Polycystic ovary syndrome is known to be a more complexed rather than a simple reproductive disorder and involves a vicious cycle of endocrine/reproductive and metabolic disarray. The current study reports the deranged endocrine, metabolic parameters and stress burden in women affected with PCOS and reveals that the treatment intervention with combined resveratrol and myoinositol for a period of twelve weeks significantly alleviated different alterations associated with this disorder. Women with PCOS suffer from multifarious derangements in endocrine, metabolic indices and present with extreme stress response and treatment with the standard drugs including different insulin sensitizers alone or along with the contraceptive pills may relieve the signs and symptoms associated with syndrome; however there is no efficient and safe medicinal intervention yet to alleviate the signs and symptoms associated with this multifaceted disorder. Here, the current clinical trial supports that the improvement in these alterations in response to combined resveratrol and myoinositol is comparable to or rather much more pronounced than that of the observed combined effect of metformin and pioglitazone. This combined regimen was very well tolerated with none of the participants requiring discontinuation due to any intolerable side effects and the treatment resulted in the improvement of the anthropometric measures including a significant decrement in weight, BMI, waist-hip circumference and waist-to-hip ratio (Table.1). We also reported that the use of aforementioned remedy ameliorated the endocrine, metabolic alterations and relieved stress load along with the resumption of regular menstrual cycles in women with oligo/amenorrhea (Table. 2).
It has been previously reported that approximately 44% of PCOS women are obese and an adipocyte-derived hormone, adiponectin might be involved for the endocrine and metabolic derangements [33, 34]. Obesity increases the risk of co-morbidities associated with PCOS, such as impaired glucose tolerance and type II diabetes mellitus, hyperlipidemia and hypoadiponectinemia. Orio et al., evaluated the levels of serum adiponectin in a cohort of obese PCOS and revealed that adiponectin level was significantly low in these women . Several other studies have reported that adiponectin level is significantly low in PCOS women, making them more susceptible to the likelihood of developing metabolic syndrome and future myocardial infarction . Another similar study by Panidis et al., found that PCOS women with the BMI greater than 25 kg/m² had low serum adiponectin level when compared to the women with BMI less than 25 kg/m² . Currently, to the best of our knowledge there is no available literature on the effects of resveratrol alteration of serum adiponectin level in PCOS women. However, Mousavi et al,. analyzed the effects of resveratrol on body weight, body mass index and waist circumference in obese adults and revealed a notable reduction in the weight parameters . Le Donne et al., reported a remarkable depletion in the body weight, BMI, waist and hip circumferences while treating obese PCOS women with 4 grams per day of myoinositol for three months . Here, we included only obese PCOS women with the BMI greater than 30 kg/m² and their serum adiponectin level were found significantly low. The current finding is in agreement with those of Tschritter et al.,  and Pangaribuan et al.,  who reported that adiponectin can be suppressed by increased body fat. Furthermore, the current study shows that combined treatment with resveratrol and myoinositol significantly augmented serum adiponectin level along with the remarkable reduction in BMI, waist and hip circumference and waist to hip ratio when compared to metformin and pioglitazone arm-1 participants (Table. 1 and Figure. 2).
Subsequent studies have reported that PCOS, in addition to the reproductive dysfunction is also associated with the broad range of metabolic and endocrine derangements [42–44]. Several researchers have delineated the hormonal disorders such as raised circulating levels of androgens and hyperinsulinemia as well as the increased secretion of gonadotropins, as the key aspect of PCOS etiology [45, 46]. Ovarian hyperandrogenism in PCOS is mainly attributed to an inherent steroidogenic defect of theca cells . The first clinical trial by Banaszewska et al., evaluated the effects of resveratrol 1500 mg per day on PCOS patients and reported a significant decline in serum testosterone and DHEAS levels through the melioration of insulin resistance . Interestingly, Bahramrezaie et al., reported a significant reduction in serum LH and testosterone in PCOS affected women with the use of resveratrol 800 mg per day for a 40 days period . Pizzo et al., evaluated the effects of myoinositol on endocrinological PCOS aspects and reported a significant depreciation of LH, LH/FSH ratio and serum testosterone level . In a study by Genazzani et al,. plasma LH, testosterone, insulin levels and LH/FSH ratio significantly reduced after 12 weeks of myoinositol administration . Effects of resveratrol and myoinositol on hormonal profile of PCOS have been checked separately in different studies. However, to the best of our knowledge no study has reported the combined effect of resveratrol and myo-inositol hitherto. In the present study where both the drugs were combined, we found significant amelioration of the metabolic, endocrine response as previously reported studies, however, our results were astonishing in the sense that the combination therapy significantly enhanced most of the clinical and biochemical parameters compared to the standard drug regimen. Moreover the present study also delineated the significant lessening in the dermatological manifestations associated with the hormonal malfunctions, including hirsutism (FG scores <0.001) and acne scores (Table. 2).
The massive disappointment for women with PCOS is their inability to conceive as it is considered to be the most common cause of anovulatory infertility . Oligomenorrhoea/ anovulation is a major clinical concern and is present in 70–80% of women with PCOS . Several studies suggest that the hormonal imbalance associated with PCOS might be the cause of subfertility issue . The effect of resveratrol has been insufficiently studied on the abnormal menstrual cycles in PCOS. Benrik et al., while evaluating the effects of resveratrol in rats with androgen-induced PCOS, reported significant enhancement of menstrual cycles . Mansour et al., recently reported improved menstrual irregularities with the use of natural resveratrol 1gram, once daily for the three months duration . Papaleo et al., evaluated the effects of myoinositol 2 grams per day on the menstrual irregularity in PCOS and demonstrated restoration of spontaneous ovulation and menstrual cycles . The present results are in line with other studies, reporting a significant reduction in the volumes of both the ovaries and normalization of menstrual cycles. Interestingly, in our study regular menstruation was restored in 84.1% (Table.2) in combined resveratrol and myoinositol group along with the substantial depletion in the ovarian volumes (Figure. 4).
Insulin resistance and the associated compensatory hyperinsulinemia are frequently observed dysfunctions in PCOS . Women with PCOS are insulin resistant and are at higher risk of glucose intolerance which may lead to crucial metabolic consequences with an increased possibility of developing type II diabetes mellitus . Ortega et al., suggested that resveratrol has been observed to have antidiabetic effect . Hoseini et al., investigated the effects of 500 mg per day resveratrol for 4 weeks on the metabolic status of the type II diabetic patients and reported significantly reduced levels of insulin and HOMA-IR score . The effect of resveratrol on the regularization of insulin sensitivity has been reported previously [62, 63]. Talbott et al., proposed periodic screening of PCOS women for the timely detection of diabetes . Costantino et al., performed a double-blind trial in which 23 insulin resistant PCOS women were treated with 4 gram once daily of myoinositol for 12 weeks that resulted in a significant reduction in the circulating insulin levels and improved glucose tolerance . A similar study by Fruzzetti et al., reported that myoinositol is effective in diminishing serum insulin levels . Our study is similar to the above stated studies where we observed a significant reduction in serum insulin levels in both the arms but reduction was statistically significant in arm-2 participants (Figure. 3).
Increased rates of stress, anxiety and depression in PCOS affected women are irrefutable throughout the literature [67–69]. Several studies suggest that PCOS women exhibit up to four fold increased risk of depressive symptoms and six fold risk of anxiety symptoms compared with normal women [68, 70, 71]. The observations made in a recent study by Tianyao et al., indicated that resveratrol administration alleviated the anxiety and depression like symptoms in ovariectomized rats . The potency of resveratrol in treating depression and anxiety was confirmed by several other studies [73, 74]. Here, in this study we used Cohen’s perceived stress scale to evaluate perceived stress response in PCOS women and revealed significant reduction in PSS scores in participants given combined resveratrol and myoinositol for 12 weeks (Figure. 5).
This study, to the best of our knowledge is the first of its kind, assessing the efficacy of 12 weeks supplementation with combined resveratrol and myoinositol while addressing multiple outcome variables in women with PCOS. This randomized, double-blinded trial reports that the extent of betterment in the metabolic, endocrine alterations and stress burden observed in the PCOS affected women in response to combined resveratrol and myoinositol supplementation is comparable to or more pronounced than that observed in response to the combined use of metformin and pioglitazone.
The most important limitation to this study was that there were no separate groups to evaluate the efficacy of resveratrol and myoinositol alone on the altered parameters in PCOS affected women.
In order to confirm our data and to make it more obvious that the above-stated combination regimen can be recommended in the clinical situation, further randomized clinical trials with extended duration are warranted to be carried out in women with PCOS. The findings of this study could have public health importance and clinical implications for high risk PCOS women.