Tests of Pituitary Function: Prolactin

From Lewis Blevins, MD  –  Photo abstract blend  –  Prolactin is produced by the anterior pituitary gland. Its secretion is largely regulated by dopamine from the hypothalamus which inhibits prolactin production and release. TRH (which stimulates TSH release by the pituitary) and vasoactive intestinal peptide are two hypothalamic hormones that stimulate prolactin release.
Normal ranges for prolactin vary from one institution to another. I was trained to believe that a normal prolactin should be less than 20 ng/mL.

Prolactin can be slightly elevated under certain physiologic conditions such as stress, in response to food, manipulation of the breasts during a breast examination, and after sexual activity. These conditions must be kept in mind when a prolactin level is checked. Generally, we check the prolactin routinely. If, however, the level is elevated and there is no evidence for pituitary tumor it is best done fasting prior to a physician’s visit. Modest elevations in prolactin should be further evaluated by simply repeating the test.

The most common cause of lack of menses and hyperprolactinemia is pregnancy! Prolactin levels can increase to as high as 120 ng/mL during the third trimester of a normal pregnancy. A pregnancy test is advised in the setting of hyperprolactinemia and amenorrhea and especially if there has been weight gain and abdominal distention!! I would add that birth control pills can also cause hyperprolactinemia. The estrogens in the pills, just like the estrogens produced during pregnancy, cause an increase in number and size of the prolactin-producing cells in the pituitary gland.

Primary hypothyroidism can cause hyperprolactinemia because the hypothalamic hormone TRH, elevated in the severe thyroid hormone deficiency, stimulates prolactin release from the normal pituitary gland. Sometimes, patients with marked primary hypothyroidism have pituitary hyperplasia as a result of TRH stimulation of TSH production and secretion. The TSH producing cells increase in number and cause pituitary enlargement. These patients may appear to have a pituitary adenoma on scan when it is simply hyperplasia. The prolactin level might be slightly elevated. Some of these patients are, unfortunately, taken to surgery for a presumed nonfunctioning macroadenoma with pituitary stalk effect causing mild hyperprolactinemia when the simple and required response is to treat the thyroid hormone deficiency.

A number of drugs used to treat psychiatric disorders cause hyperprolactinemia by blocking the dopamine receptor on the pituitary gland. Thus, the normal pituitary does not “see” dopamine and produces prolactin in an unrestrained fashion. The most commonly offending drugs are in the class of anti-psychotic medications but some antidepressant medications cause this problem, too. There is a long list of other drugs that can cause hyperprolactinemia. Generally, prolactin levels are less than 150 ng/mL.

Hyperprolactinemia can also be seen in patients with liver failure, kidney failure, spinal cord tumors, breast cancer, and other disorders that might affect the chest wall thereby stimulating reflex arcs that raise prolactin much as does suckling of the breast during breast feeding. Prolactin levels are usually mildly to modestly elevated and the underlying disorders are usually obvious prior to the detection of hyperprolactinemia.

Any disease process that affects the hypothalamus or pituitary skull and interrupts the flow of dopamine to the anterior pituitary can cause hyperprolactinemia. Some of these disease processes include Langerhans cell histiocytosis, neuroinfundibulohypophysitis, sarcoidosis, fungal infections, and a number of tumors including craniopharyngioma, choristoma, glioma, etc. Rarely, head trauma will affect the pituitary stalk causing hyperprolactinemia, diabetes insipidus, and hypopituitarism. Prolactin levels are usually less than 150 ng/mL.

The finding of hyperprolactinemia in the setting of diabetes insipidus suggests disease of the hypothalamus or pituitary stalk.
We are still trying to understand prolactin secretion in patients with prolactinoma. Microadenomas can be associated with prolactin levels of any degree of elevation. I have seen patients with micro-prolactinomas and prolactin levels in the 30s and also patients with small tumors and prolactin levels in the 800s. Usually, macro prolactinomas are associated with prolactin levels greater than 200 ng/mL. Thus, a large pituitary tumor and a prolactin level greater than 200ng/mL is usually taken to be a prolactinoma rather than some other type of tumor with stalk effect hyperprolactinemia. I have, however, seen a number of patients with macroprolactinomas and prolactin levels less than 200 ng/mL. These are usually atypical prolactinomas or acidophil stem cell adenomas. Interestingly, they usually do not respond very well, in regards to tumor size reduction, in response to dopamine agonist drugs.

One-quarter to one-third of patients with acromegaly also have hyperprolactinemia. This can be due to stalk effect hyperprolactinemia or co-secretion of prolactin by one of three separate tumor types that can produce both growth hormone and prolactin. Thus, every patient with hyperprolactinemia and a pituitary tumor should be at least reviewed with the eye to determine whether they have acromegaly. An IGF-I level is highly recommended.

A trap for the unwary traveler in the realm of hyperprolactinemia is the “hook effect.” This is a particular situation that relates to the way a double antibody radioimmunoassay is used to determine the prolactin concentration in the bloodstream. Basically, in some assays, marked elevations in prolactin overwhelm the ability of the test to detect prolactin. Prolactin levels are reported as normal or only slightly elevated. In the setting of a large pituitary tumor this can lead to the erroneous diagnosis of stalk hyperprolactinemia in the setting of a macroadenoma rather than the correct diagnosis of a macroprolactinoma. Thus, in the setting of a large pituitary tumor and only modest elevations in prolactin, it is recommended that the prolactin be measured on serial diluted samples of the blood to overcome this “hook effect.” Some assays perform very well and are not affected by this problem. For example, the assay in my laboratory can reportedly detect prolactin levels as high as 4000 ng/mL without requiring dilutions.

Some patients have macroprolactinemia. This is a condition where there are antibodies in the bloodstream that cause prolactin to form clumps in the bloodstream. The clumps of prolactin are not readily cleared by the kidneys and thus accumulate in the bloodstream. In most patients, the prolactin in clumps does not have access to its receptor so there are no associated manifestations of hyperprolactinemia such as galactorrhea or irregular menses. Most studies show, however, that macroprolactinemia may also occur in patients with prolactinoma. Thus, clinical judgment is required when making decisions regarding further evaluation and management. In patients with prolactinomas who fail to normalize prolactin in response to dopamine agonist therapy but have restoration of menses and resolution of galactorrhea it is useful to know whether they have macroprolactinemia accounting for the persistent elevations in prolactin because treatment is then directed at restoring the free prolactin to normal even in the setting of an elevated total and macroprolactin level.

Prolactin deficiency is common in patients with hypopituitarism. Usually, prolactin levels are less than 5 ng/mL. The hypopituitary woman who has undergone in vitro fertilization or other fertility treatments may have difficulty breast-feeding following pregnancy. Of course, hypo-prolactinemia and failure to successfully breast-feed an infant is common in Sheehan’s Syndrome.

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