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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
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
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
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.
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
Clin Endocrinol
75:692.
Metab
1992;
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.