We read with interest the comments by Garcia-Velasco et al in response to our article in which we detail the lack of correlation between 25-hydroxy vitamin D levels and reproductive outcomes during in vitro fertilization with euploid blastocysts. As the authors indicated, they have concomitantly published a recent article that shows similar findings in women undergoing oocyte donation, an experimental model that also makes attempts to control for embryonic factors. They also completed additional analyses that address some of the discussion points raised in our article regarding vitamin D binding protein and free vitamin D.

What remains of interest is the discussion point raised in our article regarding timing of serum sampling when determining vitamin D status in infertility patients. In our study, serum was obtained on the day of ovulatory trigger and in the study by Garcia-Velasco et al the serum was obtained after 2 weeks of hormone replacement therapy. To date, there remains few data on how endogenous or exogenous hormones, particularly estradiol, affect vitamin D binding protein levels and thus free vitamin D levels. Pharmacodynamics studies are needed, both in the normal physiologic hormonal milieu of the menstrual cycle as well as the nonphysiologic milieu induced by exogenous gonadotropins or hormonal therapy.

The authors agree with Garcia-Velasco et al that the lack of correlation between vitamin D status and in vitro fertilization outcomes when controlling for embryonic factors–either by utilizing euploid blastocysts or by utilizing the donor gamete model–does not rule out the possibility that vitamin D has important implications at the level of oocyte and/or embryonic development or at the level of the endometrium when inferior embryos are present. Indeed, future study designs need to consider a number of factors. When addressing questions regarding ethnicity and vitamin D status, should one consider self-reported ethnicity vs genotypic ethnicity that we have found to be nonconcurrent in >15% in some cases? As discussed, does analysis of vitamin D depend significantly on the time during the menstrual cycle or during assisted reproductive care that serum is drawn? These and other questions must be further characterized to clarify the mixed results reported in the literature to date regarding vitamin D’s impact on reproductive success in assisted reproductive technology.