The

new england journal

of

medicine

clinical practice

Prolactinoma
Janet A. Schlechte, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.

A 22-year-old woman who wants to become pregnant has had no menses since she
discontinued the use of an oral contraceptive one year ago, and recently, galactorrhea
developed. She takes no medications and has had no headaches, visual loss, dyspareunia, or decreased libido. Physical examination shows no abnormalities, except for the
bilateral breast discharge. A test for serum human chorionic gonadotropin is negative, the thyrotropin level is normal, and the serum prolactin level is 95 g per liter.
Magnetic resonance imaging (MRI) reveals a mass, 3 mm in diameter, in the anterior
lobe of the pituitary. How should she be treated?

the clinical problem

Prolactin-secreting tumors are benign neoplasms that account for about 40 percent of
all pituitary tumors. Over 90 percent are small, intrasellar tumors that rarely increase in
size.1-4 The primary action of prolactin is to stimulate lactation, but it is the effect of
prolactin on gonadal function that warrants clinical attention. Hypersecretion of prolactin leads to infertility and gonadal dysfunction by interrupting secretion of gonadotropin-releasing hormone, inhibiting the release of luteinizing hormone and folliclestimulating hormone, and impairing gonadal steroidogenesis.5,6

From the Department of Internal Medicine,

University of Iowa, Iowa City. Address reprint requests to Dr. Schlechte at the Department of Internal Medicine, 157 MRF,
University of Iowa Hospitals and Clinics,
200 Hawkins Dr., Iowa City, IA 52242, or at
janet-schlechte@uiowa.edu.
N Engl J Med 2003;349:2035-41.
Copyright 2003 Massachusetts Medical Society.

clinical presentation

The most common symptoms of hyperprolactinemia in premenopausal women are

amenorrhea and infertility. Galactorrhea occurs in about 80 percent of such women,
and some women with prolactinomas have infrequent menstrual flow (oligomenorrhea) or regular menses.1 Hyperprolactinemia is often detected after discontinuation
of the use of an oral contraceptive, but there is no apparent relation between the use of
oral contraceptives and the formation of prolactinomas.7 The majority of prolactinomas
in women are small at the time of diagnosis, and headaches and neurologic deficits are
rare.1 In contrast, prolactinomas in men typically tend to be large at the time of diagnosis and may cause cranial-nerve dysfunction, visual loss, and hypopituitarism.8 In men,
hyperprolactinemia leads to impotence, infertility, and decreased libido, but these are
rarely the initial symptoms; galactorrhea and gynecomastia are uncommon.8 In both
sexes, long-standing hyperprolactinemia leads to low bone density in the spine.9-11
After prolactin has returned to the normal range, bone density will increase but does
not reach normal values.9-11
causes of hyperprolactinemia

The secretion and release of prolactin are mediated by dopamine, and any process that
disrupts dopamine secretion or interferes with the delivery of dopamine to the portal
vessels may cause hyperprolactinemia. Normal prolactin levels in women and men are
below 25 g per liter and 20 g per liter, respectively. There is a 10-fold increase in pro-

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lactin during pregnancy, and levels rise after exercise, meals, and stimulation of the chest wall. Physical and psychological stress increases the secretion
of prolactin, but the level rarely exceeds 40 g per
liter. Breast examination is infrequently associated
with elevation of the prolactin level.12
Metoclopramide, phenothiazines, and butyrophenones antagonize lactotroph dopamine receptors, leading to prolactin levels that exceed 100 g
per liter.13 Risperidone causes a similar elevation,
and monoamine oxidase inhibitors and tricyclic
antidepressants raise prolactin levels through effects on the delivery of dopamine to the portal vessels.13,14 Serotonin-reuptake inhibitors may cause
hyperprolactinemia, but the prolactin levels rarely
exceed the normal range.15 Nearly 10 percent of
patients taking verapamil have elevated prolactin
levels, but other calcium-channel blockers are not
associated with hyperprolactinemia.16 Less commonly used antihypertensive agents that are associated with hyperprolactinemia include reserpine
and methyldopa.17 Prolactin levels may also be mildly elevated after the administration of estrogen.18
The magnitude of medication-induced elevations
in the prolactin level is variable, and the level returns to normal within days after the cessation of
therapy.19 In general, medication-induced hyperprolactinemia is associated with levels of prolactin
in the range of 25 to 100 g per liter.
Craniopharyngioma, acromegaly, granulomatous infiltration of the hypothalamus, severe head
trauma, and large nonfunctioning pituitary tumors
may also lead to hyperprolactinemia. In patients
with acromegaly, prolactin may be secreted along
with growth hormone. The development of large
nonfunctioning pituitary tumors can compress the
pituitary stalk and lead to prolactin levels in the
range of 25 to 200 g per liter, with increases to
levels of less than 100 g per liter in most cases.20
In some patients with primary hypothyroidism, mild
hyperprolactinemia develops owing to the increased
synthesis of thyrotropin-releasing hormone.21 Prolactin levels are elevated in patients with chronic
renal failure because of decreased clearance of the
hormone.22
When no cause of hyperprolactinemia can be
identified, the diagnosis is idiopathic hyperprolactinemia. A prolactinoma may be present but may
be too small to be detected radiographically. In one
third of patients with idiopathic hyperprolactinemia, the level of prolactin later returns to the normal
range, and in nearly half, it remains unchanged.2,23

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In one study, only 10 percent of patients with idiopathic hyperprolactinemia had radiographic evidence of a pituitary tumor during a follow-up period of six years.23

strategies and evidence

diagnostic studies

A single measurement of the prolactin level in a

blood sample obtained at any time of the day is usually adequate to document hyperprolactinemia. Because of the pulsatile nature of prolactin secretion
and the effect of stress, a test that shows a level of
25 to 40 g per liter should be repeated before hyperprolactinemia is diagnosed. Most causes of hyperprolactinemia can be ruled out on the basis of
the history and physical examination, a pregnancy
test, and assessments of thyroid function and renal
function. Provocative tests with the use of insulininduced hypoglycemia, levodopa, and thyrotropinreleasing hormone are not helpful in the evaluation
of patients for hyperprolactinemia.
When other causes of hyperprolactinemia have
been ruled out, the diagnosis of a prolactinoma is
confirmed by gadolinium-enhanced MRI. Computed tomography with intravenous contrast enhancement is an alternative, but MRI is more effective in
revealing small adenomas and the extension of large
tumors.24 Prolactinomas are classified as microadenomas if they are less than 10 mm in diameter
(Fig. 1A) and as macroadenomas if they are 10 mm
or greater in diameter (Fig. 1B). Patients with macroadenomas that extend beyond the sella should undergo visual-field examination and testing of anterior pituitary function.
In general, serum prolactin levels parallel tumor
size fairly closely. Macroadenomas are typically associated with levels of over 250 g per liter, and in
some cases the level exceeds 1000 g per liter. Care
must be taken in interpreting a moderate elevation
of the prolactin level (<100 g per liter) in the presence of a macroadenoma. The discrepancy between
a large tumor and a mildly elevated level of prolactin may be due either to compression of the pituitary stalk by the tumor or to an artifact in the immunoradiometric assay for prolactin.25 This artifact
(called the hook effect) can be eliminated by serial dilution of the serum samples.25
therapy

The decision to provide treatment is based on the

size of the tumor, the presence or absence of go-

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clinical practice

Figure 1. Gadolinium-Enhanced, T1-Weighted Coronal MRI Scans Showing a Microadenoma and a Macroadenoma.
The microadenoma (arrow, Panel A) is a hypodense intrasellar mass, 4 mm in diameter. The macroadenoma (arrow,
Panel B) is a mass, 1 cm in diameter, with extension toward the optic chiasm.

nadal dysfunction, and the patients desires with

respect to fertility. The primary therapy for all prolactinomas is a dopamine agonist. Transsphenoidal surgery does not reliably lead to a long-term
cure,26,27 and a recurrence of hyperprolactinemia
is common.28,29 The dopamine agonists approved
for use in the United States are bromocriptine and
cabergoline. Bromocriptine is an ergot derivative
that has been used for two decades and is now off
patent. Cabergoline is a nonergot agonist with a
high affinity for lactotroph dopamine receptors.
Microadenomas

Both bromocriptine and cabergoline decrease prolactin secretion and reduce the size of tumors,30 but
on the basis of its safety record in pregnancy, bromocriptine is the treatment of choice when restoration of fertility is the patients goal. Bromocriptine normalizes the secretion of prolactin in 82
percent of women with microadenomas and restores menses and fertility in over 90 percent.30
Therapy is initiated with a dose of 0.625 mg administered at bedtime with a snack. After one week,
a morning dose of 1.25 mg is added to the regimen.
At weekly intervals, the dose is increased by 1.25 mg,
for a total dose of 5.0 mg, and the immunoradiometric assay for prolactin is repeated after one month.
A daily dose of 5.0 to 7.5 mg is usually required to
restore menses and normalize the level of prolac-

n engl j med 349;21

tin, and for maximal effect, the drug should be administered twice daily. Side effects, including nausea, orthostatic hypotension, and depression, are
minimized if the therapy is initiated at night. Intravaginal administration is associated with diminished gastrointestinal side effects, and the effect of
the drug lasts for 24 hours.31,32 Some vaginal irritation may occur, but, in general, this approach is
well tolerated.31,32 In most women, a regimen of 2.5
to 5.0 mg daily is necessary to normalize the level of
prolactin.
Women should be advised to use a mechanical
form of contraception until two regular menstrual
periods have occurred, and bromocriptine should
be stopped when one menstrual cycle has been
missed. Used in this fashion, bromocriptine has
not been associated with an increased incidence
of spontaneous abortion, ectopic pregnancy, or congenital malformation.33 Among infants of mothers who conceived after taking cabergoline, the incidence of congenital malformations is no higher
than that in the general population, but the number of pregnancies studied has been small.34,35 Until there is more information about cabergolineinduced pregnancy, cabergoline should not be used
as a therapy for infertility.
The risk of symptomatic enlargement of a microadenoma during pregnancy is about 1 percent.
Formal visual-field testing is not necessary during

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pregnancy,33 nor is serial measurement of prolactin levels, because increased levels do not correlate
reliably with tumor enlargement. Lactation is not
associated with tumor growth. Women wishing to
breast-feed their infants should not be given bromocriptine.
Transsphenoidal surgery is an option in an infertile patient who cannot tolerate bromocriptine
or in whom bromocriptine is ineffective. Surgery
for microadenomas has a success rate of 74 percent,36 but higher rates have been achieved among
carefully selected patients with prolactin levels that
were lower than 200 g per liter, small tumors, and
a short duration of amenorrhea.26,27
In 95 percent of patients with microadenomas,
the tumors do not progressively increase in size,2-4
so that suppression of tumor growth is not an indication for therapy. When pregnancy is not an issue, either bromocriptine or cabergoline will restore
menses and eliminate galactorrhea. Bromocriptine is less expensive but requires administration
twice daily; about 5 percent of patients cannot tolerate bromocriptine, and in 10 percent it is not effective.33 Cabergoline appears to be more effective
in decreasing prolactin secretion and restoring ovulatory cycles; it is effective in 70 percent of patients
who do not have a response to bromocriptine and
is associated with fewer side effects.37,38 Cabergoline therapy is begun at a dose of 0.25 mg administered twice weekly, and the dose is increased
monthly until prolactin secretion normalizes, to a
maximal dose of 1 mg twice weekly; doses ranging
from 0.25 to 0.5 mg twice weekly are usually sufficient to normalize the prolactin level.37
The use of a dopamine agonist should be continued unless the patient becomes pregnant, and
the prolactin level should be checked yearly. In some
patients, the drug may ultimately be discontinued.
In approximately 25 percent of women treated with
bromocriptine for at least 24 months, the prolactin
level remains normal after the discontinuation of
therapy.39,40 If the prolactin level does not return to
the normal range with therapy, or if the patient cannot tolerate the first dopamine agonist, changing
to the other drug may be effective.
When fertility is not a concern, another option
is to treat microadenomas with an oral contraceptive that contains estrogen and a progestin. This
therapy will not normalize bone density, but it may
prevent progressive bone loss. Although estrogen
can induce lactotroph hyperplasia, short-term use
of oral contraceptives in women with microadeno-

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mas does not appear to be associated with tumor

growth.41,42 A woman with a microadenoma who
is taking estrogen will need to have her prolactin levels measured yearly. MRI should be repeated if clinical signs of tumor expansion appear or if the prolactin level exceeds 250 g per liter.
Macroadenomas

Because of the large potential for growth, a macroadenoma is an absolute indication for therapy.
Treatment should be initiated with a dopamine agonist and should be managed by an endocrinologist.
Both of the dopamine agonists that are currently
available provide effective therapy for macroadenomas,37,43 but, as in patients with microadenomas, bromocriptine should be used when fertility
is the goal of treatment.
A macroadenoma that is confined to the sella is
not likely to enlarge sufficiently during pregnancy
to cause clinically serious complications, and patients with intrasellar macroadenomas who wish to
become pregnant should be followed in the same
way as patients with microadenomas. When suprasellar extension of a macroadenoma is detected in
a patient who wishes to become pregnant, there is
a 15 to 35 percent risk of tumor enlargement during gestation.33 These tumors should be surgically
debulked before pregnancy, and after surgery, therapy with bromocriptine should be initiated. Bromocriptine has been used throughout pregnancy
in a small number of patients, without major complications or fetal abnormalities,44 and its use is
probably less harmful than surgical intervention
during pregnancy.45 Visual-field testing should be
performed at least once every three months during
pregnancy, and MRI should be repeated if symptoms of tumor enlargement develop.
Hypogonadism

When fertility is not an issue, the goals of treatment

are restoration of gonadal function and reduction
of the size of the tumor. Either dopamine agonist
can be used, but cabergoline may be more effective
in reducing the prolactin levels, decreasing the size
of the tumor, and eliminating visual-field abnormalities.46 There have been no studies that directly
compared the efficacy of cabergoline with that of
bromocriptine for the treatment of macroadenomas, but cabergoline has been shown to be effective
for bromocriptine-resistant tumors.46
Patients with macroadenomas generally require
higher doses of bromocriptine (usual range, 7.5 to

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clinical practice

10.0 mg daily) or cabergoline (usual range, 0.5 to

1.5 mg twice weekly) than do patients with microadenomas. With both dopamine agonists, a decrease in prolactin levels occurs within two to three
weeks after treatment begins and usually precedes
a decrease in the size of the tumor and the restoration of anterior pituitary function.43 The length of
time necessary to achieve a reduction in tumor size
ranges from weeks to years.43,47-49 Visual-field testing should be repeated one month after the initiation of therapy, and MRI should be repeated after
six months of treatment. Prolactin levels should be
measured yearly.
When the prolactin level has been normal for
two years and the size of the tumor has decreased
by at least 50 percent, the dose of cabergoline or
bromocriptine can be gradually decreased, with
close follow-up to rule out tumor enlargement. After two years of uninterrupted therapy, even low
doses of these medications inhibit prolactin secretion and control tumor growth.48 In patients with
macroadenomas, discontinuation of the drug usu-

ally leads to renewed expansion of the tumor and

to a recurrence of hyperprolactinemia and should
therefore be undertaken with extreme caution.
Given the potential for growth of macroadenomas, the use of estrogen is generally discouraged. If
a macroadenoma does not respond to medical therapy, transsphenoidal surgery should be undertaken. Surgery is rarely curative, however, and therapy
with a dopamine agonist will be necessary afterward to normalize prolactin secretion. External radiation may be required if substantial tumor tissue
remains after surgery. The major side effects of radiation therapy are hypopituitarism, damage to the
optic nerve, and neurologic dysfunction.

areas of uncertainty
There is limited information regarding the effects
of the discontinuation of therapy for prolactinoma.
Studies of patients with microadenomas or macroadenomas that were treated with bromocriptine
over a period of 24 to 48 months have shown that

Hyperprolactinemia

Rule out secondary causes

MRI

Microadenoma

Regular
menses

Infertility

No treatment

Bromocriptine

Macroadenoma

Amenorrhea

Intrasellar

Dopamine
agonist or
estrogen
progesterone

Suprasellar

Infertility

Amenorrhea

Infertility

Amenorrhea

Bromocriptine

Dopamine
agonist

Bromocriptine,
surgery, or both

Dopamine
agonist, surgery,
or both

Figure 2. Management of Prolactinoma in Women.

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in 6 to 37 percent of patients, prolactin levels remain normal after the withdrawal of bromocriptine.40,47-53 Elsewhere in this issue of the Journal,
Colao et al. report that prolactin levels remained
normal in over 60 percent of patients after the withdrawal of cabergoline.54 Although there are no precise criteria for predicting whether drug withdrawal will be successful, this prospective analysis of
cabergoline withdrawal and the retrospective studies conducted with bromocriptine suggest that lifelong treatment of hyperprolactinemia may not be
inevitable. Possible explanations for the persistence
of normal prolactin levels after drug withdrawal include a cytocidal effect of the dopamine agonist and
the natural history of the tumor.39,40,55

guidelines
There are no formal guidelines for the management
of prolactinoma.

conclusions
and recommendations
The diagnosis of a prolactinoma is established on
the basis of a sustained elevation of serum levels of
prolactin and radiographic evidence of a pituitary
adenoma after other causes of hyperprolactinemia
have been ruled out. The indications for therapy include infertility, the presence of a macroadenoma,
and hypogonadism. The primary therapy for all prolactinomas is a dopamine agonist. Bromocriptine
and cabergoline are both effective in reducing the
size of the tumor and restoring gonadal function,

of

medicine

but bromocriptine should be used when pregnancy

is the goal (Fig. 2). Cabergoline is more expensive
than bromocriptine but easier to administer, usually
better tolerated, and effective in patients who do not
have a response to bromocriptine. Surgery is rarely
curative in patients with prolactinomas and should
be recommended only when medical therapy is ineffective. Although discontinuation of drug therapy
for macroadenomas usually leads to recurrent hyperprolactinemia and expansion of the tumor, the
dose of the medication can often be decreased after two years or more of therapy. My approach is to
taper the medication at three-month intervals (reducing the weekly dose of cabergoline by 0.25 mg
or the daily dose of bromocriptine by 2.5 mg), check
the prolactin level after each dose reduction, and obtain an MRI scan six months after the initiation of
tapering, in order to rule out tumor enlargement.
The young woman described in the vignette
has a prolactin-secreting microadenoma. There is
no indication to test for anterior pituitary dysfunction or to perform formal visual-field testing. She
should be treated with bromocriptine and should
use mechanical contraception until regular menstrual cycles have been established. When she becomes pregnant, the bromocriptine should be discontinued, though the medication is likely to be
needed again, after pregnancy and lactation. For patients who have been receiving drug therapy for
two years or more, I would attempt to discontinue
the medication, with reassessment of prolactin levels, to determine whether there is an ongoing need
for treatment.

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