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Author: Paula J. Hillard, MD

Editor: Daniel Martingano, DO

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Prolactin is a protein mainly synthesized and secreted by the lactotroph cells in the pituitary gland. Hyperprolactinemia is defined by a high level of serum prolactin above the standard limit of normal range, and is frequently identified in women with secondary amenorrhea, oligomenorrhea, galactorrhea, and infertility. A serum prolactin concentration above 20-25 ng/mL is considered abnormally high in most laboratories.

Hyperprolactinemia can result from both physiologic and pathologic processes in addition to iatrogenic causes including medication side-effects. Physiologic causes include general stress, nipple stimulation, sleep, exercise, coitus, pregnancy, and lactation.  

Pathologic causes include:

  • hypothalamic-pituitary stalk damage due to trauma, radiation, Rathke’s cysts, infiltrative diseases, and parasellar tumors.
  • Pituitary disorders such as prolactinomas (adenomas), acromegaly, and macroprolactinemia.
  • Systemic disorders such as primary hypothyroidism, chest wall injury due to trauma, surgery, or herpes zoster, chronic renal failure with decreased clearance of prolactin, cirrhosis, and malignancies such as renal and lung cancer.

Medications known to have side effects of hyperprolactinemia include antipsychotics, gastric motility drugs, antihypertensives, dopamine receptor blockers, opiates, and H-2 antihistamines. In cases of suspected drug-induced hyperprolactinemia, medication can be discontinued or a substitute given for three days, followed by repeat measurement of prolactin.

The clinical manifestations of hyperprolactinemia in premenopausal women include oligomenorrhea, primary and secondary amenorrhea, anovulatory infertility, and galactorrhea. Patients with macroadenomas may have headaches and visual disturbances. In general, symptoms correlate with the magnitude of the hyperprolactinemia.

The evaluation should include reviewing the history of nipple stimulation, medications, pregnancy/postpartum status, headache, visual symptoms, endocrine (e.g., hypothyroidism) symptoms, and renal and liver disease. The physical examination should be directed for signs of hypothyroidism (e.g., HEENT exam to detect possible goiter), hypogonadism, visual field loss, and chest wall injury.

Laboratory tests should include prolactin and TSH. An MRI of the sella turcica is required to diagnose an adenoma and differentiate between other lesions in the hypothalamic-pituitary region. Microadenomas are defined as prolactinomas less than 10 mm, and macroadenomas are those greater or equal to 10 mm.

Women with regular menstrual cycles and hyperprolactinemia have a very low incidence of the clinically relevant disease and may have macroprolactinemia. Macroprolactinemia is due to large polymeric forms of prolactin and circulating anti-prolactin autoantibodies. These forms of prolactin are less biologically active. Consequently fewer patients are symptomatic and prolactinomas are present is only about 10-20%. Idiopathic hyperprolactinemia is diagnosed in the absence of pituitary and central lesions on MRI, and the absence of secondary causes of hyperprolactinemia.

Symptomatic patients with hyperprolactinemia may be treated with the dopamine agonists bromocriptine or cabergoline unless they have a stalk compressing lesion. Bromocriptine is a reasonable first choice given its low cost and favorable side effect profile. Cabergoline, however, is more effective in reducing prolactin levels and adenoma size than bromocriptine, and has fewer side effects. Monitoring with prolactin levels is necessary to adjust medication dosages.

Repeat MRIs may be indicated if symptoms persist or there is no response on prolactin levels. Treatment during pregnancy is usually limited to symptomatic patients and those with macroadenomas. Treatment resistance has been defined as a failure to normalize prolactin levels and to decrease macroadenoma size by >=50%, although recent studies have suggested that higher dose cabergoline regimens may be effective. Transsphenoidal surgery may be required for symptomatic patients with prolactinomas who do not respond or cannot tolerate high doses of cabergoline, and may improve fertility measures in affected women.

Further Reading:

Melmed S, Casanueva FF, Hoffman AR, et al, Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Feb;96(2):273-88. doi: 10.1210/jc.2010-1692.

Vilar L, Vilar CF, Lyra R, Freitas MDC. Pitfalls in the Diagnostic Evaluation of Hyperprolactinemia. Neuroendocrinology. 2019;109(1):7-19. doi: 10.1159/000499694. Epub 2019 Mar 20. PMID: 30889571.

Lamba N, Noormohamed N, Simjian T, Alsheikh MY, Jamal A, Doucette J, Zaidi H, Smith TR, Mekary RA. Fertility after transsphenoidal surgery in patients with prolactinomas: A meta-analysis. Clin Neurol Neurosurg. 2019 Jan;176:53-60. doi: 10.1016/j.clineuro.2018.11.024. Epub 2018 Dec 1. PMID: 30529652.

Initial Approval April 2012; Revised July 2018. Reaffirmed January 2020; Reaffirmed September 2021; Revised May 2023.


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