GnRH Stimulation Reduces Implantation and Live Birth Rate but Not Miscarriage Rate in IVF treatment
In vitro fertilization (IVF) therapies were revolutionised by gonadotropins. Gonadotropins stimulate the growth of many follicles and allow the retrieval of several oocytes. In spontaneous menstrual cycles, only the largest follicle of a cohort survives and the development of the other follicles are inhibited by inhibin B, released from the largest follicle. In gonadotropin-stimulated IVF therapies, this physiological regulatory efect is inactivated by the constantly high concentration of exogenous gonadotropins. The growing cohort of follicles leads to a polyfollicular ovarian response and the number of collected oocytes as well as the success of the IVF therapy per cycle is increased. However, gonadotropin stimulation and the use of gonadotropin-releasing hormone (GnRH) analogues have shown to negatively affect cumulative livebirth rates in cycles where a large number of oocytes was collected at oocyte pick-up (OPU).
This might be due to some effects on follicular endocrinology. In gonadotropin-stimulated follicles, luteinising hormone (LH), androgen, oestradiol (E2) and anti-Mullerian hormone (AMH) concentrations are several-fold reduced at the time of follicle aspiration compared to naturally matured follicles. This includes follicular AMH, which is known as a marker for the implantation potential of the oocyte in gonadotropin-stimulated IVF cycles as well as in unstimulated, natural IVF cycles (NC-IVF). Ovarian stimulation leads to alterations in the production of steroids and other hormones in luteal granulosa cells, which preserve the pregnancy.
The aim of the study by Vera Ruth Mitter and team was to evaluate the impact of gonadotropin stimulation on the potential of fresh embryos to develop into a pregnancy and a live birth and its risk for a miscarriage. They compared embryos generated in conventionally gonadotropin stimulated IVF (cIVF) cycles with embryos generated in unstimulated NC-IVF cycles.
In a cohort of 728 couples, 1310 IVF cycles with successful embryo transfer were analysed; 857 cycles were stimulated with gonadotropins>75 IU/day (333 poor responder<4 oocytes; 524 normal responders), and 453 were unstimulated. In total, 1913 fresh cleavage-stage embryos were transferred. Zygote but no embryo selection was performed, and supernumerous zygotes were vitrifed. The implantation rate was defned as number of sonographically detected amniotic sacs; live birth rate as number of children born per transferred embryo. Modifed mixed efect Poisson regression was used to account for the dependency of cycles and embryos within the same women and the same transfer cycle. Adjustments were made for maternal age, parity, primary or secondary infertility and indication for IVF. Per transferred embryo, implantation rates (rate ratio (RR) 1.37; 95% CI 1.04–1.81; p=0.028; aRR 1.42; 95% CI 1.10–1.84; p=0.008) and live birth rates (RR 1.33; 95% CI 0.95–1.86; p=0.093; aRR 1.38; 95% CI 1.01–1.88; p=0.044) were higher in NC-IVF compared to cIVF normal responders. Miscarriage did not difer (RR 0.99; 95% CI 0.59–1.65; p=0.965; aRR 0.90; 95% CI 0.52–1.53 p=0.698). Similar results were obtained in poor responders. ><4 oocytes; 524 normal responders), and 453 were unstimulated.
In total, 1913 fresh cleavage-stage embryos were transferred. Zygote but no embryo selection was performed, and supernumerous zygotes were vitrifed.
- The implantation rate was defined as number of sonographically detected amniotic sacs; live birth rate as number of children born per transferred embryo.
- Per transferred embryo, implantation rates (p=0.008) and live birth rates (p=0.044) were higher in NC-IVF compared to cIVF normal responders.
- Miscarriage did not differ (p=0.698). Similar results were obtained in poor responders.
The study revealed that embryos derived from naturally matured follicles as in NC-IVF had a higher implantation potential leading to higher implantation and live birth rates, but miscarriage rates did not differ. These results seemed not to be influenced by the number of oocytes gained at oocyte-pickup and the response to stimulation, as results in poor responders were similar to normal responders within cIVF.
The better outcome in unstimulated NC-IVF cycles as shown by study could be due to the following reasons:
- First, hormonal stimulation could cause higher aneuploidy rates in embryos, which would lead to higher rates of miscarriages in cIVF.
- Second, subtle differences of follicular function due to gonadotropin stimulation might affect the potential of embryos to develop into a clinical pregnancy or a live birth.
- Third, a negative hormonal impact on endometrial function could be the reason.
To what extent each factor contributes to the decrease in the implantation potential of embryos in gonadotropin stimulated IVF treatments remains an unsolved question. Most likely, interactions of gonadotropin stimulation on different levels within the IVF process can be discussed.
In conclusion, this study including only cycles without embryo selection demonstrates that gonadotropin stimulation reduces the potential of fresh embryos to implant. Whether this is due to lower oocyte quality, altered hormonal milieus or lower endometrial receptivity remains unknown. Ideally, this finding would be confirmed in a randomized controlled study.
Source: Vera Ruth Mitter, Flavia Grädel, Alexandra Sabrina Kohl Schwartz et al; Reproductive Sciences
https://doi.org/10.1007/s43032-022-01016-8
