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Hyperprolactinemia: Causes, Symptoms, Prognosis, Diagnosis and Latest Treatment

Hyperprolactinemia is one of the most common pituitary abnormalities, which is caused by an increased secretion of prolactin (above 20ng/ml) from the pituitary gland.  Although the disorder is detected in less than 1% of the general population, it has been found in up to 25% of patients with secondary amenorrhea. 

The most common symptoms of hyperprolactinemia are secondary amenorrhea (cessation of menstruation) and/or galactorrhea (the secretion of breast milk in men, or in women who are not breastfeeding an infant).  In men, hyperprolactinemia may also lead to decreased libido or erectile dysfunction. 

 

Causes and Treatments

Pathologic hyperprolactinemia can have many different causes.  It can be caused by prolactinomas (benign tumors of the pituitary glands), hypothyroidism or treatment with certain medications (e.g. clozapine, methyldopa, phenothiazine derivates and metoclopramide).

Among all the different causes of hyperprolactinemia, prolactinomas is the most common endogenous cause.  In the U.S., hyperprolactinemia due to prolactinomas affects 3% of the female population.  Since dopamine is the chemical in the brain that normally inhibits prolactin secretion, doctors may treat prolactinomas with dopamine agonists like Parlodel® or Dostinex® (Table 1). 

For patients who developed hyperprolactinemia secondary to hypothyroidism or to the adverse effects of other medications, thyroid hormone therapy and dose reduction of the causative drugs have been recommended.  If symptoms of hyperprolactinemia persist after the above measures, dopamine agonist therapy will be prescribed to control those symptoms.  In patients who cannot tolerate medical treatment or in patients for whom medical treatment has failed, transsphenoidal surgical removal of prolactin-secreting pituitary adenoma is reserved as the last resort.

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Table 1.  Selected product comparison of the Hyperprolactinemia category
 
Dostinex®
Parlodel®
Bromocriptine
Efficacy
+++
++
++
Side-effect
+
++
++
Dosage
Twice per week
OD
OD

+++ – Strong

++ – Moderate

+ – Low

Bromocriptine

Introduced by Novartis in 1978, Parlodel® (bromocriptine) a dopamine agonist, reduces serum prolactin levels, inhibits prolactin secretion, and decreases the size of pituitary tumor in 70% to 100% of patients.  Until the introduction of Dostinex® in 1996, bromocriptine was the only agent approved by the FDA for the treatment of amennorrhea/galactorrhea secondary to hyperprolactinemias and this product was once considered the gold standard.

Today, Dostinex® has replaced bromocriptine in the treatment of galactorrhea with the latter being used for other purposes.  Bromocriptine is now mainly used for the treatment of Parkinson’s disease, acromegaly and infertility.

Therapy with bromocriptine for hyperprolactinemia should begin with 2.5 mg daily, taken at bedtime to minimize the side effects of nausea, dizziness, and nasal congestion.  The dose may be increased by 2.5 mg every week, as needed, to achieve normal serum prolactin concentrations, eliminate symptoms or both.  Typical dosage of bromocriptine is 2.5 mg two or three times daily.

Dostinex®

Dostinex® (cabergoline), a dopamine receptor agonist, is the most commonly used product for hyperprolactinemia.  Launched by Pharmacia in 1996, Dostinex® is indicated only for the treatment of hyperprolactinemia. 

Unlike bromocriptine, however, Dostinex® possesses (1) stronger prolactin-lowering effect, (2) lower incidence of serious adverse effects and (3) a better dosing schedule.

In a large, multi-center, sequential double-blind study involving 459 women with hyperprolactinemic amenorrhea, Dostinex® was shown to be more effective than bromocriptine in normalizing the prolactin level and in achieving complete clinical success (resumption of ovulatory cycles or occurrence of pregnancy).5 After two weeks of treatment, higher percentage of patients treated with Dostinex® achieved a normal prolactin level than those treated with bromocriptine (83.4% vs. 58.5%, P<0.0001).  Furthermore, complete clinical success (resumption of ovulatory cycles or occurrence of pregnancy) and global success (resumption of ovulation plus either prolactin normalization or lowering to <50% of baseline) were also significantly higher in the Dostinex®-treated patients than in the bromocriptine-treated patients (71.7% versus 52.5%, (P<0.0001) and 70.4% versus 47%, (P<0.0001)).

Severe adverse events associated with Dostinex® were also significantly less frequent than with bromocriptine (13.6% vs. 20.3%, P = 0.056).   The most common side effects associated with Dostinex® are nausea (27%), constipation (10%) and abdominal pain (5%).  As with bromocriptine therapy, side effects may be avoided if treatment is started gradually.

Besides having a superior efficacy and improved tolerability profile, Dostinex® also possesses an excellent dosing schedule, which improves the compliance of patients on this drug.  Whereas bromocriptine requires multiple daily dosages for effectiveness, Dostinex®, with its long half-life of 80 hours, requires only twice-weekly administration.

With its superior efficacy, favorable tolerability profile and convenient dosing schedule, it is expected that Dostinex® will continue to be the principle treatment of hyperprolactinemia.

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