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INTRODUCTION |
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Background: Hyperprolactinemia
is a condition of elevated serum prolactin. Prolactin is a 198 amino acid
protein (23-kD) produced in the lactotroph cells of the anterior pituitary
gland. Its primary function is to enhance breast development during pregnancy
and to induce lactation. However, prolactin also binds to specific receptors in
the gonads, lymphoid cells, and liver. Secretion is pulsatile; it increases with
sleep, stress, pregnancy, and chest wall stimulation or trauma, and therefore
must be drawn after fasting. Normal fasting values generally are less than 30 ng/mL
depending on the individual laboratory.
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Pathophysiology: The primary action of prolactin is to
stimulate breast epithelial cell proliferation and induce milk production.
Estrogen stimulates the proliferation of pituitary lactotroph cells, resulting
in an increased quantity of these cells in premenopausal women, especially
during pregnancy. However, lactation is inhibited by the high levels of estrogen
and progesterone during pregnancy. The rapid decline of estrogen and
progesterone in the postpartum period allows lactation to occur. During
lactation and breastfeeding, ovulation may be suppressed due to the suppression
of gonadotropins by prolactin.
Dopamine has the dominant influence over prolactin secretion. Secretion of
prolactin is under tonic inhibitory control by dopamine, which acts via D2-type
receptors located on lactotrophs. Prolactin production can be stimulated by the
hypothalamic peptides, thyrotropin-releasing hormone (TRH) and vasoactive
intestinal peptide (VIP). Thus, primary hypothyroidism (a high TRH state) can
cause hyperprolactinemia. VIP increases prolactin in response to suckling,
probably because of its action on receptors that increase adenosine 3?5?cyclic
phosphate (cAMP).
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Frequency:
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- In the US: This condition occurs in less than 1% of the
general population and in 10-40% of patients presenting with secondary
amenorrhea. Approximately 75% of patients presenting with galactorrhea and
amenorrhea have hyperprolactinemia. Of these patients, approximately 30% have
prolactin-secreting tumors.
Mortality/Morbidity:
- Mortality is unlikely; however, in cases where the condition is due to a
large prolactin-secreting tumor, local mass effect can lead to significant
morbidity.
- The condition causes systemic complaints that often resolve when the
prolactin level returns to normal or once the tumor shrinks.
Sex:
- Clinical presentation in women is more obvious and occurs earlier than in
men. They typically present with oligomenorrhea, amenorrhea, galactorrhea, or
infertility. Galactorrhea is less common in postmenopausal women due to lack
of estrogen. If a pituitary tumor is present, it is a microadenoma (<10 mm)
approximately 90% of the time.
- Prolactinoma is less common in men than in women, typically presenting as
an incidental finding on a brain CT scan or MRI, or with symptoms of tumor
mass effect. This is most evident as a complaint of visual disturbances or
headache. By the time of diagnosis in men, approximately 60% have
macroprolactinomas.
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CLINICAL |
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History:
- Women typically present with a history of oligomenorrhea, amenorrhea, or
infertility, which generally result from prolactin suppression of gonadotropin-releasing
hormone (GnRH). Galactorrhea is due to the direct physiologic effect of
prolactin on breast epithelial cells.
- Men typically present with complaints of sexual dysfunction, visual
problems, or headache and are subsequently diagnosed with hyperprolactinemia
in the evaluation process. Prolactin suppresses GnRH, causing a decrease in
luteinizing hormone and follicle-stimulating hormone, ultimately leading to
decreased serum testosterone levels and hypogonadism. Prolactinoma in men also
may cause neurological symptoms, particularly visual-field defects.
- In both sexes, the presence of a pituitary tumor may cause visual-field
defects or headache. Most patients with a prolactinoma (the most common type
of pituitary adenoma) are women.
Physical: Physical findings most commonly encountered in
patients with hyperprolactinemia are galactorrhea and, occasionally,
visual-field defects. Typically, the diagnosis is made via the aid of laboratory
studies.
Causes: The diagnosis of hyperprolactinemia should be
included in the differential for female patients presenting with oligomenorrhea,
amenorrhea, galactorrhea, or infertility or for male patients presenting with
sexual dysfunction. The condition is discovered in the course of evaluating the
patient’s problem. Once discovered, hyperprolactinemia has a broad differential
that includes many normal physiologic conditions.
- Pregnancy always should be excluded unless the patient is postmenopausal
or has had a hysterectomy. In addition, hyperprolactinemia is a normal finding
in the postpartum period.
- Other common conditions to exclude include a nonfasting sample, excessive
exercise, a history of chest wall surgery or trauma, renal failure, and
cirrhosis. Postictal patients also develop hyperprolactinemia within 1-2 hours
after a seizure. These conditions usually produce a prolactin level of less
than 50 ng/mL.
- Hypothyroidism, an easily treated disorder, also may produce a similar
prolactin level.
- Detailed drug history should be obtained because many common medications
cause hyperprolactinemia, usually with prolactin levels of less than 100 ng/mL.
Drugs that may cause the condition include the following:
- Dopamine receptor antagonists (eg, phenothiazines, butyrophenones,
thioxanthenes, risperidone, metoclopramide, sulpiride, pimozide)
- Dopamine-depleting agents (eg, methyldopa, reserpine)
- Others (eg, isoniazid, danazol, tricyclic antidepressants, monoamine
antihypertensives, verapamil, estrogens, antiandrogens, cyproheptadine,
opiates, H2-blockers [cimetidine], cocaine)
- If no obvious cause is identified or if a tumor is suspected, MRI should
be performed.
- Although no single test can help determine the etiology of
hyperprolactinemia, a prolactinoma is likely if the prolactin level is
greater than 250 ng/mL and less likely if the level is less than 100 ng/mL.
- Prolactin-secreting adenomas are divided into 2 groups: (1)
microadenomas (more common in premenopausal women), which are smaller than
10 mm and (2) macroadenomas (more common in men and postmenopausal women),
which are 10 mm or larger.
- If the prolactin level is greater than 100 ng/mL or less than 250 ng/mL,
the evaluating physician must decide whether a radiographic study is
indicated. In many cases, with the availability of MRI scanners, imaging is
performed earlier and at lower prolactin levels to rule out a non–prolactin-producing
tumor.
- When the underlying cause (physiologic, medical, pharmacologic) cannot
be determined and an MRI does not identify an adenoma, idiopathic
hyperprolactinemia is diagnosed.
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DIFFERENTIALS |
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Acromegaly
Acute Renal Failure
Erectile Dysfunction
Herpes Zoster
Hypothyroidism
Pituitary Macroadenomas
Pituitary Microadenomas
Prolactinoma
Other Problems to be Considered:
Alcoholic cirrhosis
Pregnancy
Postparturition
Nipple stimulation
Nonfasting specimen
Drug effect
Postictal state
Chest wall trauma
Chest wall tumors
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WORKUP |
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Lab Studies:
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- Generally, hyperprolactinemia is discovered in the course of evaluating a
patient's presenting complaint, ie, amenorrhea, galactorrhea, erectile
dysfunction. Occasionally, several fasting measurements of prolactin must be
obtained.
- Current thyroid-stimulating hormone assays are very sensitive for
detecting hypothyroid conditions.
- Measuring blood urea nitrogen and creatinine is important for detecting
renal failure.
- History of alcohol abuse and abdominal examination may give clues for
cirrhosis as a possible etiology.
- Pregnancy testing is required unless the patient is postmenopausal or has
had a hysterectomy.
- Patients with macroadenoma should be evaluated for possible
hypopituitarism. Male patients should have testosterone levels checked.
- Many patients with acromegaly have prolactin cosecreted with growth
hormone. Anyone thought to have acromegaly should be evaluated with an
insulin-like growth factor-1 (IGF-1) level measurement and a glucose tolerance
test for nonsuppressible growth hormone levels if needed.
Imaging Studies:
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- Although modern high-speed helical CT scanners produce very detailed
images, MRI is the imaging study of choice. MRI can detect adenomas that are
as small as 3-5 mm.
Other Tests:
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- These would be determined by any identified cause, eg, visual-field
testing especially if a pituitary macroadenoma is found or if optic nerve
involvement is noted on imaging studies.
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TREATMENT |
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Medical Care: Direct treatment is
geared toward resolving hyperprolactinemic symptoms or reducing tumor size.
Patients on medications causing hyperprolactinemia should have them withdrawn if
possible. Patients with hypothyroidism should be given thyroid hormone
replacement therapy.
- When symptoms are present, medical therapy is the treatment of choice.
Patients with hyperprolactinemia and no symptoms (idiopathic or
microprolactinoma) can be monitored without treatment. Consider treatment for
women with amenorrhea. In addition, duel-energy x-ray absorptiometry (DEXA)
scanning should be considered to evaluate bone density.
- The persistent hypogonadism associated with hyperprolactinemia can lead to
osteoporosis. Treatment significantly improves the patient's quality of life.
If the goal is to treat hypogonadism only, patients with idiopathic
hyperprolactinemia or microadenoma can be treated with estrogen replacement
and prolactin levels can be monitored.
- Radiation treatment is another option. However, the risk of
hypopituitarism makes this a poor choice. It may be necessary for rapidly
growing tumors, but its benefits in routine treatment have not been shown to
outweigh the risks.
- The dopamine agonist, bromocriptine mesylate, is the initial drug of
choice. It lowers the prolactin level in 70-100% of patients. Agents other
than bromocriptine have been used (eg, cabergoline, quinagolide).
Cabergoline and pergolide are available in the United States. Cabergoline,
in particular, probably is more effective and causes fewer adverse effects
than bromocriptine. However, it is much more expensive. Cabergoline often is
used in patients who cannot tolerate the adverse effects of bromocriptine or
in those who do not respond to bromocriptine. Pergolide has not been
approved by the US Food and Drug Administration (FDA) for use in patients
with this condition.
- Response to therapy should be monitored by checking fasting serum
prolactin levels and checking tumor size with MRI. Most women (approximately
90%) regain cyclic menstruation and achieve resolution of galactorrhea.
Testosterone levels in men increase but may remain below normal.
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- Therapy should be continued for approximately 12-24 months (depending on
the degree of symptoms or tumor size) and then withdrawn if prolactin levels
have returned to the normal range. After withdrawal, approximately one sixth
of patients maintain normal prolactin levels.
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- Bromocriptine also is used to shrink macroadenomas. Normalization of
visual fields is observed in as many as 90% of patients. A failure to
improve within 1-3 months is an indication for surgery. Tumors usually
shrink to 50% of their original size in approximately 90% of patients
treated for macroadenomas for 1 year. In patients with nonprolactinoma
tumors (masses that are compressing the pituitary stalk), medical treatment
reduces serum prolactin levels but does not reduce tumor size. Cabergoline
is somewhat more effective than bromocriptine in terms of tumor shrinkage.
Surgical Care: General indications for pituitary surgery
include patient drug intolerance, tumors resistant to medical therapy, patients
who have persistent visual-field defects in spite of medical treatment, and
patients with large cystic or hemorrhagic tumors.
Consultations: Physicians who are comfortable with the
initial evaluation of a patient (without evidence of tumor mass effect) can
easily initiate therapy and provide follow-up. However, given the time
constraints of modern ambulatory medicine, consultation with an endocrinologist
often is necessary.
|
MEDICATION |
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The goal of pharmacotherapy is to reduce morbidity
and prevent complications.
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Drug Category: Dopamine agonists -- These
agents directly stimulate postsynaptic dopamine receptors. Dopaminergic neurons
in tuberoinfundibular processes modulate the secretion of prolactin from the
anterior pituitary by secreting a prolactin inhibitory factor, believed to be
dopamine.
Drug Name
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Bromocriptine (Parlodel) --
Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor
agonist; partial dopamine D1-receptor agonist. Inhibits prolactin secretion
with no effect on other pituitary hormones. May be given with food to
minimize possibility of GI irritation. |
Adult Dose |
1.25-2.5 mg PO initially; increase
gradually every few days to approximately 5-10 mg daily in divided doses.
|
Pediatric Dose |
Not recommended |
Contraindications |
Documented hypersensitivity; ischemic
heart disease, uncontrolled hypertension, peripheral vascular disorders;
breastfeeding |
Interactions |
Toxicity may increase with ergot
alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa,
phenothiazines, and reserpine may decrease effects |
Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
Precautions |
Caution in renal or hepatic disease;
generally stopped during pregnancy but can be restarted if symptoms recur;
perform regular visual-field testing during pregnancy to monitor for tumor
growth; should be given hs to minimize postural hypotension or nausea |
Drug Name
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Cabergoline (Dostinex) -- Semisynthetic
ergot alkaloid derivative; strong dopamine D2-receptor agonist with low
affinity for D1 receptors. |
Adult Dose |
0.25-1 mg twice/wk; start with a low
dose and increase q4wk based on prolactin levels |
Pediatric Dose |
Not recommended |
Contraindications |
Documented hypersensitivity; ischemic
heart disease, uncontrolled hypertension, peripheral vascular disorders;
breastfeeding |
Interactions |
Toxicity may increase with ergot
alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa,
phenothiazines, and reserpine may decrease effects |
Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
Precautions |
Caution in renal or hepatic disease;
generally stopped during pregnancy but can be restarted if symptoms recur;
perform regular visual-field testing during pregnancy to monitor for tumor
growth; can be given hs to minimize postural hypotension or nausea |
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FOLLOW-UP |
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Further Outpatient Care:
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- Once the diagnosis has been established and therapy initiated, fasting
prolactin levels should be monitored monthly. Later, prolactin levels can be
monitored every 3-6 months. Shrinkage of the tumor should be followed by
formal visual-field testing and MRI.
Complications:
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- Potential complications of hyperprolactinemia are primarily related to
tumor size and the physiologic effects of the condition. These include
blindness, hemorrhage, osteoporosis, and infertility.
Prognosis:
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- When followed for longer than 7 years, 90-95% of microadenomas remained
stable or gradually decreased prolactin secretion.
- One third of patients with idiopathic hyperprolactinemia may experience
resolution without treatment. This number increases to two thirds if the
patient's basal prolactin level is less than 40 ng/mL.
- Surgery often is not curative for macroprolactinomas, with a recurrence
rate of as high as 40% within 5 years.
- Recurrence rates of hyperprolactinemia are as high as 80%, and,
subsequently, patients require long-term medical therapy.
Patient Education:
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- A decrease in prolactin levels may restore ovulation. Advice about birth
control methods should be given when prolactin levels approach the normal
range.
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MISCELLANEOUS |
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Medical/Legal Pitfalls:
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- The primary reason physicians are sued is for failure to diagnose,
regardless of the diagnosis. The diagnosis of hyperprolactinemia often is made
during the evaluation of the patient's complaints. This condition is easily
diagnosed unless the physician fails to consider it in his or her
differential.
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BIBLIOGRAPHY |
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- Biller MKB, Daniels GH: Neuroendocrine regulation and diseases of the
anterior pituitary and hypothalamus. In: Braunwald E, Isselbacher KJ, Wilson
J, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York,
NY: McGraw-Hill; 1998: 1974-8.
- Blackwell RE: Hyperprolactinemia. Evaluation and management. Endocrinol
Metab Clin North Am 1992 Mar; 21(1): 105-24[Medline].
- Conner P, Fried G: Hyperprolactinemia; etiology, diagnosis and treatment
alternatives. Acta Obstet Gynecol Scand 1998 Mar; 77(3): 249-62[Medline].
- Davies PH: Drug-related hyperprolactinaemia. Adverse Drug React Toxicol
Rev 1997 Jun; 16(2): 83-94[Medline].
- Hartog M, Hull MG: Hyperprolactinaemia. BMJ 1988 Sep 17; 297(6650): 701-2[Medline].
- Jones TH: The management of hyperprolactinaemia. Br J Hosp Med 1995 Apr
19-May 2; 53(8): 374-8[Medline].
- Kaye TB: Hyperprolactinemia. Causes, consequences, and treatment options.
Postgrad Med 1996 May; 99(5): 265-8[Medline].
- Lancet: Management of prolactinoma. Lancet 1990 Sep 15; 336(8716): 661[Medline].
- Molitch ME: Medical treatment of prolactinomas. Endocrinol Metab Clin
North Am 1999 Mar; 28(1): 143-69, vii[Medline].
- Prescrire International: Cabergoline and hyperprolactinaemia: new
preparation. Better than bromocriptine. Prescrire Int 2000; Feb;9(45): 195-7[Medline].
- Wilson JD: Endocrine Disorders of the Breast. In: Braunwald E, Isselbacher
KJ, Wilson J, et al, eds. Harrison's Principles of Internal Medicine. 14th ed.
New York, NY: McGraw-Hill; 1998: 2116-7.
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