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


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

In This Article

Abstract and Introduction


Context: The impact of vitamin D deficiency on the success of ovarian stimulation according to underlying infertility diagnosis has not been investigated.

Objective: To evaluate the relationship between vitamin D deficiency and reproductive outcomes after ovarian stimulation in women with either polycystic ovary syndrome (PCOS) or unexplained infertility.

Design: Retrospective cohort study.

Setting: Analysis of randomized controlled trial (RCT) data.

Participants: Participants from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) RCT (n =607); participants from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) RCT of unexplained infertility (n = 647).

Interventions: Serum 25(OH)D levels measured in banked sera.

Main Outcome Measures: Primary: live birth; secondary: ovulation (PPCOS II), pregnancy, and early pregnancy loss.

Results: In PPCOS II, subjects with vitamin D deficiency [25(OH)D < 20 ng/mL or 50 nmol/L] were less likely to ovulate (adjusted OR, 0.82; 95% CI, 0.68 to 0.99; P = 0.04) and experienced a 40% lower chance of live birth (adjusted OR, 0.63; 95% CI, 0.41 to 0.98; P = 0.04) than those not deficient. In AMIGOS, no significant association between vitamin D deficiency and live birth was noted. In pregnant subjects from both studies, vitamin D deficiency was associated with elevated risk of early pregnancy loss (OR, 1.6; 95% CI, 1.0 to 2.6; P = 0.05).

Conclusions: In this investigation of women pursuing ovarian stimulation, the association between vitamin D deficiency and diminished live birth relied on carrying the diagnosis of PCOS and was not observed in unexplained infertility. Given the generally modest success of ovarian stimulation, addressing vitamin D deficiency may prove an important treatment adjunct for many infertile women.


There is a growing acknowledgment of the important role of vitamin D in human reproduction. Vitamin D receptors (site of action) and 1 α-hydroxylase (site of synthesis) are present throughout the female reproductive tract, and vitamin D is known to regulate genes responsible for aspects of ovarian, endometrial, and placental function.[1–3] Consistent with the relevance of vitamin D to female reproductive physiology is emerging evidence that women with infertility and vitamin D deficiency have diminished chance of conceiving a pregnancy in response to treatment compared with those who are vitamin D replete. However, the bulk of this evidence derives from studies in women undergoing in vitro fertilization (IVF)[4–7] rather than from non-IVF treatments, which are more commonly performed to treat infertility. The clinical significance of a putative role for vitamin D in reproduction is underscored by the prevalence of vitamin D insufficiency or deficiency in 45% to 90% of reproductive age women.[8,9] The paucity of data evaluating the impact of vitamin D status on the efficacy of non-IVF infertility treatments represents an important gap in reproductive research.

There are numerous etiologies for infertility including polycystic ovary syndrome (PCOS) and unexplained infertility. PCOS, a condition causing anovulatory infertility, is the most common endocrinopathy affecting reproductive-age women (5% to 10% prevalence).[10–12] PCOS and vitamin D deficiency have overlapping metabolic features in their strong associations with obesity and insulin resistance.[13,14] Unexplained infertility affects 15% to 37% of infertile couples and is diagnosed when no clinical barrier to fertility is identified after extensive testing has been performed.[11,15,16] Current treatment paradigms for each disorder include the use of ovarian stimulation medications to either induce ovulation (in PCOS) or increase the number of follicles recruited and oocytes released (in unexplained infertility).[11,16,17] Ovarian stimulation treatment pitfalls include lack of response in up to 25% of patients with PCOS[17,18] and overall modest per cycle pregnancy rates in all women necessitating numerous repeated treatments.[10,16,17]

The primary hypothesis of this study was that vitamin D deficiency is an important modifiable contributor to diminished treatment success in women with either PCOS or unexplained infertility undergoing ovarian stimulation (which, going forward, represents either oral ovulation induction or oral/injectable ovarian stimulation). To test this hypothesis, we performed an assessment of vitamin D status in stored sera from completed randomized controlled trials conducted by the Reproductive Medicine Network (RMN): (i) The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial[10] and (ii) The Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation (AMIGOS) trial.[19] The RMN is funded by the National Institute of Child Health and Human Development as a cooperative effort of seven clinical sites charged with conducting high-quality clinical studies in reproductive medicine.