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NEW TREATMENTS FOR PROLACTINOMA

Prolactinomas are the most common of the hormone-secreting pituitary tumors. Rarely life-threatening, they cause symptoms primarily as a result of hyperprolactinemia, which results in alterations in reproductive/sexual function but may also cause symptoms owing to mass effects. Medical and surgical therapy provide excellent results, and most patients do very well.

Hyperprolactinemia caused by lesions of the hypothalamus and of the pituitary stalk results from the disinhibition of the tonic PIF (dopamine) acting at the level of the pituitary lactotrophs. Many of these patients have normal adrenocorticotropic hormone and TSH function, implying that there still is significant transmission of hypothalamic-releasing factors to the pituitary.

Some theories have suggested that prolactinomas arise because of underlying hypothalamic dysregulation, either too little dopamine or too much PRF reaching the pituitary. Other lines of evidence weigh strongly against such underlying hypothalamic dysregulation. For instance, studies have shown that there is little or no hyperplasia in the nontumorous pituitary tissue.

Prolactinomas in MEN-1

Prolactinomas occur in approximately 20% of patients with multiple endocrine neoplasia type 1 (MEN-1). The MEN-1 gene has been localized to chromosome 11q13 and is thought to be a constitutive tumor suppressor gene. An inactivating mutation results in tumor development.

Natural History of Untreated Prolactinomas

Data obtained from six series of patients with microadenomas who were observed for long periods without treatment show that the risk of progression from microadenoma to macroadenoma is only 7%. In another series of patients carefully observed for as many as 15 years, Jeffcoate and co-workers found that about one third of patients who were untreated.

TREATMENT OF PROLACTINOMAS

Although the emphasis in this article is on medical therapy, various treatment modalities are available for prolactinomas.

Observation

The indications for therapy in patients with prolactinomas can be divided into two categories: (1) effects of tumor size and (2) effects of hyperprolactinemia. In almost 95% of patients, microprolactinomas do not enlarge over a 4- to 6-year period of observation. Thus, the simple argument that therapy is indicated for a microadenoma to prevent it from growing is fallacious. On the other hand, if a documented adenoma exists, it needs to be observed closely to determine whether it is growing. It is unlikely that a prolactinoma will grow significantly with no increase in serum prolactin levels; however, prolactin levels may change significantly.

ertainly, a microadenoma that is documented to be growing demands therapy for the change in size alone, because it may be one of the 7% of lesions that will grow to be a macroadenoma. Because patients with macroadenomas have already indicated a propensity for the growth of tumor, the author is hesitant to just observe such lesions.

Other indications for therapy are related to the effects of hyperprolactinemia. These include decreased libido, sexual dysfunction, menstrual dysfunction, galactorrhea, infertility, hirsutism, and premature osteoporosis. In the woman with a microadenoma with normal menses and libido and galactorrhea that is not bothersome, there is no specific reason for therapy. Without therapy, prolactin levels may return to normal in about one-third of patients.

Surgery

Transsphenoidal surgery is the preferred technique for microadenomas and most macroadenomas. Craniotomy is rarely performed. Surgical success rates are highly dependent on the experience and skill of the surgeon as well as the size of the tumor. In a report summarizing the surgical results in 31 published series, 872 of 1224 patients (71.2%) with

Postoperative recurrence of hyperprolactinemia often occurs within the first year following surgery, with recurrence rates ranging from 0% to 50%. In the 31 series mentioned previously, recurrence rates for microadenomas (82 of 471 or 17.4%) and macroadenomas (48 of 235 or 18.6%) were similar. Two recent long-term follow-up studies have shown remarkably similar findings. In a series of patients operated on at the University of California, San Francisco, in which 83% of the patients were followed up for a mean of 9.2 years, 51.8% of patients.

Radiotherapy

Because of the excellent therapeutic responses to transsphenoidal surgery and medical therapy, radiotherapy is generally not considered as a primary treatment for prolactinomas. A total of approximately 100 patients have been treated with conventional radiotherapy alone or in combination with bromocriptine for prolactinomas or after failure of surgical cure. Normal prolactin levels were achieved in only 6 of 16 (38%) patients treated with radiotherapy alone over a period of 2 to 14 years. When radiotherapy was performed after noncurative surgery, normalization of prolactin levels occurred in 4 of 35 (11%) patients. In a recent series of 63 patients treated with radiotherapy following noncurative surgery, actuarial analysis showed that, by 10 years, approximately 30% of patients had normal prolactin levels.

Medical Therapy

Bromocriptine (2-bromo-alpha-ergocryptine mesylate) is an ergot derivative that binds to and stimulates dopamine (D₂ ) receptors on normal and adenomatous lactotroph cells. Pharmacokinetic studies show that after a single oral dose of 2.5 mg, serum levels peak after 3 hours. The nadir is observed at 7 hours, with little bromocriptine detectable in the circulation after 11 to 14 hours.  The biologic activity parallels the serum levels.

In rats, measurable tissue levels of bromocriptine can be found in almost all organs 2 hours after an oral dose. The highest levels are found in liver, lung, kidney, and pituitary.

The mechanism by which bromocriptine causes tumor size reduction is essentially a turning off of the intracellular prolactin-synthesizing machinery, that is, an inhibition of transcription of prolactin mRNA and prolactin synthesis. Morphologically within the first 6 weeks, there is a decrease in the number of exocytoses and an initial increase and later decrease in the number of prolactin secretory granules and involution of the rough endoplasmic reticulum and Golgi apparatus, with a decrease in cytoplasmic volume. By 6 months, there is a paucity of cellular organelles.

Treatment to Reduce Hyperprolactinemia

Bromocriptine treatment results in normoprolactinemia or a return of ovulatory menses in 80% to 90% of patients. When both prolactin levels and the return of menses were studied.

Corenblum and co-workers were the first to report that bromocriptine could reduce tumor size in humans. Subsequently, several individual case reports documented tumor size reduction, and a number of series of patients have now been reported on.

Side Effects of Bromocriptine Treatment

Bromocriptine is, in general, well-tolerated. The most common side effects are nausea and, occasionally, vomiting; these are usually transient but may recur with each dose increase. Orthostatic hypotension may occur when initiating therapy and rarely recurs with dose increases. Limiting nausea and vomiting occur in 3% to 5% of patients; and digital vasospasm.

Between 5% and 10% of patients either do not respond to bromocriptine or have only minimal responses. Decreased response to bromocriptine in vivo has been shown to correspond to decreased numbers of dopamine receptors on lactotroph cell membranes.  Because resistance is associated with a decrease in the relative proportion of the short receptor isoform.

Vermesh and co-workers initially reported that similar reductions in prolactin levels are achieved with oral and intravaginal administration of oral bromocriptine tablets. Bromocriptine levels rise more slowly but to eventually higher levels with the intravaginal route in comparison with the oral. With vaginal administration, the drug effect lasts for up to 24 hours with a single dose, and gastrointestinal side effects are much less than with the oral route. Jasonni and co-workers reported normalization of prolactin levels in all 15 women with hyperprolactinemia given 2.5 to 5 mg of bromocriptine in a single dose intravaginally. Katz and co-workers described the case of a woman with a macroadenoma who could not tolerate oral bromocriptine.

A long-acting, injectable, depot preparation of bromocriptine (Parlodel-LAR) causes high blood levels of bromocriptine within 5 hours with only minimal side effects, with prolactin levels falling to 10% to 20% of basal levels within 12 to 24 hours. Prolactin levels remain low.

Pergolide (Permax) has been approved by the US Food and Drug Administration for the treatment of Parkinson's disease. Although such approval for the treatment of hyperprolactinemia is lacking, there is considerable experience with its use in patients with prolactinoma, and such use is well-documented in the literature.

Cabergoline

Cabergoline (1-ethyl-3,3-[3-dimethylamino-propyl]3-[6allylergoline-8beta-carbonyl]-urea diphosphate, Dostinex) is different from the other drugs in that it has a long half-life and can be given orally once weekly.

Several studies have shown that cabergoline is at least as effective as bromocriptine in lowering prolactin levels and reducing tumor size but with a substantial reduction in side effects.  In the multicenter European collaborative study of 459 women in which bromocriptine and cabergoline were administered in a double-blind fashion for 8 weeks, normoprolactinemia was achieved.

Other Dopamine Agonists

Several other dopamine agonists have been developed to treat hyperprolactinemia. Although efficacy has been found for a number of these medications (lergotrile, lisuride, metergoline, mesulergine, dihydroergocristine, dihydroergocryptine, Hydergine, terguride, and CQP 201-403).

PREGNANCY AND DOPAMINE AGONIST THERAPY

Hyperprolactinemia is usually associated with anovulation and infertility. Correction of the hyperprolactinemia with dopamine agonists restores ovulation in approximately 90% of cases.

Effects of Dopamine Agonists on the Developing Fetus

As a general principal, fetal exposure to the dopamine agonist should be limited to as short a period as possible. Mechanical contraception should be used until the first two to three cycles have occurred so that an intermenstrual interval can be established, and the woman will know when she has missed a menstrual period. In this manner, the dopamine agonist can be stopped.

Recommendations for Management

For the hyperprolactinemic woman with a microadenoma or macroadenoma that is intrasellar or that extends infrasellarly, bromocriptine is preferred as the primary treatment because of its efficacy in restoring ovulation and low (1% to 5%) risk of clinically significant tumor enlargement. Such a patient should be carefully observed throughout gestation. Prolactin levels do not always rise during pregnancy in women with prolactinomas as they do in normal women.