Quercetin and polycystic ovary syndrome, current evidence and future directions: a systematic review

Polycystic ovary syndrome (PCOS), as a polygenic endocrine disorder, is the most common gynecological endocrinopathy, which is estimated to affect 2–20% of reproductive-aged women [1]. Common physiological manifestations of this syndrome include ovarian enlargement, hyperandrogenism, androgenic alopecia, hirsutism, acne, menstrual irregularity, anovulation or oligo-amenorrhea, miscarriage, and infertility [2]. PCOS-related symptoms also impair the quality of life through affecting psychiatric aspects of patient’s life [3]. Women with PCOS exhibit an increased incidence of several chronic diseases including obesity, dyslipidemia, hypertension, heart disease, and type 2 diabetes mellitus (T2DM) [4‐6]. It is documented that both obese and lean women with PCOS mostly exhibit insulin resistance, a major risk factor for the development of metabolic abnormalities such as impaired glucose tolerance (IGT) and T2DM [7, 8]. According to recent studies, oxidative stress is demonstrated as another contributing factor in the development of PCOS and its corresponding symptoms such as increased androgen production and infertility [9]. Although the definite etiology of PCOS remains unclear, complex interactions between genetic, behavioral, and environmental factors play critical roles in the development of PCOS and subsequent therapeutic options [10]. Current remedies are often used only to control its signs and symptoms, while they are not thoroughly able to prevent complications. Therefore, natural products became a topic of interest for the management of PCOS and its complications [11]. Herbal plants are extensively used to prevent chronic diseases due to their polyphenolic compounds, multi-targeted effectiveness, and low toxicity [12]. Quercetin is an herbal bioactive flavonoid with radical scavenging and antioxidant properties, which is extensively used for the treatment of metabolic and inflammatory disorders [13]. Fruits and vegetables, particularly onions, apples, berries, citrus, red grapes, nuts, seeds, and tea, are a good source of quercetin [14]. Several pharmacological studies revealed that, Quercetin supplements are effective in the regulation of redux status [15], reducing inflammation [16], protecting cardiovascular system [17], inhibiting platelet aggregation [18], relaxing vessels smooth muscles [19], and preventing LDL oxidation [20], hypertension [21], cancer development [22, 23] and diabetes [24]. It is postulated that hypoglycemic effect of the quercetin is related to insulin signal transduction, such as enhanced protein expression, and tyrosine phosphorylation of insulin receptor (IR), several insulin receptor substrates (IRSs) and glucose transporters (GLUTs) [25]. Moreover, quercetin exerts the insulin-sensitizing effect by promoting the proliferation of pancreatic β-cells and enhancing glucose metabolism and insulin secretion [26]. Oxidative stress is considered as a potential stimulant of PCOS, and serum levels of antioxidants are reduced in patients with PCOS. Therefore, the use of anti-oxidative agents in the management of PCOS has attracted a lot of attention [27, 28]. Quercetin could be considered as an anti-oxidative agent due to its ability to inhibit xanthine oxidase through reducing the generation of free radicals, modifying antioxidants and inhibiting lipid peroxidation [29].

The current study aimed to systematically summarize the scientific literature regarding therapeutic effects of quercetin on PCOS, as the most common endocrinopathy in reproductive-aged women.

The current systematic review suggests that quercetin possesses an intrinsic potential to correct hormonal disturbances and subsequent metabolic disorders occurred in PCOS. The ovarian follicles of patients with PCOS are large, with a thickened theca cell layer and a degenerated granulosa cell progressed to form cysts [33, 39]. Evidence suggests that the effects of quercetin on the improvement of ovarian histological and histomorphological analysis are similar to or higher than metformin. Animal models suggest beneficial effects of quercetin on folliculogenesis and luteinisation processes through improved ovarian tissue along with the prominent decrease of atretic and cystic follicles, improvement of hirsutism, marked an increase in normal follicles with different stages and vascularization of the thecal layer [31‐33]. More luteal together with an increase in the thickness of ovarian granulosa cells were also reported following quercetin administration; however, the changes in the ovaries weight were not statistically significant [30].

Histological changes of the ovarian follicles seem to be mediated by elevated levels of androgens and disrupted folliculogenesis resulting from an irregular estrous cycle [40]. Quercetin decreased testosterone levels and reversed the low levels of estradiol and progesterone to near-normal levels [31]. Studies also reported the existence of more corpora lutea accounting for the restoration of the estrous cycle [31, 41]. It is in line with the reduced activities of 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase and the modified concentrations of testosterone and estradiol, as well as ovary structure following administration of quercetin [34].

Indeed, the evidence suggests that quercetin is able to counteract the mechanisms of androgen biosynthesis related to LH [31, 33]. The increased levels of LH in PCOS, which are due to the impaired hypothalamic-pituitary axis, stimulate PI3K/Akt pathway leading to the over expression of ovarian CYP17A1 gene together with 17-α hydroxylase enzyme levels, which catalyze the conversion of progesterone to androgens [31, 42, 43]. Two studies reported that the lowering effects of quercetin on the levels of testosterone and LH are linked to resistin, as a possible agent in the steroidogenesis [36]. The potential mediators by which resistin elevates steroidogenesis include LH receptor, steroidogenic acute regulatory protein, and insulin receptor [44]. Resistin not only stimulates the synthesis of androgens by increasing theca cells thickness and 17α-hydroxylase activity [45], but also potentiate the activities of 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenases accompanied with the increased release of androgens [46]. Resistin, along with LH, also up-regulate gene expression of insulin receptor leading to overproduction of androgens [44]. It was found that quercetin effectively ameliorates serum levels of testosterone and LH through reducing resistin levels [36]. In summary, Fig. 2 indicates the possible mechanisms of the quercetin potential roles on hormonal status in ovarian cells. Hyperandrogenaemia may lead to PCOS-related excessive weight gain and insulin resistance [47]. Moreover, chronic inflammation and oxidative stress, as two hallmarks of PCOS, are closely related in PCOS women and cause impaired insulin action and hyperinsulinemia [48, 49] leading to anovulation [50]. Although quercetin could not make significant changes in body weight in PCOS subjects [31, 33, 34], there is evidence suggesting the ability of quercetin to redistribute fat mass [51]. Quercetin has also exhibited a potential capacity to sensitize insulin receptors attributed to its antioxidant and anti-inflammatory features. The overproduction of ROS derived from NADPH oxidation in PCOS condition leads to higher levels of oxidized LDL (ox-LDL) [52]. The interaction between ox-LDL and Toll-like receptor 4 (TLR4) activates NF-κB path way resulting in elevated expression of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α which induce insulin resistance [30, 53]. Wang et al. [30] showed that quercetin suppresses the expression of NADPH oxidase subunit p22phox, ox-LDL, and TLR-4 and thereby inhibit TLR-4-NF-κB signaling pathway leading to reduced insulin resistance.

In addition, investigations demonstrated that increasing the levels of antioxidant enzymes such as SOD, CAT, POD, GR, GSHPX, and NADPH oxidase by quercetin, are the other protective effects of quercetin against oxidative stress [31, 34]. Since the oxidative stress is positively related to testosterone levels, insulin resistance, ovarian mesenchyme hyperplasia, and infertility [54, 55]; quercetin may be considered as a potential agent to attenuate PCOS complications. Another possible mechanism by which quercetin reduces insulin resistance is mediated by its beneficial effect on the dominant adipokine regulating insulin resistance named adiponectin [37]. AdipoR1 and AdipoR2 are the prominent receptors of adiponectin which interact with the substrate and activate several signaling cascades such as AMP-activated protein kinase (AMPK) to regulate glucose and fatty acid metabolism [56]. Rezvan et al. [37] indicated that quercetin up-regulates gene expression of ADIPOR1 and ADIPOR2 along with a marked increment in AMPK levels in patients with PCOS.

In another study by Khorshidi et al. [36] FBG, insulin, and HOMA-IR were improved after supplementation with quercetin; however, the differences between quercetin and placebo groups were not significant. The authors attributed the glycaemia-mimic effect of quercetin to resistin, which showed a significant decrease in the quercetin group [36]. Resistin diminishes the phosphorylation of AMPK and Akt pathways and decreases the production of IRS-1 as well as tyrosine phosphorylation of IRS-1, leading to increased insulin resistance [57, 58]. Resistin promoter has several binding sites for sterol regulatory element-binding protein 1c and CCAAT enhancer-binding protein alpha (C/EBPα), which bind to resistin promoter and overexpress resistin gene [59].

Quercetin potentially decreases resistin through down-regulating gene expression of C/EBPα [60]. Several indirect mechanisms have been suggested for quercetin to counteract insulin resistance [32]. Lower activity of GK coupled with the increased rate of HK activity observed in PCOS indicates that liver cells in IR state potentiate the activity of HK to compensate decreased GK activity and improve glucose metabolism in the liver [32, 61]. Quercetin increased the activity of both enzymes along with the expression of GLUT4 and reversed lowered activity of GK in PCOSrat liver [32].

Dyslipidemia, as a common metabolic disorder in PCOS, appears to occur due to the hormonal imbalance and insulin resistance [62, 63]. Although the available evidence suggests a highly significant improvement in lipid profile following quercetin administration, more studies are required to confirm these beneficial effects. Based on these studies, anti-hyperlipidemic potential of quercetin can be attributed to its capacity in correcting hyperinsulinemia and hyperandrogenemia [31, 33]. In general, the possible mechanisms of quercetin effects on metabolic indicators are summarized in Fig. 3.

The current evidence indicates that supplementation with quercetin effectively ameliorate hyperandrogenaemia and irregular estrous and consequently, improve the folliculogenesis and luteinisation processes. However, there are not enough studies to make robust conclusions. While data on the impact of quercetin on metabolic profiles is relatively scarce, there is evidence that quercetin may be able to counteract PCOS complications by improving insulin resistance and chronic inflammation. Mechanisms by which quercetin suppress insulin resistance include reducing testosterone, LH and resistin levels and increasing adiponectin activity.