Official reprint from UpToDate

www.uptodate.com.sci-hub.io 2015 UpToDate

Clinical Manifestations And Evaluation Of Hyperprolactinemia

Author
Peter J Snyder, MD
Section Editor
David S Cooper, MD
Deputy Editor
Kathryn A Martin, MD
Literature review current through: Nov 2015. | This topic last updated: Aug 13, 2014.

INTRODUCTION The
clinical
manifestations of hyperprolactinemia are
relatively few and usually easy to
recognize. Once the presence of prolactin
excess is identified, further evaluation to
establish the underlying cause is usually
straightforward.
The
clinical
manifestations
and
evaluation
of
hyperprolactinemia are reviewed here. The
causes
and
treatment
of
hyperprolactinemia
are
discussed
elsewhere.
CLINICAL
PRESENTATION Hyperprolactinemia
causes typical symptoms in premenopausal
women and in men, but not in
postmenopausal women.
Premenopausal
women
Hyperprolactinemia in premenopausal
women causes hypogonadism, with
symptoms
that
include
infertility,
oligomenorrhea, or amenorrhea [1,2], and
less often galactorrhea.
Menstrual cycle dysfunction Excluding
pregnancy, hyperprolactinemia accounts
for approximately 10 to 20 percent of
cases of amenorrhea. The mechanism
appears to involve inhibition of luteinizing
hormone (LH), and perhaps folliclestimulating hormone (FSH) secretion, via

inhibition of the release of gonadotropinreleasing hormone (GnRH). As a result,

serum gonadotropin concentrations are
normal or low, as in other causes of
secondary hypogonadism.
The symptoms of hypogonadism due to
hyperprolactinemia in premenopausal
women correlate with the magnitude of the
hyperprolactinemia. In most laboratories, a
serum prolactin concentration above 15 to
20 ng/mL (15 to 20 mcg/L SI units) is
considered abnormally high in women of
reproductive age.
A serum prolactin concentration greater
than 100 ng/mL (100 mcg/L SI units) is
typically
associated
with
overt
hypogonadism,
subnormal
estradiol
secretion and its consequences, including
amenorrhea, hot flashes, and vaginal
dryness.
Moderate degrees of hyperprolactinemia,
eg, serum prolactin values of 50 to 100
ng/mL (50 to 100 mcg/L SI units), cause
either amenorrhea or oligomenorrhea.
Mild degrees of hyperprolactinemia, eg,
serum prolactin values of 20 to 50 ng/mL
(20 to 50 mcg/L SI units), may cause only
insufficient progesterone secretion and,
therefore, a short luteal phase of the

menstrual
cycle
[3,4].
Mild
hyperprolactinemia can cause infertility
even when there is no abnormality of the
menstrual cycle; these women account for
about 20 percent of those evaluated for
infertility.
Bone density Women with amenorrhea
secondary to hyperprolactinemia have a
lower spine and forearm bone mineral
density compared with normal women or
women with hyperprolactinemia and
normal menses [5,6]. Restoration of
menses following therapy results in an
increase in bone density, although it may
not return to normal [5,6]. Adolescents,
when compared with adults with
prolactinomas, have lower bone density at
the time of diagnosis and less
improvement after two years of dopamine
agonist therapy [7].
Galactorrhea Hyperprolactinemia
in
premenopausal women can also cause
galactorrhea [8], but most premenopausal
women who have hyperprolactinemia do
not have galactorrhea. In a retrospective
study
of
104
patients
with
hyperprolactinemia ages 30 to 44 years,
the most commonly reported symptoms
were
infertility,
headache,
and
oligomenorrhea in 48, 39, and 29 percent,
respectively [9]. Galactorrhea was slightly
less common (24 percent). Many women
who have galactorrhea have normal serum
prolactin concentrations [8].
Postmenopausal
women Postmenopausal women, by
definition, are already hypogonadal, and
hyperprolactinemia does not change that
situation. Because postmenopausal women
are also markedly hypoestrogenemic,
galactorrhea is rare. Hyperprolactinemia in
these women is recognized only in the
relatively unusual situation when a
lactotroph adenoma becomes so large as to
cause headaches or impair vision, or is
detected as an incidental finding when a

magnetic resonance imaging (MRI) is

performed for an unrelated reason.
Men Hyperprolactinemia also causes
hypogonadotropic hypogonadism in men,
which is manifested by decreased libido,
impotence, infertility, gynecomastia, or
rarely, galactorrhea [10,11]. As in women,
there is a rough correlation between the
presence of any of these symptoms and the
degree of hyperprolactinemia.
Hypogonadotropic hypogonadism
Hyperprolactinemia causes decreased
testosterone secretion and low serum
testosterone concentrations that are not
associated with an increase in LH secretion
[10]. As in women, the effect of prolactin
must be on the pituitary or hypothalamus.
The consequences of the hypogonadism
are similar to those of hypogonadism due
to other causes and include, in the shortterm, decreased energy and libido, and in
the long-term, decreased muscle mass and
body hair, and osteoporosis. In one study
of 20 men, for example, 16 had osteopenia
in the spine and six in the hip [12].
Erectile
dysfunction

Hyperprolactinemia appears to cause

erectile dysfunction by a mechanism
unrelated to hypogonadism because
correcting the hyperprolactinemia with a
dopamine agonist drug corrects the
impotence. One report suggests that
correcting the hypogonadism by the
administration of testosterone does not
correct the impotence, which corresponds
to the authors anecdotal observations.
[10].
Infertility Although hyperprolactinemia
can cause infertility in men, probably by
decreasing LH and perhaps FSH secretion,
it is not a common finding among men
who present for evaluation of infertility. In
a study of 171 infertile men, as an
example, only seven (4 percent) had
hyperprolactinemia [11].

Galactorrhea

Men
with
hyperprolactinemia
may
develop
galactorrhea. This occurs less often than in
women, presumably because the glandular
breast tissue in men has not been made
sensitive to prolactin by preceding
stimulation by estrogen and progesterone.
DIAGNOSIS The
diagnosis
of
hyperprolactinemia is made by a serum
prolactin concentration that is well above
the normal range (>20 ng/mL [20 mcg/L]).
If an initial serum prolactin concentration
is only slightly elevated, (21 to 40 ng/mL
[21 to 40 mcg/L SI units]), the test should
be repeated before the patient is considered
to have hyperprolactinemia.
Hyperprolactinemia is a potential cause of
oligomenorrhea, amenorrhea, galactorrhea,
and
infertility
in
women,
and
hypogonadism and/or erectile dysfunction
in men. Therefore, serum prolactin should
be measured in a patient who presents with
any of these symptoms [13].
Serum prolactin concentrations The
usual normal range for serum prolactin is 5
to 20 ng/mL (5 to 20 mcg/L). The
measurement can be performed at any
time, since usual daily activities have little
effect on prolactin secretion. However,
serum prolactin concentrations may
increase slightly during sleep, strenuous
exercise, and occasionally with emotional
or physical stress, intense breast
stimulation, and high-protein meals.
Therefore, if an initial prolactin level is
only borderline high, the test should be
repeated. Normal values are higher in
women than men, and dynamic testing is
not needed.
Pitfalls in diagnosis
Hook
effect Caution
should
be
exercised in interpreting serum prolactin
concentrations between 20 and 200 ng/mL
(20 to 200 mcg/L SI units) in the presence
of a macroadenoma, because of possible

artifactually low values due to the "hook

effect" [14-16]. This effect occurs when a
very high serum prolactin, eg, 5000 ng/mL
(5000 mcg/L SI units), saturates both the
capture and signal antibodies used in
immunoradiometric and chemiluminescent
assays, preventing the binding of the two
in a "sandwich." The result is an apparent
prolactin concentration that is only
modestly elevated, suggesting that the
macroadenoma
is
clinically
nonfunctioning. The artifact can be
avoided by repeating the assay using a
1:100 dilution of serum [13].
Macroprolactin Two
causes
of
hyperprolactinemia due to decreased
clearance of prolactin include chronic
renal failure and macroprolactin. The latter
is prolactin bound to immunoglobulin G
(IgG), which is usually 150 to 170 kDa in
size, compared with 23 kDa for
monomeric prolactin [17]. This entity is
not of clinical significance directly, but
patients can be misdiagnosed and treated
as
ordinary
hyperprolactinemia.
Misdiagnosis can be avoided by asking the
laboratory to pretreat the serum with
polyethylene glycol to precipitate the
macroprolactin before the immunoassay
for prolactin. This entity is discussed in
greater detail separately.
EVALUATION
OF
HYPERPROLACTINEMIA If
an
initial serum prolactin concentration is
only slightly elevated, (21 to 40 ng/mL [21
to 40 mcg/L SI units]), the test should be
repeated before the patient is considered to
have hyperprolactinemia. If serum
prolactin is elevated on the second sample,
hyperprolactinemia is confirmed and the
next step is to determine the cause. Most
patients with hyperprolactinemia have a
lactotroph adenoma. Therefore, the
evaluation is aimed at (1) exclusion of
pharmacologic or extrapituitary causes of
hyperprolactinemia
and
(2)
neuroradiologic
evaluation
of
the
hypothalamic-pituitary region [18].

History A search for the cause of the

hyperprolactinemia should begin with the
history. One should inquire about
pregnancy
(nonpathologic
hyperprolactinemia) and medications that
can cause hyperprolactinemia (such as
estrogen, neuroleptic drugs such as
risperidone,
metoclopramide,
antidepressant
drugs,
cimetidine,
methyldopa, reserpine, and verapamil).
One should also inquire about headache,
visual
symptoms,
symptoms
of
hypothyroidism, and a history of renal
disease.
Physical examination The physical
examination should be directed toward
testing for a chiasmal syndrome (eg,
bitemporal field loss), and looking for
chest wall injury and signs of
hypothyroidism or hypogonadism.
Laboratory/imaging
tests Studies
should be performed to test for
hypothyroidism and renal insufficiency.
Magnetic resonance imaging (MRI) of the
head should be performed in a patient with
any degree of hyperprolactinemia to look
for a mass lesion in the hypothalamicpituitary region, unless the patient is taking
a
medication
known
to
cause
hyperprolactinemia.
If a mass lesion is found in the region of
the sella turcica, secretion of other
pituitary hormones should also be
evaluated. Only a pituitary adenoma can
cause hypersecretion of other pituitary
hormones, but any mass lesion in the area
of the sella can cause hyposecretion of one
or more pituitary hormones.
If the MRI shows a normal hypothalamicpituitary region and there are no obvious
causes
of
hyperprolactinemia,
the
diagnosis of idiopathic hyperprolactinemia
is made. This syndrome may, in some
patients, be due to microadenomas that are
too small to be seen on imaging.

MRI
in
drug-induced
hyperprolactinemia The degree
of
elevation that can be attributed to a drug
depends upon the drug. Most drugs do not
cause an elevation to over 100 ng/mL, but
the antipsychotic drug risperdal can cause
an elevation up to 300 or even 400 ng/mL
[19]. Therefore, we recommend ordering
an MRI if the serum prolactin
concentration is greater than 100 ng/mL in
patients taking a drug known to elevate the
prolactin concentration, but greater than
300 ng/mL in those taking risperidone.
There are no stimulatory or suppressive
endocrine tests that distinguish between
the causes of hyperprolactinemia.
GALACTORRHEA
HYPERPROLACTINEMIA

WITHOUT

Incidence The
serum
prolactin
concentration is often normal in women
who present with galactorrhea. In the
largest series of patients presenting with
galactorrhea, prolactin was normal in 46
percent [8]. The likelihood that the
prolactin is normal is even higher if
menses are normal. No cause of this
phenomenon has been documented, but
often it represents persistent milk secretion
following correction of elevated prolactin,
most commonly after nursing or druginduced hyperprolactinemia. Galactorrhea
in the absence of hyperprolactinemia is not
the result of any ongoing disease
Diagnosis The first step in diagnosis is
to be sure the breast secretion is clear or
milky. Green or black fluid also usually
represents milk, which can be confirmed
by staining the fluid for fat. Blood in the
fluid is a reason for referral for evaluation
of a breast tumor. If the fluid is milk, the
next step is to measure the serum prolactin
concentration. If the prolactin is elevated,
the cause should be sought, as described
above. If the prolactin is not elevated,
there is no ongoing disease, and no further
tests are needed. Other causes of nipple
discharge are discussed elsewhere.

Treatment Galactorrhea in the absence

of hyperprolactinemia usually does not
need to be treated because it is not
associated with ongoing disease and it is
usually not bothersome. For the unusual
patient
whose galactorrhea
occurs
spontaneously and to a degree that causes
staining of the clothes, treatment with a
low dose of dopamine agonist, such as
0.25 mg of cabergoline twice a week, will
reduce the prolactin concentration to
below normal and reduce or eliminate the
galactorrhea.
INFORMATION
FOR
PATIENTS UpToDate offers two types
of patient education materials, The
Basics and Beyond the Basics. The
Basics patient education pieces are written
in plain language, at the 5th to 6th grade
reading level, and they answer the four or
five key questions a patient might have
about a given condition. These articles are
best for patients who want a general
overview and who prefer short, easy-toread materials. Beyond the Basics patient
education pieces are longer, more
sophisticated, and more detailed. These
articles are written at the 10th to 12th grade
reading level and are best for patients who
want in-depth information and are
comfortable with some medical jargon.

infertility (luteal phase abnormalities or

anovulation). Less often, galactorrhea
occurs. Hyperprolactinemia accounts for
approximately 10 to 20 percent of cases of
amenorrhea.
The symptoms of hypogonadism due to
hyperprolactinemia in premenopausal
women correlate with the magnitude of the
hyperprolactinemia.
Most premenopausal women with
hyperprolactinemia
do
not
have
galactorrhea; among women who present
with galactorrhea as an isolated finding,
nearly 50 percent have normal serum
prolactin concentrations.
Postmenopausal women:
Postmenopausal women are already
hypogonadal, so hyperprolactinemia in
them is recognized only when a lactotroph
adenoma becomes large enough to cause
headaches or impair vision, or is detected
as an incidental sellar mass by magnetic
resonance imaging (MRI). In the setting of
estrogen deficiency, hyperprolactinemia
rarely causes galactorrhea.
Men:

SUMMARY

Hyperprolactinemia
also
causes
hypogonadotropic hypogonadism in men,
resulting in decreased libido and infertility.
Other
manifestations
of
hyperprolactinemia
are
erectile
dysfunction, gynecomastia, and rarely,
galactorrhea. As in women, there is a
rough correlation between the presence of
any of these symptoms and the degree of
hyperprolactinemia.

Premenopausal women:

Evaluation:

The
clinical
manifestations
of
hyperprolactinemia in premenopausal
women are mainly those of hypogonadism
and include menstrual cycle dysfunction
(oligomenorrhea or amenorrhea) and

Women
with
oligomenorrhea,
amenorrhea, or galactorrhea, and men with
symptoms of hypogonadism, impotence,
or gynecomastia should have a serum
prolactin determination. The usual normal

Here are the patient education articles that

are relevant to this topic. We encourage
you to print or e-mail these topics to your
patients. (You can also locate patient
education articles on a variety of subjects
by searching on patient info and the
keyword(s) of interest.)

range for serum prolactin is 5 to 20 ng/mL

(5 to 20 mcg/L).
If the prolactin concentration is only
slightly high (21 to 40 ng/mL [21 to 40
mcg/L SI units]), it should be repeated
before the patient is considered to have
hyperprolactinemia. If the repeat value is
still elevated, the next step is to determine
the cause.
Serum prolactin values above 200 ng/mL
usually indicate the presence of a
lactotroph adenoma (figure 1).
We recommend ordering an MRI if the
serum prolactin concentration is greater
than 100 ng/mL in patients taking a drug
known
to
elevate
the
prolactin
concentration, but greater than 300 ng/mL
in those taking risperidone.
REFERENCES
1. Gmez F, Reyes FI, Faiman C.
Nonpuerperal galactorrhea and
hyperprolactinemia.
Clinical
findings, endocrine features and
therapeutic responses in 56 cases.
Am J Med 1977; 62:648.
2. Schlechte J, Sherman B, Halmi N,
et al. Prolactin-secreting pituitary
tumors in amenorrheic women: a
comprehensive study. Endocr Rev
1980; 1:295.
3. Seppl M, Ranta T, Hirvonen E.
Hyperprolactinaemia and luteal
insufficiency. Lancet 1976; 1:229.
4. Corenblum B, Pairaudeau N,
Shewchuk
AB.
Prolactin
hypersecretion and short luteal
phase defects. Obstet Gynecol
1976; 47:486.
5. Biller BM, Baum HB, Rosenthal
DI, et al. Progressive trabecular
osteopenia
in
women
with
hyperprolactinemic amenorrhea. J

Clin Endocrinol
75:692.

Metab

1992;

6. Schlechte J, Walkner L, Kathol M.

A
longitudinal
analysis
of
premenopausal bone loss in healthy
women
and
women
with
hyperprolactinemia.
J
Clin
Endocrinol Metab 1992; 75:698.
7. Colao A, Di Somma C, Loche S, et
al. Prolactinomas in adolescents:
persistent bone loss after 2 years of
prolactin
normalization.
Clin
Endocrinol (Oxf) 2000; 52:319.
8. Kleinberg DL, Noel GL, Frantz
AG. Galactorrhea: a study of 235
cases, including 48 with pituitary
tumors. N Engl J Med 1977;
296:589.
9. Bayrak A, Saadat P, Mor E, et al.
Pituitary imaging is indicated for
the
evaluation
of
hyperprolactinemia. Fertil Steril
2005; 84:181.
10. Carter JN, Tyson JE, Tolis G, et al.
Prolactin-screening tumors and
hypogonadism in 22 men. N Engl J
Med 1978; 299:847.
11. Segal S, Yaffe H, Laufer N, BenDavid
M.
Male
hyperprolactinemia:effects
on
fertility. Fertil Steril 1979; 32:556.
12. Di Somma C, Colao A, Di Sarno A,
et al. Bone marker and bone
density responses to dopamine
agonist
therapy
in
hyperprolactinemic males. J Clin
Endocrinol Metab 1998; 83:807.
13. Melmed
S,
Casanueva
FF,
Hoffman AR, et al. Diagnosis and
treatment of hyperprolactinemia:
an Endocrine Society clinical
practice
guideline.
J
Clin
Endocrinol Metab 2011; 96:273.

14. St-Jean E, Blain F, Comtois R.

High prolactin levels may be
missed by immunoradiometric
assay
in
patients
with
macroprolactinomas.
Clin
Endocrinol (Oxf) 1996; 44:305.
15. Petakov MS, Damjanovi SS,
Nikoli-Durovi MM, et al.
Pituitary adenomas secreting large
amounts of prolactin may give
false
low
values
in
immunoradiometric assays. The
hook effect. J Endocrinol Invest
1998; 21:184.
16. Barkan AL, Chandler WF. Giant
pituitary prolactinoma with falsely
low serum prolactin: the pitfall of
the "high-dose hook effect": case
report. Neurosurgery 1998; 42:913.

17. Kavanagh-Wright L, Smith TP,

Gibney
J,
McKenna
TJ.
Characterization of macroprolactin
and assessment of markers of
autoimmunity
in
macroprolactinaemic patients. Clin
Endocrinol (Oxf) 2009; 70:599.
18. Casanueva FF, Molitch ME,
Schlechte JA, et al. Guidelines of
the Pituitary Society for the
diagnosis and management of
prolactinomas. Clin Endocrinol
(Oxf) 2006; 65:265.
19. David SR, Taylor CC, Kinon BJ,
Breier A. The effects of olanzapine,
risperidone, and haloperidol on
plasma prolactin levels in patients
with schizophrenia. Clin Ther
2000; 22:1085.

GRAPHICS
Ranges of serum prolactin concentrations in several causes of hyperprolactinemia

The serum prolactin concentration is much higher in most patients who have lactotroph
macroadenoma than in patients with any other cause of hyperprolactinemia. The prolactin
concentrations among other causes overlap with each other.
Data from:
1. Tyson JE, Hwang P, Guyda H, Friesen HG. Studies of prolactin secretion in human
pregnancy. Am J Obstet Gynecol 1972; 113:14.
2. Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48
with pituitary tumors. N Engl J Med 1977; 296:589.
3. David SR, Taylor CC, Kinon BJ, Breier A. The effects of olanzapine, risperidone, and
haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther 2000;
22:1085.
4. Rivera JL, Lal S, Ettigi P, et al. Effect of acute and chronic neuroleptic therapy on
serum prolactin levels in men and women of different age groups. Clin Endocrinol
1976; 5:273.
5. McCallum RW, Sowers JR, Hershman JM, Sturdevant RA. Metoclopramide
stimulates prolactin secretion in man. J Clin Endocrinol Metab 1976; 42:1148.
6. Mancini AM, Guitelman A, Vargas CA, et al. Effect of sulpiride on serum prolactin
levels in humans. J Clin Endocrinol Metab 1976; 42:181.
7. Sowers JR, Sharp B, McCallum RW. Effect of domperidone, an extracerebral
inhibitor of dopamine receptors, on thyrotropin, prolactin, renin, aldosterone, and 18hydroxycorticosterone secretion in man. J Clin Endocrinol Metab 1982; 54:869.
8. Steiner J, Cassar J, Mashiter K, et al. Effects of methyldopa on prolactin and growth
hormone. Br Med J 1976; 1:1186.

9. Lee PA, Kelly MR, Wallin JD. Increased prolactin levels during reserpine treatment of
hypertensive patients. JAMA 1976; 235:2316.
10. Fearrington EL, Rand CH Jr, Rose JD. Hyperprolactinemia-galactorrhea induced by
verapamil. Am J Cardiol 1983; 51:1466.
11. Veldhuis JD, Borges JL, Drake CR, et al. Divergent influences of the structurally
dissimilar calcium entry blockers, diltiazem and verapamil, on thyrotropin- and
gonadotropin-releasing hormone-stimulated anterior pituitary hormone secretion in
man. J Clin Endocrinol Metab 1985; 60:144.