Causes of hyperprolactinemia
- Peter J Snyder, MD
Peter J Snyder, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease; Male Reproductive Endocrinology
- Professor of Medicine
- University of Pennsylvania School of Medicine
Prolactin is secreted solely by the lactotroph cells of the pituitary gland. As a result, hyperprolactinemia results almost exclusively from diseases that cause hypersecretion of prolactin by lactotroph cells. Some of these causes are physiologic and others pathologic.
This topic will review the major causes of hyperprolactinemia. The clinical manifestations, diagnosis, and treatment are discussed separately. (See "Clinical manifestations and evaluation of hyperprolactinemia" and "Management of hyperprolactinemia".)
Serum prolactin concentrations normally increase substantially during pregnancy and to a lesser degree in response to nipple stimulation during breastfeeding, physical exertion, and stress. The upper normal value for serum prolactin in most laboratories is approximately 20 ng/mL (20 mcg/L SI units). Food does not appear to affect serum prolactin concentrations; therefore, fasting is not necessary when having serum prolactin measured.
Pregnancy — Serum prolactin increases throughout pregnancy, reaching a peak at delivery (figure 1) . The magnitude of the increase, however, is quite variable; in one study, the mean value at term was 207 ng/mL, but the range was from 35 to 600 ng/mL (35 to 600 mcg/L SI units) . The probable cause of the hyperprolactinemia is the increasing serum estradiol concentrations during pregnancy. By six weeks after delivery, estradiol secretion has decreased, and the basal serum prolactin concentration is usually normal, even when the mother is breastfeeding.
Nipple stimulation and breast exams — Nipple stimulation during breastfeeding increases serum prolactin concentrations, presumably via a neural pathway. The magnitude of the increase is directly proportional to the degree of preexisting lactotroph hyperplasia due to estrogen. In the first weeks postpartum, as an example, the serum prolactin concentration increases up to 300 ng/mL above baseline in response to suckling (figure 2); in contrast, several months after delivery, the increase in prolactin in response to suckling in the breastfeeding woman is usually less than 10 ng/mL (10 mcg/L SI units) above baseline (figure 2) .
- Tyson JE, Hwang P, Guyda H, Friesen HG. Studies of prolactin secretion in human pregnancy. Am J Obstet Gynecol 1972; 113:14.
- Saraç F, Tütüncüoğlu P, Ozgen AG, et al. Prolactin levels and examination with breast ultrasound or mammography. Adv Ther 2008; 25:59.
- Jarrell J, Franks S, McInnes R, et al. Breast examination does not elevate serum prolactin. Fertil Steril 1980; 33:49.
- Hammond KR, Steinkampf MP, Boots LR, Blackwell RE. The effect of routine breast examination on serum prolactin levels. Fertil Steril 1996; 65:869.
- Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 1977; 296:589.
- Alexander JM, Biller BM, Bikkal H, et al. Clinically nonfunctioning pituitary tumors are monoclonal in origin. J Clin Invest 1990; 86:336.
- Herman V, Fagin J, Gonsky R, et al. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 1990; 71:1427.
- Zhang X, Horwitz GA, Heaney AP, et al. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 1999; 84:761.
- Vlotides G, Eigler T, Melmed S. Pituitary tumor-transforming gene: physiology and implications for tumorigenesis. Endocr Rev 2007; 28:165.
- Corenblum B, Sirek AM, Horvath E, et al. Human mixed somatotrophic and lactotrophic pituitary adenomas. J Clin Endocrinol Metab 1976; 42:857.
- Mindermann T, Wilson CB. Age-related and gender-related occurrence of pituitary adenomas. Clin Endocrinol (Oxf) 1994; 41:359.
- Delgrange E, Trouillas J, Maiter D, et al. Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study. J Clin Endocrinol Metab 1997; 82:2102.
- Prosser PR, Karam JH, Townsend JJ, Forsham PH. Prolactin-secreting pituitary adenomas in multiple endocrine adenomatosis, type I. Ann Intern Med 1979; 91:41.
- Walker JD, Grossman A, Anderson JV, et al. Malignant prolactinoma with extracranial metastases: a report of three cases. Clin Endocrinol (Oxf) 1993; 38:411.
- Petakov MS, Damjanović SS, Nikolić-Durović MM, et al. Pituitary adenomas secreting large amounts of prolactin may give false low values in immunoradiometric assays. The hook effect. J Endocrinol Invest 1998; 21:184.
- St-Jean E, Blain F, Comtois R. High prolactin levels may be missed by immunoradiometric assay in patients with macroprolactinomas. Clin Endocrinol (Oxf) 1996; 44:305.
- Barkan AL, Chandler WF. Giant pituitary prolactinoma with falsely low serum prolactin: the pitfall of the "high-dose hook effect": case report. Neurosurgery 1998; 42:913.
- Molitch ME. Drugs and prolactin. Pituitary 2008; 11:209.
- Ajmal A, Joffe H, Nachtigall LB. Psychotropic-induced hyperprolactinemia: a clinical review. Psychosomatics 2014; 55:29.
- Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96:273.
- Kearns AE, Goff DC, Hayden DL, Daniels GH. Risperidone-associated hyperprolactinemia. Endocr Pract 2000; 6:425.
- David SR, Taylor CC, Kinon BJ, Breier A. The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther 2000; 22:1085.
- Rivera JL, Lal S, Ettigi P, et al. Effect of acute and chronic neuroleptic therapy on serum prolactin levels in men and women of different age groups. Clin Endocrinol (Oxf) 1976; 5:273.
- Bushe C, Yeomans D, Floyd T, Smith SM. Categorical prevalence and severity of hyperprolactinaemia in two UK cohorts of patients with severe mental illness during treatment with antipsychotics. J Psychopharmacol 2008; 22:56.
- Cowen PJ, Sargent PA. Changes in plasma prolactin during SSRI treatment: evidence for a delayed increase in 5-HT neurotransmission. J Psychopharmacol 1997; 11:345.
- Meltzer H, Bastani B, Jayathilake K, Maes M. Fluoxetine, but not tricyclic antidepressants, potentiates the 5-hydroxytryptophan-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression or with obsessive compulsive disorder. Neuropsychopharmacology 1997; 17:1.
- McCallum RW, Sowers JR, Hershman JM, Sturdevant RA. Metoclopramide stimulates prolactin secretion in man. J Clin Endocrinol Metab 1976; 42:1148.
- Sowers JR, Sharp B, McCallum RW. Effect of domperidone, an extracerebral inhibitor of dopamine receptors, on thyrotropin, prolactin, renin, aldosterone, and 18-hydroxycorticosterone secretion in man. J Clin Endocrinol Metab 1982; 54:869.
- Steiner J, Cassar J, Mashiter K, et al. Effects of methyldopa on prolactin and growth hormone. Br Med J 1976; 1:1186.
- Fearrington EL, Rand CH Jr, Rose JD. Hyperprolactinemia-galactorrhea induced by verapamil. Am J Cardiol 1983; 51:1466.
- Veldhuis JD, Borges JL, Drake CR, et al. Divergent influences of the structurally dissimilar calcium entry blockers, diltiazem and verapamil, on thyrotropin- and gonadotropin-releasing hormone-stimulated anterior pituitary hormone secretion in man. J Clin Endocrinol Metab 1985; 60:144.
- Romeo JH, Dombrowski R, Kwak YS, et al. Hyperprolactinaemia and verapamil: prevalence and potential association with hypogonadism in men. Clin Endocrinol (Oxf) 1996; 45:571.
- Newey PJ, Gorvin CM, Cleland SJ, et al. Mutant prolactin receptor and familial hyperprolactinemia. N Engl J Med 2013; 369:2012.
- Schlechte J, Dolan K, Sherman B, et al. The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 1989; 68:412.
- Martin TL, Kim M, Malarkey WB. The natural history of idiopathic hyperprolactinemia. J Clin Endocrinol Metab 1985; 60:855.
- Sluijmer AV, Lappöhn RE. Clinical history and outcome of 59 patients with idiopathic hyperprolactinemia. Fertil Steril 1992; 58:72.
- Murdoch FE, Byrne LM, Ariazi EA, et al. Estrogen receptor binding to DNA: affinity for nonpalindromic elements from the rat prolactin gene. Biochemistry 1995; 34:9144.
- Malayer JR, Gorski J. The role of estrogen receptor in modulation of chromatin conformation in the 5' flanking region of the rat prolactin gene. Mol Cell Endocrinol 1995; 113:145.
- Frantz AG. Prolactin. N Engl J Med 1978; 298:201.
- Honbo KS, van Herle AJ, Kellett KA. Serum prolactin levels in untreated primary hypothyroidism. Am J Med 1978; 64:782.
- Snyder PJ, Jacobs LS, Utiger RD, Daughaday WH. Thyroid hormone inhibition of the prolactin response to thyrotropin-releasing hormone. J Clin Invest 1973; 52:2324.
- Groff TR, Shulkin BL, Utiger RD, Talbert LM. Amenorrhea-galactorrhea, hyperprolactinemia, and suprasellar pituitary enlargement as presenting features of primary hypothyroidism. Obstet Gynecol 1984; 63:86S.
- Grubb MR, Chakeres D, Malarkey WB. Patients with primary hypothyroidism presenting as prolactinomas. Am J Med 1987; 83:765.
- Kavanagh-Wright L, Smith TP, Gibney J, McKenna TJ. Characterization of macroprolactin and assessment of markers of autoimmunity in macroprolactinaemic patients. Clin Endocrinol (Oxf) 2009; 70:599.
- Leslie H, Courtney CH, Bell PM, et al. Laboratory and clinical experience in 55 patients with macroprolactinemia identified by a simple polyethylene glycol precipitation method. J Clin Endocrinol Metab 2001; 86:2743.
- Strachan MW, Teoh WL, Don-Wauchope AC, et al. Clinical and radiological features of patients with macroprolactinaemia. Clin Endocrinol (Oxf) 2003; 59:339.
- Gibney J, Smith TP, McKenna TJ. Clinical relevance of macroprolactin. Clin Endocrinol (Oxf) 2005; 62:633.
- Lim VS, Kathpalia SC, Frohman LA. Hyperprolactinemia and impaired pituitary response to suppression and stimulation in chronic renal failure: reversal after transplantation. J Clin Endocrinol Metab 1979; 48:101.
- Sievertsen GD, Lim VS, Nakawatase C, Frohman LA. Metabolic clearance and secretion rates of human prolactin in normal subjects and in patients with chronic renal failure. J Clin Endocrinol Metab 1980; 50:846.
- Morley JE, Dawson M, Hodgkinson H, Kalk WJ. Galactorrhea and hyperprolactinemia associated with chest wall injury. J Clin Endocrinol Metab 1977; 45:931.
- PHYSIOLOGIC CAUSES
- Nipple stimulation and breast exams
- PATHOLOGIC CAUSES
- Hypothalamic-pituitary disease
- - Lactotroph adenomas
- - Decreased dopaminergic inhibition of prolactin secretion
- - Other hypothalamic or pituitary disorders
- DRUG INDUCED
- OTHER CAUSES
- Germline loss-of-function mutation
- Idiopathic hyperprolactinemia
- Decreased clearance of prolactin
- - Macroprolactinemia
- - Chronic renal failure
- Chest wall injury
- INFORMATION FOR PATIENTS