The quality and quantity of the retrieved oocytes are the major factors affecting IVF outcomes. For poor responders, numerous ovarian reserve tests have been developed to predict the response to ovarian stimulation [1, 2, 11, 12]. Methods using endocrine and ultrasound markers for assessing the quantity of follicles are widely performed. However, few methods have been established to evaluate the quality of the oocytes. In the present study, we found a role for the oocyte-derived factor, BMP-15, in predicting IVF outcome in poor responders, which may facilitate the further management of these patients.
First, we divided the 207 poor responders into a high BMP-15 group and a low BMP-15 group according to their FF BMP-15 levels. Both groups were comparable in terms of age, but the implantation and pregnancy rates were significantly higher in the high BMP-15 group. These data suggest that FF BMP-15 may be an effective marker of oocyte quality and IVF performance independent of age. This result is consistent with our previous study, which showed that oocytes retrieved from follicles with a high FF BMP-15 level had higher fertilisation rates and a better quality of developed embryos .
The potential role of BMP-15 in oocyte development competence and pregnancy outcome is well grounded. In ovary, it is exclusively produced by oocytes . BMP-15 has been shown to stimulate undifferentiated granulosa cell proliferation, regulate granulosa cell differentiation , and inhibit FSH action by suppressing the sensitivity of granulosa cells to FSH stimulation . Importantly, BMP-15 is also involved in the selection of the dominant follicle and in oocyte maturation by cooperating with FSH . Moreover, BMP-15 may contribute to the maintenance of the low incidence of cumulus cell apoptosis by establishing a localized gradient , and it induces cumulus cell expansion by enhancing the expression of epidermal growth factor-like growth factor . Interestingly, BMP-15 can promote glycolysis in cumulus cells for oocyte development as mammalian oocytes are unable to initiate glycolysis [5, 17].
Many reports have identified the hormones and other factors in FF and their roles in evaluating oocyte quality. The FF concentrations of hormones, prolactin, interleukin-1, inhibin B, tumour necrosis factor, free fatty acids and dehydroepiandrosterone have been associated with the rates of normal fertilisation and good embryo development and the quality of the embryos [10, 18, 19]. However, their predictive accuracy and sensitivity is very limited, and some reports did not replicate these findings [20, 21]. In contrast to all of the factors mentioned above, BMP-15 is oocyte-derived, indicating that it may be a more direct and valuable marker than others for predicting oocyte quality. Unsurprisingly, therefore, poor responders with a higher FF BMP-15 level had better IVF outcomes, including a higher live birth rate.
Ageing is well-known to reduce the biological capacity of a woman to reproduce. In this study, we found that poor responders with both low FF BMP-15 and age >35 years had the worst IVF outcomes. Meanwhile, young responders with high FF BMP-15 showed a better outcome. Even in the high BMP-15 group, increased maternal age was also associated with a significantly greater miscarriage rate. These clinical consequences may be due to the increase in the incidence of oocyte meiotic errors with age . Notably, the miscarriage rate of women with high FF BMP-15 and aged less than or equal to 35 years was just 5.3%.
Because IVF is an invasive and expensive treatment, informing poor responders when to give up further IVF cycles is important. The combination of BMP-15 and age appears more accurate than any single marker in predicting the clinical outcome, which may help poor responders decide whether to continue with further attempts. Moreover, for poor responders with one or two mature follicles, proceeding to IVF may represent their best chance for a successful pregnancy. Conversion to intrauterine insemination or cancelling the current cycle and making another attempt later does not improve outcome . Our and other studies suggest that proceeding to IVF may still be the best choice for these patients, especially for those younger than 35 years and with a higher BMP-15 in FF. However, patients with both low FF BMP-15 levels and aged >35 years should be adequately warned of the possibility of the worst pregnancy outcome. We did not determine the value of FF BMP-15 in another IVF cycle in these patients, and whether the BMP-15 level would be changed in the following IVF cycle with adjusted stimulation protocols remains unknown. Further studies using large samples sizes should be undertaken before a clear conclusion is made.