With this PSM study, we aimed to achieve more certain conclusions than previous cohorts or case control studies. Although the samples size was small, it was statistically capable of reflecting differences in effectiveness on CLBRs among the three regimens, given the obvious differences. The outcomes of this study showed that both the rFSH + rLH therapy and the rFSH therapy alone significantly increased the cumulative live birth rate in LH over-suppression patients when compared with hMG therapy; it also resulted in a significantly reduced dose of FSH. Furthermore, rFSH + rLH therapy produced a better outcome than rFSH alone.
Previously, there has been controversy over the value of supplemental exogenous LH during ART. Evidence from early studies suggested that LH did not affect clinical pregnancy outcome [10–12]. On the other hand, several studies had given a confirmation on the clinical value of exogenous LH [13, 14]. We supposed the timing of LH supplementary was the key point of this issue. In previous studies, LH were administrated late follicular phase , or at the day LH decrease to < 0.5 mU/ml . The LH administration was carried out during the whole course in this study, since rFSH initiate, in rFSH + rLH group. One reason was that we defined the LH over suppression by the data at Gn initiation day and baseline. It is possible to distinguish the patients occurred LH over suppression since the treatment started. The other reason was that we believe exogenous LH supplyment as early as possible could improve the clinical outcomes more. The results of this study showed that rFSH + rLH therapy significantly increased the cumulative live birth rate in LH over-suppression patients when compared with rFSH treatment alone. Similar results have been reported elsewhere [16–18]. Sonntag et al. report that long-term use of GnRH-a can lead to low levels of endogenous LH , thus it is important to supplement exogenous LH in patients with low LH levels . Previous studies also found that patients with low serum LH levels achieved better clinical pregnancy rates after adding exogenous LH [15, 21–24]. Franco et al. report that supplementation with rLH significantly increases the number of fertilized oocytes obtained and the rate of cumulative live births . In the current study, patients whose LH level decreased by ≥ 50% on the day of Gn initiation were included as subjects. The results of this study further validated the significant effect of rLH on maternity outcomes in patients with LH over-suppression after GnRH-a pituitary down-regulation.
The secondary outcomes, including biochemical pregnancy and clinical pregnancy in fresh cycles, showed no difference between the three groups. Furthermore, endometrial thickness at the time of HCG injection, or the number of fertilized oocytes obtained, or embryo number, were all similar among the three groups. It is not surprising that results in fresh cycles showed no difference, as the number of oocytes obtained, or embryo number, were more closely related to the effect of controlled ovarian hyperstimulation. However, these numbers were also similar in the current study. We propose that there are some unobserved factors that influence embryo or endometrial quality that result in an improved CLBR.
It is possible that some detailed differences in clinical practice, such as drugs administered from different manufacturers, might result in different conclusions. Furthermore, the definition of LH over-suppression might influence these results. Several efforts were made in this study to obtain a more certain conclusion; for example, we clarified the definition of LH over-suppression, which was set at a decrease of ≥ 50%, to reduce the impact of individual factors, such as baseline extreme high or low LH. Furthermore, we also balanced both an actual decrease and a decrease in rate of LH level among the three groups using PSM. This definition differed from previous studies, and could therefore be a reason for the difference in results.
By comparing the hMG group and the other two groups, we found a significantly lower CLBR, which suggested a benefit from LH supplementation could only be achieved following administration of rLH. Even though hMG has an active function similar to rLH, the actual component of HCG is different from rLH, with the former being extracted from the urine of menopausal women while the latter comes from recombinant DNA technology. A previous study obtained a similar conclusion in women > 35 y ; the ongoing pregnancy rate was higher in an rFSH + rLH group than that in an hMG group (17.3% vs. 12.2%). However, in another study, the supplementation of LH did not show any significant improvement in clinical outcomes . There should be differences in effectiveness between HCG and rLH based on their mechanism of action, thus we propose that the inconsistency of the effectiveness of rLH supplementation is related to the extent of decrease in LH. Interestingly, we found that the outcome in the rFSH alone group was also better than that in hMG group, a finding which has not been previously reported. The above-mentioned difference between rLH and HCG, patient characteristics of LH over-suppression, and probably the chosen outcome of CLBR, could be reasons why such obvious differences were found among the three groups.
Previous studies report that rLH supplementation reduces FSH dose requirement [28, 29]. In the current study, the FSH dose was reduced when compared with the hMG group, while it was not significantly decreased when rFSH alone was compared with rFSH + rLH; this may have been related to factors such as the relative fixed drug dose in clinical practice, and also the small sample size.
There were several limitations in this study. Firstly, this was only a retrospective study, not a randomized controlled trial; which leaves the opportunity for potential bias. Secondly, this study was a single-center clinical study with a small sample size. Additional multi-center clinical studies with larger sample sizes are warranted.