The present study was conducted to response the question of whether changing the type of luteal phase support (LPS) in patients with POR diagnosis improves the rates of clinical pregnancy and live birth. The results of the study showed that the type of luteal phase support did not affect the clinical pregnancy and live birth rates in POR patients, just the rate of twin pregnancy in the hCG -alone group was a little more than progesterone- alone group.
Fundamentally, LPS has been demonstrated as a vital part in IVF cycles because ovarian stimulation disrupts the particular function of corpus luteum (CL) by different mechanisms. The formation of several mature ovarian follicles, E2 levels reach to supraphysiological ranges specifically during the follicular phase; moreover, progesterone levels increase in early days of luteal phase due to numerous CLs affected by triggering doses of hCG. Thus LH secretion decompressed during luteal phase afterwards, CL support by pituitary LH will not precede [6, 7]. Notwithstanding the foregoing, it is important to realize that the CL does not require supraphysiologic levels of LH/hCG to secrete high values of progesterone [8]. During the natural menstrual cycle, the LH level in the luteal phase rarely rises over 5–10 IU/L and most commonly is capable to elicit P levels up to 25–35 nmol/L. When ten CLs are exist, each will secrete P in amounts similar to the natural menstrual cycle when exposed to physiologic concentrations of LH/hCG [8]. Collectively, this results in high concentration of P. However, this condition occurs when the ovarian response is normal or excessive, and therefore in POR patients due to limited AFC and growing follicles and the lack of existence of suitable CL, the possibility of hormonal defects in the LPS is higher.
Several protocols have been developed to correct this hormonal inadequacy in IVF cycles, based on the substances used or the route of administration. The development of new regimens for LPS based on ‘‘low-dose’’ or ‘‘microdose’’ hCG supplementation was considered recently. In preliminary studies, four injections of 1500 to 2500 IU of hCG were administrated after final oocyte triggering with 10000 IU of hCG [9]; since then, several studies have examined different methods of luteal phase support using hCG alone or with progesterone in normal patients or donor patients[10-13]. With these regimes, the LH/ hCG concentration in the luteal phase often reaches more than five to ten times that observed in the normal menstrual cycle which make powerful luteal phase support; however, significantly increase the risk of OHSS[4]. In a recent Cochrane review study reported that the administration of hCG alone or in combination with progesterone to support the luteal phase should be avoided due to increase the risk of OHSS[3].
Moreover, a number of studies have suggested that in cases where GnRH agonist is used for the final oocyte triggering, very low doses of hCG of 100 to 150 IU per day could be appropriate option for the LPS [14, 15]. Progesterone levels in the middle of the luteal phase in this procedure were similar to the use of progesterone with 6500 IU of hCG to induce ovulation[8]. The limitation of this strategy that prevents from being applied to routine procedures is that the difficulty HCG dilution over time with normal saline to achieve a dose of 100 to 150 units and daily injection for the patient[4].
Considering that there is no risk of OHSS in POR patients, it seems that the study of this new LPS regime with low-dose hCG for improving pregnancy rate is valuable. Furthermore, women appear to prefer low-dose hCG administration to exogenous P administration, especially by the vaginal route.
In present study, when twin pregnancy rate was compared among groups, it was higher in the hCG–only group than that of in the P-only and hCG + P groups; however, it was close to significant level. In this regard, Var et al. reported that multiple pregnancies rate were significantly higher in the hCG+ P group than in the P-only and E2 + P groups [11]. Similar to their findings, Ludwig et al. also found that multiple pregnancy rate were higher in the hCG +P group than in the P-only group [10]. However, Ghanem and colleagues reported no statistical difference among the groups in terms of multiple pregnancies; they determined a higher tendency in the E2 + P and hCG + P groups compared with the P-only group [16]. It is likely that the use of hCG for LPS are involved in increasing the rate of multiple pregnancies and more studies are necessary in this regard.
The main limitation of the study is that we did not consider the good quality euploid blastocysts and unique COH protocol as inclusion criteria. Although, in data analysis the number and quality of transferred embryos and the proportions of two COH protocols were similar among groups, it is recommended that these points be considered in future studies to eliminate these confounding factors.
In conclusion the present study is the first clinical trial to compare the effect of low-dose hCG with routine protocol for LPS in patients with POR diagnosis on the basis of the Bologna criteria. We found the same pregnancy and live birth rates in different regimes for LPS. Interestingly, the use of two bolus of low- dose hCG 1500 was associated a slight increase in multiple pregnancies. We recommend a multi-center clinical trial with a larger sample size in this field to confirm or refute our findings.