Adolescent Health Care: A Practical Guide

Chapter 57

Galactorrhea

Sandra Loeb Salsberg

Norman P. Spack

Galactorrhea is the discharge of milk or a milk-like fluid from the breast in the absence of parturition or beyond 6 months postpartum in a nonbreast-feeding woman. It is usually bilateral, may occur intermittently or persistently, and may be spontaneous or expressed. Fluid that is yellow, green, purulent, serosanguineous, or bloody is suggestive of local breast disease and will not be included in this discussion.

Prolactin secretion is necessary for normal lactation. During pregnancy, prolactin concentrations rise and stimulate the mammary gland to produce colostrum. Elevated prolactin levels are a major cause of galactorrhea in women, but rarely cause galactorrhea in men. Male mammary tissue, unexposed to high levels of estrogen and progesterone, is less sensitive to the lactogenic effects of prolactin.

Regulation of Prolactin Secretion

Prolactin is secreted by the lactotrophs of the anterior pituitary under the neuroendocrine control of hypothalamic prolactin-releasing factors (PRFs) and prolactin-inhibiting factors (PIFs) (Fig. 57.1).

 

FIGURE 57.1 Schema of prolactin control. PIF, prolactin-inhibiting factors; PRF, prolactin-releasing factors; TRH, thyrotropin-releasing hormone.

  1. Dopamine is the predominant regulator of prolactin release. It traverses the hypothalamic-pituitary portal vasculature and binds to lactotrophs, where it inhibitsprolactin secretion.
  2. Transection or compression of the pituitary stalk increasesprolactin secretion by interfering with dopaminergic pathways.
  3. Prolactin secretion is increased by stress, suckling, sleep, and intercourse.

Differential Diagnosis

The most common etiologies of galactorrhea are medication-induced and prolactinomas.

  1. Associated with hyperprolactinemia
  2. Medications (Table 57.1)
  3. Hypothalamic and infundibular lesions (which inhibit dopamine release increase prolactin through hyperplasia of lactotrophs)
  • Space-occupying lesions (e.g., craniopharyngiomas, meningiomas) and infiltrative disorders (e.g., lymphocytic hypophysitis, sarcoidosis, Langerhans cell histiocytosis, and tuberculosis)
  • Damage to the infundibulum from surgery or head trauma
  1. Pituitary
  • Prolactinomas are benign anterior pituitary neoplasms that secrete prolactin through hyperplasia of lactotrophs
  • –Microprolactinomas are <10 mm in diameter
  • –Macroprolactinomas are >10 mm in diameter
  • Primary hypothyroidism: Thyrotropin-releasing hormone Thyrotropin-Releasing Hormone (TRH) stimulates lactotroph activity
  • Acromegaly: Lactotrophs and somatotrophs have common precursor cells. Prolactin can be directly secreted from a GH-secreting tumor
  • Cushing Disease: Prolactin can also be cosecreted along with adrenocorticotropic hormone (ACTH)
  • Empty Sella Syndrome: Retained lactotrophs have lost dopaminergic inhibition
  1. Idiopathic: 10% of these patients have a prolactinoma that is too small to be visualized on magnetic resonance imaging Magnetic Resonance Imaging (MRI)
  2. Extracranial

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  • Neurogenic: Stimulation of the spinal cord (directly or by intercostal nerves) inhibits release of dopamine
  • –Chest wall including Surgery, burns, Herpes zoster and Breast stimulation from suckling, self-manipulation, sexual activity, or nipple piercing.
  • –Spinal cord injury
  • Renal failure: Decreased clearance of prolactin
  • Cirrhosis: Decreased dopamine synthesis
  • Adrenal insufficiency: Lack of glucocorticoid increases prolactin gene transcription
  1. Associated with normal prolactin levels
  2. Women with an unexplained hypersensitivity to prolactin
  3. Acromegaly: growth hormone Growth Hormone (GH) is homologous to prolactin and is a potent lactogen

TABLE 57.1
Medications Causing Hyperprolactinemia

Antipsychotics

Antihypertensive Agents

Risperidone

Verapamil

Butyrophenones (haloperidol)

α-Methyldopa

Benzamines

Reserpine

Sulpiride

 

Thioxanthenes

Gastrointestinal Medications

Phenothiazines

Metoclopramide

 

Domperidone

Antidepressants

 

Tricyclic antidepressants

Others

Monoamine oxidase inhibitors

Opiates

Elective serotonin reuptake inhibitors

Estrogens

Diagnosis

Given that most of the etiologies of galactorrhea are mediated by elevations in prolactin, the work-up should start with a carefully drawn serum prolactin level.

  1. Prolactin is secreted in a pulsatile manner and is augmented by stress, eating, and breast stimulation. Levels should be drawn in the morning in a fasting, nonexercised state without prior breast manipulation (including tight-fitting clothes or physical examination). If results are abnormal, the tests must be repeated.
  2. Level of prolactin elevation may be helpful in predicting diagnosis.

Normal is <25 ng/mL in females and <20 ng/mL in males. 25 to 150 ng/mL suggests nonprolactin-secreting tumor or dysfunction in dopaminergic pathway.

150 to 250 ng/mL is indicative of microprolactinoma.

>250 ng/mL is indicative of macroprolactinoma.

  1. Pregnancy, hypothyroidism, estrogen use, and renal failure should always be evaluated first with a blood test for TSH, pregnancy, blood urea nitrogen Blood Urea Nitrogen (BUN), and creatinine.
  2. With persistent prolactin elevation, an evaluation should attempt to identify a pharmacological cause. If possible, the offending drug should be changed or discontinued. If prolactin levels fail to decrease by 2 weeks, an intracranial mass should be considered.
  3. Exogenous estrogen (e.g., high-estrogen–content birth control pills) has been linked to mild hyperprolactinemia and galactorrhea. However, oral contraceptive pills that are currently on the market are no longer thought to cause prolactinomas.
  4. Galactorrhea is a common side effect of risperidone and the older antipsychotic agents (see Table 57.1). It occurs less frequently with the atypical antipsychotic agents, such as, clozapine, olanzapine, aripiprazole, quetiapine, and ziprasidone. A trial of one of these drugs is recommended.
  5. Any patient with persistent hyperprolactinemia with no known underlying etiology, or prolactin >200 ng/mL, requires an MRI with contrast to evaluate for an intracranial lesion

Prolactinomas

  1. Microadenomas, which do not cause any local symptoms have <10% chance of increasing in size, and a 7% risk of progressing to macroprolactinomas. The decision to treat should be based on severity of symptoms and the woman's desire to conceive. Regardless of treatment, serum prolactin levels should be followed closely and an MRI repeated if the prolactin levels increase.
  2. If estrogen levels are within the reference range, menses are unaltered, and galactorrhea is tolerable, treatment is not necessary.
  3. For restoration of gonadal function and prevention of decreased bone mass, treatment should start with either a dopamine agonist (see “Specific Therapeutic Options and Monitoring” section) or estrogen replacement.
  4. If a patient wishes to conceive, initial treatment should be with bromocriptine. Barrier contraceptive should be used until two normal menstrual cycles have occurred, and bromocriptine should be discontinued after the first missed menstrual cycle.
  5. Macroadenomas have a significant potential for growth. They can be associated with visual field defects, headaches, neurological deficits, and their compressive mass may lead to the loss of anterior pituitary function.
  6. Because of the increased risk of progression, initial treatment with dopamine agonists is recommended. MRI should be done annually or with any increase in symptoms or serum prolactin level.
  7. There is a 26% chance of enlargement during pregnancy.
  8. Bromocriptine should be used to induce ovulation, but should be stopped when pregnancy is confirmed.
  9. With suprasellar expansion of the adenoma, tumor debulking should be considered before pregnancy, with postoperative bromocriptine to induce ovulation.
  10. Visual fields and serum prolactin should be evaluated throughout the pregnancy. An MRI is necessary when prolactin increases, there is a loss of visual fields, or headaches ensue. With enlargement, bromocriptine should be restarted.

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Specific Therapeutic Options and Monitoring

  1. Dopamine agonists decrease prolactin secretion and synthesis.
  2. Bromocriptine
  • Outcome: Between 80% and 90% of patients with microprolactinomas will improve (restoration of menses or normoprolactinemia). In patients with macroprolactinomas, 80% will have a reduction in tumor size, and 80% to 90% will have improved visual fields. Bromocriptine improves, but may not normalize, bone density in amenorrheic and oligomenorrheic patients with osteopenia.
  • Dosing: Bromocriptine has a short half-life and multiple daily doses are necessary to maintain therapeutic levels. Therapy may be started at 1.25 mg at bedtime, and increased to 2.5 to 5 mg twice a day.
  • Side effects: Nausea, vomiting, and dizziness are intolerable in 12% of patients.
  • Pregnancy risk: When bromocriptine is used to restore fertility, and stopped when pregnancy is confirmed, there is no increased risk of spontaneous abortions, ectopic pregnancies, or congenital malformations.
  1. Cabergoline
  • Outcome: Cabergoline has consistently been shown to be as effective as bromocriptine, and may be effective in patients resistant to bromocriptine. It is the drug of choice in large tumors invading vital spaces (cavernous sinus) or compressing optic nerves, where fast-action is required.
  • Dosing: Cabergoline has a long half-life and is given at a dose of 0.5 to 1 mg, 1 to 2 times a week.
  • Side effects: Only 3% of patients are unable to tolerate the drug because of side effects. However, it is considerably more expensive than bromocriptine.
  • Pregnancy risk: Experience is much more limited than for bromocriptine. Although there are no known detrimental fetal effects, current recommendations are to discontinue the drug 1 month before attempting conception.
  1. Pergolide is a dopamine agonist approved in the United States for the treatment of Parkinson disease. It is used outside the United States for treatment of hyperprolactinemia.
  2. Transsphenoidal surgery is rarely required, and reserved for patients who are resistant to or intolerant of dopamine-receptor agonists or have invasive macroprolactinomas with compromised vision. Prolactin levels normalize in approximately 70% of patients who have been operated on for microprolactinomas, and in 30% with macroprolactinomas. However, the recurrence risk is 20% to 50%.
  3. Radiation has been used rarely in patients with aggressive tumors that do not respond to dopamine agonists or surgery.
  4. It is important to evaluate estrogen status in young women with hyperprolactinemia because of the known risk of low bone density associated with the accompanying hypoestrogenic amenorrhea (e.g., using a vaginal smear or progestin challenge). Bone density appears to improve with therapy, but does not return to normal. Fracture risk also appears to be increased in adult patients even before a diagnosis of a prolactinoma is confirmed. Therefore, a baseline bone density measurement should be considered in teenage girls with hyperprolactinemia and amenorrhea.

Web Sites

For Teenagers and Parents

http://massgeneral.org/pituitary/htm Program's Web site containing patient information on prolactinomas.

http://familydoctor.org/673.xml. American Academy of Family Physicians Web site about galactorrhea.

http://endocrine.niddk.nih.gov/pubs/prolact.htm. National Institutes of Health site on prolactinomas.

http://patients.uptodate.com/topic.asp?file=endo_hor/8753. Up To Date Web site on prolactinomas.

http://www.merck.com/mmhe/sec13/ch162/ch162f.html. Merck manual's website on galactorrhea.

For Health Professionals

http://www.postgradmed.com/issues/2000/06_00/whitman.htm. Web site for physicians on the evaluation of galactorrhea.

http://www.emedicine.com/med/topic1915.htm. E-medicine article discussing prolactinomas.

http://www.mayoclinic.com/health/galactorrhea/DS00761

http://www.mayoclinic.com/health/prolactinoma/DS00532. Web sites on prolactinoma and galactorrhea from the Mayo Clinic.

References and Additional Readings

Alvarez-Tutor E, Forga-Llenas L, Rodriguez-Erdozain R, et al. Persistent increase of prolactin after oral contraceptive treatment. Alterations in dopaminergic regulation as possible etiology. Arch Gynecol Obstet 1999;263:45.

Bankowski B, Zacur HA. Dopamine agonist therapy for hyperprolactinemia. Clin Obstet Gynecol 2003;46:349.

Benjamin F. Normal lactation and galactorrhea. Clin Obstet Gynecol 1994;37:887.

Biller BM. Diagnostic evaluation of hyperprolactinemia. J Reprod Med 1999;44:1095.

Biller BM, Luciano A, Crosignani PG, et al. Guidelines for the diagnosis and treatment of hyperprolactinemia. J Reprod Med 1999;44:1075.

Colao A, Loche S, Cappa M, et al. Prolactinomas in children and adolescents. Clinical presentation and long-term follow-up. J Clin Endocrinol Metab 1998;83:2777.

Galli-Tsinopoulou A, Nousia-Arvanitakis S, Mitsiakos G, et al. Osteopenia in children and adolescents with hyperprolactinemia. J Pediatr Endocrinol Metab 2000;13:439.

Jaquet P. Medical therapy of prolactinomas. Acta Endocrinol 1993;129(Suppl 1):31.

Kane LA, Leinung MC, Scheithauer BW, et al. Pituitary adenomas in childhood and adolescence. J Clin Endocrinol Metab 1994;79:1135.

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Katz E, Adashi EY. Hyperprolactinemia disorders. Clin Obstet Gynecol 1990;33:622.

Klibanski A, Biller BMK, Rosenthal DI, et al. Effects of prolactin and estrogen deficiency in amenorrheic bone loss. J Clin Endocrinol Metab 1988;67:124.

Klibanski A, Greenspan SL. Increase in bone mass after treatment of hyperprolactinemic amenorrhea. N Engl J Med 1986;315:542.

Klibanski A, Zervas NT. Diagnosis and management of hormone-secreting pituitary adenomas. N Engl J Med 1991; 324:822.

Leung AKC, Pacaud D. Diagnosis and management of galactorrhea. Am Acad Fam Physicians 2004;70(3):543.

Losa M, Mortini P, Barzaghi R, et al. Surgical treatment of prolactin-secreting pituitary adenoma: early results and long-term outcome. J Clin Endcorinol Metab 2002;87:3190.

Luciano AA. Clinical presentation of hyperprolactinemia. J Reprod Med 1999;44:1085.

McCutcheon IE. Management of individual tumor syndromes. Pituitary neoplasia. Endocrinol Metab Clin North Am 1994;23:37.

Modest GA, Fangman JJW. Nipple piercing and hyperprolactinoma. N Engl J Med 2002;347:1626.

Molitch ME. Disorders of pituitary secretion. Endocrinol Metab Clin North Am 2001;30:585.

Molitch ME. Prolactinoma. In: Melmed S, ed. The pituitary. 2002:455.

Molitch ME. Medical management of prolactin-secreting pituitary adenomas. Pituitary 2003;5:55.

Molitch MA. Medication-induced hyperprolactinemia. Mayo Clin Proc 2005;80(8):1050.

Olive D. Indications for hyperprolactinemia therapy. J Reprod Med 1999;44:1091.

Rohn RD. Benign galactorrhea/breast discharge in adolescent males probably due to breast self-manipulation. J Adolesc Health Care 1984;5:210.

Scamoni C, Balzarini C, Crivelli G, et al. Treatment and long-term follow-up results of prolactin secreting pituitary adenomas. J Neurosurg Sci 1991;35:9.

Schelechte JA. Prolactinoma. N Engl J Med 2003;349:2035.

Schlechte J, Walkner L, Kathol M. A longitudinal analysis of premenopausal bone loss in healthy women and women with hyperprolactinemia. J Clin Endocrinol Metab1992;75:698.

Taler SJ, Coulam CB, Annegers JE, et al. Case-control study of galactorrhea and its relationship to the use of oral contraceptives. Obstet Gynecol 1985;65:665.

Tyson D, Reggiardo D, Sklar C, et al. Prolactin-secreting macroadenomas in adolescents. Response to bromocriptine therapy. Am J Dis Child 1993;147:1057.

Vestegaard P, Jorgensen JO, Hagen C, et al. Fracture risk is increased in patients with GH deficiency or untreated prolactinomas—a case control study. Clin Endocrinol (Oxf)2002;56:159.

Webster J, Piscitelli G, Polli A, et al. A Comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904.

Whitman-Elia GF, Windham NQ. Galactorrhea may be clue to serious problems. Patients deserve a thorough work-up [Review]. Postgrad Med 2000;107:165.

Wudarsky M, Nicolson R, Hamburger SD, et al. Elevated prolactin in pediatric patients on typical and atypical antipsychotics. J Child Adolesc Psychopharmacol 1999;9: 239.

Yarkony GM, Novick AK, Roth EJ, et al. Galactorrhea: a complication of spinal cord injury. Arch Phys Med Rehabil 1992;73:878.