Dose vitamin D supplementation affect reproductive outcomes in patients with polycystic ovary syndrome?

INTRODUCTION

Polycystic ovary syndrome (PCOS) is a prevalent female endocrine condition that affects between 6% and 12% of women of reproductive age worldwide.^[1] It manifests itself through monthly irregularity, hyperandrogenism, anovulatory infertility, obesity, and also metabolic abnormalities such as type 2 diabetes, insulin resistance, and dyslipidemia.^[2] These complaints can have a major influence on patients’ health and their life quality. Nevertheless, owing to the disease’s intricacy, the pathophysiology is unknown, and an appropriate therapeutic regimen has not been found.^[3] It is typical for people with PCOS to have vitamin D deficiency (VDD), which may be linked to endocrine and metabolic disorders.^[4,5,6,7]

Bone mineralization and calcium phosphate control are two of the functions of vitamin D.^[8] Over 30 tissues, involving the liver, immune cells, pancreas, brain, and ovaries, have vitamin D receptors that operate as transcription factors for 229 genes.^[9] The body obtains vitamin D from vulnerability to the sunshine. Vitamin D is necessary for many functions in the body including immune system, muscle functions, cardiovascular functions, brain development, fertility, and has an anticancer effect.^[10]

Vitamin D affects fertility by many mechanisms. Its receptors were detected in the placenta, ovary, and endometrium suggesting that vitamin D has an important role in fertility and conception. Some studies found that deficiency of vitamin D leads to poor response to ovarian stimulation as well as little success with in vito fertilization (IVF). Some studies found that the higher the concentrations of vitamin D, the higher pregnancy success rates. When it comes to PCOS, several studies have established a correlation between lowered vitamin D3 levels and an elevated insulin resistance risk.^[5] Vitamin D is accumulated in adipose tissues in obese individuals, rendering it inaccessible for use by the body. Therefore, obese individuals are predicted to have reduced serum vitamin D levels.^[11]

PATIENTS AND METHODS

Study design and settings: This multicenter randomized controlled clinical trial was conducted in the infertility clinics of Tanta University Hospital and Benha University Hospital during the period between April 2019 and March 2021.

Patients: One hundred and sixty patients were recruited according to inclusion and exclusion criteria.

The inclusion criteria were: (a) PCOS was diagnosed by modified Rotterdam criteria,^[2] which required at least two of these three criteria to make the diagnosis; oligo/anovulation, clinical, or biochemical hyperandrogenism and polycystic ovarian morphology; (b) infertile patients; (c) age between 20 and 35 years; (d) BMI ≤ 30 kg/m²; and (e) vitamin D deficient participants. Exclusion criteria were: (a) pregnant or nursing, (b) kidney stones, (c) current vitamin D use, (d) insulin sensitizing drug use within 3 months, (e) non-PCOS patients, (f) obese patients BMI > 30 kg/m², and (g) previous ovarian surgery or oophorectomy to one ovary.

RESULTS

Initial enrollment included 185 patients. Fifteen cases were excluded either due to nonfulfillment of inclusion criteria (n = 9) or declined to participate (n = 6). The flow of cases throughout the study was presented in Figures 1 and 2.

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Figure 1

CONSORT flow chart of cases throughout the study.

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Figure 2

Box plot of the progesterone level in the control and study group.

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Baseline data

There were no significant differences in demographic data, and hormonal levels between both groups [Table 1].

Table 1 Baseline data of enrolled patients in both groups

Clomiphene citrate dose and number of cycles were lower in the study group; however, the number of mature follicles was greater. No significant differences were seen in mature follicle size or serum progesterone levels between the two groups, but the study group’s levels were much greater [Figure 1]. There were no variations in the pregnancy rate between groups. Insulin resistance was greater in the control group and resumption of the cycle was higher in the study group (P ˂ 0.001, for both) [Table 2].

Table 2 Contrasting of the findings between study and control groups

Ovulation was significantly increased in treatment group than control group (p=0.001). On the same side serum progesterone was significantly increased in treatment than in control group as shown in Figure 2.

Factors affecting progesterone level

Vitamin D3 supplementations and Prolactin were associated with higher serum progesterone [Table 3].

Table 3 Factors affecting progesterone levels in a multivariable regression model

Factors affecting the size of the mature follicles

The higher size of the mature follicle is significant with increased age and lower BMI. Treatment increased the size of the follicle, but it did not reach a significant level [Table 4].

Table 4 Factors affecting mature follicle size in a multivariable regression model

DISCUSSION

PCOS affects 6% to 12% of reproductive age women over the world. Resistance, loss, and ovarian hyperstimulation syndrome (OHSS) are among the many issues that can arise during the tough induction process. Therefore, we need adjuvant therapy to avoid these complications and improve pregnancy rate. One of the adjuvant therapies is vitamin D.^[9,10]

Jamilian et al.^[13] conducted a study to assess the effect of vitamin D supplementation on the metabolic profile in women with PCOS. They randomly allocated 90 participants into three groups. Each group included 30 patients where the first group received vitamin D 4000 IU/day and the second group received 1000 IU/day for 12 weeks, while the third group received placebo. They found that high dose of vitamin D (4000 IU) led to a great reduction of total testosterone, inflammatory biomarkers (high sensitivity C-Reactive Protein (hs-CRP) levels), and antioxidant levels in insulin-resistant women with PCOS if compared to those who received 1000 IU/day of vitamin D or placebo.^[13]

In a study with Trummer et al.^[14], 180 women with PCOS and 25-hydroxyvitamin D concentrations < 75 nmol/L were randomized into 2:1 ratio to receive either vitamin D or placebo by a computer-generated randomization. They aimed to study the effects of vitamin D supplementation on metabolic and endocrine parameters in PCOS. They found no significant effect on metabolic and endocrine parameters in PCOS with the exception of a reduced plasma glucose.^[14] Similar results were obtained by Łagowska et al.^[15] in their systematic review.

Another study demonstrated that vitamin D supplementation (4000 IU/day) for 12 weeks to PCOS women resulted in significant decreases in serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), serum total testosterone levels, free androgen index (FAI), and hirsutism, and a significant increase in sex hormone binding globulin (SHBG).^[16]

Akl et al.^[17] conducted a randomized controlled study to evaluate the effect of vitamin D supplementation on ovulation and metabolic profiles in patients with PCOS in Shams University Maternity Hospital. They included 300 women in their study after assessing their levels of vitamin D. They allocated patients into vitamin D deficient group and vitamin D normal group and control group. They found that vitamin D supplementation improved ovulation rates and metabolic profiles with restoration of menstrual patterns in the group of VDD.^[17]

In the present study, we attempted to replenish vitamin D3 level in patients with PCOS through oral vitamin D3 administration. We evaluated ovulation rate, pregnancy rate, serum progesterone, resumption of normal menstruation, and insulin resistance in these patients to those who did not obtain vitamin D3. This was in accordance with the study of Al-Bayyari et al.^[18] who recommended supplementation of vitamin D3 to obese patients with PCOS to maintain low levels of vitamin D3 in that category of patients.

In our study, clomiphene citrate (CC) dose and number of cycles were lower in the study group; however, the number of mature follicles was higher. No significant differences were seen in mature follicle size or serum progesterone levels between the two groups, but the study group’s levels were much greater [Figure 1]. There were no variations in the pregnancy rate between groups. Insulin resistance was greater in the control group and resumption of the cycle was higher in the study group.

Numerous publications have proposed a link between VDD and metabolic malfunctions in women with PCOS, notably insulin resistance. Nevertheless, the outcomes of randomized controlled trials evaluating the role of vitamin D supplementation on glucose homeostasis in PCOS patients remain inconclusive.^[18] Vitamin D supplementation showed no effect on PCOS patients’ fasting glucose, serum HOMA-IR, fast insulin, or quantitative insulin sensitivity check index (QUICKI), according to a recent meta-analysis that involved only the findings of controlled randomized trials.^[19]

Additionally, insulin receptor gene upregulation, modulation of insulin production from pancreatic β-cells, and promotion of β-cell proliferation and adiponectin production have all been demonstrated to enhance metabolic state by supplementation with vitamin D, vitamin K, and calcium.^[20]

CONCLUSION

Vitamin D addition to induction of ovulation in women with PCOS resulted in enhancement of ovulation and pregnancy rates. Larger studies are still required to add to the evidence to reach to a solid conclusion regarding this issue.