Individualized High-Dose Cabergoline Therapy for Hyperprolactinemic Infertility in Women With Micro- and Macroprolactinomas

Abstract

The dopamine receptor agonist, bromocriptine, has been first-line treatment for hyperprolactinemic infertility in young women of reproductive age with pituitary hormone-producing adenomas for the past 30 years. Several studies have shown that cabergoline has superior efficacy and tolerability, and in recent years, it has replaced bromocriptine as the first-choice dopamine agonist in this population. In women with hyperprolactinemic amenorrhea, cabergoline corrects hyperprolactinemia and is more effective than bromocriptine in achieving recovery of the ovulatory cycle. Although cabergoline can induce pregnancy in prolactinoma patients, the rate of pregnancy induction in these women is unknown. In patients with macroprolactinomas (macroadenomas), its effectiveness for controlling tumor growth and thereby inducing successful pregnancy is also unknown. The aim of this study was to determine the efficacy and safety of cabergoline in pregnancy induction and its outcomes in infertile women with prolactinomas. Between 2001 and 2005, the participants—85 infertile women with macroprolactinomas (n = 29) or microprolactinomas (n = 56)—received prospective, high-dose cabergoline therapy for suppression of prolactin and tumor shrinkage. Of the 85 subjects, 31 were bromocriptine resistant, 32 were bromocriptine intolerant, and 22 were newly diagnosed untreated patients. Conception was withheld in patients with microadenomas or macroadenomas until 3 regular menstrual cycles returned and in women with macroadenomas until tumors shrunk to less than 1 cm in height. The drug was withdrawn at the fourth gestational week. Cabergoline corrected and normalized hyperprolactinemia, increased serum progesterone levels and achieved recovery of the ovulatory cycle in all patients. Within 6 to 24 months after the initiation of cabergoline therapy, all tumors contracted, and 11 of the 29 macroadenomas and 29 of the 56 microadenomas disappeared. Of the 85 patients, 80 (94%) conceived 95 pregnancies; 2 of the 95 were second pregnancies conceived without use of cabergoline. The drug dose at the first pregnancy varied widely (0.25-9 mg/week overall and 2-9 mg/week in bromocriptine-resistant patients). Of the 93 pregnancies induced with cabergoline, 86 resulted in 83 single live births, 1 stillbirth, and 2 abortions (1 of which was spontaneous); the remaining 7 pregnancies were ongoing. All newborns were healthy, without malformations or abnormal development. None of the mothers experienced impaired vision or headache suggestive of abnormal macroprolactinoma re-expansion during pregnancy. These findings show that cabergoline can safely induce and promote successful pregnancy in most infertile women with prolactinoma, independent of tumor size or bromocriptine resistance and intolerance. Cabergoline monotherapy has the potential to substitute for the conventional combination therapy of surgery or radiotherapy plus bromocriptine in patients with macroadenomas.