The impact of a standardized micronutrient supplementation on PCOS-typical parameters: a randomized controlled trial

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects about 6–10% of women of reproductive age [1, 2]. In obese patients, lifestyle interventions are generally considered the first-line treatment. Pharmaceutical treatment options include contraceptive pills and hypoglycemic agents [2]. However, contraindications for the oral contraceptive pills are common in this patient population, especially in overweight women, [3] and hypoglycemics often lead to unpleasant side effects [4, 5]. Thus, it is reasonable that women with PCOS were found to seem unsatisfied with pharmaceutical treatment including oral contraceptives and clomiphene citrate and tended to seek out effective alternative management options [6]. This would obviously include nutritional supplements. However, as reviewed recently, there is insufficient high-quality evidence about the effectiveness of nutritional supplements and herbal medicine for PCOS and its related symptoms. Only some low-quality evidence suggests that PCOS women might benefit from inositols and omega-3 fish oil supplements [7].

However, women with PCOS reveal significantly increased levels of oxidative stress [8] and antioxidants have been claimed to exert positive effects on PCOS [9]. Antioxidants that might positively influence the hormonal profile in PCOS include omega-3 fatty acids [7, 9‐14], Vitamin E [11, 13, 14], and selenium [15, 16]. Notably, it has been suggested that the anti-inflammatory action of metformin also contributes to the substance’s positive effect in PCOS [17].

Notably, meta-analyses question the effects of an omega-3 fatty acid-only treatment [18, 19]. This raises the question whether single micronutrient supplementations would be of major impact. We, thus, aimed to test the impact of a standardized, multinutrient supplementation on hormonal profile in PCOS women. We chose a micronutrient supplementation preparation that included a high amount of omega-3 unsaturated acids, other anti-oxidants and co-enzyme Q10—the latter had also been shown to improve inflammation and glucose metabolism parameters in previous studies [20, 21]—for our prospective, randomized, controlled study.

Baseline patient and PCOS-specific characteristics of the multinutrient supplementation and the control groups are shown in Table 2. There were no differences between the groups (p > 0.05).

Details on outcome in terms of PCOS-specific hormonal patterns are provided in Table 3. No differences between the baseline and the 3-month follow-up visits were found for the control group. In the multinutrient supplementation group, the LH:FSH ratio (2.5 ± 1.1 versus 1.9 ± 0.5, p = 0.001), testosterone (0.50 ± 0.19 versus 0.43 ± 0.15, p = 0.001), and AMH (8.2 ± 4.2 versus 7.3 ± 3.6, p < 0.001) declined significantly, whereas the other parameters, namely estradiol, LH, FSH, androstenedione, and SHBG remained stable. When comparing the baseline to follow-up changes in hormonal patterns between the multinutrient supplementation and the control groups, significant differences were found for FSH, the LH:FSH ratio, testosterone, and AMH (p < 0.05; Table 4). None of the patients reported any side effects.

This prospective, randomized study on PCOS women demonstrated that the use of a multinutrient supplementation containing omega-3 fatty acids, folic acid, selenium, vitamin E, catechin, glycyrrhizin, and co-enzyme Q10 led to a significant reduction in the LH:FSH ratio, testosterone and AMH, when compared to the use of 400 mg folic acid alone. These data support previous reports about beneficial effects of micronutrients, at least of those with an antioxidant activity, on PCOS-specific hormonal profiles [7, 9‐16].

It has to be mentioned that previous meta-analyses questioned the effects of a supplementation with omega-3 fatty acids only [18, 19]. It seems obvious that the positive effect which was seen in the present study might be due to the multinutrient approach. However, this approach makes it impossible to attribute the treatment’s positive impact to one of the ingredients. The included ingredients might affect the specific parameters of PCOS via different mechanisms. While omega-3 fatty acids, selenium, vitamin E, and also co-enzyme Q10, known to scavenge free radicals and inhibit lipid and protein oxidation [25], might have acted as antioxidants and thereby likely influenced the proinflammatory PCOS state [9], licorice with its active component glycyrrhizin has been shown to affect androgen metabolism, probably via blocking the activity of 3-β-hydroxysteroid dehydrogenase (3HSD), 17-hydroxysteroid dehydrogenase (17HSD) and 17–20 lyase [26‐33] and stimulation of the aromatase activity [31]. Notably, a lowering effect on ovarian androgens has already been reported for licorice [33], even in PCOS women [32]. Last not least, catechin has been reported to decrease testosterone production, at least in male rats. While the authors concluded that the demonstrated decrease in androgens were due to changes in enzymatic activities [34], an antioxidant mechanism cannot be excluded for our study [35].

Thus, one could raise the issue of the used preparation’s composition. PROfertil^® female was chosen, since it was a standardized and commercially available multinutrient supplementation. Taken all these considerations together, the fact that the exact impact of each of the ingredients cannot be assessed in detail needs to be considered a study limitation.

Notably, there was one other important difference between the two groups. Since many women with PCOS suffer from infertility, the recommended standard folic acid supplementation of a daily dose of 400 µg [36] was provided to the control group. However, the multinutrient supplementation group received twice the dose. Notably, high-dose folic acid supplementation has been suggested to lead to an improvement in inflammatory factors, biomarkers of oxidative stress [37] as well as metabolic parameters in PCOS women [38]. This might have also contributed to the beneficial effects observed in the multinutrient supplementation group.

Our results must be interpreted with care due to the following additional considerations: although the study seems well randomized (Table 2), patients could have searched for the actual look of the PROfertil^® female soft capsules and the pills, for example on the internet. Since the look of the commercially available preparation differs from that of the folic acid capsules, patients could have identified the control medications. This kind of blinding was not according to standards and could have introduced some kind of bias. Moreover, despite the small sample size to achieve, the study period was quite long. Empirically, this was a result of the delay in standardized PCOS treatment for 90–100 days. Accordingly, repeatedly women were not willing to participate. In addition, no data about patients’ dietary habits were collected. Last not least, one could argue that the power was only sufficient to test an AMH difference of 2 ng/mL, whereas a difference of only 1 ng/mL was found in our study, which still reached statistical significance. However, in the sample size calculation, a much higher AMH standard deviation of 3 ng/mL had been expected in contrast to the actual standard deviation of about 1.2 ng/mL, which explains why the lower mean difference in AMH was still found to be significant.

In conclusion, our data suggest that a micronutrient supplementation that includes omega-3 fatty acids, folic acid, selenium, vitamin E, catechin, glycyrrhizin, and co-enzyme Q10, given for a minimum of 3 months, is beneficial for women with PCOS in terms of PCOS-specific parameters, namely the LH:FSH ratio, serum testosterone and serum AMH. Although the clinical relevance of these results can be challenged, the presented date should encourage future studies about the influence of micronutrients on PCOS, hopefully including data about specific symptoms and infertility treatment outcomes as additional outcome parameters.