Vitamin D Deficiency Is Associated With Poor Ovarian Stimulation Outcome in PCOS but Not Unexplained Infertility

Samantha F. Butts; David B. Seifer; Nathanael Koelper; Suneeta Senapati; Mary D. Sammel; Andrew N. Hoofnagle; Andrea Kelly; Steven A. Krawetz; Nanette Santoro; Heping Zhang; Michael P. Diamond; Richard S. Legro for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Reproductive Medicine Network

Disclosures

J Clin Endocrinol Metab. 2019;104(2):369-378. 

In This Article

Discussion

This investigation demonstrates that the association between vitamin D deficiency and ovarian stimulation treatment outcomes differs according to infertility diagnosis. The data showed that vitamin D deficiency in women with PCOS who underwent ovarian stimulation for the treatment of infertility was associated with significantly diminished rates of ovulation, of pregnancy, and ultimately a reduced chance of live birth. In contrast, the live birth rate in women with unexplained infertility treated with ovarian stimulation did not diminish in association with vitamin D deficiency. Our findings support the concept that vitamin D deficiency negatively affects pathways specific and integral to the phenotype of women with PCOS. Furthermore, the association between vitamin D deficiency and increased risk of miscarriage observed when pregnant subjects from the AMIGOS and PPCOS II cohorts were evaluated together suggests that vitamin D deficient status may negatively affect pathways involved in the maintenance of early pregnancy, regardless of the underlying infertility diagnosis.[6]

Vitamin D deficiency was associated with lack of ovulation independent of baseline reproductive/metabolic features of PCOS severity and demographic factors, suggesting that additional pathways regulated by vitamin D that could not be accounted for in this investigation. One potential pathway involves advanced glycation endproducts (AGEs), which are proinflammatory molecules that have been identified in the ovarian granulosa and theca layers of women with PCOS.[26,27] Current evidence suggests that correcting vitamin D deficiency in women with PCOS leads to a substantial increase in levels of sRAGE, the soluble AGE receptor that binds to AGEs, reducing their ability to activate receptors in the ovary that could disrupt follicular development.[28,29] Ongoing studies should clarify the effect of vitamin D deficiency and its treatment on pathways of reproductive function.

The association between high AMH and diminished ovulatory response to ovarian stimulation has been demonstrated in a recent secondary analysis of the PPCOS II cohort and by additional investigators.[30,31] In vitro and epidemiologic studies have suggested a role for vitamin D in regulating AMH and AMHR-II expression such that vitamin D deficiency could result in AMH elevation or altered signaling through the AMH receptor.[28,32,33] Although we did not observe an important association between vitamin D deficiency and mean AMH, a substantial positive correlation between total 25(OH)D and AMH was noted. This result is consistent with evidence in the epidemiologic literature,[34] but contrasts with the data supporting vitamin D as a negative regulator of AMH action. The relationship among vitamin D status, AMH, and ovulation in women with PCOS is undeniably complex, requiring additional study.

The unique association between vitamin D deficiency and features of PCOS may explain the potential salutary effects of normalizing vitamin D on reproductive[28,32] and metabolic[28,35] pathways related to ovarian stimulation treatment outcomes. The underpinnings of unexplained infertility for any given couple could encompass subtle derangements in a wide array and combination of female and male factors, many of which may not be prone to the effects of vitamin D deficiency. In a separate secondary analysis of the AMIGOS trial, Hansen et al.[15] described increased duration of infertility and annual income, <$50,000 as substantial independent predictors of diminished rate of live birth in women with unexplained infertility, whereas obesity and insulin resistance were not associated with live birth. This suggests that barriers to accessing care impede the likelihood of treatment success in women with unexplained infertility undergoing ovarian stimulation in ways that metabolic and anthropometric indicators do not.

Correcting vitamin D deficiency in women with PCOS has been shown to significantly improve ovarian follicular growth, dominant follicle formation, and regularity of menstrual cycles.[36,37] These findings are consistent with recent evidence that vitamin D may have a direct trophic impact upon folliculogenesis and oocyte maturation that is dose and follicle stage dependent.[38] We propose that the reproductive effect of vitamin D status may be influential in the context of aberrant folliculogenesis present in women with PCOS.

Among the strengths of this study is using large, wellcharacterized study populations allowing for statistical power to test associations and the ability to thoroughly address confounding. The association between vitamin D deficiency and live birth in PPCOS II was independent of the effects of race, age, treatment, degree of hyperandrogenemia, degree of insulin resistance, and obesity. Our results support the idea that vitamin D deficiency is detrimental to reproduction in women with modified Rotterdam criteria for PCOS, which was used to enroll subjects in PPCOS II. Prior work demonstrating diminished live birth in sujbects who were vitamin D deficient in the PPCOS I study focused on women with PCOS based on National Institutes of Health diagnosticcriteria.[39] The reproducibility of the finding that vitamin D deficiency has negative reproductive consequences for women with PCOS regardless of which diagnostic criteria are applied speaks to the robustness of this association.

As with prior studies in reproduction,[4,7,39] 25(OH)D was measured at a single pretreatment time point, making it impossible to characterize variation resulting from season or vitamin supplementation. However, any potential bias introduced by vitamin D variation was likely nondifferential with respect to the outcomes under study. It is extremely unlikely that such variation would entirely explain the null finding between vitamin D deficiency and treatment outcomes in the AMIGOS study. In this investigation, we did not have access to serum from the male partners and were unable to ascertain whether partner vitamin D deficiency contributes to treatment outcomes in either AMIGOS or PPCOS II. The receptor for vitamin D is present on sperm and in the male reproductive tract, making this an important line of future investigation in fertility.[40]

The presence of a 60% increased risk of early pregnancy loss among all pregnant patients with preconception vitamin D deficiency (AMIGOS and PPCOS II combined) approached statistical significance (P = 0.05). Although this finding is in line with existing epidemiological evidence of detrimental decidual-placental effects of vitamin D deficiency,[6] it does not preclude the possibility of embryonic effects of vitamin D deficiency contributing to pregnancy loss. Additional studies exploring larger numbers of early pregnancies are needed to clarify this association.

Our finding that women with PCOS who are vitamin D deficient have impaired chances of ovulation, pregnancy, and live birth with ovarian stimulation builds upon the evidence supporting a role for vitamin D in human reproduction. Considering the prevalence of PCOS and vitamin D deficiency alongside the vast number of unsuccessful ovarian stimulation cycles conducted in this country every year, these results are pertinent to the reproductive outcomes of a substantial number of infertile women. As the results of future studies of vitamin D and reproduction accumulate, potentially building toward well-designed intervention studies, a reexamination of current periconceptual screening, and treatment guidelines may be warranted.

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