Hyperprolactinemia: Etiology, Diagnosis, and Management

Peak Mann Mah, BM, BS, MRCP; Jonathan Webster, MA, MD, FRCP


Semin Reprod Med. 2002;20(4) 

In This Article

Epidemiology & Etiology


Hyperprolactinemia occurs more commonly in women. The prevalence of hyperprolactinemia ranges from 0.4% in an unselected normal adult population (10,000 normal Japanese adults working at a single factory) to as high as 9 to 17% in women with reproductive disorders. Its prevalence was found to be 5% in a family planning clinic population, 9% in a population of women with adult-onset amenorrhea, and 17% among women with polycystic ovary syndrome.[4]


The diagnosis of hyperprolactinemia is made when serum prolactin levels are found on two separate occasions to be above the norm established for the laboratory used (usually 20 to 25 ng/mL or 400 to 500 mU/L).[5] Its etiology may be physiological, pharmacological, or pathological ( Table 1 ).

Physiological hyperprolactinemia is usually only mild or moderate. During normal pregnancy, serum prolactin rises progressively to around 200 to 500 ng/mL (4000 to 10000 mU/L), an increase thought to be due to rising estrogen concentrations. Hyperprolactinemia occurs during nipple stimulation and lactation, particularly within the first 4 to 6 weeks postpartum, an effect mediated via the mammary nerve. A variety of stresses including hypoglycemia, myocardial infarction, and surgery can elevate serum prolactin. Physical exercise, food ingestion, and sleep are also potent stimuli to prolactin release.

Some patients have an apparently high prolactin level without any clinical features of hyperprolactinemia. This may be caused by "big" prolactin or macroprolactin, representing dimers, trimers, or polymers of prolactin, or prolactin-immunoglobulin immune complexes. Such forms are rarely physiologically active but may register in certain prolactin assays.[4]

Any drug that affects the hypothalamic dopamine system and/or pituitary dopamine receptors can result in an elevated prolactin level.[5] This includes drugs that reduce central dopamine neurotransmission by blocking dopamine receptors (e.g., phenothiazines, butyrophenones, metoclopramide) or depleting central catecholamine stores (e.g., reserpine). Other drugs that can result in hyperprolactinemia include tricyclic antidepressants, opiates, verapamil, and large parenteral doses of cimetidine.

Prolactinomas account for 25 to 30% of functioning pituitary tumors and are the most frequent cause of chronic hyperprolactinemia.[6] Occasionally, raised prolactin levels are caused by pituitary adenomas cosecreting prolactin and other anterior pituitary hormones. Lesions affecting the hypothalamus and pituitary stalk such as nonfunctioning adenomas, craniopharyngiomas, and gliomas rarely result in prolactin elevation of greater than 250 ng/mL (5000 mU/L).[7]

Pathological hyperprolactinemia can be caused by nonhypothalamic-pituitary disease. Forty percent of patients with primary hypothyroidism have mild elevation of prolactin levels that can be normalized by thyroid hormone replacement.[2] About 30% of patients with chronic renal failure and up to 80% of patients on hemodialysis have elevated prolactin levels. This is probably secondary to decreased clearance and increased production of prolactin as a result of disordered hypothalamic regulation of prolactin secretion. Correction of the renal failure by transplantation results in normoprolactinemia.


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