Effects of multiple doses of gonadotropin-releasing hormone agonist on the luteal-phase support in assisted reproductive cycles: A clinical trial study

Abstract Background The effect of adding gonadotropin-releasing hormone (GnRH) agonist on the luteal phase support in assisted reproductive technique (ART) cycles is controversial. Objective To determine the effects of adding multiple doses of GnRH agonist to the routine luteal phase support on ART cycle outcomes. Materials and Methods This clinical trial study included 200 participants who underwent the antagonist protocol at the Research and Clinical Center for Infertility, Yazd, Iran, between January and March 2020. Of the 200, 168 cases who met the inclusion criteria were equally divided into two groups – the case and the control groups. Both groups received progesterone in the luteal phase, following which the case group received GnRH agonist subcutaneously (0/1 mg triptorelin) zero, three, and six days after the fresh embryo transfer, while the control group did not receive anything. Finally, chemical and clinical pregnancy rates, number of mature oocytes, fertilization rate, total dose of gonadotropin, and the estradiol level were determined. Results The baseline characteristics were similar in both groups. No significant difference was observed between embryo transfer cycles. Clinical results showed that differences between the fertilization rate, chemical and clinical pregnancies were not significant. Conclusion The results showed that receiving multiple doses of GnRH agonist in the luteal phase of ART cycles neither improves embryo implantation nor the pregnancy rates; therefore, further studies are required.


Introduction
In a normal menstrual cycle, follicular maturation and ovulation is followed by corpus luteum. It is responsible for the progesterone production, is essential for the endometrium growth, formation of endometrial receptivity, successful implantation, and finally the maintenance of early pregnancy (1).
In a normal reproductive cycle, the luteal phase is formed by the stimulation of the corpus luteum by pituitary luteinizing hormone (LH). However, in assisted reproductive technique (ART) cycles, the luteal phase is defective because the presence of a considerable number of corpora lutea leads to its secretion (2).
It has been reported that luteal-phase defect in the ART cycles cause a decrease in the granular cells by follicular aspiration, inhibition of LH release by the negative feedback of the hypothalamic-pituitary axis, and seeks to increase steroids as well as the suppression of the LH release by analogs (agonists and antagonists) of gonadotrophin-releasing hormone (GnRH) (3).
Controlled ovarian stimulation can accelerate the rate of endometrial maturation, prohibiting both endometrial receptivity and embryo implantation.
Besides, defects in ART cycles are a major concern. The luteal phase support (LPS) in ART is generally performed by the administration of human chorionic gonadotropin (HCG), progesterone, and occasionally estradiol (E2) (4).
Recently, effective use of GnRH agonists for LPS has been reported in both subcutaneous and intrauterine routes. GnRH agonists are effective for LPS, perhaps because in certain doses it shows stimulatory features on corpus luteum, that is, it stimulates LH secretion from the hypophysis and activates local GnRH receptors in the endometrium. However, in some studies, adverse results have been reported regarding the positive effects of using GnRH for LPS (5)(6)(7)(8).
The objective of the present work was to investigate the effect of administrating different doses of GnRH agonist to normal LPS on both implantation and pregnancy rate.

Controlled ovarian hyperstimulation and laboratory procedures
After an applied stimulation protocol of

Clinical outcomes
The main outcomes were chemical and clinical pregnancy rates. The number of mature oocytes (MII), fertilization rate, total gonadotropin dose, and the E2 level were measured. Women were followed for biochemical pregnancy (β-hCG > 50 IU/L, 14 days after the embryo transfer [ET] in the serum) and clinical pregnancy (diagnosis of one or more gestational sac with a fetal heartbeat on ultrasound after 6 wk) (10).

Statistical analysis
The results were statistically analyzed using the Statistical Package for the Social Sciences (SPSS software, version 20.0, Chicago, Illinois). We used the Mann-Whitney test for comparison of non-parametric variables and the student's t test for parametric data between the groups. Also, Chi-square tests were used to determine the significant differences between the groups; the significance level was set at p < 0.05.

Results
In total, 168 women were selected to participate in this study. The study groups had similar baseline characteristics (

Discussion
The study was targeted at evaluating the Also, it seems necessary to analyze the subgroups to eliminate some confounding variables.

Conclusion
In conclusion, the results showed the administration of multiple doses of GnRH agonist in the luteal phase of ART cycles did not improve embryo implantation and pregnancy rates and needs further research.