POR, defined as the development of an insufficient number of mature follicles after Gn stimulation, results in cycle cancellation or a small number of retrieved oocytes [14]. The number of oocytes retrieved and the number of embryos available for transfer are crucial for the success of IVF treatment[15]. Although different ovarian stimulation protocols have been developed for POR improvement[16], there is still controversy over the preferred clinical protocol.
In the 1980s, GnRH-a was introduced in assisted reproductive medicine to prevent premature LH surge, resulting in a higher clinical pregnancy rate, lower cycle cancellation rate and higher number of retrieved oocytes[17]. However, GnRH-a, especially long-acting GnRH-a, has a strong inhibitory effect on the pituitary gland. Increasing the dosage and duration of Gn will inhibit the synthesis of steroid hormones in granulosa cells, which is unfavorable to the implantation of embryos and the continuation of pregnancy[18]. Excessive GnRH-a may lead to adverse ovarian reactions. Therefore, long-term use of GnRH-a may further reduce ovarian reactivity in POR patients.
Both the GnRH-ant regimen and GnRH-a short regimen have the advantage of less ovarian suppression and are considered to be effective treatments for POR patients. However, there are inconsistent reports on the therapeutic effects of the two protocols. Our study showed that the duration of stimulation, total Gn dose, E2 on the day of hCG, LH on the day of HCG, P on the day of HCG, premature LH peak, the number of oocytes retrieved, 2PN, high-quality embryos and transferable embryos in the GnRH-ant regimen group were significantly lower than those in the GnRH-a short regimen group, but the oocyte unretrieved rate, fertilization rate and high-quality-embryo rate were similar between the two regimens. The possible reasons were explained as follows. First, the GnRH-a short regimen had a downregulatory effect on the pituitary gland, which reduced ovarian reactivity to a certain extent, resulting in prolonged time and an increased dosage of Gn. However, the GnRH-ant regimen does not require downregulation, and direct application of Gn on the second or third day of menstruation will interfere less with the normal function of the ovary, so the dosage of Gn is lower. Second, the Flare-up activation of the GnRH-a short regimen led to a sudden rise in the level of FSH and induced the development of more follicles. However, in the early stage, the ovarian stimulation of the GnRH-ant regimen was mild, and the rise in FSH was slight. Follicle recruitment was relatively low. The number of follicles collected was different with the two regimens, so the number of 2PN, high-quality embryos, available embryos and E2 on HCG day were also significantly different. Third, LH on the HCG day and the premature LH peak were significantly lower in the GnRH-ant regimen group than in the GnRH-a short regimen group, indicating that the GnRH-ant regimen had a significant effect on inhibiting endogenous LH levels. P levels decreased significantly in HCG days, perhaps because GnRH-ant delayed P production when inhibiting LH levels in the late follicular phase. It is worth noting that, on the premise that the number and quality of embryos transferred were similar between the two groups, compared with those in the GnRH-a short regimen group, the implantation rate, clinical pregnancy rate and continued pregnancy rate in the GnRH-ant regimen group showed an increasing trend, while the early abortion rate showed a decreasing trend, although the difference was not significant. The results of this study are basically consistent with those of AKman MA[19]. In 2015, Ting Niu et al.’s meta-analysis showed that between the GnRH-ant regimen and GnRH-a short regimen in the treatment of POR patients, the GnRH-ant regimen was more favorable in terms of clinical pregnancy rate[8].
The cost of economic research should include direct cost, indirect cost and hidden cost[20]. Due to the different economic conditions of the patients' families, it is difficult to calculate direct nonmedical costs such as transportation costs, and it is also difficult to calculate indirect costs such as delay costs and hidden costs. Therefore, we calculated the treatment costs based on the IVF costs from the initiation of ovulation induction drugs to the time of oocyte retrieval or embryo transfer. Our study found that total oocytes retrieved cost and total embryos transferred cost were similar between the GnRH-ant regimen group and the GnRH-a short regimen group, and the difference was not significant. The oocyte retrieved cost/oocyte retrieved cycle, high-quality embryo cost/oocyte retrieved cycle, and transferable embryo cost/oocyte retrieved cycle in the GnRH-ant regimen group were higher than those in the GnRH-a short regimen group, but the clinical pregnancy cost/embryo transferred cycle and ongoing pregnancy cost/embryo transferred cycle in the GnRH-ant regimen group were lower than those in the GnRH-a short regimen group, with the cost decreases being 12526 RMB and 26754 RMB, respectively.
At present, there is no sufficient evidence to show which regimens would provide satisfactory clinical outcomes for patients with POR. An important reason for patients to refuse infertility treatment is economic factors[21, 22]. The pregnancy outcome of infertile patients with a heavy financial burden is worse than that of patients with a light financial burden. POR patients may have experienced several IVF-assisted pregnancy failures, and their desire for clinical pregnancy is much higher than that of ordinary patients. Therefore, considering the clinical effect and economic benefits comprehensively, the GnRH-ant regimen seems to be more beneficial for POR patients. However, this study has some limitations. First, this study considered only the costs from the beginning of ovulation induction to oocyte pick-up and embryo transfer and did not include the costs of examination before infertility treatment or other indirect and hidden costs. Second, there are certain differences in the efficacies and prices of different drugs for COS. At the same time, the retrospective nature of the study itself has inherent bias. Therefore, more sample sizes are still needed for subsequent verification.
In conclusion, for POR patients, the GnRH-ant regimen is more economically advantageous than the GnRH-a short regimen. Our research results can provide a reference for reducing the economic burden on patients, promoting the rational allocation of health resources and developing individualized COS in clinical practice.