Evaluation and Management of Galactorrhea WENYU HUANG, MD, and MARK E. MOLITCH, MD, Northwestern University Feinberg School of Medicine, Chicago, Illinois Galactorrhea is commonly caused by hyperprolactinemia, especially when it is associated with amenorrhea. Hyperprolactinemia is most often induced by medication or associated with pituitary adenomas or other sellar or suprasellar lesions. Less common causes of galac- torrhea include hypothyroidism, renal insufficiency, pregnancy, and nipple stimulation. After pathologic nipple discharge is ruled out, patients with galactorrhea should be evaluated by measurement of their prolactin level. Those with hyperprolactinemia should have pregnancy ruled out, and thyroid and renal function assessed. Brain magnetic resonance imaging should be performed if no other cause of hyperprolactinemia is found. Patients with prolactinomas are usually treated with dopamine agonists (bromocriptine or cabergoline); surgery or radia- tion therapy is rarely required. Medications causing hyperprolactinemia should be discon- tinued or replaced with a medication from a similar class with lower potential for causing hyperprolactinemia. Normoprolactinemic patients with idiopathic, nonbothersome galactor- rhea can be reassured and do not need treatment; however, those with bothersome galactor- rhea usually respond to a short course of a low-dose dopamine agonist. (Am Fam Physician. 2012;85(11):1073-1080. Copyright © 2012 American Academy of Family Physicians.) ▲ Patient information: alactorrhea is nonlactational The pituitary lactotroph and PRL secre- A handout on galactor- milk production, which is usu- tion are also directly stimulated by estrogen,6 rhea, written by the ally defined as milk production which explains why pregnant women have authors of this article, is 7 available at http://www. one year after pregnancy and elevated PRL levels. Following delivery, PRL aafp.org/afp/2012/0601/ G cessation of breastfeeding. It can also occur increases with each suckling episode, stimu- p1073-s1.html. Access to in nulliparous and postmenopausal women, lating milk production. Over the next several the handout is free and and even in men.1 The incidence is variable, weeks, as breastfeeding gradually shifts from unrestricted. Let us know what you think about AFP but it can occur in up to 90 percent of women being on demand to a schedule, the increases putting handouts online with hyperprolactinemia.2 The marked vari- in PRL levels become less. By two to three only; e-mail the editors at ability is likely a result of the difference in months, PRL levels no longer increase with [email protected]. how the milk is expressed and how galactor- each suckling episode, but milk production rhea is defined. continues. Following cessation of breast- Before evaluation of galactorrhea, it is feeding, milk production rapidly decreases important to understand the mechanism so that it is usually gone after a month. underlying breast development and lactation. Breast development is affected by a number Causes of factors, including estrogen, progesterone, When galactorrhea is accompanied by and prolactin (PRL) levels. PRL is essential amenorrhea, it is usually caused by hyper- for morphologic breast development and lac- prolactinemia. However, when a patient has tation, which includes synthesis of milk and normal ovulatory menses and galactorrhea, maintenance of milk production.3 PRL levels are usually normal.3 Table 1 lists PRL is synthesized and secreted from the causes of galactorrhea. lactotrophs in the anterior pituitary gland. Hypothalamic dopamine inhibits PRL secre- PHYSIOLOGIC tion.4 There are several possible hypotha- Excessive nipple manipulation, including lamic releasing factors for PRL. Vasoactive during sex or suckling, can cause hyperpro- intestinal polypeptide stimulates PRL syn- lactinemia and galactorrhea.8,9 In the neo- thesis. Thyrotropin-releasing hormone can natal period, the high level of estrogen from increase PRL secretion in the short term, but the mother can cause transient galactorrhea plays only a minor role overall4,5 (Figure 1). in the newborn, called witch’s milk.10,11 Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright © 2012 American Academy of Family Physicians. For the private, noncommer- June 1, 2012cial use ◆ ofVolume one individual 85, Number user of the 11 Web site. All other rights reserved.www.aafp.org/afp Contact [email protected] for copyright questionsAmerican and/or Family permission Physician requests. 1073 Galactorrhea SORT: KEY RECOMMENDATIONS FOR PRACTICE Evidence Clinical recommendation rating References If a cause for hyperprolactinemia cannot be found by history, examination, and C 11, 31, 32 routine laboratory testing, an intracranial lesion might be the cause and brain magnetic resonance imaging with specific pituitary cuts and intravenous contrast media should be performed. In patients with normoprolactinemic galactorrhea, no further evaluation C 33 (i.e., additional hormone testing and magnetic resonance imaging) is needed. Treatment of hyperprolactinemia should be targeted primarily to correct the cause (e.g., C 32 treatment of hypothyroidism, replacement or discontinuation of offending medications). Patients with symptomatic prolactinomas should be treated with dopamine agonists, with C 15, 16, 32, 33 cabergoline preferred over bromocriptine. Treatment is not recommended for patients with asymptomatic microprolactinoma. C 15, 16, 32, 33 A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml. During pregnancy, especially during the Levels Mechanisms third trimester, women can have galactor- Hypothalamus Hypothyroidism rhea with PRL levels up to 200 mcg per L (8,695.60 pmol per L).10 Other causes of transient hyperprolactinemia are vigorous exercise and physical stress.12 TRH VIP Dopamine Antipsychotic drugs Some antidepressants DISORDERS INVOLVING THE HYPOTHALAMUS Signals from spinal cord OR PITUITARY STALK Suprasellar or sellar lesions extending dor- sally to involve the pituitary stalk can lead to hyperprolactinemia and galactorrhea. Hypophyseal This is called the “stalk effect.” Such lesions portal system Suprasellar and cause impairment of dopamine secretion Anterior infundibular lesions pituitary from the hypothalamus or its transport from the hypothalamus to the pituitary gland.13 Prolactinoma These lesions include large nonfunction- Some growth hormone– ing pituitary adenomas, germ cell tumors, Prolactin secreting adenomas craniopharyngiomas, Rathke’s cleft cysts, meningiomas, neural sarcoidosis, and Lang- Estrogen erhans cell histiocytosis. Generally, PRL levels are rarely higher than 100 mcg per L (4,347.80 pmol per L) with these conditions.14 Systemic Renal Renal insufficiency/ PITUITARY DISORDERS circulation clearance failure Pituitary adenomas are the most common ILLUSTRATION DAVID BY KLEMM cause of hyperprolactinemia, which results Figure 1. Regulation of prolactin level under physiologic and pathologic from either direct production by the ade- conditions. Arrows indicate stimulation, whereas bars depict inhibition. noma (prolactinoma) or the stalk effect. The regulation of serum prolactin occurs at different levels, which is illustrated on the left. The right side lists the common causes of hyper- Prolactinomas are the most common pitu- prolactinemia and relevant mechanisms. (TRH = thyrotropin-releasing itary adenomas and are classified into two hormone; VIP = vasoactive intestinal polypeptide.) types based on size: microadenomas (less 1074 American Family Physician www.aafp.org/afp Volume 85, Number 11 ◆ June 1, 2012 Galactorrhea which saturates the detecting antibody used Table 1. Causes of Galactorrhea in the PRL assay, thus resulting in a falsely low reported value.17 Hyperprolactinemic galactorrhea About 20 to 50 percent of the pituitary Physiologic adenomas in patients with acromegaly also Nipple or breast manipulation secrete PRL.18 In addition, growth hormone Pregnancy has a lactogenic effect, which explains why Pathologic some patients with acromegaly have galac- Hypothalamic or infundibular lesions torrhea without hyperprolactinemia. Tumors THYROID DISORDERS Craniopharyngioma Germinoma Hypothyroidism has been associated with Meningioma hyperprolactinemia and galactorrhea,3 likely Infiltrative disorders because of elevated thyrotropin-releasing Histiocytosis hormone levels resulting from less negative Sarcoidosis feedback from the thyroid hormone. This Others in turn stimulates PRL secretion directly by Rathke’s cleft cysts activating thyrotropin-releasing hormone Pituitary lesions receptors in the lactotrophs4 or indirectly by Prolactinoma regulating hypothalamic dopamine release.19 Acromegaly RENAL INSUFFICIENCY Others Lesions involving chest wall Hyperprolactinemia has also occurred in Breast surgery patients with renal insufficiency.20 PRL levels Burns up to 1,000 mcg per L (43,478.00 pmol per L) Herpes zoster have been reported. The mechanism is likely Spinal cord injury a result of decreased clearance of PRL, as well Trauma as continued secretion. After renal transplan- Systemic disease tation, hyperprolactinemia and galactorrhea Hypothyroidism can usually be corrected or significantly Renal insufficiency improved, sometimes within days.21 Medication-induced