Women with PCOS who undergo IVF: a comprehensive review of therapeutic strategies for successful outcomes.

Polycystic ovarian syndrome (PCOS) is a widespread syndrome that poses unique challenges and constraints to the field of assisted reproductive technology. This condition is the most common cause of anovulation among infertile couples. Debate exists over the best therapeutic course of action when patients with PCOS proceed to IVF. In this review, we evaluate the best-performing and safest methods of IVF preparation, ovarian stimulation, trigger method for maturation of stimulated egg growth, and planning for embryo transfer. Pre-IVF considerations include being aware of individual AMH and vitamin D levels as well as BMI prior to selecting an ovarian stimulation protocol. Numerous supplements such as myo-inositol complement the benefits of lifestyle change and may enhance IVF performance including oocyte yield and pregnancy rate. Concerning stimulation protocols, antagonist cycles with the judicious use of GnRH agonist trigger, pre-treatment with metformin and vitamin D repletion may help mitigate the accompanied risk of ovarian hyperstimulation syndrome (OHSS). Following ovarian stimulation, PCOS patients typically undergo programmed frozen embryo transfer (FET) cycles which are more conducive for women with irregular cycles, but likely carry a higher risk of hypertensive disorders of pregnancy. However, newer stimulated FET protocols using Letrozole may offer improved outcomes. Overall, patients with PCOS require careful individual tailoring of their IVF cycle to achieve optimal results.

Vitamin D3 Regulates Follicular Development and Intrafollicular Vitamin D Biosynthesis and Signaling in the Primate Ovary.

There is an increasing recognition that vitamin D plays important roles in female reproduction. Recent studies demonstrated that 1α,25-dihydroxyvitamin D3 (VD3), the biologically active form of vitamin D, improved ovarian follicle survival and growth in vitro. Therefore, we investigated the direct effects of VD3 at the specific preantral and antral stages of follicular development, and tested the hypothesis that vitamin D receptor (VDR) and enzymes critical for vitamin D biosynthesis are expressed in the primate ovary. Fourteen adult rhesus macaques provided ovarian tissue. Secondary and antral follicles were isolated for PCR analysis on VDR, vitamin D3 25-hydroxylase, and 25-hydroxyvitamin D3-1α-hydroxylase. VDR protein localization was determined by immunohistochemistry on ovarian sections. Isolated secondary follicles were cultured under conditions of control and VD3 supplementation during the preantral or antral stage. Follicle survival, growth, steroid and anti-Müllerian hormone (AMH) production, as well as oocyte maturation were evaluated. In vivo- and in vitro-developed follicles were also assessed for genes that are critical for vitamin D biosynthesis and signaling, gonadotropin signaling, steroid and paracrine factor production, and oocyte quality. The mRNA encoding VDR, 25-hydroxylase, and 1α-hydroxylase was detectable in in vivo- and in vitro-developed preantral and antral follicles. The 25-hydroxylase was elevated in cultured follicles relative to in vivo-developed follicles, which further increased following VD3 exposure. VD3 treatment increased 1α-hydroxylase in in vitro-developed antral follicles. The absence of VD3 during culture decreased VDR expression in in vitro-developed antral follicles, which was restored to levels comparable to those of in vivo-developed antral follicles by VD3 supplementation. Positive immunostaining for VDR was detected in the nucleus and cytoplasm of granulosa cells and oocytes. While only survival was improved in preantral follicles treated with VD3, VD3 supplementation promoted both survival and growth of antral follicles with increased estradiol and AMH production, as well as oocyte maturation. Thus, Vitamin D biosynthesis and signaling systems are expressed in primate ovarian follicles. Our findings support a role for VD3 in regulating follicular development in a stage-dependent manner, as well as the intrafollicular vitamin D biosynthesis and signaling, directly in the ovary.

Vitamin D Decreases Serum VEGF Correlating with Clinical Improvement in Vitamin D-Deficient Women with PCOS: A Randomized Placebo-Controlled Trial.

Vascular endothelial growth factor (VEGF) has been suggested to play a role in the pathophysiology of polycystic ovary syndrome (PCOS) and may contribute to increased risk of ovarian hyperstimulation syndrome (OHSS) in affected individuals. Vitamin D (VitD) supplementation improves multiple clinical parameters in VitD-deficient women with PCOS and decreases VEGF levels in several other pathologic conditions. Unveiling the basic mechanisms underlying the beneficial effects of vitamin D on PCOS may enhance our understanding of the pathophysiology of this syndrome. It may also suggest a new treatment for PCOS that can improve it through the same mechanism as vitamin D and can be given regardless of vitamin D levels. Therefore, we aimed to explore the effect of VitD supplementation on serum VEGF levels and assess whether changes in VEGF correlate with an improvement in characteristic clinical abnormalities of PCOS. This is a randomized placebo-controlled trial conducted between October 2013 and March 2015. Sixty-eight VitD-deficient women with PCOS were recruited. Women received either 50,000 IU of oral VitD3 or placebo once weekly for 8 weeks. There was a significant decrease in serum VEGF levels (1106.4 ± 36.5 to 965.3 ± 42.7 pg·mL-1; p < 0.001) in the VitD group. Previously reported findings of this trial demonstrated a significant decrease in the intermenstrual intervals, Ferriman-Gallwey hirsutism score, and triglycerides following VitD supplementation. Interestingly, ∆VEGF was positively correlated with ∆triglycerides (R² = 0.22; p = 0.02) following VitD supplementation. In conclusion, VitD replacement significantly decreases serum VEGF levels correlating with a decrease in triglycerides in women with PCOS. This is a novel molecular explanation for the beneficial effects of VitD treatment. It also suggests the need to investigate a potential role of VitD treatment in reducing the incidence or severity of OHSS in VitD-deficient women with PCOS.

Direct vitamin D3 actions on rhesus macaque follicles in three-dimensional culture: assessment of follicle survival, growth, steroid, and antimüllerian hormone production.

OBJECTIVE: To investigate the direct actions of active 1,25-dihydroxy vitamin D3 (VD3) upon primate follicular development at specific stages of folliculogenesis. DESIGN: Secondary preantral follicles were isolated from rhesus monkeys ovaries, encapsulated in alginate, and cultured for 40 days. Follicles were randomly assigned to experimental groups of control, low-dose VD3 (LVD3; 25 pg/mL), and high-dose VD3 (HVD3; 100 pg/mL). SETTING: National primate research center. ANIMAL(S): Adult, female rhesus macaques (Macaca mulatta). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Follicle survival and growth, as well as oocyte size, were assessed. Progesterone (P4), androstenedione (A4), E2, and antimüllerian hormone (AMH) concentrations in culture media were measured. RESULT(S): Compared with the control group, LVD3 increased preantral follicle survival at week 2 by >66%, while HVD3 increased antral follicle diameters at week 5. Follicles with diameters ≥500 µm at week 5 were categorized as fast-growing follicles. Higher percentages of fast-growing follicles were obtained after HVD3 treatment. Although P4, A4, and E2 production by antral follicles was not altered by VD3, AMH concentrations were 36% higher in the LVD3 group relative to controls at week 5. Oocytes with larger diameters were retrieved from antral follicles developed in both LVD3 and HVD3 groups compared with controls. CONCLUSION(S): The addition of LVD3 increased preantral follicle survival and maintained AMH production by antral follicles, while HVD3 improved antral follicle growth. VD3 supplement promoted oocyte growth in in vitro-developed follicles. Direct actions of VD3 on the primate follicle appear to be both dose and stage dependent.

Vitamin D Supplementation Decreases TGF-ß1 Bioavailability in PCOS: A Randomized Placebo-Controlled Trial.

CONTEXT: There is an abnormal increase in TGF-ß1 bioavailability in women with polycystic ovary syndrome (PCOS), which might play a role in the pathophysiology of this syndrome. Vitamin D (VD) supplementation improves various clinical manifestations of PCOS and decreases TGF-ß1 levels in several diseases including myelofibrosis. OBJECTIVE: The objective of the study was to determine the effect of VD supplementation on TGF-ß1 bioavailability in VD-deficient women with PCOS and assess whether changes in TGF-ß1/soluble endoglin (sENG) levels correlate with an improvement in PCOS clinical manifestations. DESIGN: This was a prospective, randomized, placebo-controlled trial. SETTING: The study was conducted at an academic-affiliated medical center. PARTICIPANTS: Sixty-eight VD-deficient women with PCOS who were not pregnant or taking any exogenous hormones were recruited between October 2013 and January 2015. INTERVENTIONS: Forty-five women received 50 000 IU of oral vitamin D3 and 23 women received oral placebo once weekly for 8 weeks. MAIN OUTCOMES MEASURES: Serum TGF-ß1, sENG, lipid profile, testosterone, dehydroepiandrosterone sulfate, and insulin resistance were measured. The clinical parameters were evaluated before and 2 months after treatment. RESULTS: The VD level significantly increased and normalized after VD supplementation (16.3 ± 0.9 [SEM] to 43.2 ± 2.4 ng/mL; P < .01), whereas it did not significantly change after placebo. After the VD supplementation, there was a significant decrease in the following: the interval between menstrual periods (80 ± 9 to 60 ± 6 d; P = .04), Ferriman-Gallwey score (9.8 ± 1.5 to 8.1 ± 1.5; P < .01), triglycerides (138 ± 22 to 117 ± 20 mg/dL; P = .03), and TGF-ß1 to sENG ratio (6.7 ± 0.4 to 5.9 ± 0.4; P = .04). In addition, the ΔTGF-ß1 to sENG ratio was positively correlated with Δtriglycerides (r = 0.59; P = .03). CONCLUSIONS: VD supplementation in VD-deficient women with PCOS significantly decreases the bioavailability of TGF-ß1, which correlates with an improvement in some abnormal clinical parameters associated with PCOS. This is a novel mechanism that could explain the beneficial effects of VD supplementation in women with PCOS. These findings may support new treatment modalities for PCOS, such as the development of anti-TGF-ß drugs.

Vitamin D increases serum levels of the soluble receptor for advanced glycation end products in women with PCOS.

CONTEXT: Elevation of serum proinflammatory advanced glycation end products (AGEs) is involved in the pathogenesis of polycystic ovary syndrome (PCOS). The soluble receptor for AGEs (sRAGE) acts as a decoy by binding circulating AGEs. Vitamin D supplementation attenuates the deposition of AGEs in the vascular system of diabetic animals and improves some metabolic aspects of vitamin D-deficient women with PCOS. Additionally, serum anti-Mullerian hormone (AMH) is elevated in women with PCOS, reflecting abnormal ovarian folliculogenesis. OBJECTIVE: The objective of the study was to evaluate the effect of 1,25 dihydroxyvitamin D3 (vit D3) supplementation on serum sRAGE and AMH in vitamin D-deficient women with PCOS. DESIGN, SETTINGS, PARTICIPANTS, AND INTERVENTION: Sixty-seven women with (n = 22) or without (control; n = 45) PCOS who were diagnosed with vitamin D deficiency were enrolled. Fifty-one women were replaced with oral vit D3 for 8 weeks (16 with PCOS and 35 controls) and 16 women were not treated (six with PCOS and 10 controls). Serum 25-hydroxyvitamin D (25 OH-D), sRAGE, and AMH concentrations were measured at baseline and after vit D3 supplementation in the treated group and 8 weeks apart in the nontreated group. MAIN OUTCOME MEASURE(S): Changes in serum sRAGE and AMH concentrations after vit D3 replacement were measured. RESULTS: In all participants, there was a negative correlation between body mass index and serum sRAGE levels (r = -0.3, P = .01). In women with PCOS, but not in controls, vit D3 increased serum sRAGE (P = .03) and decreased serum AMH levels (P < .001). The increase in serum sRAGE positively correlated with the increase in serum 25 OH-D after supplementation in women with PCOS (r = 0.6, P = .01). CONCLUSION: In women with PCOS, vit D3 might exert a protective effect against the inflammatory action of AGEs by increasing circulating sRAGE. The normalization in serum AMH induced by vit D3 replacement suggests an improvement in folliculogenesis.