Natural Molecules in The Management Of Polycystic Ovary Syndrome (PCOS): An Analytical Review Part 2
Apr 18, 2022
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6. Vitamin D
Vitamin D is a secosteroid hormone with progesterone-like activity [72], well known for maintaining calcium homeostasis and promoting bone mineralization [73]. The name vitamin D usually refers only to when this molecule is administered exogenously in cases of hormone D deficiency [74].
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To become active, vitamin D requires two hydroxylation steps, yielding first calcidiol (or calcifediol or 25(OH)D), and eventually calcitriol(1,25(OH)2D). Calcidiol and calcitriol are considered pre-hormones and hormones, respectively. A growing body of literature suggests mechanistic implications of hormone D deficiency in insulin resistance, inflammation, dyslipidemia, and decreased fertility, namely, clinical and metabolic phenomena commonly encountered in PCOS[75-78].
Kadoura S.and colleagues investigated the effects of combining calcium and vitamin D supplements with metformin on menstrual cycle abnormalities, gonadotropins, and the IGF-1 system in vitamin D-deficient/insufficient PCOS women. In this randomized, placebo-controlled clinical trial,40 PCOS women with low 25-OH-vitamin D serum levels (<30 ng/mL), were randomly assigned to take either metformin (1500 mg/daily) plus a placebo, or metformin (1500 mg/daily) plus calcium(100 mg/daily) and vitamin D3 (6000 IU/daily) orally for 8 weeks. The authors observed that calcium and vitamin D supplements can support the metformin effect on the regulation of menstrual cycle irregularity in vitamin D-deficient/insufficient PCOS patients,(desert cistanche) but this effect is not associated with any significant changes in gonadotropins or the IGF-1 system [79].
The meta-analysis by Miao and co-workers, concerning 11 studies, aimed to evaluate the effect of vitamin D supplementation on 483 women with PCOS. The main outcomes included body mass index (BMI), total testosterone, dehydroepiandrosterone sulfate (DHEA), homeostasis model assessment of insulin resistance(HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-B), triglycerides, total cholesterol, or low-density lipoprotein-cholesterol. The results failed to show a positive effect of vitamin D supplementation on BMI, dehydroepiandrosterone sulfate, triglyceride levels, or high-density lipoprotein cholesterol. (desertliving cistanche)The data from the available randomized controlled trials (RCTs) on vitamin D indicate that supplementation may reduce insulin resistance and hyperandrogenism in patients with PCOS [80]. However, the evidence reported seems to still be contradictory, and further studies are necessary to validate the findings and draw conclusive results.
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In a double-blind, randomized, placebo-controlled trial, Trummer and colleagues randomized 180 PCOS women to receive either vitamin D (200 IU/week) or a placebo for 24 weeks [81]. Supplementation with vitamin D led to a decrease in plasma glucose, one hour after the oral glucose tolerance test (OGTT), compared to the placebo.
Furthermore, in 2014, Lerchbaum E. et al. investigated the role of vitamin D in modulating the human reproductive process. They observed a greater thickness of the endometrium in women who had normal levels of vitamin D, which resulted in a better chance of becoming pregnant [82].
The molecular mechanism between vitamin D supplementation and improvement of PCOS is currently unknown. However, recent studies have claimed there are positive effects of vitamin D3 replacement in the treatment of PCOS. Indeed, vitamin D supplementation may attenuate the harmful effects of advanced glycation end products (AGEs) in women with PCOS, by enhancing androgen synthesis and improving abnormal folliculogenesis [83,84]. Namely, vitamin D attenuates the adverse effects of AGEs on steroidogenesis by human granulosa cells (GCs),(flavonoid) possibly by downregulating the expression of the pro-inflammatory cell membrane receptor for AGEs (RAGE)[83,84].
All these results highlighted the potential positive effects of vitamin D supplementation on different pathologic features of PCOS. Nevertheless, more studies are needed to ascertain the benefits of vitamin D supplementation in PCOS management, also in association with other molecules.
7. Omega-3 Fatty Acids
Omega-3 belongs to the class of polyunsaturated fatty acids (PUFAs). Among them, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the most biologically active, and they are mainly present in fatty fish such as salmon, mackerel, tuna, herring, and other types of small and bluefish.
Omega-3 fatty acids have antioxidant, anti-inflammatory, anti-obesity, and insulin-sensitizing properties [85-87]. In detail, they can improve insulin sensitivity by decreasing the production of inflammatory cytokines, including tumor necrosis factor-a (TNF) and IL-6, and by increasing the secretion of anti-inflammatory adiponectin [88]. The positive effect of EPA and DHA supplementation on inflammatory processes and cardiovascular parameters has long been studied [89,90] in pathological contexts such as obesity [91]atherosclerosis [92], and diabetes mellitus[93]. Of note, PCOS disorder commonly involves insulin resistance and obesity, predisposing to cardiometabolic-related alterations (dyslipidemia, diabetes, hypertension), which usually occur after 40 years of age in affected women [94,95]. Interestingly, several studies investigated the effect of omega-3 fatty acids administration in PCOS women, with inconclusive results. While Sadeghi and colleagues [96] observed that omega-3 supplementation may have no beneficial effects on insulin resistance in PCOS patients, Khani B.[97] and co-workers reported that a 6-month treatment with omega-3 fatty acids improves waist circumference, HDL, LDL, triglycerides, and regularity of menstrual cycle compared to non-PCOS subjects. However, no significant changes were observed in other parameters such as body weight, number of ovarian follicles, size of ovaries, bleeding volume, menstrual bleeding, and hirsutism score, between intervention and control groups. On the other hand, a meta-analysis by Yang K. (flavonoids) and colleagues [98] reported that omega-3 fatty acids positively affect insulin resistance (improving HOMA index and increasing adiponectin levels) and decrease the level of total cholesterol (TC), TG, and LDL. However, there are no indications that omega-3 fatty acids directly affect BMI, fasting insulin, fasting glucose, and levels of HDL, FSH, LH SHGB, and total testosterone [98]. These results further indicate that omega-3 fatty acids increase insulin sensitivity, also acting on an inflammatory state, stimulating the production of anti-inflammatory adipokine and reducing pro-inflammatory cytokines. However, the above-mentioned analysis of Yang has some limitations, including small sample sizes and the short duration of omega-3 administration. Indeed, beneficial effects derived from treatments with omega-3 fatty acids over 6 months are still largely under-investigated.
Recently, Tosatti and colleagues [99] studied the influence of omega-3 fatty acid supplementation on inflammatory and oxidative stress markers in PCOS patients, through a systematic literature search of Medline/PubMed, Cochrane Central Register of Controlled Trials, Scopus, and Lilacs, until November 2019. They retrieved data from 323 studies suggesting that supplementation with omega-3 fatty acids could reduce the inflammatory state in PCOS women, due to decreased high-sensitivity C-reactive protein (hs-CRP)and increased adiponectin levels [99].
Based on evidence regarding the positive effects of omega-3 supplementation on inflammatory state and cardiometabolic alterations, and considering that cardiovascular problems may occur only after 40 years of age in PCOS women, a generalized administration of omega-3 fatty acids in all PCOS patients, regardless of age and needs, seems unnecessary. Therefore, the administration of omega-3 fatty acids should be specific only for PCOS women who already exhibit inflammatory and cardiovascular-related symptoms, which usually occur between 40 and 45 years of age [94,95]. Daily intake of omega-3 fatty acids should range between 0.5 and 2% of energy requirement at any age, according to the latest revision of LARNs(the Reference IntakeLevels of nutrients and energy for the Italian population). (herba cistanches) Moreover, studies on cardiovascular and anti-inflammatory effects in adults reported that the recommended minimum dose for combined EPA: DHA administration is 500 mg/day, reaching 2000-4000 mg/day in patients with recent myocardial infarction or in those with altered triglycerides levels [100].
The possible occurrence of side effects related to omega-3 fatty acids supplementation should be considered. They include mild gastrointestinal discomfort, intestinal gas (especially if the source of omega-3 fatty acids is fish oil), nausea, diarrhea, and headache [101]. Notably, the intake of omega-3 fatty acids is contraindicated during antiplatelet and anticoagulant treatment, because they exert synergistic effects[102]. Consulting with doctors is always advised before beginning supplementation with omega-3 fatty acids, in order to rule out possible side effects or interference with other drugs, especially during pregnancy or breastfeeding. Indeed, current guidelines recommend avoiding EPA administration during pregnancy because of the possible competitive effects of arachidonic acid, which is essential for growth processes at the fetal: stage [103]. Finally, omega-3 fatty acids have a higher calorific value compared to other dietary supplements, and their use should be carefully evaluated in obese or overweight patients to avoid a negative impact on metabolic alterations, which are common in PCOS women.
8. Conclusions
Natural molecules reported here represent different chemical compounds acting with several mechanisms of action on pathological aspects of PCOS, such as ovarian functionality, hormonal and metabolic profile, inflammatory state, and oxidative stress(Table S1).
The administration of Myo-Ins and D-Chiro-Ins in the 40:1 ratio seems to be the most effective choice to restore ovulation in PCOS women and normalize hormonal parameters (progesterone, LH, SHBG, estradiol, and testosterone). Such an approach proved to consistently ameliorate the metabolic profile of obese PCOS patients, reducing the risk of cardiovascular problems. Besides inositols, other natural antioxidants and anti-inflammatory molecules seem to be effective in the management of PCOS. These natural molecules include resveratrol, flavonoids, flavanones, such as naringenin and rutin, vitamins such as vitamin C, vitamin E, and vitamin D, and omega-3 fatty acids. In particular, omega-3 fatty acids appeared to improve symptoms of PCOS in women over 40 years of age. However, careful monitoring is necessary because of both possible adverse effects and interference with some pharmacological treatments. Finally, guidelines on the correct use of dietary EPA and DHA supplementation in pregnancy will discourage the administration of EPA.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/nu13051677/s1, Table S1:Supplements, and mechanisms of action. Description of the main mechanisms of action of the natural supplements mentioned in the review in relation to individual symptoms of PCOS.
Author Contributions: All authors contributed to writing and revising this review. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable.
Data Availability Statement: This is not applicable, since this review does not present any innovative data.
Conflicts of Interest: Iervolino, M., Lepore, E., Forte, G.and Under, V.are employees at Lo.Li. Pharma Srl. All other authors declare that they have no conflict of interest.
This article is extracted from Nutrients 2021, 13, 1677. https://doi.org/10.3390/nu13051677 https://www.mdpi.com/journal/nutrients
