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A Therapeutic Role of Prolactin Supplementation in Ovarian Stimulation for in Vitro Fertilization: The Bromocriptine-Rebound Method

Department of Obstetrics and Gynecology (M.J., Y.K., T.H., Y.N.), Kyorin University School of Medicine, Tokyo; the Faculty of Biology-Oriented Science and Technology (K.M.), Kinki University, Wakayama; the Department of Obstetrics and Gynecology (Y.Y.), Keio University School of Medicine, Tokyo, Japan

Address all correspondence and requests for reprints to: Masao Jinno, M.D., Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6–20-2 Shinkawa, Mitaka City, Tokyo 181, Japan.

In a prospective randomized study, we examined whether a novel method of ovarian stimulation, the bromocriptine-rebound method, improves in vitro fertilization (IVF) outcomes compared with the conventional long protocol using GnRH agonist and human menopausal gonadotropin (hMG). Ovulatory women with previous failed IVF-embryo transfer using the long protocol were prospectively assigned to either the bromocriptine-rebound method (group 1, 82 cycles) or the long protocol (group 2, 80 cycles). The bromocriptine-rebound method was the same as the long protocol, except that bromocriptine was administered daily from day 4 of the preceding cycle until 7 days before hMG stimulation. The numbers of follicles, fertilized oocytes, and embryos with superior morphology were higher in group 1 than in group 2. The rates of clinical pregnancy and live birth delivery per cycle were significantly higher in group 1 (38% and 33%, respectively) than in group 2 (21% and 19%, respectively). The mean concentration of serum PRL during hMG administration was significantly higher in group 1 than group 2. A significant correlation between the number of superior embryos and PRL concentrations was observed in group 1, but not in group 2.

Next, we performed a retrospective study to investigate how the bromocriptine-rebound method exerts its beneficial effects. In the initial IVF with the long protocol, the mean concentration of serum PRL during hMG administration and the expression of PRL receptor (PRLr) messenger ribonucleic acid (mRNA) in granulosa cells were significantly higher in nonpregnant patients than in pregnant ones. When IVF was repeated with the bromocriptine-rebound method in the nonpregnant patients, the expression of PRLr mRNA decreased significantly. In conclusion, the bromocriptine-rebound method enhances embryonic development and the rate of live birth delivery in patients with previous failed IVF using the long protocol. We hypothesize that in the nonpregnant patients using the long protocol, the serum PRL concentration and PRLr mRNA expression are increased to compensate for poor postreceptor responsiveness of granulosa cells to PRL during oocyte maturation. The bromocriptine-rebound method may improve oocyte maturation in such patients by restoring postreceptor responsiveness of granulosa cells to PRL during the hypoprolactinemic period and increasing the PRL concentration by a rebound phenomenon after discontinuation of bromocriptine.