The Christ Hospital Grand Rounds
(March 1, 2000)
Advances in the Management of Hyperprolactinemia
Michael Scheiber, M.D.
INTRODUCTION
Hyperprolactinemia is an extremely common disorder, especially among
reproductive aged women. It prevalence is especially high in those women
presenting with reproductive or menstrual dysfunction. This discussion will
briefly touch upon the molecular biology and physiology of prolactin. In
addition, the neuroendocrine regulation of prolactin release will be discussed.
The clinical manifestations of hyperprolactinemia will be reviewed, and I will
discuss the clinical and diagnostic workup of patients presenting with signs or
symptoms of hyperprolactinemia. Finally, I will cover the details of treatment
strategies for hyperprolactinemia in female patients.
BIOLOGY
Prolactin is secreted by lactotrophs in the anterior pituitary gland.
Lactotrophs normally comprise 15-25% of the total pituitary cells. However,
during pregnancy, there is considerable hypertrophy and hyperplasia of the
lactotrophs, largely due to the effects of estrogen.
The human prolactin gene has been very well characterized and is localized to
chromosome 6 in humans. It is approximately ten kilobases long. There is
significant homology between the genes for human prolactin, human placental
lactogen, and human growth hormone.
Translation of the human prolactin gene results in a product that is 227
amino acids long. Circulating hormone weighs approximately 23,000 mw. Several
post translational modifications occur (e.g. glycosolation, polymerization and
cleavage) that result in different circulating subtypes. Approximately three
quarters of circulating prolactin is non-glycosolated monomers. Polymerization
results in the circulating dimer known as "big prolactin" and the
tetramer known as "big, big prolactin". These polymers have a lower
bioactivity and slower clearance than the monomeric form but can be detected by
the radioimmunoassays frequently used in the laboratory evaluation of prolactin.
These circulating polymers may explain the presence of eumenorrhea and fertility
despite hyperprolactinemia in some women.
NEUROENDOCRINE REGULATION
The neuroendocrine regulation of prolactin is complex, but a thorough
understanding of the regulatory mechanisms of prolactin release provides an
important foundation for the understanding of the clinical pathology. Prolactin
is the only pituitary hormone to be under tonic inhibitory control. This is
demonstrated by the fact that interruption of the pituitary stock will result in
decreased secretion of all other pituitary hormones, but increased secretion of
prolactin. Dopamine secreted from neurons in the the hypothalamus is the primary
inhibitor of prolactin secretion from the pituitary gland. Dopamine acts through
the D-2 receptor and uses a cyclic AMP as a second messenger. It is important to
remember that there is also a D-1 receptor, as a lack of receptor specificity is
both the cause of some pharmacologic-related episodes of hypoprolactinemia and
is responsible for some side effects from the dopaminergic agonist drugs used to
treat hyperprolactinemia. In addition to dopamine control, there are a number of
other substances which have been shown to effect prolactin release. Some of the
better known agents causing an increase in prolactin release include thyrotropin
releasing hormone (TRH) and estrogen.
The effect of thyrotropin releasing hormone on the release of prolactin is
quite pronounced. Intravenous injection of TRH will cause a rapid increase in
circulating prolactin levels. This response is more pronounced in women than in
men. This fact highlights the importance of checking thyroid function in
patients presenting with signs or symptoms of hyperprolactinemia.
Prolactin is secreted in a pulsatile fashion with a diurnal variation and a
non-REM sleep associated rise of uncertain significance. This fact demonstrates
the importance of repeating elevated prolactin values early in the morning in a
fasting state.
In addition to neuroendocrine factors, other factors may cause temporary
elevations in prolactin lasting for minutes to days, and these should be kept in
mind when ordering prolactin or working up galactorrhea. A partial list includes
acute stress of any nature (including surgical), food ingestion, chest wall
stimulation from breast implants, surgery, or even herpes zoster. Nipple
stimulation such as suckling and possibly breast examination will cause
temporary increases in prolactin levels as will coitus and orgasm.
The prolactin receptor is extremely widely distributed. In humans and in rats
the prolactin receptor has been isolated in tissue from the breast, liver,
kidney tubules, adrenal cortex, lung, ovary, lymphocytes, myocardium, seminal
vesicles, epididymis, prostate, testes, and brain. Such a wide distribution of
the prolactin receptor indicates that we probably do not know many of prolactin’s
significant circulating effects.
PRL MEASUREMENT
The measurement of prolactin has recently come a long way. Prolactin was
first isolated in the 1930s by Riddle and his co-workers. However, this hormone
was difficult to distinguish and separate from growth hormone and prolactin was
not fully isolated until 1971 by Friesen’s group. Development of immunoassays
in the early 1970s led to the characterization of the clinical syndromes and
their relationship to prolactin. Most laboratories today use radioimmunoassays.
There is significant interlaboratory variation and it is important that each
clinician become comfortable with the range of his or her own laboratory values.
In most laboratories, normal ranges are less than 26 ng/ml.
CLINICAL HYPERPROLACTINEMIA
Clinical descriptions of galactorrhea and its association with menstrual
dysfunction can be found in the literature dating all the way back to
Hippocrates, thus demonstrating that this not a new clinical association. The
association of hyperprolactinemia and reproductive dysfunction really represents
a continuum of disease, starting perhaps with mild luteal phase dysfunction and
then progressing to oligoamenorrhea and eventually amenorrhea as prolactin
levels rise. Galactorrhea is the classic presentation of hyperproplactinemia. It
is defined as the presence of any amount of milk either expressed or
spontaneously discharged from one or both breasts in the absence of pregnancy or
if persistent for more than one year after the cessation of breast feeding.
Galactorrhea is usually obvious, but can be distinguished from blood or pus in
the office by doing a simple microscopic smear looking for fat globules.
The mechanisms by which hyperprolactinemia induces reproductive dysfunction
are not entirely understood. Alterations in homeostatic mechanisms act at
several different levels. The predominant mechanism, however, seems to be that
an increase in prolactin stimulates an increase in dopamine secretion in the
hypothalamus. This increase in hypothalamic dopamine interferes with the
pulsatile secretion of GnRH which subsequently causes a decrease in circulating
gonadotropins to act at the level of the ovarian follicle. There are several
other mechanisms which are less well understood and include interference with
steroid metabolism (both peripherally and centrally).
There are multiple etiologies of hyperprolactinemia. There are two very good
reasons for physiologic hyperprolactenima. These are pregnancy and lactation.
Serum prolactin levels rise steadily throughout pregnancy and peak at 200 ng/ml
near term. Circulating levels in the fetus also rise throughout pregnancy.
Prolactin will remain elevated in lactating women for approximately six weeks
and will spike with each suckling episode thereafter. In non-lactating women,
prolactin will return to normal values within the first 2-3 weeks post-partum.
Pharmacologic agents are another extremely frequent inciting agent for
hyperprolactinemia, especially in certain populations. Of the pharmacologic
agents known to cause hyperprolactinemia, the neuroleptics are the most common
offenders. Others that we think of less frequently include antidepressants, such
as MAO inhibitors and tricyclics. The antiemetics that effect dopamine
metabolism such as Reglan can cause hyperprolactinemia. In addition,
antihypertensives that act through central mechanisms such as reserpine and
methyl-dopa as well as calcium channel blockers may cause hyperprolactinemia.
And, of course, estrogens are known to induce hyperprolactinemia. However, it is
extremely uncommon that estrogens in dosages contained in either oral
contraceptives or hormone replacement therapy would elevate prolactin into the
grossly abnormal range. Neuroleptics on the other hand can commonly cause
elevations of prolactin in the range of 50-200 ng/ml.
Hypothalamic disease can also cause hyperprolactinemia. These are
particularly important causes of hyperprolactinemia to exclude as they may
include other life-threatening pathology. Hypothalamic tumors, especially
craniopharyngiomas, can interfere with the normal prolactin inhibition and cause
circulating hyperprolactinemia. Infiltrating diseases of the hypothalamus may
also present what hyperprolactinemia. Most notably, sarcoid and histiocytosis
are occasionally found. Central pituitary disease is the most common cause with
prolactinomas being extremely frequent. We will discuss prolactinomas in more
detail shortly. The empty sella syndrome is an occasional cause of
hyperprolactinemia, and any pituitary stalk lesion which may interfere with
input to the pituitary such as stalk tumors or traumatic interruptions can
result in hyperprolactinemia. Other neurogenic causes of hyperprolactinemia
include chest wall pathology, spinal cord pathology, and excessive breast
stimulation.
Hyperprolactinemia may occasionally be induced by systemic illness. We have
already discussed the importance of hypothyroidism contributing to
hyperprolactinemia. Renal failure and cirrhosis cause altered metabolism and
clearance of prolactin and may result in hyperprolactinemia. Many cases of
hyperprolactinemia, if no clear etiology is found, are classified as idiopathic.
When it comes to imaging of the pituitary region, some controversy exists as
to the best methods. It is my own personal view that the coned-down view of the
sella turcica is now obsolete. CT scanning will demonstrate calcified lesions
better than MRI. However, special care must be taken with the radiologist to
inform them that you specifically are seeking pituitary pathology. Many serial
cuts on CT are one centimeter apart. Since microprolactinomas are, by
definition, smaller than one centimeter, many of these will be missed on
traditional CT. With the decreasing cost of MRI scans, I firmly believe that MRI
imaging is the modality of choice for the hypothalamic pituitary region.
Microprolactinomas are easily seen on MRI. Microprolactinomas are a very
common cause of hyperprolactinemia. These are prolactin secreting pituitary
adenomas that are less than one centimeter in diameter. They comprise
approximately 95% of prolactinomas, they rarely spontaneously enlarge or
infarct, and they rarely cause compressive CNS side effects. In fact, they are
extremely common, with selected autopsy series in asymptomatic individuals
revealing a 15-20% prevalence. The treatment of microprolactinnomas is based on
symptomatology (i.e. reversal of galactorrhea, restoration of fertility, and
prevention of long-term sequelae). The prevention of long-term sequelae is
especially important, as the hyproestrogenism associated with hyperprolactinemia
in young healthy women may result in significant osteoporosis over time.
Macroprolactinomas, on the other hand, are prolactin secreting pituitary
adenomas that are greater than one centimeter in the widest diameter. They often
present with CNS mass effect such as headaches, visual disturbances, early
morning nausea, etc. General pituitary function testing is warranted in
individuals with macroprolactinoma as resulting thyroid and adrenal dysfunction
can be life threatening. It is important to distinguish other tumors invading
the hypothalamus or compressing the pituitary stock from true
macroprolactinenomas. Serum prolactin levels can often be helpful in this
regard, as stock impression usually presents with levels less than 200, and
tumors frequently present with levels greater than 250 ng/ml.
Towards that end, I think it is very important to discuss serum prolactin
levels in various diseases. While any process causing hyperprolactinemia may
present with a variety of elevations, I think it is worthy to note that most
prolactin secreting tumors will present with a relatively highly elevated
prolactin levels, frequently greater than 100 ng/ml. Traditional medical
teaching for many years dictated that patients with serum prolactin levels less
that 100 ng/ml do not need evaluation of the central nervous system. However a
review of the literature will demonstrate that the vast majority of infiltrating
hypothalamic diseases, as well as life threatening brain tumors resulting in
hyperprolactinemia, fall into the mildly elevated prolactin range with levels
frequently between 40 and 100 ng/ml of serum prolactin. For this reason, if I
had to limit the number of scans I was doing, I would preferentially image those
patients with mild prolactin elevations. I believe that all patients with
hyperprolactinemia deserve a imaging study of the central nervous system.
However, patients with significantly elevated prolactin levels almost always
have a prolactin screening tumor which should respond to medical therapy. It is
the patients with modest elevations and other life threatening conditions whom
we do not want to miss during the clinical evaluation of the process.
TREATMENT
My next goal is to convince you that medical treatment is the preferred
therapy for the vast majority of patients with hyperprolactinemia. The medical
options are all dopaminergic agonists. These medications act centrally in a long
acting fashion to inhibit prolactin secretion at the pituitary level.
Bromocriptine is an ergot derivative with a therapeutic range of 2.5 to 15
milligrams per day, usually given in divided doses two 2-3 times per day.
Cabergoline is the most newly approved ergot derivative. A longer half-life
allows twice weekly dosing, usually in the range of .25 milligrams to one
milligram twice weekly. Pergolide mesylate has not been approved in the United
States for use with hyperprolactinemia, but is used in many other countries. It
is currently approved for use with Parkinson’s disease in the United States.
It has somewhat fewer side effects than Bromocriptine but has less D-2 receptor
selectivity than cabergoline and, therefore, a higher side effect profile.
The gratifying part of medical therapy is that the vast majority of patients
with either idiopathic hyperprolactinemia or microadenomas will resume normal
menstrual function and lower their prolactin levels in response to medical
therapy. In fact, barrier contraception must be provided to those patients who
do not desire pregnancy as many of them will start to ovulate relatively soon
after the induction of dopaminergic agonist therapy. The doaminergic agonists
are probably safe in pregnancy but for most patients they should be discontinued
once pregnancy is established. The old strategy was that patients with
microadenomas should remain on Bromocriptine life long. However recent studies
have shown that allowing patients an interval without medication every 1-2 years
to re-evaluate the hyperprolactinemia is warranted in those patients for whom
close clinical and laboratory follow-up is available.
The down side to medical therapy is certainly the side effects. These are
predominantly GI in nature but may include postural hypotension or other central
side effects. These side effects can be bypassed by starting with low doses at
night in bed and working up to a therapeutic range slowly. The vaginal
administration of bromocriptine may also allow for a longer half-life with a
decrease to once daily dosing and many fewer gastrointestinal side effects.
For macroprolactinomas transsphenoidal surgery used to be the main stay of
therapy. However there is a high rate of panhypopituitarism and other
post-operative complications. In addition, recurrence rates after surgery
approach 80% for microadenomas and 50% for macroprolactinomas after 3-5 years.
For these reasons, I think that stalk compressing tumors warrant surgical
decompression but otherwise, even for macroprolactinomas, an adequate trial of
medical therapy should be initiated first.
Medial and surgical failures warrant radiation therapy. The traditional means
of therapy has been with the Linear Accelerator. However the new Gama Knife
provides a much higher computer generated precision with a lower incidence of
subsequent panhypopituitarism following therapy. In fact, resent studies suggest
that the Gama Knife may be better than transsphenoidal surgery for the treatment
of large tumors.
For patients with idiopathic hyperprolactinemia, medical therapy should be
the mainstay. For those patients whose hyperprolactinemia resulting from medical
problems, it is usually enough to treat the underlying cause. This may include
dialysis for renal failure, medical therapy for sclerosis, thyroid replacement
for patients with hypothyroidism or the removal of inciting pharmacologic
agents.
SUMMARY
In summary, recent advances have been made in understanding the molecular
biology of hyperprolactinemia. We discussed the physiology of prolactin
secretion and regulation. We discussed the prevalence of hyperprolactinemia as
well as its varied clinical presentations. And, finally, I have discussed the
multiple therapeutic options with a special emphasis towards starting with the
medical therapies. I hope you have found this brief discussion useful in your
clinical practice.
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