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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 , renal insufficiency, , and stimulation. After pathologic is ruled out, patients with galactorrhea should be evaluated by measurement of their level. Those with hyperprolactinemia should have pregnancy ruled out, and and renal function assessed. Brain magnetic resonance imaging should be performed if no other cause of hyperprolactinemia is found. Patients with are usually treated with dopamine agonists (bromocriptine or ); 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- production, which is usu- tion are also directly stimulated by ,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 - 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 . 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 . 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 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

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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 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 These lesions include large nonfunction- Some growth hormone– ing pituitary adenomas, germ cell tumors, Prolactin secreting adenomas craniopharyngiomas, Rathke’s cleft cysts, meningiomas, neural , 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

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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 hyperprolactinemia MEDICATION-INDUCED Idiopathic hyperprolactinemia Normoprolactinemic galactorrhea Hyperprolactinemia and galactorrhea are often caused by medications,22-25 most com- NOTE: Causes are listed in order of anatomic relevance, monly , gastrointestinal pro- importance, and prevalence. motility agents, and verapamil (Table 2). Antipsychotics and gastrointestinal promo- tility agents block the dopamine receptor than 1 cm) and macroadenomas (1 cm or on the pituitary lactotrophs, decreasing the greater).15,16 Circulating PRL levels usually normal inhibition of PRL release and leading parallel tumor size, such that microadeno- to hyperprolactinemia. mas rarely result in PRL levels higher than 200 mcg per L and macroadenomas usually HYPERESTROGENEMIA result in PRL levels higher than 200 mcg per Estrogen stimulates lactotroph proliferation L. On the other hand, if a very large mac- and PRL secretion directly 4 and indirectly roadenoma (greater than 3 cm) is found in a by inhibiting the hypothalamic dopamine patient with a normal or only mildly elevated neurons.6 An ovarian hyperstimulation PRL level, the “hook effect” must be sus- syndrome due to a follicle-stimulating hor- pected. The hook effect is an assay artifact mone–secreting tumor has been associated caused by an extremely high level of PRL, with hyperprolactinemia and galactorrhea,

June 1, 2012 ◆ Volume 85, Number 11 www.aafp.org/afp American Family Physician 1075 Galactorrhea Table 2. Medication Classes and Substances That Can Cause Hyperprolactinemia

Antipsychotics PRL level will remain stable.29 The PRL levels Gastrointestinal motility medications: are usually less than 100 mcg per L.30 (Reglan) Antidepressants: rare Evaluation Antihypertensive medications (not a class- Galactorrhea should be distinguished specific effect): verapamil, , from pathologic nipple discharge, which reserpine can involve breast tumors. Galactorrhea is Others: opioids, cocaine usually bilateral, multiductal, and milky, 8 NOTE: The classes of medications are listed in order of but can be yellow, green, or brown. Patients prevalence based on the authors’ experience. with nipple discharge that comes from a sin- gle duct, is bloody or serosanguineous, or is associated with a palpable or radiologically both of which resolved after tumor removal, evident will need further evalu- indicating that the very high estrogen level ation for breast tumors.9 If the diagnosis of contributes to the previously mentioned milk production is in doubt, a Sudan IV clinical features.26 Clinically, the effects of staining for fat droplets in the nipple dis- estrogen are most evident during pregnancy, charge can confirm the diagnosis (Figure 2). when the high estrogen levels cause lacto- troph hyperplasia, hyperprolactinemia, and HISTORY AND PHYSICAL EXAMINATION even stimulation of growth of a preexisting Taking a history, especially a medication prolactinoma.7,27 Despite the well-known history, is important. A pregnancy history stimulatory effect of estrogen on lacto- should be taken before further workup to trophs, the effect of oral contraceptives and rule out pregnancy-related galactorrhea. The hormone therapy, especially low-dose estro- patient should also be evaluated for symp- gen (30 mcg or less of ethinyl estradiol), on toms related to hyperprolactinemia, such as hyperprolactinemia and prolactinoma is not amenorrhea or oligomenorrhea, low libido, well established. erectile dysfunction, , gynecomas- tia, or fractures, and symptoms related to LESIONS INVOLVING THE CHEST WALL mass effect of a , such as Various chest wall irritations have been headache or vision changes. reported to cause hyperprolactinemia and The physical examination can confirm galactorrhea, such as mammoplasty, burns, a diagnosis of galactorrhea. The patient herpes zoster, trauma, and spinal cord should be examined sitting up and leaning injury.12,28 The signal from the chest wall is forward. The areolae should be gently mas- postulated to be first transmitted to the spi- saged toward the nipple in all four quad- nal cord, then further relayed to the hypo- rants. The physician should keep in mind thalamus to reduce the dopamine signal, that breast and nipple manipulation can thereby inducing hyperprolactinemia.28 transiently increase PRL secretion, so PRL levels should not be checked shortly after a IDIOPATHIC HYPERPROLACTINEMIA breast examination. Occasionally, no apparent cause of hyper- prolactinemia is identified; this is termed LABORATORY EVALUATION AND IMAGING idiopathic. With long-term follow-up, some Vigorous exercise and nipple stimulation women with idiopathic hyperprolactinemia should be avoided for at least 30 minutes are found to have micropro- before checking PRL levels.10 An elevated lactinomas that were too small PRL level should be confirmed at least once. Prolactin levels are usually to be detected originally.20 In If the hook effect is suspected, such as in a normal when a patient has one-third of patients with idio- patient with a very large pituitary adenoma galactorrhea and normal pathic hyperprolactinemia, the (greater than 3 cm) and a normal or only ovulatory menses. elevated PRL level will resolve, mildly elevated PRL level, a 1:100 dilu- and in one-half of patients, the tion of the original sample should

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be obtained to confirm the PRL level.17,29 In magnetic resonance imaging (MRI) with addition, thyroid-stimulating hormone and specific pituitary cuts and intravenous con- creatinine levels should be obtained to rule trast media should be performed.11,31,32 Char- out secondary causes of hyperprolactinemia. acteristics of the lesion and mass effects on If is suspected, reproductive adjacent structures, such as the optic chiasm, such as estrogen or testosterone, stalk, and hypothalamus, should be investi- luteinizing hormone, and follicle-stimulat- gated at the same time. Visual field testing ing hormone should also be checked. should also be performed in patients with If no cause for the hyperprolactinemia is vision problems or whose adenoma is found found by history, examination, and the pre- to abut the optic chiasm on MRI. Computed viously mentioned routine testing, an intra- tomography can be performed if MRI is cranial lesion might be the cause and brain not available, but the resolution is inferior.

Evaluation of Galactorrhea

Nipple discharge

Rule out breast pathology (e.g., by history, physical examination, mammography)

Galactorrhea

Elevated prolactin level?

No Yes

No further evaluation Check thyroid-stimulating Treat with dopamine agonist only hormone, creatinine, human if galactorrhea is bothersome chorionic gonadotropin levels Ask about medications and recent breast/nipple manipulation

Elevated thyroid- Elevated human chorionic Elevated creatinine level Medication related No other causes identified stimulating gonadotropin level hormone level Renal insufficiency Discontinue or replace Magnetic resonance imaging Pregnancy causative medication of the pituitary gland Hypothyroidism

Thyroid hormone therapy Sellar or suprasellar lesion Normal

Dopamine agonist Idiopathic hyper- or surgery (see text) prolactinemia

Monitor patient or initiate dopamine agonist

Figure 2. Algorithm for evaluation of galactorrhea.

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In patients with macroadenomas, other pitu- no potential to cause hyperprolactinemia itary hormones should also be checked to would be the most appropriate manage- evaluate for hypopituitarism. A bone density ment option.24,34 For patients with symp- scan should be performed in patients with tomatic prolactinomas, medical therapy is hyperprolactinemia and hypogonadism who the treatment of choice.15,16,32,33 Dopamine are at risk of osteoporosis or fracture. agonists have been shown to be effective in If the patient’s PRL level is not elevated, normalizing PRL, restoring reproductive then no further evaluation (i.e., additional hormones, shrinking adenomas, and hormone testing and MRI) is needed.33 increasing bone density via normalization of estrogen/testosterone levels.33 Treat- Management ment is not recommended for patients with After breast pathology is excluded, treatment asymptomatic microprolactinoma.15,16,32,33 is usually indicated for patients with bother- Bromocriptine and cabergoline are avail- some galactorrhea, hypogonadotropic hypo- able in the United States. Compared with gonadism, or a concerning causative lesion. bromocriptine, cabergoline is more effective Otherwise, it is reasonable to reassure the and better tolerated (Table 3).33 Both drugs patient and monitor his or her condition.10,12 are safe for the facilitation of ovulation and Because most galactorrhea is associated pregnancy, although the safety database for with hyperprolactinemia, the treatment can bromocriptine is about 10-fold larger.35 Sur- be classified based on the underlying causes gery or radiation therapy is rarely needed for or effects of hyperprolactinemia.13,32 prolactinomas.16 Patients with hypothalamic or pituitary lesions other than prolactino- TREATMENT OF THE CAUSES OF mas should be referred to a neurosurgeon, HYPERPROLACTINEMIA especially if the lesions also present with For medication-induced hyperprolactin­ mass effects.13 emia, ideally the causitive medication should be discontinued. If the underlying TREATMENT OF HYPERPROLACTINEMIA OR ITS EFFECTS condition warrants continuation of such medications, switching to another medi- Sometimes it is not clinically appropriate or cation in a similar class that has lower or safe to treat the cause of hyperprolactinemia

Table 3. Medications to Treat Hyperprolactinemia and Prolactinoma

Dopamine Common Cost of generic agonist dosages Common adverse effects Comments (brand)*

Bromocriptine 2.5 to 15 mg Both medications have similar Compared with bromocriptine, the $136 ($206) daily adverse effects, including adverse effects of cabergoline are based on 5 mg gastrointestinal (nausea, usually less frequent, of shorter daily Cabergoline 0.25 to 1 mg vomiting), cardiovascular duration, and less severe $286 (NA) based twice weekly (postural hypotension, Bromocriptine is preferred by on 0.5 mg or dizziness), and neurologic some women who are trying to twice weekly (drowsiness, headache); conceive because of the larger 0.5 to 2 mg cardiac valvulopathy reported once weekly safety database; it typically should with high dose of cabergoline be discontinued once pregnancy is (more than 4 mg daily) confirmed

NA = not available. *—Estimated retail price of one month’s treatment based on information obtained at http://www.drugstore.com (accessed October 20, 2011). Generic price listed first, brand price listed in parentheses. Information from reference 33.

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(e.g., a patient with a nonresectable brain Data Sources: We searched relevant biomedical sources tumor). Thus, treatment should focus on including PubMed, Cochrane database, Essential Evi- dence Plus, and Guidelines.gov using the keywords galac- correcting the hyperprolactinemia with a torrhea, hyperprolactinemia, prolactinoma, prolactin, dopamine agonist, or the resulting hypo- lactotroph, dopamine agonist, pituitary, estrogen, and gonadism by simply replacing estrogen or medication-induced. Search date: December 2011. testosterone in patients who do not have mac- roprolactinomas. Use of dopamine agonists The Authors is sometimes indicated in patients with WENYU HUANG, MD, is an endocrinology fellow at North- antipsychotic-induced hyperprolactinemia; western University Feinberg School of Medicine, Chicago, Ill. however, it is not always successful.36 In MARK E. MOLITCH, MD, is the Martha Leland Sherwin addition, such use carries a very small risk Professor of Endocrinology at Northwestern University of exacerbation of the underlying psychiatric Feinberg School of Medicine. disorder because of activation of the dopa- Address correspondence to Wenyu Huang, MD, North- mine receptors.37 western University, 645 N. Michigan Ave., Ste. 530, Chi- If the major concern is decreased repro- cago, IL 60611 (e-mail: [email protected]. ductive hormones (e.g., estrogen), they can edu). Reprints are not available from the authors. be replaced. Estrogen replacement is consid- Author disclosure: No relevant financial affiliations to ered safe for the patient with a microadenoma disclose. or idiopathic hyperprolactinemia. However, its use should be individualized in patients REFERENCES with macroadenomas because estrogen has 1. Kleinberg DL. Endocrinology of mammary development, lactation and galactorrhea. In: DeGroot LJ, Jameson JL, the potential to increase tumor growth in eds. Endocrinology. 4th ed. London, United Kingdom: patients with macroadenomas, although this W.B. Saunders; 2000:2464-2475. is generally limited to the very high levels of 2. Colao A, Sarno AD, Cappabianca P, et al. Gender differ- estrogen found in pregnancy and not with ences in the prevalence, clinical features and response to cabergoline in hyperprolactinemia. Eur J Endocrinol. exogenous estrogen use. Because estrogen 2003;148(3):325-331. replacement does not correct the luteinizing 3. Molitch ME. Disorders of prolactin secretion. Endocrinol hormone and follicle-stimulating hormone Metab Clin North Am. 2001;30(3):585-610. deficiencies, women should be advised that 4. Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol such replacement will not restore ovulation. Rev. 2000;80 (4):1523-1631. Likewise, in men, replacement of testoster- 5. van den Pol AN. Excitatory neuromodulator reduces one may not help with spermatogenesis. If dopamine release, enhancing prolactin secretion. Neu- the patient has osteoporosis, a bisphospho- ron. 2010;65(2):147-149. 6. Morel GR, Carón RW, Cónsole GM, et al. Estrogen inhibits nate can be added for bone protection. tuberoinfundibular dopaminergic neurons but does not cause irreversible damage. Brain Res Bull. 2009;80(6): TREATMENT OF GALACTORRHEA WHEN 347-352. PRL LEVELS ARE NORMAL 7. Molitch ME. Pituitary disorders during pregnancy. Endo- crinol Metab Clin North Am. 2006;35(1):99-116, vi. If the galactorrhea is not associated with 8. Santen RJ, Mansel R. Benign breast disorders. N Engl breast tenderness and swelling, and is not J Med. 2005;353(3):275-285. particularly bothersome, the patient can be 9. Vaidyanathan L, Barnard K, Elnicki DM. Benign breast reassured. He or she should also be advised disease: when to treat, when to reassure, when to refer. Cleve Clin J Med. 2002;69(5):425-432. to not check for persistence of the galactor- 10. Leung AK, Pacaud D. Diagnosis and management of rhea, because repeated milking of the breast galactorrhea. Am Fam Physician. 2004;70(3):543-550. will stimulate PRL production and delay the 11. Casanueva FF, Molitch ME, Schlechte JA, et al. Guide- resolution of the galactorrhea. If the galac- lines of the Pituitary Society for the diagnosis and man- agement of prolactinomas. Clin Endocrinol (Oxf). 2006; torrhea is bothersome, treatment with a low- 65(2):265-273. dose dopamine agonist, such as 0.5 mg of 12. Peña KS, Rosenfeld JA. Evaluation and treatment of cabergoline once weekly, will generally cause galactorrhea. Am Fam Physician. 2001;63(9):1763-1770. the galactorrhea to resolve, usually within a 13. Melmed S, Kleinberg DL. Anterior pituitary. In: Kronen- berg H, Williams RH, eds. Williams Textbook of Endo- couple of months. The drug should then be crinology. 11th ed. Philadelphia, Pa.: Elsevier Saunders; tapered off. 2007:155-262.

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14. Karavitaki N, Thanabalasingham G, Shore HC, et al. Do 26. Cooper O, Geller JL, Melmed S. Ovarian hyperstimu- the limits of serum prolactin in disconnection hyper- lation syndrome caused by an FSH-secreting pituitary prolactinaemia need re-definition? A study of 226 adenoma. Nat Clin Pract Endocrinol Metab. 2008;4(4): patients with histologically verified non-functioning 234-238. pituitary macroadenoma. Clin Endocrinol (Oxf). 2006; 27. Christin-Maître S, Delemer B, Touraine P, Young J. Pro- 65(4):524-529. lactinoma and estrogens: pregnancy, contraception and 15. Schlechte JA. Clinical practice. Prolactinoma. N Engl hormonal replacement therapy. Ann Endocrinol (Paris). J Med. 2003;349(21):2035-2041. 2007;68(2-3):106-112. 16. Klibanski A. Clinical practice. Prolactinomas [published 28. Serri O, Chik CL, Ur E, Ezzat S. Diagnosis and man- correction appears in N Engl J Med. 2010;362(22): agement of hyperprolactinemia. CMAJ. 2003;169(6): 2142]. N Engl J Med. 2010;362(13):1219-1226. 575-581. 17. Barkan AL, Chandler WF. Giant pituitary prolactinoma 29. Chahal J, Schlechte J. Hyperprolactinemia. Pituitary. with falsely low serum prolactin: the pitfall of the “high- 2008;11(2):141-146. dose hook effect”: case report. Neurosurgery. 1998; 30. Berinder K, Stackenäs I, Akre O, Hirschberg AL, Hult- 42(4):913-916. ing AL. in 271 women: up to three 18. Katznelson L, Kleinberg D, Vance ML, et al. Hypogonad- decades of clinical follow-up. Clin Endocrinol (Oxf). ism in patients with acromegaly: data from the multi- 2005;63(4):450-455. centre acromegaly registry pilot study [published correc- 31. Mancini T, Casanueva FF, Giustina A. Hyperprolac- tion appears in Clin Endocrinol (Oxf). 2001;55(5):699]. tinemia and prolactinomas. Endocrinol Metab Clin Clin Endocrinol (Oxf). 2001;54(2):183-188. North Am. 2008;37(1):67-99, viii. 19. Lyons DJ, Horjales-Araujo E, Broberger C. Synchronized network oscillations in rat tuberoinfundibular dopa- 32. Melmed S, Casanueva FF, Hoffman AR, et al. Diagno- mine neurons: switch to tonic discharge by thyrotropin- sis and treatment of hyperprolactinemia: an Endocrine releasing hormone. Neuron. 2010;65(2):217-229. Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273-288. 20. Verhelst J, Abs R. Hyperprolactinemia: pathophysiology and management. Treat Endocrinol. 2003;2(1):23-32. 33. Gillam MP, Molitch ME, Lombardi G, Colao A. Advances 21. Saha MT, Saha HH, Niskanen LK, Salmela KT, Pasternack in the treatment of prolactinomas. Endocr Rev. 2006; AI. Time course of serum prolactin and sex hormones fol- 27(5):485-534. lowing successful renal transplantation. Nephron. 2002; 34. Kinon BJ, Ahl J, Liu-Seifert H, Maguire GA. Improve- 92(3):735-737. ment in hyperprolactinemia and reproductive comor- 22. Molitch ME. Drugs and prolactin. Pituitary. 2008;11(2): bidities in patients with schizophrenia switched from 209-218. conventional antipsychotics or to olanzap- ine. Psychoneuroendocrinology. 2006;31(5):577-588. 23. Coker F, Taylor D. Antidepressant-induced hyperpro- lactinaemia: incidence, mechanisms and management. 35. Molitch ME. Prolactinomas and pregnancy. Clin Endo- CNS Drugs. 2010;24(7):563-574. crinol (Oxf). 2010;73(2):147-148. 24. Molitch ME. Medication-induced hyperprolactinemia. 36. Cavallaro R, Cocchi F, Angelone SM, Lattuada E, Smer- Mayo Clin Proc. 2005;80(8):1050-1057. aldi E. Cabergoline treatment of risperidone-induced 25. Johnsen E, Kroken RA, Wentzel-Larsen T, Jørgensen hyperprolactinemia: a pilot study. J Clin Psychiatry. 2004; HA. Effectiveness of second-generation antipsychotics: 65(2):187-190. a naturalistic, randomized comparison of , 37. Smith S. Neuroleptic-associated hyperprolactinemia. Can , risperidone, and ziprasidone. BMC Psychia- it be treated with bromocriptine? J Reprod Med. 1992; try. 2010;10:26. 37(8):737-740.

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