Farid Farid, M.D.

Case Report

A 40-year-old female complained of spontaneous painless bilateral breast discharge, especially at night, for several months. She also noted bilateral palpable breast masses. She was married for three years and had never been pregnant. Her previous medical history was significant for bloody nipple discharge three years earlier diagnosed by biopsy as benign duct papillomas which were excised. Yearly mammography thereafter was normal. Since menarche at age 12, menstrual periods have been regular, though usually prolonged for seven days. The patient had recurrent iron deficiency anemia attributed to excessively prolonged menstrual periods resulting from an intramural uterine fibroid. She had allergic rhinitis for which she had been taking Claritin, 10 mg tablet daily. Hyperacidity and symptoms of GERD and H. pylori had been treated and maintained on robepraxole 20 mg, 1 tablet daily.

Her family history was strongly positive for breast cancer. Two sisters were diagnosed at ages 40 and 48, and five half-sisters from her father\'s side, all developed breast cancer.

Laboratory results showed elevated prolactin level at 50.2 mg/L. A repeat prolactin level 3 months later showed an elevated level of 41.8 mg/L. The patient cut down on Claritin and robeprazole but continued to have mild galactorrhea. Repeated lab data showed a normal BUN, creatinine, LFT\'s, and thyroid function tests. Follicle stimulating hormone (FSH), luteinizing hormone (LH), estrogen, progesterone, ACTH, AM cortisol, testosterone DHEA, and 17-hydroxyprogesterone were all normal. C-peptide level was minimally elevated at 4.7 (normal 0.9-3.9), and prolactin was elevated at 43.8 mg/L. MRI, with and without contrast, revealed a 3 mm focus of decreased contrast enhancement in the left side of the pituitary gland which is highly suggestive of a microadenoma, with no compression of the optic chiasma or involvement of the cavernous sinuses.

The patient was started on a small dose of Bromocriptine, half a tablet of 2.5 mg once daily and within a few weeks, the galactorrhea stopped, and her prolactin level returned to normal limits at 17 mg/L. The patient was maintained at this dose and continued to feel well.

Discussion

Estradiol causes the growth of the female breast by inducing the growth, division, and elongation of the tubular duct system and maturation of the nipples. To produce true alveolar development at the ends of the ducts, the synergistic action of progesterone is required with an optimal ratio of estrogen to progesterone of1:20 to 1:100. Once the anatomic development iscompleted, the continued action of estrogen and progesterone does not appear to be required for lactation.

The endocrine control of milk formation is complex requiring in addition to appropriate priming by estrogen and progesterone, specific lactogenic hormone and the action of glucocorticoids, insulin, thyroxine, and growth hormone.¹There are two lactogenic hormones. Human placental lactogen is secreted in large amounts by the placenta during the latter part of gestation and prepares the breast for milk production. It disappears from the fetal and maternal circulation shortly after termination of pregnancy. Pituitary prolactin is essential in the initiation and maintenance of lactation during the puerperium. Under ordinary basal conditions, inhibitory hypothalamic hormones, mostly dopamine, is delivered to the pituitary via the hypothalamic portal system. The anterior pituitary gland secretes prolactin at a low basal rate with secretion continually being suppressed by the hypothalamic prolactin inhibiting factor. Prolactin acts at the breast to promote milk secretion and at the ovaries to regulate the release of LH and FSH. Prolactin levels are cyclic and are highest during sleep. The normal level is 1.9-11.7 mg/L in men and 2.2-19.2 mg/L in women becoming lower in post menopausal age. Prolactin level increases during pregnancy and can be as high as 300 mg/L. It is also high during lactation.

Suckling, stress, dehydration, exercise, sexual intercourse, sleep, estrogen, thyrotropin releasing hormone, and serotonin increase the prolactin secretion rate from the pituitary gland. The precipitous drop in the levels of estrogen and progesterone after delivery in the presence of an elevated prolactin level facilitates the initiation of lactation. Ironically, high levels of estrogen and progesterone also inhibit lactation at the receptor sites in the breast tissue. Prolactin, which is also called somatomammotropin, is cleared from the serum, 75% via the liver and 25% via the kidney.

Elevated prolactin level in men or in women whose breasts have not been appropriately primed by estrogen and progesterone may not produce milk production. Hence, hyperprolactinemia is more common than galactorrhea. On the other hand, although enhanced prolactin secretion is necessary for the initiation of lactation, continued production of milk can be maintained in the presence of minimally or intermittently elevated prolactin levels so that the basal prolactin plasma level may not be elevated in patients with galactorrhea. An example is the so-called \"wet nurse phenomenon\" in which repeated stimulation of the nipples of women who have previously been pregnant can cause galactorrhea with minimal elevation of basal plasma prolactin levels. Basal prolactin levels fall following delivery but prolactin secretion is enhanced by stimulation of the breasts by the act of nursing through the suckling reflex, a phenomenon probably mediated by the reflex release of oxytocin. In the post gestational state, the normal woman is capable of forming about a liter of milk per day. Normal lactation can be suppressed by the administration of estrogen or diethylstilbestrol, which inhibit milk production, by direct effects on the breast. If a woman does not nurse or empty her breasts postpartum, lactation usually ceases on its own in one to two weeks.²

It is estimated that 20-25% of women experience galactorrhea at some time in their life. Galactorrhea is inappropriate production of milk that is persistent or worrisome to the patient and is caused by many conditions.³ Up to 5 % of neonates produce \"Witch\'s Milk\" for the first month of life. This milk production is considered physiologic resulting from the precipitous drop in maternal estrogen and progesterone levels after delivery. Galactorrhea may be considered physiologic in pregnancy. Pregnant women may lactate as early as the second trimester and some continue to produce milk for up to two years after cessation of breastfeeding. Fluctuation of hormone levels during puberty and menopause can also cause lactation. Nipple stimulation with sexual activity or repeated self-breast examinations can cause increased prolactin secretion and lactation.

Galactorrhea can also be caused by numerous medications and disease conditions including pituitary adenomas, hypothyroidism, systemic diseases, hypothalamic conditions, neurologic disorders, chest wall irritation, and neoplastic processes. Sometimes, galactorrhea is idiopathic when no specific cause can be identified. Patients may have elevated or normal prolactin levels. The mechanism of milk production may be an increased prolactin release in response to stimuli, with a normal basal prolactin production rate. Pituitary tumors may subsequently become apparent, especially in patients with high prolactin levels and persistent galactorrhea. In four published series totaling 500 cases, a pituitary tumor was identified in about 20% of the patients. Other known causes could be identified in another 25% and no cause could be identified in over 50% of the patients.⁴

Due to the episodic nature of prolactin secretion, if hyperprolactinemia is suspected but a blood test returns normal, it is best to repeat it. Excluding pregnancy, serum prolactin levels in excess of 300 mg/L are almost always the result of a prolactinoma. Hyperprolactinemia from causes other than prolactin-omas is usually mild and rarely exceeds 150-200mg/L. The degree of hyperprolactinemia tends to correlate with tumor size but not in all cases.⁵ Macroadenomas (prolactinomas greater than 10 mm in diameter) can be associated with extremely high levels, more than 1000 mg/L. Microadenomas (prolactinomas less than 10 mm in diameter) produce less impressive elevations. Three types of pituitary tumors may be associated with hyperprolactinemic galactorrhea: pure prolactin secreting tumors, mixed tumors which secrete prolactin and growth hormone, and null cell adenomas which interfere with the delivery of the hypothalamic inhibitory factors to the pituitary.

Prolactin can also be secreted by non-pituitary malignant tumors such as bronchogenic carcinoma, renal adenocarcinoma, Hodgkin\'s lymphomas, and T cell lymphomas. Hydatiform moles and choriocarcinomas may secrete placental lactogens.

Certain drugs and herbs can cause galactor-rhea.(Table 1)^6-10 Most drugs act by diminishing the normal hypothalamic inhibition of prolactin release.

The evaluation of galactorrhea needs a complete and thorough history followed by a physical examination and in certain cases, lab and imaging studies. The

Treatments

Therapy should be initiated when there is hypogonadism or reproductive dysfunction, especially when osteoporosis is already present. Simply providing estrogen therapy for hyperprolactinemic women to maintain bone mass is unsatisfactory and may increase the size of the tumor. Dopamine agonists are the mainstay of therapy. Many women are diagnosed with having prolactinomas during infertility evaluations. Restoration of infertility can be attempted with dopamine agonists. The pituitary of a normal woman will increase in size by about 70% during pregnancy because of the increased levels of estrogen in pregnancy. It is estimated that 5% of women with microadenoma and 25% of women with macroadenoma run the risk of developing symptoms due to increased size of tumor with pregnancy. While bromocriptine is not apparently teratogenic, it is recommended that therapy be discontinued at the first missed menses. If a mass effect develops during pregnancy, bromocriptine or surgery for the tumor can be considered.

Dopamine agonists such as bromocriptine and pergolide may be difficult to tolerate. The main side effects are nausea, constipation, and dizziness with orthostasis. It is best to start with a low nightly dose with food and slowly titrate up to three times a day as necessary. Cabergoline as well as bromocriptine activate the lactotroph D2 receptor sites and similar to dopamine, inhibit the synthesis of prolactin. Side effects are experienced less often with cabergoline. Cabergoline is the agent of choice in patients not wishing to conceive.¹⁵ Its long half-life, twice weekly dosing and tolerability improve patient compliance. Cabergoline is also effective in reducing prolactin levels in some tumors that are resistant to bromocriptine.

Microadenomas typically respond very well with normalization of prolactin levels in about 90% of cases, resolution of infertility in about 80%, and a decrease in tumor size in 70%. Remission may occur in about 20% of these patients after 1 to 2 years of therapy.

In macroadenomas, about two-thirds of patients will have reduction of prolactin levels to normal, half will have a reduction in tumor size of greater than 50%, and 90% will have some decrease in tumor size. The size reduction is often rapid and may begin to occur within days to weeks and frequently continues for up to six months. Higher doses are needed and should not be discontinued as the tumor may rapidly increase in size.

Surgery should be reserved for patients with rapid visual loss or poor response to dopaminergic agents or for those who cannot tolerate the dopaminergic agents. Transsphenoidal resection has an initial cure rate of up to 80% but with 50% recurrence. Morbidity includes hypopituitarism, diabetes insipidus, sinusitis, meningitis, and CSF rhinorrhea. Repeat surgery for recurrent disease has a significantly higher risk of complications.

Radiation therapy may be considered although it is usually reserved as a secondary line of therapy, as it may cause permanent hypopituitarism.