OVERVIEW: What every practitioner needs to know

While elevated prolactin levels are not uncommon, prolactinomas are relatively rare. Moderate elevations in prolactin levels are usually due to stress or dopamine D2 receptor antagonists.

Are you sure your patient has a prolactinoma? What are the typical findings for this disease?

The most common symptoms of a prolactinoma in children and adolescents result from elevated prolactin and include delayed puberty in males and females, amenorrhea and galactorrhea in females and tumor mass effects (headaches and visual field defects). Visual field defects are associated with macroadenomas, are a medical emergency, and may result in exophthalmia and blindness. Although the causality is not established, hyperprolactinemia has been associated with gynecomastia in prepubertal boys.

What other disease/condition shares some of these symptoms?

Elevated prolactin levels may be seen in patients taking estrogen, tricyclic antidepressants, opiates, amphetamines, hypertension drugs (reserpine, verapamil, methyldopa), and some drugs that are used to treat gastroesophageal reflux (cimetidine). The stress associated with a venipucture may result in an elevated prolactin level. Hpothyroidism may also result in elevated prolactin levels.

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What caused this disease to develop at this time?

Most prolactinomas are sporadic, but may occur as part of multiple endocrine neoplasia type 1 syndrome.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of a prolactinoma requires both biochemical evidence of elevated serum prolactin levels and radiographic evidence of a pituitary adenoma.

Prolactin secretion is pulsatile, and release may occur due to stress (for example, during blood drawing). Therefore, 2 to 3 prolactin levels should be drawn at intervals, 20 to 30 minutes after venipuncture. Normal prolactin values are higher in women than in men and are usually lower than 25 μg/dl.

A prolactin level above normal obtained without excessive venipuncture-induced stress confirms the diagnosis. Prolactin levels associated with stress or dopamine antagonists are usually below 100 μg/dl. A prolactin level greater than 250 μg/dl usually indicates the presence of a prolactinoma. A prolactin level greater than 500 μg/dl is diagnostic of a macroprolactinoma (>10 mm).

Would imaging studies be helpful? If so, which ones?

Hyperprolactinemia in the presence of a pituitary adenoma detected by MRI is consistent with the diagnosis of a prolactinoma. However, pituitary microadenomas (incidentalomas) occur in 10% of the population; hence, a radiologic finding must be followed by a biochemical evaluation to detect the presence of elevated hormone levels in the blood. Patients with macroprolactinomas should have a visual field assessment due to potential involvement of the optic nerves.

Confirming the diagnosis

· Hyperprolactinemia may also be caused by any lesion compressing or interrupting the pituitary stalk.

· Asymptomatic pituitary microadenomas (also referred to as incidentalomas) may be present in approximately 10% of the population. Hence, a pituitary microadenoma associated with only moderate elevations in prolactin does not confirm the diagnosis of a prolactinoma. High levels of prolactin found in tests repeated several times on different days associated with a shrinkage in the size of the tumor usually confirm the diagnosis. However, prolactin levels usually correlate with tumor size, hence microadenomas may be associated with moderate levels of prolactin.

· Elevated prolactin levels may be seen in pregnancy. Adolescents with hyperprolactinemia should have a pregnancy test performed.

· High prolactin levels are also seen in renal insufficiency due to decreased clearance. This may be associated with hypogonadal symptoms that may resolve with treatment with pharmacologic agents.

· Hypothyroidism may be associated with elevated prolactin levels; hence, thyroid function studies should be performed in patients with hyperprolactinemia.

· Hyperprolactinemia is also associated with dopamine antagonists with prolactin levels usually below 100 μg/dl. Hypogonadal symptoms may be present.

· Estrogens may cause a small increase in prolactin. A causative role of estrogen in hyperprolactinemia is controversial.

If you are able to confirm that the patient has a prolactinoma, what treatment should be initiated?

Therapy for prolactinomas with dopamine agonists should be initiated to decrease prolactin levels, restore or maintain gonadal function, and to shrink the pituitary mass. Dopamine agonists bind to the D2 receptor, a G-protein-coupled receptor, which is expressed on lactotrophs. Binding leads to a decrease in adenylate cyclase activity and inhibition of inositol phosphate production and phospholipase C activity. This cascade of signaling events leads to a decrease in prolactin synthesis and secretion. We initiate therapy with carbergoline since it has a higher efficiency of tumor shrinkage and normalizing prolactin levels.

The dopamine agonists, dose ranges, and possible adverse effects are shown in Table I.

Table I.
Dopamine agonist Dose Adverse effects
Bromocriptine Dose range: 2.5–15 mg/day divided bid or tidInitiate dosing at 1.25 mg/day Gastrointestinal: nausea, vomiting, abdominal pain; may be decreased with reduced initial dosing
Cabergoline 0.5 – 3.5 mg/week

Cardiovascular: orthostatic hypotension, cardiac valvular alterations (noted with high dose, long-term treatment)

What are the adverse effects associated with each treatment option?

· The most common side effects of dopamine agonists are gastrointestinal and include nausea, vomiting and abdominal pain. These side effects can be decreased or avoided by initiating therapy at the lowest dose and increasing gradually as tolerated. We incrementally increase the dose every two to four weeks as tolerated.

· Dopamine agonists have been reported to increase the risk of valvular heart disease in a few, but not most, reports of hyperprolactinemic patients. Bromocriptine may have a lower risk of valvulopathy than cabergoline; it requires more frequent dosing and is associated with lower tolerability and therapeutic efficacy. There is insufficient evidence to make recommendations for whether echocardiograms should be performed. Our approach is to explain the potential risks and perform an echocardiogram. Since the risk of valvular abnormalities is unknown, adolescents on a high dose cabergoline for long periods of time are encouraged to undergo an echocardiogram every 1 – 2 years.

· Surgery is an option only in cases where drug therapy has failed or for neurosurgical emergencies.

· Radiotherapy is rarely used to treat prolactinomas, with no reports being found in children. Radiotherapy in adult patients is reserved for those who have failed pharmacologic therapy and surgery.

· Management of medication-induced hyperprolactinemia is difficult. We suggest discontinuing the medication for 3 days or substituting an alternative medication followed by measurement of prolactin. If the medication cannot be discontinued, we obtain an MRI. We do not treat patients with asymptomatic medication-induced hyperprolactinemia.

· In adolescents with symptoms associated with hypogonadism, we replace either the estrogen or testosterone.

What are the possible outcomes of prolactinomas?

· Follow-up includes measurement of prolactin levels 1 month after initiating or increasing therapy to guide the step-up in dosage. We repeat the MRI after 6 months to 1 year to document tumor shrinkage. Visual field exams are repeated for patients who had optic chiasm impingement by the tumor. Symptoms of hypogonadism are monitored. Treatment with oral contraceptives is continued as needed since there is no conclusive evidence of an associated increase in tumor size.

· In the majority of patients, pharmacologic management restores prolactin levels to normal and shrinks tumor size. The exact success rate is not well established in the pediatric population. In adults, greater than about 75% of patients will have resolution of galactorrhea, amenorrhea, with shrinkage of tumor size and decrease in prolactin levels.

· Less than 10% of patients fail to respond to therapy after graded increases in medication dosage. Transsphenoidal surgery should be reserved for only those patients with prolactinomas who cannot tolerate cabergoline.

· After 2 years of therapy, in patients who have normal prolactin levels and no MRI evidence of tumor, we taper and discontinue medication. We monitor prolactin levels in these patients at 3 month intervals for the first year after discontinuing therapy. We repeat the MRI if prolactin levels rise above normal.

What causes this disease and how frequent is it?

Prolactinomas are the most frequent hormone-secreting pituitary tumors, with a prevalence estimated at 100 per million in adults. Prolactinomas have been reported in children as young as 2 years of age. The frequency of diagnosis increases in women from the age of 20 years to 50 years. Fifty percent of all pituitary tumors diagnosed in children are prolactinomas. The incidence in females and males is nearly equivalent; however, macroadenomas are found more frequently in males. This may be due to late diagnosis occurring more frequently in males, likely due to later onset of symptoms with delayed referral. Tumor biology may also play a role in gender differences.

How do these pathogens/genes/exposures cause the disease?

Other clinical manifestations that might help with diagnosis and management

What complications might you expect from the disease or treatment of the disease?

Of con­cern is a possible association between treatment with dopamine agonists and cardiac­ valve abnormalities, although data from long­-term, prospective, controlled studies are lacking. The doses of dopamine agonist used to treat prolactinomas are significantly lower than those used in patients reported to have valvular disease; however, patients with prolactinomas are treated for decades, raising concerns regarding this risk.

Are additional laboratory studies available; even some that are not widely available?

How can this disease be prevented?

What is the evidence?

Melmed, S, Casanueva, FF, Hoffman, AR. “Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab. vol. 96. 2011. pp. 273-88. (This is the most current available reference discussing diagnosis and treatment of hyperprolactinemia.)