Emma Hitt, PhD
| language=_javascript_ src="" type=text/_javascript_></SCRIPT> |
Nov. 19, 2003 Withdrawal of cabergoline appears to be safe if no evidence of prolactinoma is present or tumor size has decreased by at least 50%, according to the findings of a new observational, prospective study.
According to the researchers, cabergoline, a selective dopamine D2-receptor agonist with long-lasting action, is highly effective in treating microprolactinoma and macroprolactinoma. However, a definitive cure of these tumors is considered possible only with surgery.
Limited data suggest that hyperprolactinemia recurs more often when medical treatment is withdrawn than when surgery is performed. To explore this issue further, Annamaria Colao, MD, PhD, from Federico II University of Naples, Italy, and colleagues investigated the effect of cabergoline withdrawal on rates of remission of prolactinoma.
The study, published in the Nov. 20 issue of the New England Journal of Medicine, included 200 patients. Of the patients, 25 had nontumoral hyperprolactinemia, 105 had microprolactinomas, and 70 had macroprolactinomas.
Dr. Colao and her team withdrew cabergoline treatment if prolactin levels were normal or the study subjects experienced a 50% tumor reduction, with the tumor at a distance of more than 5 mm from the optic chiasm and not invading the cavernous sinuses or other critical areas, and if follow-up after withdrawal could be continued for at least 24 months.
Two to five years after withdrawal of cabergoline, recurrence rates were 24% in patients with nontumoral hyperprolactinemia, 31% in patients with microprolactinomas, and 36% in patients with macroprolactinomas, the researchers report.
Prolactin levels at the time of recurrence were significantly lower than at diagnosis in all groups (P < .001). In addition, new tumor growth did not occur in any patient, although in patients with recurrent hyperprolactinemia, gonadal dysfunction recurred in 10 female patients (22%) and seven male patients (39%).
Recurrence at five years was significantly higher among patients with macroprolactinomas (78%) and those with microprolactinomas who had small remnant tumors at the time of treatment withdrawal (42%) than among patients with no evidence of tumor at the time of withdrawal (macroprolactinomas 33%; P = .001 and microprolactinomas 26%; P = .02).
They note that the risk of recurrent hyperprolactinemia with each millimeter increment in the size of the tumor remnant was 19%.
According to Dr. Colao and colleagues, bromocriptine has traditionally been used to manage prolactinomas and has been found to normalize prolactin levels in more than 70% of patients with prolactinomas, while normoprolactinemia is sustained in 7% to 38% of patients upon bromocriptine withdrawal.
"Our data support the concept of periodic withdrawal of cabergoline therapy, especially in patients with negative MRI studies during treatment," Dr. Colao and colleagues conclude.
"However, until data from a study with a longer follow-up period are available, close monitoring for recurrent hyperprolactinemia and renewed tumor growth is important, particularly in patients with macroprolactinomas, in whom renewed growth may compromise vision," they add.
N Engl J Med. 2003;349:2023-2033
Question
Do patients who have been diagnosed with pituitary microadenoma have to take bromocriptine for life at a maintenance dose of 0.625 mg? The reason for the question is that several of my patients start to have headaches and menstrual irregularities when they stop bromocriptine. - Joan Tan Garcia, MD
Response from Peter Kovacs, MD Clinical Instructor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, New York, and Fellow in Reproductive Endocrinology, Albert Einstein College of Medicine, Bronx, New York
![]()
Hyperprolactinemia can induce characteristic reproductive abnormalities (luteal phase defect, menstrual irregularities, amenorrhea). Therefore, measuring serum prolactin level is part of the work-up recommended for women with menstrual irregularities or recurrent miscarriages or those who present with galactorrhea. It is important to point out that galactorrhea can also be seen with normal prolactin levels. In these cases, the target organ (breast) has increased sensitivity to the hormone. This is most likely to be found among parous women.
Once pregnancy is excluded, other secondary causes need to be evaluated. Physiologic conditions (sleeping, eating, stress) and certain drugs can result in hyperprolactinemia. Hypothyroidism and other medical conditions (eg, kidney disease) can cause elevation of prolactin levels. Once these possibilities are excluded, the patient should be evaluated for pituitary and extrapituitary lesions that influence pituitary function. About one fifth of women with amenorrhea have pituitary lesions, and this rate increases further if galactorrhea is also present. Imaging the brain is especially important if the patient has headaches or if other neurologic signs, such as visual field defects, accompany hyperprolactinemia.
There are several options to treat pituitary adenomas (medical, surgical, radiation). The first-line treatment is medical, with a dopamine agonist. For clinicians, the important question is, "Who needs to be treated and for how long?" As hyperprolactinemia can suppress ovarian function, any patient who shows signs of hypoestrogenism (osteopenia, osteoporosis, amenorrhea) should be treated. Patients trying to become pregnant and those with galactorrhea, large pituitary lesions (macroadenoma), or neurologic signs also require treatment.
The natural course of adenomas needs to be evaluated when we plan the duration of treatment. Several research groups have followed women with pituitary adenomas who were not treated for an extended period and found that up to 40% of these patients showed normalization of prolactin levels and reduced clinical symptoms. Whether dopamine agonist treatment can be discontinued has also been studied and, similar to the natural course, normoprolactinemia persists in up to 40% of patients. Hyperprolactinemia was more likely to recur after a brief treatment period (< 1 year). Other clinical variables (tumor size, prolactin level, age, sex, drug dose) did not seem to affect recurrence rates. Recurrence of hyperprolactinemia was most likely to occur during the first 3 months following the discontinuation of drug treatment. Dopamine agonists should be restarted if symptoms recur. It also needs to be mentioned that there are studies that showed adverse effects of hyperprolactinemia on bone, even in patients with regular menstrual cycles.
In summary, because a subset of patients maintain normoprolactinemia after discontinuation of dopamine agonist treatment, dose reduction with serum level monitoring can be attempted. Among those who maintain normoprolactinemia, complete discontinuation can be attempted with periodic assessment of prolactin levels. Drug treatment should be restarted if prolactin levels rise and clinical symptoms recur.
