Hyperprolactinemia (persistent excess in circulating prolactin concentration) may be associated with significant pathology.
The prolactin molecule is highly varied (heterogeneous) in both size and composition. This variability accounts for the differences frequently seen when simultaneous bioassay (biologically active substance) and immunoassay (bio-active and bio-inactive substance detectable using the antibodies present in the assay) are performed on the same sample.
The predominant size (usually about 80% of total) of prolactin is accompanied in blood by “little prolactin” (with a deletion of part of the protein at the amino terminus), “big prolactin” (with an addition in part of the protein along the carboxy tail), and “big big prolactin” (two molecules of the predominant form attached to each other). Additionally, the prolactin molecule is processed within the cell that synthesizes it (the pituitary lactotroph) through the addition of sugar moieties (glycosylation), sulfate groups (sulfation), phosphate groups (phosphorylation) and the like.
Each of the changes in the chemical structure of the prolactin protein will potentially result in tremendous changes in its bioactivity (biologic activity) while resulting in little change in its immunoreactivity (ability to be detected with the assay). This heterogeneity in the prolactin molecule accounts for why some women will have galactorrhea (milky breast discharge) due to excessive prolactin bioactivity despite a normal prolactin level on immunoassay (greater than normal percentage of total prolactin is of high bioactivity) and other women will have no galactorrhea despite very high concentrations of prolactin on immunoassay (lower than normal percentage of total prolactin is bioactive).
The system of communication within the brain that regulates prolactin concentration is predominantly inhibitory. We know this because lesions obstructing the ability of the hypothalamus to communicate with the pituitary gland result in enhanced secretion of prolactin. Dopamine is widely accepted as the major prolactin inhibiting factor, is secreted from the hypothalamus, and specifically binds to prolactin producing cells in the pituitary gland (lactotrophs) to inhibit prolactin secretion. Medications used to suppress prolactin in the circulation rely on their ability to “act like dopamine” (dopamine agonists).
An effort should be made to rule out a structural lesion in the brain for any woman with a persistently elevated prolactin concentration. If the woman has significant galactorrhea with an ovulatory dysfunction, then radiologic imaging of the brain is also suggested. This is because
- structural lesions that obstruct the blood flow from the hypothalamus to the pituitary will result in release of prolactin and
- pituitary prolactin secreting tumors (prolactinomas) are commonly found with persistent significant elevations of prolactin concentrations.
Some specialists recognize that prolactinomas are rare unless the concentration of prolactin is above a certain defined level (usually about 60-80 ng/mL) and therefore will only recommend radiologic imaging of the brain if the prolactin levels are above this determined cutoff. Others argue that structural lesions obstructing hypothalamic communication with the pituitary have been shown to cause persistent minor elevations of prolactin and therefore any woman with persistent elevation in prolactin should have radiologic imaging.
Clinical situations associated with and thought to cause elevated prolactin levels are diverse and include
- any type of chronic breast stimulation (such as a surgical scar), which may activate the neural arc to “simulate suckling.” This may follow breast reduction, breast implants or any thoracotomy incision near the breasts. Also, stimulation may be due to chest trauma, irritation from the rash of herpes zoster, or prolonged intensive suckling.
- stress (including the stress of having your blood drawn), which may suppress dopamine secretion and result in elevated prolactin concentrations. These are typically associated with minor elevations in the concentration. Even physical stresses like undergoing surgery can result in transient elevations in the prolactin concentration.
- medications of varied sorts can increase the prolactin concentration, which are usually thought to act via suppression of dopamine. The medications include (but are not limited to) psychotropics, tranquilizers, narcotics, some anesthetics, hormonal pills containing estrogen, antihypertensives like Aldomet, and tricyclic antidepressants. Medications typically do not elevate the prolactin concentration above 100 ng/mL. Estrogen containing birth control pills were more commonly associated with prolactinemia and galactorrhea when higher doses of estrogen were used. In one study of more than 100 women on low dose birth control pills there was a slight increase (22%) in the prolactin levels after placement on the pill but not into the abnormal range.
- pituitary prolactin secreting tumors called prolactinomas, which represent tumors of lactotrophs. Prolactinomas are incidental findings in about 10% of randomly chosen autopsy specimens and can be found radiologically in about 50% of women with elevated prolactin concentrations (with greater incidence the higher the prolactin level, involving nearly all women with a prolactin level greater than 200 ng/mL). Prolactinomas less than 1 cm in diameter are called “microadenomas” and those larger than 1 cm are called “macroadenomas.” It is widely accepted that microadenomas typically grow slowly (which is why they are small at the time of detection) while macroadenomas may grow rapidly. If a prolactinoma grows out of the bony confines of the sella turcica it may extend to the region of the adjacent optic nerve to compress it and result in visual problems. Rapidly growing or symptomatic prolactinomas should be treated.
- the “empty sella syndrome,” which is a congenital condition where the structures outside the bony housing for the pituitary gland (the sella turcica) herniate into this area and compress the pituitary gland to give an empty appearance on radiologic exams. The empty sella syndrome is associated with elevated prolactin and suppression of the other pituitary hormone concentrations.
- hypothalamic disease or structural lesions that interfere with the delivery of dopamine to the pituitary gland. This may include tumors, pituitary stalk lesions, or other masses comprising gummas, tuberculomas or fat deposits.
- primary hypothyroidism, which results in elevated levels of TRH. The least incremental increase in TRH that can increase TSH can also increase prolactin (the mechanism is unclear but may have a stimulatory effect on lactotrophs as a kind of “crosstalk” in the pituitary gland)
- chronic renal disease requiring dialysis and a few tumors will rarely be the cause of elevated prolactin. The cause in renal disease is decreased prolactin excretion through the kidney and urine. Many tumors produce substances like hormones (including prolactin) in an uncontrolled fashion, although it is rare that prolactinemia is due to a tumor in say the lung.
Excess prolactin may cause clinical symptoms. The most common include
- nonpuerperal (non-pregnancy related) milk secretion from the breast (called galactorrhea). Up to 60% of women with galactorrhea have excess circulating prolactin. Roughly 35% of those with excess circulating prolactin have galactorrhea.
- Breast discharge that is not clearly galactorrhea (which should be watery or milky and should NOT contain pus or blood) must be further evaluated. A quick and relatively simple test to confirm galactorrhea is to observe fat droplets in the fluid using a microscope. If the discharge does not respond to normalization of circulating prolactin, then you should review the basis for the diagnosis of galactorrhea with the doctor to be certain that a breast tumor or cancer has been ruled out (at least with as much certainty as is possible).
- Hypoestrogenemia (decreased circulating estrogen concentrations) may occur with excess prolactin. This may result in amenorrhea (a complete lack of menstrual flow) or menstrual interval irregularity. If the hyperprolactinemic patient is hypoestrogenemic then medical management that brings the prolactin into the normal range will frequently reverse the estrogen problem.