What is the role of bromocriptine (BEC) in the treatment of prolactinomas?

Updated: Mar 25, 2018
  • Author: Venkatesh Babu Segu, MD, MBBS, DM; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Answer

Bromocriptine (BEC) is generally considered to be the agent of choice in the treatment of prolactinoma because of its long track record and safety. As a DA agonist, it decreases the synthesis and secretion of PRL. [3] It also decreases the rate of tumor cell division and the growth of individual cells.

Typically, BEC is administered at an initial dose of 1.25 mg nightly with food and is gradually increased to 2.5 mg bid in 1-2 weeks, as tolerated. Doses larger than 7.5 mg/d are seldom needed except in the treatment of macroadenomas.

Common adverse effects include nausea, nasal stuffiness, and dizziness associated with orthostatic hypotension. Others include vasospasm in the peripheral circulation and exacerbation or unmasking of depression and psychosis.

In patients who are intolerant to even small doses of BEC, one alternative is to administer the same daily dose intravaginally, a method that has almost equal efficacy.

Normalization of PRL levels occurs in 85-90% of all patients with prolactinomas.

In microprolactinomas, PRL levels return to normal within days to a few weeks of starting treatment in almost all patients who can tolerate appropriate doses of BEC. If PRL levels normalize, gonadal function also typically has a near-total recovery. Menses return to normal within a few months. Sometimes, pregnancy can occur before the resumption of menstruation; therefore, the couple must be advised to use barrier methods of contraception until normal menses have returned.

In macroprolactinomas, BEC treatment results in some reduction of tumor size in up to 80-85% of the patients. Significant VF improvements have been noted to occur in as few as 1-3 days, and significant changes on imaging findings occur as soon as 2 weeks after starting treatment.

In contrast to patients with microadenomas, resolution of hyperprolactinemia is often incomplete in patients with macroadenomas. However, the extent of reduction in tumor size is not well correlated with the changes in serum PRL levels. Nevertheless, reductions in PRL levels always precede tumor shrinkage, and patients who do not show a drop in PRL do not have any tumor shrinkage.

A reduction in tumor size is often accompanied by improvement in pituitary function. Examples include improved serum testosterone levels and an increased sperm count.

Once normalization of PRL levels is achieved and sustained, the dose of BEC is gradually tapered to approximately 2.5 mg/d. If PRL levels and tumor size are stable on the above dose, consider tapering BEC to the lowest dose possible. The patient should be evaluated periodically with monitoring of symptoms, PRL levels, and radiological changes.

A study by Wu et al indicated that DA agonists can provide long-term management of invasive giant prolactinomas. The study, which had a mean 135.5-month follow-up period, found that patients on BEC achieved long-term control of their disease with regard to tumor shrinkage and normalization of PRL level. However, the investigators also determined that in patients under age 25 years, there was a tendency toward persistent hyperprolactinemia even with long-term DA agonist therapy. [25]

Other medical treatments are available for prolactinoma patients who do not respond to BEC or for those who cannot tolerate the drug.

Cabergoline, an ergot derivative, is a long-acting DA agonist and is available in the United States. It is usually better tolerated than BEC, and its efficacy profiles are somewhat superior to those of BEC. It offers the convenience of twice-a-week administration, with a usual starting dose of 0.25 mg biweekly to a maximum dose of 1 mg biweekly. Some studies have shown efficacy even with once-a-week dosing. Cabergoline appears to be more effective in lowering prolactin levels and restoring ovulation. Up to 70% of patients who do not respond to BEC respond to cabergoline. [26] The only problem is cost. Side effects are somewhat fewer than with BEC and include headache, nausea, postural hypotension, and fatigue. [27]

Quinagolide is a nonergot DA agonist that has a long duration of action but is not yet available for use in the United States. It can be administered once daily. Efficacy and tolerance are comparable to that of BEC.

A study of patients with prolactinoma demonstrated that attempting DA agonist withdrawal in patients who have been treated for 2 years is practical and safe if normalization of prolactin levels and evidence of tumor reduction are observed. [28]

Pharmacologic resistance to DA agonists refers to a failure to respond to such agents in terms of a normalization of PRL levels and a reduction in the size of prolactinoma by at least 50%. DA agonist resistance results primarily from a reduction in D2 receptors on tumor cells. [29]

In some patients with prolactinoma who have adequately responded to medical treatment, withdrawing medical treatment after about 24 months may be possible. Although no clear predictive criteria for such successful withdrawal exist, evidence indicates that the recurrence of hyperprolactinemia is generally lower in patients with microadenomas than in those with macroadenomas. Hyperprolactinemia is more likely to recur in patients with tumor remnant on pituitary MRI than it is in patients with no such remnant. In very large adenomas, regrowth of tumor is often seen after the withdrawal of medical treatment. In any case, if medical treatment is withdrawn, close clinical, biochemical, and radiologic monitoring is warranted to look for evidence of tumor recurrence.


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