized in the hypothalamus, directly inhibits PRL biosynthesis and release by pituitary lactotroph cells (Fig. 1). Processes that interfere with the secretion of dopamine or the binding of dopamine to lactotroph receptors result in elevated PRL concentrations. PRL inhibits its own secretion through short-loop feedback by stimulating dopamine production. Dopamine suppresses the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. Thus, sustained hyperprolactinemia disrupts the normal pulsatile secretion of GnRH and luteinizing hormone (LH), resulting in low estrogen levels and menstrual irregularities in women and diminished androgen secretion with concomitant hypogonadal symptoms in men.
CAUSES OF HYPERPROLACTINEMIA
Prolactinomas and Other Parasellar Lesions
Hyperprolactinemia can result from a number of physiologic, pathologic, or pharmacologic processes (Table 1). PRL-secreting pituitary adenoma is the most common cause of hyperprolactinemia. Prolactinomas account from 40% to 50% of all pituitary adenomas [8,9]. Pituitary adenomas are typically classified as microadenomas (<10 mm in diameter) or macroadenomas (>10 mm in diameter). Macroadenomas occur less frequently than microadenomas and are more common in men than women. A majority of microadenomas remain small, with only a small proportion developing into macroadenomas .
Macroadenomas in conjunction with PRL concentrations greater than 200 ng/mL are indicative of prolactinomas that are likely to respond to pharmacotherapy. Conversely, parasellar lesions associated with relatively modest increases in PRL concentrations (<150 ng/mL) are generally nonfunctional adenomas (pseudoprolactinomas) or hypothalamic and stalk lesions that interfere with dopamine transport to lactotroph cells. These lesions are associated with hyperprolactinemia, but they generally are nonfunctional and unresponsive to pharmacologic therapy. Also, approximately one third of patients with acromegaly have pituitary adenomas that cosecrete growth hormone and PRL. It is important that an insulin-like growth factor I (IGF-I) concentration be measured and acromegaly ruled out in patients with newonset hyperprolactinemia.
Other Pathologic Causes
A thorough medical history aids in the differential diagnosis of pituitary adenoma-induced hyperprolactinemia. It must be noted that a small subset of patients with primary hypothyroidism can have hyperprolactinemia . In this situation, PRL concentrations are usually lower than 100 ng/mL and the pituitary gland can be enlarged. Normalization of both prolactin concentrations and pituitary enlargement occurs with treatment of hypothyroidism. Hyperprolactinemia may develop in patients with renal or hepatic failure as a result of altered neurotransmitter function and, to a lesser degree, decreased clearance of PRL. Approximately 25% of patients with polycystic ovary disease also are likely to have hyperprolactinemia . Stimulation of neural afferents from the breast plays an important role in the maintenance of normal lactation. Therefore, skin lesions on, or trauma to, the chest wall (eg, herpes zoster) may produce hyperprolactinemia through this neural pathway. Seizure activity is associated with transient hyperprolactinemia.
Physiologic Stimulants of Prolactin
Several physiologic conditions should be considered when patients with symptoms of hyperprolactinemia are evaluated . The sleep-associated increase in PRL concentrations continues for approximately 1 hour after the patient awakens. Even mild-to-moderate physical exertion may trigger PRL release. Food, stress, and mild pain may result in mildly increased PRL concentrations. In addition, coitus, ovulation, suckling, and nipple stimulation all stimulate PRL release. During pregnancy, serum PRL concentrations increase steadily in response to increasing estrogen concentrations; at term, PRL concentrations are increased 10-fold over baseline concentrations.
Pharmacologic Stimulants of Prolactin
Dopamine is the primary inhibitor of secretion. Therefore, drugs that affect dopamine synthesis or block dopamine receptors may cause hyperprolactinemia . Long-term use of psychotropic agents is a primary cause of hyperprolactinemia. Therefore, phenothiazines, such as chlorpromazine, perphenazine, and haloperidol, and the newer classes of dopamine antagonists increase PRL concentrations. In addition, such prokinetic agents as metoclopramide and domperidone, which antagonize dopamine receptors at the level of the pituitary, have the potential to cause hyperprolactinemia. Less commonly, psychotropic drugs that affect the serotonergic system, such as fluoxetine hydrochloride, may cause elevated PRL concentrations. Tricyclic antidepressants cause a modest increase in PRL concentrations in as many as 25% of patients . Antihypertensive drugs such as calcium channel blockers and angiotensin-converting enzyme inhibitors can be associated with increased PRL concentrations, although the mechanism for this is not known. Chronic opiate or cocaine abuse may increase PRL concentrations at the hypothalamic level, and chronic therapy with such H2 antagonists as cimetidine may cause hyperprolactinemia. Although pharmacologic doses of estrogen used in oral contraceptives or estrogen replacement therapy typically do not cause hyperprolactinemia, chronic exposure to high estrogen concentrations can increase PRL concentrations by direct lactotroph stimulation and by inhibition of dopamine at the hypothalamic level.
CLINICAL FEATURES OF HYPERPROLACTINEMIA
The clinical features of hyperprolactinemia reflect both the metabolic consequences of increased PRL concentrations on gonadal and breast function and mass effects caused by compression of normal pituitary cells and surrounding parasellar structures by the expanding sellar lesion. In women, menstrual disturbances, galactorrhea (present in 30% to 80% of patients), infertility, and loss of libido reflect hyperprolactinemic hypogonadism . Seborrhea and hirsutism may be present, caused by increased androgen concentrations. Diminished estrogen concentrations may cause hot flushes, vaginal dryness, and dyspareunia. Osteopenia and osteoporosis can occur in patients with chronic hyperprolactinemia. In fact, bone mineral content is 20% to 25% lower among women with hyperprolactinemia compared with age-matched controls [15,16]. Bone loss may correlate with menstrual status because hyperprolactinemic women with normal menses appear to have normal bone density . This suggests that estrogen deficiency, rather than hyperprolactinemia, is responsible for the development of osteopenia.
In men, hypogonadism with infertility, lack of libido, and diminished sexual potency are the most common symptoms of hyperprolactinemia, occurring in about 90% of patients [18,19]. Decreased ejaculate volume is often reported, and galactorrhea or gynecomastia is present in less than 15% of patients .
Signs and symptoms of an expanding pituitary lesion may be evident. In patients with both microadenomas and macroadenomas, headache may be observed as the expanding lesion stretches sensory nerves that traverse the dura surrounding the sella. The enlarging adenoma may cause varying degrees of hypopituitarism caused by compression of the anterior pituitary lobe. Diminished visual acuity and visual field defects are common among patients with macroadenoma as a lesion grows up and out of the sella and compresses the optic chiasm. Because of the higher incidence of macroadenoma in males, the incidence of visual field defects is about 40% in men compared with 25% in women [19,20].
DIAGNOSIS OF HYPERPROLACTINEMIA
Evaluation of patients with suspected hyperprolactinemia should begin with measurement of basal circulating PRL concentrations. Because PRL concentrations are sensitive to sleep-wake cycles, stress, and physical exercise, a single increased PRL concentration is not sufficient for the diagnosis of hyperprolactinemia. Repeated PRL testing should be conducted in the morning with the patient in a rested and fasted state at least 1 hour after waking and before breast examination. A thorough history, including current medications, should be obtained, and pregnancy should be excluded. In addition, the pituitary-thyroid axis and the gonadal axis should be evaluated for abnormalities. PRL concentrations in patients with prolactinomas may vary from the upper limit of normal (15 to 20 ng/mL) to values greater than 10,000 ng/mL. Although commercial immunoassays use specific monoclonal antibodies, false-negative results may be observed in patients with extremely high PRL concentrations as a result of the high-dose hook effect. These false-negative results can be avoided by the performance of serial sample dilutions (1:1 and 1:100) . In general, pituitary adenoma size is positively correlated with PRL concentration. In some patients, PRL concentrations may be modestly increased with no clinical correlates. In such patients, circulating PRL may be the large-molecular-weight form that is less biologically active.
When physiologic and pharmacologic causes for excessive PRL secretion are excluded, diagnostic imaging is recommended. Both computed tomography and magnetic resonance imaging (MRI) have been used to visualize pituitary tumors. MRI provides better contrast and enhances viewing of anatomic detail and structural definition. MRI studies of the sellar and parasellar regions require thin slices (less than 2.5 mm) and can be conducted with or without gadolinium enhancement.
TREATMENT OF HYPERPROLACTINEMIA
The objectives of treatment of hyperprolactinemia are to normalize PRL concentrations and resolve symptoms. If a tumor is present, the goals of therapy also include reduction in tumor mass, preservation of residual pituitary function, and prevention of disease progression or recurrence.
Dopamine agonists are the agents of choice for the treatment of hyperprolactinemia, even in the setting of a prolactin-secreting adenoma. These agents bind to dopamine receptors on the surface of the lactotroph, inhibiting PRL synthesis and release. In most patients, these agents reduce tumor volume and normalize PRL concentrations. Studies have shown that dopamine agonist therapy results in normalization of PRL concentrations or resumption of menses in 70% to 95% of patients [22–26]. The effects of dopamine agonist therapy are rapid in onset (1 to 2 h), although complete normalization of PRL concentrations may take weeks. Tumor reductions are observed within 2 to 3 months of initiation of therapy, even in patients with macroadenomas [27,28].
Two dopamine agonists, cabergoline and bromocriptine, are currently approved in the United States for the treatment of hyperprolactinemia. Pergolide, although not approved by the US Food and Drug Administration (FDA), has been used for the treatment of hyperprolactinemia. Bromocriptine requires twice-daily administration, whereas cabergoline, which has a longer duration of action, is administered once or twice weekly. In a multicenter comparative study of cabergoline and bromocriptine, cabergoline treatment induced stable normoprolactinemia in 83% of patients compared with 59% of bromocriptine-treated patients (95% CI: 17% to 33%) (Fig. 2) . In addition, pregnancy or resumption of ovulation and menses was seen in 72% of women treated with cabergoline versus 52% of bromocriptine-treated patients (p < 0.001). Bromocriptine has been shown to reduce tumor size by at least 25% in up to 79% of patients . Experience with cabergoline suggests that it is at least as effective as bromocriptine, if not more so, in the reduction of tumor size. In one study, cabergoline resulted in tumor volume reduction in 73% to 90% of patients [28,29]. Other studies have shown that cabergoline causes more complete tumor volume reduction: cabergoline has demonstrated greater than 80% tumor volume reduction in 61% of patients  and the complete disappearance of tumors in 13% to 40% of patients [30–32]. Cabergoline also has been shown to further reduce tumor volume in patients previously treated with other dopamine agonists . This additional benefit associated with the use of cabergoline may prevent the need for surgery in some patients.
Adverse effects of dopamine agonist therapy include hypotension and gastrointestinal disturbances, including nausea and vomiting. Headache, fatigue, and nasal stuffiness, which are transitory and seldom severe, are commonly reported. Initiation of therapy at low doses and administration of these agents with food may decrease the incidence and severity of adverse effects. Less common adverse effects include flushing, constipation, abdominal or leg cramps, and, rarely, pituitary apoplexy. In 5% to more than 10% of bromocriptine-treated patients, adverse effects are severe enough to require that the patient stop therapy [22,24]. In contrast, only 3% to 5% of patients discontinue treatment with cabergoline as a result of intolerable adverse effects (Fig. 3) [24,26].
Surgery is second-line therapy for prolactinomas and is used when patients cannot tolerate dopamine agonist therapy or when the tumor is resistant to medical therapy. Preoperative PRL concentration, tumor size, and tumor invasiveness are factors that influence the outcome of surgical intervention . Several studies have shown that the surgical cure rate is inversely proportional to serum PRL concentration [34–36]. In patients with macroadenoma treated with transsphenoidal surgery, the success rate is poor (<40%), the frequency of postoperative hypopituitarism is relatively high, and adjunctive therapy is necessary in most cases [27,37]. In contrast, patients with microadenomas are more likely to have low preoperative PRL concentrations and better surgical results. Surgical intervention normalizes PRL concentrations and provides symptom relief in about 80% of patients with microadenomas, but recurrence rates are 15% to 50% [37–40]. Thus, even in patients with microadenomas, surgical therapy is considered only for patients who are intolerant of, or resistant to, medical therapy.
HYPERPROLACTINEMIA AND PREGNANCY
With successful dopamine agonist therapy, pregnancy rates up to 80% have been reported in women with prolactinomas . During pregnancy, the risk for tumor expansion is less than 5% in patients with microprolactinomas and 15% to 25% in patients with macroprolactinomas . It is recommended that dopamine agonist therapy be discontinued during pregnancy. However, large retrospective studies of women who continued bromocriptine therapy during pregnancy have not provided evidence of an increased incidence of spontaneous miscarriage or birth defects [42,43]. Women with microprolactinomas generally experience normal pregnancies with no increase in the frequency of miscarriage or premature birth. Women with macroprolactinomas should be carefully monitored, with formal visual field testing performed at each trimester. If headaches or visual field deficits become evident, dopamine agonist therapy should be resumed.
Hyperprolactinemia is a common endocrine disorder. Although menstrual disturbances, galactorrhea, or infertility often prompts women to seek medical care, the lack of obvious symptoms in men often results in a delayed diagnosis. Because PRL secretion is sensitive to many external stimuli, the diagnosis of hyperprolactinemia should be confirmed by 2 increased PRL measurements with the patient in a fasted state. MRI should be performed to confirm the presence of a pituitary tumor after other pathologic causes of hyperprolactinemia have been ruled out. Treatment goals include normalization of PRL concentrations, resolution of galactorrhea and symptoms of hypogonadism, and reduction in tumor size. For most patients, medical therapy with a dopamine agonist is the first line of treatment. These drugs are highly effective, restoring menses, and reducing tumor volume in up to 90% of patients.
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