The clinical outcome of Dienogest treatment followed by in vitro fertilization and embryo transfer in infertile women with endometriosis

Abstract

Background: Endometriosis is considered to be the most intractable cause of female infertility. Administering any type of treatment for endometriosis before in vitro fertilization and embryo transfer (IVF-ET) is an important strategy for improving the IVF-ET outcomes for infertile women with endometriosis. In fact, treatment with a gonadotropin-releasing hormone (GnRH) agonist just before IVF-ET has been reported to improve the clinical outcome in endometriosis patients. However, the benefit of Dienogest (DNG), a synthetic progestin, treatment just before IVF-ET remains unclear.

Methods: Sixty-eight infertile women with Stage III or IV endometriosis (ovarian endometrial cyst < 4 cm) were recruited for this study. The subjects were divided into 2 groups: a DNG group (n = 33) and a control group (n = 35). DNG was administered orally every day for 12 weeks prior to the conventional IVF-ET cycle in the DNG group. Standard controlled ovarian hyperstimulation with the GnRH agonist long protocol was performed in the control group. The numbers of mature follicles and retrieved oocytes, fertilization rates, implantation rates, and clinical pregnancy rate were compared between the two groups. In addition, the concentrations of inflammatory cytokines, oxidative stress markers, and antioxidants in follicular fluids were also measured.

Results: The numbers of growing follicles, retrieved oocytes, fertilized oocytes, and blastocysts were significantly lower in the DNG group than in the control group. The fertilization and blastocyst rates were also lower in the DNG group than in the control group. Although there was no significant difference in the implantation rate between the groups, the cumulative pregnancy rate and live birth rate were lower in the DNG group than in the control group. There was no significant difference in the abortion rate. Our results failed to show that DNG reduces the inflammatory cytokine levels and oxidative stress in follicular fluids.

Conclusions: Administering DNG treatment just before IVF-ET did not provide any benefits to improve the clinical outcomes for infertile women with endometriosis.

Keywords: Dienogest; Endometriosis; Growing follicle; IVF-ET; Infertile.

Fig. 1

Schematic representation of the study protocol for the DNG group and control group In the control group, patients received standard controlled ovarian hyperstimulation with mid-luteal phase GnRH agonist down-regulation. Nasal spray GnRH agonist was administered from the mid-luteal phase in the previous cycle to the time of HCG injection for the ovulation induction of the IVF-ET cycle. Controlled ovarian hyperstimulation was initiated from the second day of the IVF-ET cycle by FSH and HMG. In the DNG group, DNG was administered orally every day for 12 weeks from 3 months prior to the IVF-ET cycle. Withdrawal bleeding was induced using E and P. Controlled ovarian hyperstimulation was given in a manner similar to that in the control group. GnRH agonist: buserelin acetate 900 mg/day; E: conjugated estrogen; P: dydrogesterone; M: menstruation; FSH: follicle-stimulating hormone; HMG: human menopausal gonadotropin; HCG: human chorionic gonadotropin; OPU: ovum pick-up; DNG: dienogest; dinagest, 2 mg/day.

Fig. 2

CONSORT statement flow diagram

Fig. 3

Concentrations of inflammatory cytokines in follicular fluids Thirty patients received 12 weeks of Dienogest treatment (2 mg/day) followed by standard controlled ovarian hyperstimulation (COH) for IVF-ET (DNG group). Thirty-four patients received standard COH with mid-luteal phase GnRH agonist down-regulation (control group). The concentrations of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8), were measured in the follicular fluid obtained at the time of oocyte retrieval. Values are the mean ± SD. Statistical analyses were performed with the Mann-Whitney U-test using Bonferroni’s correction.

Fig. 4

Concentrations of oxidative stress markers in follicular fluids Thirty patients received 12 weeks of Dienogest treatment (2 mg/day) followed by standard controlled ovarian hyperstimulation (COH) for IVF-ET (DNG group). Thirty-four patients received standard COH with mid-luteal phase GnRH agonist down-regulation (control group). The concentrations of the oxidative stress markers 8-hydroxy-2′-deoxyguanosine (8-OHdG) as a marker of DNA damage and hexanoyl-lysine adduct (HEL) as a marker of lipid peroxidation, were measured in the follicular fluid obtained at the time of oocyte retrieval. Values are the mean ± SD. Statistical analyses were performed with the Mann-Whitney U-test using Bonferroni’s correction.

Fig. 5

Concentrations of antioxidants in follicular fluids Thirty patients received 12 weeks of Dienogest treatment (2 mg/day) followed by standard controlled ovarian hyperstimulation (COH) for IVF-ET (DNG group). Thirty-four patients received standard COH with mid-luteal phase GnRH agonist down-regulation (control group). The concentrations of the antioxidants Cu,Zu-superoxide dismutase (Cu,Zn-SOD) and melatonin were measured in the follicular fluid obtained at the time of oocyte retrieval. Values are the mean ± SD. Statistical analyses were performed with the Mann-Whitney U-test using Bonferroni’s correction.