Abstract and Introduction
Background Vitamin D plays a role in reproductive capacity. Recently, several investigators have demonstrated higher IVF pregnancy rates in vitamin D replete women. The objective of this study was to validate these findings and to further elucidate the role of vitamin D in reproduction among a diverse group of women.
Results The relationship between vitamin D status and pregnancy rates differed by race (P < 0.01). Among non-Hispanic whites, pregnancy rates declined with progressively lower levels of vitamin D, while in Asians, the reverse was true. Adjusting for age and number and quality of embryos transferred among non-Hispanic whites, the odds of pregnancy were four times higher in vitamin D replete versus deficient patients. Live birth rates mirrored pregnancy rates. Vitamin D status was not associated with ovarian stimulation parameters or with markers of embryo quality.
Conclusions Vitamin D deficiency is associated with lower pregnancy rates in non-Hispanic whites, but not in Asians, possibly due to their lower IVF success rates. Vitamin D deficiency was not correlated with ovarian stimulation parameters or with markers of embryo quality, suggesting its effect may be mediated through the endometrium.
An epidemic of vitamin D deficiency has been emerging over the last decade among all racial groups in the USA, with the prevalence of vitamin D insufficiency nearly doubling from 1994 to 2004 (Looker et al., 2008). Vitamin D deficiency has been implicated in a host of chronic diseases, including diabetes, obesity, autoimmune disease, cardiovascular disease and cancer. More recently, poor vitamin D status has been implicated as a contributing factor to poor pregnancy outcomes (Bodnar et al., 2007) and infertility (Ozkan et al., 2010).
The importance of vitamin D in reproduction is evident from murine models. Vitamin D receptor knockout mice demonstrate uterine hypoplasia, gonadal insufficiency, reduced aromatase gene expression, impaired folliculogenesis and infertility (Yoshizawa et al., 1997; Kinuta et al., 2000). Rats deficient in vitamin D demonstrate compromised mating behavior, reduced fertility, decreased litter sizes and impaired neonatal growth (Halloran and DeLuca, 1980; Kwiecinski et al., 1989). Importantly, reproductive function can be normalized with vitamin D supplementation, but not with calcium alone, suggesting that vitamin D's role in reproduction lies outside of its classic endocrine role in regulating calcium homeostasis (Halloran and DeLuca, 1980; Kwiecinski et al., 1989; Johnson and DeLuca, 2001).
The presence of the vitamin D receptor (VDR) in many tissues along the female reproductive axis, including the pituitary, ovary, uterus and placenta (Johnson and DeLuca, 2001), suggests that vitamin D is an important regulator of the female reproductive system. The active form of vitamin D (1,25 dihydroxyvitamin D3 or calcitriol), when bound to its receptor, acts as a transcription factor to regulate the expression of the CYP19 gene, which encodes aromatase, an essential enzyme in the production of estrogen (Kinuta et al., 2000). Serum calcitriol and estradiol levels track together, both in the normal menstrual cycle (Gray et al., 1982) and in stimulated IVF cycles (Potashnik et al., 1992); however, the main circulating form of vitamin D (25-hydroxyvitamin D or 25(OH)D) does not fluctuate throughout the menstrual cycle (Johnson and DeLuca, 2001).
Calcitriol is produced by the decidua in response to IL-1B secreted by the blastocyst (Vigano et al., 2006). Calcitriol regulates decidual expression of HOXA10, calbindin (Daftary and Taylor, 2006) and osteopontin (Vigano et al., 2006) genes, all integrally involved in embryo implantation. The decidua and placenta continue to secrete large quantities of calcitriol throughout pregnancy, which is important for regulating the immune response at the maternal–fetal interface. The presence of the blastocyst up-regulates the production of the active form of vitamin D in the endometrium (Vigano et al., 2006). In turn, calcitriol may help to support successful implantation by attenuating decidual T-cell function (Evans et al., 2004). Decidual NK cells treated with calcitriol show decreased synthesis of cytokines, CSF2, IL-1 and IL-6 and TNFα (Evans et al., 2006).
An IVF population provides valuable insight into the role of vitamin D since it is possible to examine each aspect of a single conception cycle from follicular development to implantation. A recent study found that women with higher 25(OH)D levels in their serum and follicular fluid were significantly more likely to achieve pregnancy from IVF compared with women with lower levels of vitamin D (Ozkan et al., 2010). The primary objective of our study was to verify this relationship between vitamin D status and IVF outcomes, and additionally to isolate the effect of vitamin D either to ovarian stimulation, embryo quality or endometrium. As a secondary objective, we aimed to evaluate the relationship between vitamin D and IVF outcomes in the context of patient race.
Hum Reprod. 2012;27(11):3321-3327. © 2012 Oxford University Press