Evaluation of Galactorrhea and Hyperprolactinemia
David M. Slovik
Discharge of milk or colostrum from the breast in the absence of nursing is referred to as galactorrhea. When it is accompanied by disturbed menses or infertility, it suggests the possibility of hyperprolactinemia and the associated risk for pituitary neoplasm. When a patient presents with galactorrhea, underlying pituitary disease must be carefully considered.
Galactorrhea
Galactorrhea may occur in the context of normal hormonal function or as a consequence of inappropriately sustained prolactin synthesis. Prolactin, a polypeptide hormone synthesized and secreted by the lactotroph cells of the anterior pituitary gland, induces and maintains lactation of the primed breast. During pregnancy and lactation, the prolactin content of the pituitary increases 10- to 20-fold. Tonic inhibitory control of prolactin synthesis is maintained by hypothalamic dopamine; synthesis and secretion are stimulated by estrogen, thyrotropin-releasing hormone (TRH), epidermal growth factor, and dopamine-receptor antagonists.
Normoprolactinemic galactorrhea in the absence of sustained hyperprolactinemia is usually noted as an isolated symptom or an incidental finding on breast examination, often occurring in the setting of local breast stimulation or irritation in women
with hormonally primed breast tissue. It is hypothesized that stimulation of the breast may cause a mild, transient elevation in prolactin secretion, although this is not sustained. Many cases are associated with a distant pregnancy or the use of oral contraceptives. Gonadal function is preserved, with menses and fertility remaining normal.
with hormonally primed breast tissue. It is hypothesized that stimulation of the breast may cause a mild, transient elevation in prolactin secretion, although this is not sustained. Many cases are associated with a distant pregnancy or the use of oral contraceptives. Gonadal function is preserved, with menses and fertility remaining normal.
Hyperprolactinemic galactorrhea develops as a consequence of excessive prolactin production, caused either by a loss of hypothalamic inhibition of lactotrophs or by the development of an autonomously functioning pituitary adenoma. In rare instances, such as renal insufficiency, hyperprolactinemia may occur due to impaired degradation and clearance of prolactin. Even in the context of high prolactin levels, galactorrhea does not occur unless the breast is primed by estrogen, which accounts for the rarity of the condition in men. Amenorrhea and infertility are common accompaniments.
Hyperprolactinemia
Elevations in prolactin may be a consequence of physiologic stimulation, medications, pituitary/hypothalamic disease, and prolactinoma.
Physiologic and Drug-Induced Hyperprolactinemia
Pregnancy and lactation are the most important physiologic causes of hyperprolactinemia. Because the secretion and release of prolactin are under tonic inhibition by dopamine, any process that interferes with dopamine secretion and release will cause hyperprolactinemia. Prolactin levels rise after exercise, meals, chest wall stimulation, and physical and psychological stress, but under such physiologic circumstances, the levels are rarely higher than 40 ng/mL. Higher levels (up to 100 ng/mL) are seen with medications that affect dopaminergic activity.
Medications are the most frequent cause of nontumoral hyperprolactinemia. Drugs most commonly associated with hyperprolactinemia include the neuroleptics and antipsychotic agents (40% to 90% exhibit hyperprolactinemia) by virtue of their central dopaminergic blocking activity. The list includes phenothiazines, thioxanthenes, butyrophenones, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, reserpine, methyldopa, verapamil, metoclopramide, cimetidine, estrogen, opiates, and cocaine. Elevated prolactin levels are usually between 25 and 100 ng/mL, but use of drugs such as metoclopramide, risperidone, and phenothiazines may result in prolactin levels greater than 200 ng/mL.
Hypothalamic/Pituitary Disease
Prolactin elevations may result from pituitary or hypothalamic pathology. Examples include infiltration by granulomatous disease, compression of the pituitary stalk by nonsecreting pituitary tumors and craniopharyngiomas, acromegaly, and primary hypothyroidism (owing to thyroid-releasing hormone stimulation of lactotrophs). Prolactin levels also may be elevated in patients with chronic renal failure due to decreased clearance.
Prolactinomas
Except in pregnancy, serum prolactin in excess of 250 to 300 ng/mL is almost always the result of a prolactinoma. Prolactinomas account for 30% to 40% of all clinically recognized pituitary adenomas, having a peak prevalence in women between ages 25 and 34 years and noted earlier in women than men due to disturbances in menstrual function. They are rare in children and adolescents. Most prolactin-secreting adenomas arise from monoclonal expansion of a single anterior pituitary lactotroph cell that has undergone somatic mutation; 10% involve somatotroph-secreting growth hormone. Autonomously functioning prolactinomas result in very high serum concentrations of prolactin, with the degree of hyperprolactinemia tending to correlate with tumor size. Macroadenomas (larger than 10 mm in diameter) are typically associated with prolactin levels greater than 250 ng/mL, sometimes exceeding 1,000 ng/mL, and have a risk of growing and causing hypogonadism. Microadenomas (<10 mm in diameter) typically produce less impressive prolactin elevations, exhibit a benign course, and undergo little additional enlargement.
Associated Symptoms
Because patients with hyperprolactinemia are at risk for hypogonadism, they may experience, in addition to galactorrhea, disturbed menses, amenorrhea, infertility, and osteoporosis. Bone density of the spine may decline by as much as 25% in women with hyperprolactinemia and not necessarily recover, even with normalization of prolactin levels. In premenopausal women, symptoms of hyperprolactinemia correlate with the degree of prolactin elevation. Elevations greater than 100 ng/mL are typically associated with findings of hypogonadism, a consequence of estrogen deficiency due to impaired release of gonadotropin-releasing hormone and subsequent inhibition of luteinizing hormone and follicular stimulating hormone production. Moderate elevations of 50 to 100 ng/mL may cause a short luteal phase of the menstrual cycle due to insufficient progesterone secretion, but even mild hyperprolactinemia can cause infertility. Macroadenomas may encroach upon the optic chiasm and cause visual field defects.
Men with hyperprolactinemia commonly have hypogonadism and report impotence, infertility, decreased libido, gynecomastia, and, rarely, galactorrhea. The pituitary tumors tend to be large. Men and women with a substantially enlarging sellar mass may complain of headache or a visual field cut.
The differential diagnosis of galactorrhea can be organized according to whether prolactin is elevated and whether an elevation in prolactin is the result of a decrease in hypothalamic inhibition or overproduction by a functioning adenoma (Table 100-1). Only 20% of patients with galactorrhea have hyperprolactinemia. Prolactinoma is a leading cause in patients with galactorrhea, amenorrhea, and hyperprolactinemia. Pregnancy should be ruled out in women of childbearing age with hyperprolactinemia. Other causes originating in the region of the pituitary include empty sella syndrome, craniopharyngioma, pinealoma, and parasellar sarcoidosis. Nonprolactinomic disease about and within the pituitary accounts for about one third of cases of galactorrhea and amenorrhea. Persistent galactorrhea after childbirth accounts for just less than 10% of cases. As noted, drugs associated with galactorrhea include oral contraceptives and agents with central dopaminergic blocking activity (see Table 100-1).
