Hyperprolactinemia

1. What every clinician should know

Clinical Features and Incidence

Hyperprolactinemia can be defined as circulating plasma prolactin concentrations exceeding the upper limit of normal. Causes of hyperprolactinemia include a variety of physiological, iatrogenic or pathologic conditions. The prevalence of hyperprolactinemia ranges from 0.4% in an unselected adult population to a 5% incidence among women of reproductive age. In postmortem studies, pituitary microadenomas have been found in 1.5%-26.7% of autopsies.

Most common symptoms of hyperprolactinemia:

Oligomenorrhea
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Amenorrhea
Galactorrhea
Infertility
Headaches
Visual impairment
Hypopituitarism

Those at Risk for Hyperprolactinemia

Hyperprolactinemia is common in women taking conventional antipsychotics that block dopamine receptors.

2. Diagnosis and differential diagnosis

Diagnosis and Work-up

Hyperprolactinemia should be investigated in all women who present with menstrual disturbances such as amenorrhea. Women with hyperprolactinemia may also present with infertility and/or galactorrhea.

Galactorrhea

Galactorrhea refers to nipple discharge, either spontaneous or expressed, that contains milk.

Galactorrhea can be diagnosed by viewing fat globules in a droplet of discharge under light microscopy. Prolactin levels will actually be normal in 85% of women with galactorrhea. However, when both galactorrhea and amenorrhea are present, the odds of hyperprolactinemia is 90%.

Laboratory Diagnosis:

Hyperprolactinemia is defined as elevation of circulating prolactin hormone above the normal level, usually 20 ng/mL in women.

Blood drawing for prolactin is ideally performed in an awake, fasting state.
The follicular phase of the menstrual cycle is the most appropriate time to check serum prolactin levels.
Per Endocrine Society practice guidelines, a single measurement of serum prolactin above normal confirms the diagnosis, as long as the serum sample was obtained without excessive venipuncture stress.

Additional Labs to Order

Diagnosis of “pathologic” hyperprolactinemia requires exclusion of other physiologic or iatrogenic causes of excess prolactin secretion.

Once elevated serum prolactin levels have been confirmed, the following labs should also be ordered to rule out other conditions that may result in elevated prolactin levels.
Additional labs include:

Thyroid stimulating hormone (TSH)

Human chorionic gonadotropin (HCG)

Blood urea nitrogen (BUN)

Creatinine

Causes of Hyperprolactinemia

Physiologic variation due to stimulation or irritation of the chest wall by suckling, breast implants, herpes zoster or local trauma.
Pregnancy, which can increase prolactin levels to as high as 600 ng/mL.
Medications that block dopamine receptors, most notably conventional antipsychotics, can increase prolactin levels up to tenfold.

Up to 65% of women taking antipsychotics experience hyperprolactinemia.

Other medications that increase prolactin include selective serotonin reuptake inhibitors, tricyclic antidepressants, H₂ receptor blockers, methyldopa, verapamil, reserpine, metoclopramide and protease inhibitors.
Endocrine conditions such as acromegaly or hypothyroidism.
Chronic renal insufficiency may cause increased prolactin levels due to impaired clearance.

When Drug-induced Hyperprolactinemia Is Suspected

In a patient with suspected drug-induced hyperprolactinima, the etiology can be confirmed by discontinuing or substituting the drug with another agent for 3 days as long as the patient’s physician agrees.
A serum prolactin level can then be rechecked in 3 days.
If the drug cannot be discontinued or the onset of hyperprolactinemia does not coincide with the medication, pituitary magnetic resonance imaging (MRI) is recommended to assess for a pituitary mass.

Pituitary Imaging

Pituitary imaging is indicated with any degree of unexplained hyperprolactinemia.

About 40% of hyperprolactinemic patients will have a detectable pituitary abnormality even when prolactin levels are only mildly elevated.
MRI is the most sensitive diagnostic modality, although contrast-enhanced computed tomography scanning (CT scan) may also be performed.

Microadenoma: A lesion <10 mm in diameter

Macroadneoma: A lesion >10 mm in diameter
If the tumor extends beyond the sella turcica or is adjacent to the optic chiasm, the patient should be referred to neuro-ophthalmology for visual field testing.

If a pituitary lesion is identified

Screening tests should be performed to rule out an elevation of other pituitary hormones since non-prolactin-secreting lesions may cause hyperprolactinemia.
Labs include:

24-hour urine free cortisol (to rule out corticotropin-secreting lesion)

Serum insulin-like growth factor (IGF-1), to rule out somatotropin-secreting lesion)

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH), to rule out gonadotropic adenomas.

Thyroid stimulating hormone (TSH), to rule out thyrotropic adenomas

Observation

These women do not require pituitary imaging but should be screened for acromegaly since elevated somatotropin levels may stimulate milk secretion.

3. Management

Overview of Management Options

Observation

Observation is a valid option for patients with hyperprolactinemia not associated with a mass or a microprolactinoma not causing neurological symptoms.

90%-95% of microadenomas remain stable or shrink over time.
Most patients can be safely monitored with serial prolactin levels, while repeat imaging is reserved for cases of significant serum elevations or development of neurological symptoms.
Patients should be advised that osteopenia or osteoporosis may result from prolonged hypoestrogenism and hyperprolactinemia.

Estrogen therapy or an estrogen-containing contraceptive should be considered.

Medical Therapy

Medical therapy is directed at stimulating dopamine receptors. Bromocriptine and cabergoline are the only medications currently approved by the Food and Drug Administration (FDA) for the treatment of primary hyperprolactinemia.

Bromocriptine

Bromocriptine (Parlodel), an ergot derivative and dopamine agonist.

In addition to treating hyperprolactinemia, it carries the additional indication of ovulation induction

Available in an oral form in the United States

Side effects: Nausea, vomiting, postural hypotension, dizziness, syncope, headache, constipation, nasal congestion

Dosage: Initiated with one half of a 2.5 mg tablet taken with food at night. The dose is then increased by one half to one tablet every few days as needed. Vaginal administration of 2.5 to 5 mg daily is also effective and may reduce side effects.

Therapeutic response is assessed by checking serum prolactin level several days after initiating therapy and after each dose adjustment.
Cabergoline

Cabergoline (Dostinex) is an ergot dopamine agonist with the added benefit of once- or twice-weekly dosing and decreased side effects.

Effective in normalizing prolactin levels and restoring ovulation in 85-90% of women.

Oral dosing is started at 0.25 mg weekly, then twice weekly if needed. Dosage may then be titrated up as needed.

In 2007, two reports associated cabergoline with valvular heart disease in patients with Parkinson disease.

Relationship appears dose dependent and with doses much higher than used to treat hyperprolactinemia.

Recent studies examining the frequency of cardiac valvulopathy in hyperprolactinemic patients treated with cabergoline only found a slightly increased risk of mild tricuspid regurgitation.

Data on safety of cabergoline in pregnancy is limited so it is currently recommended the drug be discontinued one month prior to attempting conception. In our practice, a patient attempting to conceive would be switched to bromocriptine while trying to conceive. If the patient cannot tolerate bromocriptine or is only well-controlled while taking cabergoline, she is counseled that cabergoline is not approved by the Food and Drug Administration for use in pregnancy.

Surgery

Surgical resection of prolactinomas is most often accomplished as a transsphenoidal partial hypophysectomy.
Recommended today only if medical therapy is not effective or tolerated.
Complications of transsphenoidal pituitary surgery include pituitary insufficiency, diabetes insipidus, cerebrospinal fluid fistulas, carotid artery injury, loss of vision, and meningitis.
In recent years an endonasal endoscopic approach has been used with less morbidity than the transsphenoidal approach.

Irradiation

Currently gamma knife radiotherapy is used on a limited basis to treat residual lesions.
Cure rates have been inconsistent.
Side effects include hypopituitarism, increased risk of stroke and vision loss.

Individualized Management Recommendations

No Prolactinoma – Pregnancy Not Desired

Observation and dopamine agonist therapy are options.
If observation is selected, patient should be informed of potential for negative impact on bone density.
Combined oral contraceptive pills can be safely taken.
For those treated medically, prolactin levels should be checked annually after normalization.

Prolactinoma Present – Pregnancy Not Desired

When a pituitary lesion is seen, other hormone-producing adenomas should be excluded.
Patients with microadenomas can be offered observation or dopamine agonist therapy.
Combined oral contraceptives may be taken in presence of microadenomas and may protect against bone loss, but prolactin levels should be monitored.
Patients with macroadenomas should be treated with dopamine agonist therapy.

MRI should be repeated 6 months after dopamine agonist therapy.

Consider surgical resection if macroprolactinoma threatens to compromise the optic nerve or does not respond to medical therapy.

No Prolactinoma – Pregnancy Desired

Bromocriptine is first-line therapy when pregnancy is desired.
The drug is discontinued when pregnancy is diagnosed.
Discontinuation does not increase risk of pregnancy loss.
There is no clinical utility in measuring prolactin levels during pregnancy due to normal elevation of prolactin levels during pregnancy.
Hyperprolactinemic women who do not respond to dopamine agonists should be referred to a reproductive endocrinologist for ovulation induction with gonadotropins.

Prolactinoma Present – Pregnancy Desired

Other hormone-producing adenomas must be excluded prior to treatment.
Dopamine agonists or ovulation induction agents can then be used.
Patients must be counseled that prolactinoma enlargement my occur during pregnancy due to elevated estrogen levels.
When pregnancy is achieved:

Dopamine agonists are discontinued by tapering the daily dose to avoid adenoma infarction.

A baseline neuro-opthalmologic examination is recommended.

In patients with macroprolactinomas, visual field testing should be performed each trimester.

Measuring prolactin levels during pregnancy is not useful in monitoring prolactin growth.

Any suggestion of optic nerve compression should prompt MRI evaluation.

Breastfeeding is not contraindicated.

Asymptomatic Medication-Induced Hyperprolactinemia

Endocrine Society practice guidelines recommend clinicians not treat patients with asymptomatic medication-induced hyperproactinemia.

4. Complications

Multiple studies implicate hyperprolactinimia with decreased bone mineral density. One study of premenopausal women with prolactinomas reported a relative risk for osteoporosis of 4.5 compared to healthy controls. While bone loss may stop after successful treatment, bone density does not return to baseline levels.

Potential Management Complications

Observation

Patients should be advised that osteopenia or osteoporosis may result from prolonged hypoestrogenism and hyperprolactinemia. Estrogen therapy or an estrogen-containing contraceptive should be strongly considered.

Medical Therapy

Side effects of bromocriptine include nausea, vomiting, postural hypotension, dizziness, syncope, headache, constipation, nasal congestion. Cabergoline has milder side effects but presents an association with cardiac valvulopathy and increased risk of mild tricuspid regurgitation.

Surgery

Complications of transphenoidal pituitary surgery include pituitary insufficiency, diabetes insipidus, cerebrospinal fluid fistulas, carotid artery injury, loss of vision and meningitis.

Irradiation

Side effects include hypopituitarism, increased risk of stroke and vision loss.

5. Prognosis and outcome

Prognosis of Management Options

Observation

Patients who select observation can be counseled that up to 95% of microadenomas remain stable over time.
In roughly one third of cases, an elevated prolactin level will normalize within 5 years.

Medical Therapy

Recent evidence suggests that lifelong dopamine agonist therapy may not be necessary for all patients.
One study showed hyperprolactinemia recurrence in 24% of patients without prolactinomas, 31% in those with microprolactinomas and 38% in those with macroprolactinomas.
It therefore may be reasonable to consider a trial of medication withdrawal in patients who have been achieved normal prolactin levels and have been asymptomatic for two years. For those with adenomas, a reduction in tumor size should have been demonstrated.

Surgical

Patients should be aware that surgical therapy frequently fails to cure hyperprolactinemia.
One review of microadenomas and macroadenomas treated surgically reported an initial cure rate of 64%. However, the risk of recurrence was 16.9% within 50 months.

Long-term Prognosis

Studies reviewing the natural history of microadenomas show that 95% do not enlarge after four to six years of observation. Over 90% of prolactinomas are confined to the sella and do not increase in size over time. Patients should be counseled that prolactinomas are almost always benign.

6. What is the evidence for specific management and treatment recommendations

Caloa, A, Di Sarno, A, Landi, ML, Scavuzzo, F, Cappabianca, P. “Macroprolactinoma shrinkage during cabergoline treatment is greater in naive patients than in patients pretreated with other dopamine agonists: a prospective study in 110 patients”. J Clin Endocrinol Metab. vol. 85. 2000. pp. 2247-52. (Prospective study showed that cabergoline is effective in treating many patients with macroprolactinomas who received previous treatment with dopamine agonists but is most effective in agonist-naive patients.)

Lafeber, M, Stades, AM, Valk, CD, Cramer, MJ, Teding van Berkhout, F, Zelissen, PM. “Absence of major fibrotic adverse events in hyperprolactinemic patients treated with cabergoline”. Eur J Endocrinol. vol. 162. 2010. pp. 667-75.

Melmed, S, Casanueva, FF, Hoffman, AR, Kleinberg, DL, Montori, VM. “Diagnosis and treatment of of hyperprolactinemia: an Endocrine Society clinical practice guideline”. J Clini Endocrinol Metab. vol. 96. 2011. pp. 273-88.

Webster, J, Piscitelli, G, Polli, A, Ferrari, CI, Ismail, I, Scanlon, MF. “A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group”. N Engl J Med. vol. 331. 1994. pp. 904-9. (Compared cabergoline and bromocriptine in a large, multicenter, double-blind trial for the treatment of hyperprolactinemic, amenorrheic women. A dosage of 0.5 to 1 mg cabergoline twice a week was more effective than 2.5 to 5 mg of bromocriptine twice a day at restoring ovulatory cycles (72% vs 52%). Normoprolactinemia was achieved in 83% and 58% in the cabergoline and bromocriptine groups, respectively.)

Webster, J, Piscitelli, G, Polli, A, D’Alberton, A, Falsetti, L. “Dose-dependent suppression of serum prolactin by cabergoline in hyperprolactinemia: a placebo controlled, double blind, multicentre study. European Multicentre Cabergoline Dose-finding Study Group”. Clin Endocrinol (Oxf). vol. 37. 1992. pp. 534-41. (Examined dose-dependent prolactin suppression. In this placebo-controlled multicenter study, 74% of hyperprolactinemic patients had normal prolactin levels within 4 weeks of therapy with 0.5 mg twice weekly. A dosage of 1 mg twice weekly resulted in normalization in 95% of subjects.)

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