Evaluation and Treatment of Galactorrhea MED III Lecture Dr.

Elie Anastasiades OBS/GYN

The true incidence of galactorrhea is unknown, but it is estimated that 20 to 25 percent of women experience this problem at some time in their life. z Although rare, galactorrhea can also occur in males
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Before lactation, the female breast is primed by estrogen, progesterone, growth hormone, insulin, thyroid hormone and glucocorticoids. These hormones aid in the growth of the ductal system and lobules, and in the development of secretory characteristics of the alveoli. Ironically, high levels of estrogen and progesterone also inhibit lactation at receptor sites in the breast tissue. The precipitous drop in the levels of these hormones after delivery, in the presence of an elevated prolactin level, facilitates lactation. Prolactin is normally secreted by the anterior pituitary gland at a low basal rate, with secretion continuously suppressed by prolactin inhibiting factor

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Prolactin levels cycle and are highest during sleep. Levels in normal nonpregnant women range from 1 to 20 ng per mL (1 to 20 g per L), depending on the laboratory, and may increase to as high as 300 ng per mL (300 g per L) during pregnancy. Suckling, stress, dehydration, exercise, sexual intercourse and sleep increase the basal secretion rate from the pituitary gland, as do estrogen, thyrotropin-releasing hormone and possibly serotonin.

Lactation

causes
z z z z

Hyperprolactinemia can be caused by several factors such as: Tumors on the pituitary gland (called prolactinomas) Thyroid gland disorder Surgical scars on the chest wall and other chest wall irritations (such as shingles) Medications including some tranquilizers, high blood pressure medications, and antinausea drugs Oral contraceptives and recreational drugs (such as marijuana)

Physiologic conditions
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Causes of Galactorrhea
1. Physiologic conditions (14 percent) 2. Neoplastic processes (18 percent) 3. Hypothalamic-pituitary disorders (<10 percent) 4. Systemic diseases (<10 percent) 5. Medications and herbs (20 percent)* 6. Chest wall irritation (<10 percent) 7. Idiopathic (35 percent)

(14 percent)
Pregnancy and postpartum state z Breast stimulation z "Witch's milk" in neonates
z

Neoplastic processes (18 percent)

Hypothalamic-pituitary disorders (<10 percent)

Pituitary adenoma (prolactinoma) Bronchogenic carcinoma Renal adenocarcinoma Lymphoma Craniopharyngioma Hydatidiform mole Hypernephroma Mixed growth hormone-secreting and prolactin-secreting tumors Null-cell adenoma

Craniopharyngioma and other tumors Infiltrative conditions

Pituitary-stalk resection z Multiple sclerosis z Empty-sella syndrome

Systemic diseases (<10 percent

Chest wall irritation (<10 percent

Irritating clothes or ill-fitting brassieres Herpes zoster Atopic dermatitis Burns Breast surgery Spinal cord injury or surgery Spinal cord tumor Esophagitis Esophageal reflux

Idiopathic (35 percent

Neoplastic Processes
Although galactorrhea is not associated with breast cancer, it can be caused by neoplastic processes in the brain and pituitary gland. Fortunately, most of these tumors are benign. Approximately 20 percent of women with galactorrhea have radiologically evident pituitary tumors, and the prevalence increases to 34 percent in women who also have amenorrhea. The most common tumor resulting in hyperprolactinemia is the pituitary prolactinoma, a benign growth of the prolactin-secreting cells of the anterior pituitary gland. Autopsy reports indicate that prolactinomas are present in 10 to 30 percent of the population.

z z

Hyperprolactinemia Euprolactinemia

z z

Systemic Diseases
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. must also be considered in the differential diagnosis of galactorrhea. The most common is hypothyroidism. Low levels of thyroid hormone result in increased levels of the thyrotropin-releasing hormone, which increases prolactin secretion. Galactorrhea and symptoms of hypothyroidism abate with thyroid hormone replacement therapy. Chronic renal failure may cause galactorrhea as a result of decreased clearance of prolactin by the kidneys. Hypersecretion of cortisol (Cushing's disease) or growth hormone (acromegaly) may also have associated hyperprolactinemia
z

Many antipsychotic medications and metoclopramide (Reglan) have lactogenic activity because of their antidopaminergic effects serotonin may have a role in regulating prolactin secretion. Tricyclic antidepressants, the monoamine oxidase inhibitor moclobemide (and the anxiolytic buspirone (BuSpar) are also known to cause galactorrhea. At least four antihypertensive agents have been reported to The histamine H2-receptor blockers Estrogen and progesterone, found in oral contraceptive formulations and the medroxyprogesterone contraceptive injection (Depo-Provera), may cause lactation. Possible mechanisms include direct actions on the breast tissue or effects on gonadotropins.

z z

Medications and Herbs Associated with Galactorrhea

occurs more often after discontinuation of oral contraceptive pills than during prolonged use (similar to the hormone withdrawal and lactation that can occur in the postpartum period).

z z

Antidepressants and anxiolytics z Selective serotonin reuptake inhibitors z Tricyclic antidepressants Antihypertensives z Atenolol (Tenormin) z Methyldopa (Aldomet) z Reserpine (Serpasil) z Verapamil (Calan) Antipsychotics Histamine H2-receptor blockers z Conjugated estrogen and medroxyprogesterone (Premphase, Prempro) z Medroxyprogesterone contraceptive injections (DepoProvera) z Oral contraceptive formulations Phenothiazines

Other drugs
z z z z z z z z z z z

Idiopathic Galactorrhea
z

Amphetamines ,Anesthetics ,Arginine Cannabis Cisapride (Propulsid) Cyclobenzaprine (Flexeril) Danazol (Danocrine) Dihydroergotamine (DHE 45) Domperidone (Motilium; Octreotide (Sandostatin) Opiates Rimantadine (Flumadine) Sumatriptan (Imitrex) Valproic acid (Depakene)

is a diagnosis of exclusion, and patients may have normal or elevated levels of prolactin. In such situations, the mechanism of milk production may be an increased prolactin release in response to stimuli, with a normal basal prolactin rate.

The history should include

Evaluation of Galactorrhea

1. 2. 3.

the duration of galactorrhea, previous pregnancies, and other symptoms of hyperprolactinemia, such as infertility, decreased libido, acne, hirsutism and menstrual irregularity. The patient should be asked about symptoms of an intracranial mass, such as visual-field defects, cranial nerve palsy and headache. It is also important to inquire about symptoms of systemic diseases, including hypothyroidism and Cushing's disease . An accurate list of all medications, including over-the-counter and illicit substances, herbs and other supplements, is essential.

4.

5. 6. 7.

Physical Examination
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Laboratory Tests
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evaluation of the patient's visual fields, thyroid gland, breasts and skin. In galactorrhea, microscopy reveals numerous fat globules and little cellular material. If the physician is not certain that the discharge is milk, a sample may be sent to a laboratory for special staining and evaluation, including cytology.

a serum pregnancy test, a prolactin level, renal function tests and a thyroid-stimulating hormone level. Because prolactin levels are influenced by stress and breast stimulation, blood should not be drawn immediately after a breast examination. Rather, it should be drawn at least one hour after the examination and when the patient is relaxed. If the initial prolactin level is borderline, the level should be repeated one or two times because of the great fluctuation in prolactin levels throughout the day. A level greater than 200 ng per mL (200 g per L) is almost always associated with a prolactinoma or other prolactin-secreting tumor. Serum cortisol, growth hormone and insulin-like growth factor levels should be obtained if the patient has signs or symptoms of Cushing's disease (cushingoid features) or growth hormone excess (acromegalic features).

Imaging Studies
z z z z z

magnetic resonance imaging (MRI) of the brain is indicated to detect a pituitary tumor or other intracranial lesion symptoms suggestive of an intracranial mass, galactorrhea with amenorrhea, or an elevated prolactin level (greater than 20 ng per mL),. If the patient has normal menses and a normal prolactin level, the risk for pituitary adenoma is low, and imaging is not necessary. However, if a patient has galactorrhea associated with amenorrhea or oligomenorrhea, even with a normal prolactin level, the risk of a pituitary adenoma is still significant, and an imaging study of the gland is warranted.

Given the lack of association between galactorrhea and breast cancer, mammography is not necessary unless other findings on the physical examination are suggestive of breast pathology. Nipple discharge that is not milky should be evaluated because it may be caused by intraductal papilloma, papillomatosis, mammary duct ectasia, fibrocystic breasts or carcinoma

Hyperprolactinemia, possibly through its effect on estrogen, increases the risk of developing osteoporosis. z This risk can be reduced with medical therapy using dopamine agonists, even in the absence of a tumor
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Treatment
The goals of galactorrhea treatment include 1. decreasing or eliminating the patient's symptoms 2. curing any identified underlying cause 3. preventing bone loss 4. relieving the patient's anxiety and fears, and, 5. when desired, maintaining the patient's fertility and ability to lactate.
z

Normal Prolactin
Patients with idiopathic or physiologic galactorrhea and normal prolactin levels should be reassured. All patients with galactorrhea should be advised to avoid excessive breast stimulation, including repeated selfexaminations or excessive nipple manipulation during sexual activity. If galactorrhea is caused by a medication, the agent should be discontinued if possible.

High Prolactin Level With Normal MRI Studies

Prolactinoma
z

The prevention of osteoporosis is a concern in any patient with hyperprolactinemia. This risk can be reduced with medical therapy using dopamine agonists (e.g., bromocriptine [Parlodel], cabergoline [Dostinex]), even in the absence of a tumor. Medical therapy can also be effective in restoring fertility in the patient with galactorrhea, regardless of the prolactin levels. A prolactin level should be obtained every three to six months, and further studies should be performed if the level continues to rise.

The treatment of a prolactinoma depends on its size and the presence or absence of symptoms indicative of increased intracranial pressure or destruction of nearby structures. If the patient has a macroadenoma or symptoms such as headache or changes in vision= medical or surgical treatment is indicated. If the patient has no symptoms of an intracranial mass and the tumor is less than 1 cm in size (microadenoma), treatment options include close =observation or medical therapy. The prolactin level should be measured every three to six months, and imaging studies should be performed every two to three years (sooner if the prolactin levels rise).

Medical treatments for prolactinomas

Pituitary Adenomas and Pregnancy

These agents activate the lactotroph D2-receptor sites and, similar to dopamine, inhibit the synthesis of prolactin. normalize prolactin levels, rapidly shrink tumors restore vision, menses and fertility Side effects include nausea, vomiting, postural hypotension, headache and nasal congestion, although these are experienced less often with cabergoline. The dosage of either agent is gradually increased and titrated to the patient's symptoms and prolactin level.

1. 2. 3. z

1 to 5 %of microadenomas and 23 %of macroadenomas increase in size during pregnancy Because of its more extensive safety record, bromocriptine is the drug of choice in women with pituitary adenomas who wish to conceive . Although no adverse fetal effects have been reported, the drug should be discontinued once pregnancy is suspected, unless there is evidence of a very large adenoma or an enlarging adenoma. Prepregnancy surgical debulking of a large macroadenoma, followed by bromocriptine therapy, is another treatment option.

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