There was insufficient evidence to demonstrate that the use of depot GnRHa is better or worse than the NC or HRT protocol for the reproductive outcome in FET cycles, especially for patients with RIF. Pretreatment with GnRHa before HRT in FET cycles is considered to be ineffective for the elderly patients, but it could be effective for the patients with RIF [12]. Recent studies also failed to demonstrate any significant effect of depot GnRHa-FET protocol in the live birth/ongoing pregnancy rate [6]. However, that study only included younger patients (<40 years) and thus the effect of depot GnRHa-FET protocol on elderly patients (36~43years) needs to be further evaluated.
The present large-scale retrospective cohort study evaluated the reproductive outcomes in natural cycle, HRT cycle, GnRHa-HRT cycle of elderly patients with RIF when referred for FET. Our results showed that there was a significantly higher live birth rate in GnRHa-HRT treatment protocol than that in the NC and HRT protocols, while the miscarriagerate was not significantly different among the three protocols. In addition, we used low-dose drugs in our study. Patients in our study only received one intramuscular injection of 3.75 mg depot leuprolide acetate. Ill-timed administration with the double dose of depot leuprolide acetate may increased not only the hypo-estrogenic side-effects, e.g., hot flushes,vaginal dryness, decreased libido and loss of bone density,but also high cost[13].
In contrast, previous retrospective self-control study suggested that GnRHa-HRT protocol, with 28 days of full-dose depot GnRHa, prolonged downregulation before ovarian stimulation, resulting in relatively high pregnancy success rates in idiopathic RIF patients undergoing IVF [3].
Our results are consistent with previous studies showing that cryopreservation of all viable blastocysts after ICSI followed by a subsequent FET cycle can improve the implantation when compared with fresh ET [3,5,14-16]. Other studies showed that GnRHa may partially restore the endometrial secretion of implantation related factors, e.g., HOXA10, MEIS1 and LIF, which can regulate endometrial development and permit embryo implantation and decidualization [5,17-21]. Another study showed that ovarian stimulation with GnRHa partially restores the expression of endometrial integrin beta 3 and improves uterine receptivity in mice [22].
An interesting observation in our study is that the mean level of progesterone on the administration day in the HRT cycle was significantly higher than that in the GnRHa-HRT cycles (0.38±0.29 versus 0.53±0.47, P=0.001), which is consistent with the results in previous studies [12,14,22]. This might be due to a premature rise of LH levels in hormonal stimulation protocol without a GnRH agonist, which negatively alters the receptive window of the endometrium [16].
The NC protocol is one of the most frequently and widely used FET protocols in treatment cycles[24]. However, one previous study suggests that approximately two-thirds of implantation failures are due to disturbed endometrial receptivity and asynchronized embryo-endometrial cross-talk, while the quality of embryo is estimated to be responsible for the remaining one-third implantation failure [25]. However, in this study, we found that live birth rate in NC protocol was not significantly lower than that in the GnRHa-HRT protocol, which may be due to the small sample size in the NC group. According to the histologic endometrial dating, the rate of a“displaced WOI (window of implantation)” in patients with RIF can reach 31.6%, compared with 3.8% in the patients with good-prognosis ( P = 0.003) [26].
This is the first study to evaluate the optimal approach to prepare the endometrium in FET cycles of elderly patients with RIF. The limitation of this study is its retrospective design from a single medical center. However, through the analysis of large sample size using multivariate logistics model, some confounding factors were eliminated. In addition, the type of endometrial preparation was selected by the physician’s preference and such preference may introduce a potential bias. Besides, we did not exclude cleavage stage of embryo transfer. This bias may be eliminated by a Cochrane review that blastocyst transfer over cleavage stage of embryo transfer was of low quality for live birth outcome [27].