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 (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.
- * note: 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.
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