Discontinuing Dopamine Agonist Treatment for Hyperprolactinemia

Abstract & Commentary

Synopsis: Cabergoline can be safely withdrawn in patients with normalized prolactin levels and no evidence of tumor. However, because the length of follow-up in this study was insufficient to rule out a delayed increase in the size of the tumor, it suggests that patients be closely monitored, particularly those with macroprolactinomas, in whom renewed growth of the tumor may compromise vision.

Source: Colao A, et al. N Engl J Med. 2003;349: 2023-2033.

Colao and colleagues from the Federico II University of Naples, Italy, terminated cabergoline therapy after 3-4 years in 200 patients (25 with hyperprolactinemia and no evidence of a pituitary tumor, 105 with microprolactinomas, and 70 with macroprolactinomas). The guidelines for discontinuing treatment included a normal prolactin level and either no evidence of a tumor or 50% or more tumor reduction on MRI. The patients were followed for 2-5 years with the following results:

Nontumoral hyperprolactinemia: 24% of the female patients had a return of hyperprolactinemia, but menses remained normal.

Microadenomas: 30% had a return of hyperprolactinemia without MRI evidence of tumor recurrence; 20% of the female patients developed oligomenorrhea; none had galactorrhea.

Macroadenomas: 36% had a recurrence of hyperprolactinemia, but none had evidence of tumor growth.

In those patients with a recurrence of elevated prolactin levels, the average time required for recurrence was 12-18 months. The major clinical conclusions of this study are: 1) Dopamine agonist can be discontinued, and most patients have no recurrence of hyperprolactinemia; 2) Even if hyperprolactinemia recurs, tumor growth is very unlikely; and 3) Pituitary tumor treatment with a dopamine agonist should be maintained for at least 1-2 years.

Comment by Leon Speroff, MD

The low rate of side effects and the once-weekly dosage make cabergoline the drug of choice for the treatment of hyperprolactinemia. There is even evidence to indicate that response, especially tumor reduction, is superior to that with bromocriptine, and tumors resistant to bromocriptine will respond to cabergoline.

Treatment of prolactin-secreting pituitary adenomas with dopamine agonists is preferred because of the relatively high rate of recurrence after pituitary surgery. However, it has long been recognized that discontinuation of medical therapy is followed by recurrence of hyperprolactinemia. But renewed growth of a prolactin-secreting tumor is uncommon, most likely because these tumors rarely grow anyway. Nevertheless, some tumors can resume growth, and on-going surveillance will be necessary.

This study highlights some major points of disagreement regarding patient management comparing gynecologic endocrinologists with medical endocrinologists. Medical endocrinologists generally believe that elevated prolactin levels and microadenomas need to be treated with dopamine agonists. Gynecologic endocrinologists generally believe that microadenomas need be treated only if the patients are seeking fertility or experiencing disturbing galactorrhea. The fundamental reason for our belief is the rarity of tumor growth in these patients. Thus, I prefer to treat the amenorrhea or menstrual irregularity associated with elevated prolactin levels with oral contraceptives. In other words, there is no harm in allowing prolactin levels to remain elevated, and it is not necessary to use a dopamine agonist to restore normal menstrual function. I recommend the following management:

Microadenomas

The treatment of microadenomas should be directed to alleviating 1 of 2 problems: infertility or breast discomfort. Treatment with a dopamine agonist is the method of choice. The major therapeutic dilemma can be expressed by the following question: Should chronic dopamine agonist treatment be used to retrieve ovarian function in those patients with hypoestrogenic amenorrhea, or should estrogen treatment be offered? I do not advocate widespread dopamine agonist therapy for those patients not interested in becoming pregnant. This conservative approach is supported by documentation of a benign clinical course with spontaneous resolution in many patients.1-3 Patients with hypoestrogenic amenorrhea are encouraged to be on an estrogen therapy program to maintain the health of their bones and the vascular system. Low-dose oral contraception is recommended for those patients who require contraception. Estrogen-induced tumor expansion or growth has not been a problem in both my experience and in that of others.4,5

Macroadenomas

Dopamine agonist treatment is the treatment of choice for macroadenomas, using as low a dose as possible. Once shrinkage has occurred, the daily dose should be progressively reduced until the lowest maintenance dose is achieved. The serum prolactin level can be used as a marker, checking levels every 3 months until stable. In many (but not all) patients, control of tumor growth correlates with maintenance of a baseline prolactin level. Withdrawal of the drug can be associated with regrowth or reexpansion of the tumor, and, therefore, treatment must be at least several years. If there is a good response in prolactin levels, and if present, visual field defects, the MRI should be repeated after 1 year of treatment to establish size reduction of the tumor. Some patients will prefer surgery rather than long-term medical treatment, and it is certainly a legitimate option. In view of better results claimed in more recent times, this choice should be presented to the patient. Transsphenoidal surgery is recommended when suprasellar extension or visual impairment persists after dopamine agonist treatment of a macroadenoma. For some patients, side effects with dopamine agonist treatment and difficulty with medication compliance make surgery a reasonable alternative. Because tumor recurrence after surgery is high, radiotherapy should be considered. All patients receiving radiotherapy require ongoing surveillance for the development of hypopituitarism. Surgery should be considered as a debulking procedure for very large tumors with or without invasion prior to long-term dopamine agonist therapy. Even though prolactin levels usually increase when dopamine agonist treatment is discontinued after several years, many tumors (70-80%) do not regrow.6,7 Pregnancy should be deferred until repeat imaging confirms shrinkage of the macroadenoma.

Approximately 10% of macroadenomas do not shrink with dopamine agonist therapy. The failure of a tumor to shrink significantly in size despite a normalization of prolactin levels can be consistent with a nonfunctioning tumor that is interrupting the supply of dopamine to the pituitary by stalk compression. Early surgery is indicated. A tumor that continues to grow despite dopamine agonist treatment may be a rare carcinoma.

Long-Term Follow-Up

Because these tumors can grow slowly, it is appropriate in the absence of symptoms to evaluate patients with microadenomas annually for 2 years. The evaluation consists of a measurement of the prolactin level and imaging of the sella turcica. If the course is unchanged, annual evaluation can be limited to measurement of the prolactin level. It should be noted that progressively increasing prolactin levels have been observed without associated tumor growth of a microadenoma. The rare microadenoma that grows deserves treatment. Patients with macroadenomas deserve an initial period of follow-up after treatment every 6 months, and if the adenoma appears to be clinically stable, prolactin levels should be measured annually. MRI is reserved for situations suggestive of tumor expansion. If the clinician and patient need reassurance regarding tumor size, imaging intervals can be prolonged if the tumor is stable (eg, at 1 year, 2 years, 4 years, 8 years). Tumor expansion and recurrent tumors after surgery or radiotherapy deserve a trial of treatment with a dopamine agonist.

Patients who have been on dopamine agonist treatment for 2-5 years with successful tumor size reduction can have a gradual reduction, and eventually stopping of treatment, followed by monitoring of prolactin levels every 3 months. If a normal prolactin level is maintained, I recommend an imaging study 1 year later. Of course, tumor reexpansion requires resumption of treatment with the gradual program that should always be used when starting therapy.

Dr. Speroff is Professor of Obstetrics and Gynecology Oregon Health Sciences University Portland

References

1. Martin TL, et al. J Clin Endocrinol Metab. 1985;60: 855-558.

2. Sluijmer AV, Lappohn RE. Fertil Steril. 1992;58:72.

3. Jeffcoate WJ, et al. Clin Endocrinol. 1996;45:299-303.

4. Corenblum B, Donovan L. Fertil Steril. 1993;59:671.

5. Testa G, et al. Contraception. 1998;58:69-73.

6. Johnston DG, et al. Lancet. 1984;2:187-192.

7. Colao A, et al. N Eng J Med. 2003;349:2023-2033.