Type 2 diabetes in Polycystic ovarian syndrome patients

PCOS is a multifaceted condition impacting both the reproductive and metabolic well-being of women and is influenced by multiple factors. Statistical evidence demonstrates that among individuals with PCOS, 1.5% have received a diagnosis of T2DM, whereas only 0.4% of women without PCOS share the same diagnosis. This data implies that women with PCOS are at a fivefold higher risk of developing T2DM compared to those without the condition (Kakoly, Earnest, Teede, Moran, & Joham, 2019), (Glintborg, Rubin, Nybo, Abrahamsen, & Andersen, 2015). (Dargham et al., 2018) findings revealed that among individuals with undiagnosed PCOS, approximately 9.7% had been diagnosed with T2DM. As individuals ages, the occurrences of Type 2 Diabetes rises, and research indicates that women with PCOS who are over the age of 40 have a heightened susceptibility to developing T2DM (Goodman et al., 2015). Another similar study reported that about half of women diagnosed with PCOS also experience metabolic syndrome concurrently. In these cases, insulin resistance, a prevalent endocrine condition, is common, and there is a 5-8 times higher likelihood of developing T2DM compared to women without PCOS (Pan, Chen, Tsao, & Chen, 2015).

Even though the women with PCOS who are fortunate to conceive still face an elevated likelihood of encountering pregnancy complications, including conditions like gestational diabetes mellitus (GDM) and giving birth prematurely. Unlike overt T2DM, GDM is characterized by disrupted glucose tolerance caused by pregnancy. This condition might arise due to heightened physiological shifts in glucose metabolism (Karami, Mousavi, Rafiee, Heidari, & Shahrokhi, 2023). Based on emerging research findings, gestational GDM occurs in 40% of pregnancies affected by PCOS, indicating that PCOS serves as a contributing factor to the risk of developing GDM (Choudhury & Rajeswari, 2022). The consequences of poorly managed gestational GDM for both the mother and the fetus encompass occurrences such as stillbirths, macrosomia (excessive fetal growth), and birth-related injuries (Pan et al., 2015).

Polycystic Ovarian Syndrome and Gut microbiota

The exact reason behind the prognosis of PCOS is intricate and not fully comprehended yet. There is a connection between gut microbiota and disruptions in lipid, glucose, and steroid hormone metabolism. Many studies have indicated that gut microbiota has the possible capability to influence insulin production, impact androgen processing, and influence the growth of ovarian follicles. This presents an innovative avenue for comprehending the origins of PCOS. The correlation between gut microbiota and PCOS's development holds significant importance. This study has investigated recent developments in research concerning the involvement of gut microbiota in the initiation and advancement of PCOS (Sun, Gao, Ye, & Zhao, 2023).

The human intestines contain a wealth of microorganisms. The microbiome within the digestive system and the host have a lifelong symbiotic relationship that brings mutual advantages. This area has gained significant attention in the study of cancer, immune disorders, and metabolic conditions (Zhao et al., 2022). The human intestines contain a wealth of microorganisms. The gut microbiota and the host have a lifelong symbiotic relationship that brings mutual advantages. This area has gained significant attention in the study of cancer, immune disorders, and metabolic conditions. Research has indicated that the gut microbiota composition in individuals with PCOS is linked to the emergence and progression of insulin resistance, excessive androgen levels, persistent inflammation, and metabolic syndrome. Moreover, it's possible that the clinical aspects of PCOS are influenced by factors like short-chain fatty acids, lipopolysaccharides, sex hormones, and the communication between the brain and gut, as facilitated by the brain-gut axis (Gu et al., 2022). The role of gut microbiota in the onset and advancement of PCOS is not well defined. Numerous studies have highlighted the significant influence of gut microbiota on the occurrence and progression of PCOS (Duan et al., 2021). In a prior investigation, it was discovered that mice with induced PCOS through a dehydroepiandrosterone/high-fat diet exhibited reduced levels of Bacteroides bacteria in the intestines, alongside heightened levels of Firmicutes and Proteus bacteria (Lin, Wen, Wen, & Xiang, 2021).

In contrast to the group of individuals without health issues, rats with PCOS induced by letrozole exhibited reduced quantities of rumen coccus, intestinal lactobacillus, and clostridium, while having higher levels of pullorum bacteria (Zhao et al., 2022). In accordance with a different research study, there was a discernible reduction in gut microbial diversity among individuals with PCOS compared to those who were healthy. Moreover, the chemical makeup of the gut microbiota was modified, and indications showed alterations in the integrity of the intestinal mucosal barrier. (Lindheim et al., 2017). In comparison to non-obese individuals with PCOS and a healthy control group, obese individuals with PCOS exhibit elevated levels of enterobacteria, reduced amounts of lactobacillus and bifidobacteria, and alterations in gut microbiota that correspond to levels of inflammation and insulin resistance (Zhou et al., 2020). Zeng and colleagues conducted a comparison between the gut microbiota of PCOS patients with insulin resistance and that of a healthy control group. They observed a decline in the prevalence of Prevotella and an increase in Bacteroides among the former group (Zeng et al., 2019). Zeng and colleagues conducted a comparison between the gut microbiota of PCOS patients with insulin resistance and that of a healthy control group. They observed a decline in the prevalence of Prevotella and an increase in Bacteroides among the former groups (Qi et al., 2019).

In recent times, there has been a growing attention on exploring traditional medicine as a source of active components or formulas to address PCOS by specifically targeting the gut microbiota. Simultaneously, traditional Chinese herbal formulations and their active constituents have been employed in PCOS treatment for an extended duration (Li et al., 2022). These herbal remedies and their components possess the capacity to modulate gut microbiota. The available evidence indicates that prebiotics, probiotics, and synbiotics offer effective treatment possibilities for individuals with PCOS. The present research demonstrates that probiotics have the capability to reinstate the diversity of gut microbiota in PCOS mice, rectify imbalances in the microbial population, and enhance the reproductive function of the mice (Li et al., 2022). Ultimately, there exist intricate and intimate connections between PCOS and the microbial community in the gut.

Polycystic Ovarian Syndrome and dyslipidemia

Like any other woman, an individual with PCOS might possess an uncommon genetic lipid disorder, such as heterozygous familial dyslipidemia. Additionally, factors like getting older, obesity, one's way of living (including not being physically active, consuming diets rich in saturated fats and sugars while lacking in fiber, smoking, and using illicit drugs), and the use of medications can also impact how lipids are processed in women with PCOS. Persistent disruptions in lipid metabolism involving apolipoproteins ver the course of a woman's life who have PCOS magnify the susceptibility to cardiovascular disease (CVD) as they grow older (Wild, 2012). An association has been discovered between dyslipidemia and anovulation n individuals with PCOS.

Research indicates that women with anovulatory PCOS exhibit elevated levels of Total Cholesterol (TC), Triglycerides (TGs), and LDL-C, along with decreased levels of HDL-C as compared to those with ovulatory PCOS (Rizzo et al., 2009). Obesity has the potential to trigger irregular menstrual cycles, anovulation and ultimately dyslipidemia, in women who are of reproductive age. Research has demonstrated that elevated levels of TGs, Free Fatty Acids (FFAs), and oxidized LDL in the bloodstream lead to malfunctioning mitochondria, causing an increased release of ROS. Consequently, this ROS release contributes to harm to the ovaries and a heightened occurrence of follicular atresia. The activation of receptors by oxLDLs can lead to the apoptosis of human granulosa cells (GCs) and disruptions in the ovulation process (Schube et al., 2014). Furthermore, the presence of abdominal obesity encourages the production of androgens by the ovaries and adrenal glands. Simultaneously, levels of Sex Hormone-Binding Globulin Hormone (SHBG) are diminished in individuals with PCOS. Increased levels of testosterone can intensify abdominal obesity and inflammation, giving rise to a self-perpetuating cycle within PCOS (Zhang et al., 2015).

Lipid metabolism plays an important role in influencing the environment of oocytes in individuals with PCOS. Research has revealed notable elevations in glycerol and lipid content, as well as higher levels of cholesterol, particularly LDL cholesterol, in the follicular fluids of PCOS patients compared to those of healthy controls. Furthermore, PCOS follicular fluids exhibit slightly elevated levels of certain lipids such as linoleic acid palmitoleic acid (Zhang, Liu, Yin, Yang, & Xiong, 2017). These alterations imply that dyslipidemia plays a role in shaping the growth of follicles within PCOS, consequently leading to infertility.

Polycystic Ovarian Syndrome and insulin resistance

Insulin functions as a hormone that binds to its receptor located on the cellular membrane. The receptor is made up of two subunits, namely α and β, connected by disulphide bonds. The α subunit, located outside the cell, is in charge of the binding site, while the β subunit, situated inside the cell, triggers the inherent tyrosine kinase activity. Insulin functions as a hormone that binds to a receptor situated on the cell membrane (Nestler, 1997). This receptor consists of two subunits: α and β, linked together by disulphide bonds. The α subunit, found externally on the cell surface, is responsible for hosting the binding site. Meanwhile, the β subunit, positioned within the cell, initiates the intrinsic tyrosine kinase activity (Xu & Qiao, 2022). PCOS poses a health concern for females, with insulin resistance being a notable focal point. Insulin plays a vital role in managing glucose metabolism, and enhancing its responsiveness is essential to facilitate correct glucose absorption and processing.

Role of curcumin in treating Polycystic Ovarian Syndrome

Curcumin is a bioactive water insoluble compound derived from polyphenolic curcuminoids present in the rhizomes of turmeric. It contains about 2-8% of curcumin and is commonly used as a food additives and a strong coloring agent in Indian traditional system of medicine (Rani et al., 2022). Curcumin has gained significant attention due to its potent pharmacological properties and biological activities. It is a polyphenolic agent with antioxidant and anti-inflammatory characteristics and has been reported to protect against a wide range of diseases such as cancer, Parkinson's disease, inflammatory disorders atherogenic dyslipidemia, and osteoarthritis. Studies have also demonstrated its beneficial effects in managing hypoglycemic and hypolipidemic conditions in humans and different animal models (Sohaei, Amani, Tarrahi, & Ghasemi-Tehrani, 2019).

As per the research conducted earlier letrozole was administered as a treatment for 21 days with a dosage of 1 milligram for every kilogram of body weight , dissolved in a solution of 0.5% CMC (Kafali, Iriadam, Ozardalı, & Demir, 2004). The study found that administering two different doses of curcumin, low dose (100 mg/kg and high dose (200 mg/kg), helped regulate body weight after 21 days of successful induction (between days 22 and 36). The effects of curcumin were similar to those of the standard drug Clomiphene citrate, which was administered at a dose of 1 mg/kg dissolved in a 0.5% CMC solution via the oral route (Reddy, Begum, Mutha, & Bakshi, 2016). Curcumin plays a important therapeutic role in reducing symptoms of PCOS, including its effect on IL-6, CRP, and TNF-α. It helps to minimize the levels of these cytokines and inflammatory markers, thereby improving the overall health of individuals with this condition. One of the earlier conducted studies revealed that curcumin treatment resulted in a significant reduction in the thickness of the theca layer and an increase in corpus luteum diameter. Additionally, curcumin reduced the levels of inflammatory markers, IL-6 and CRP. Immunohistochemically analysis demonstrated that the expression of TNF-α was increased in PCOS group, but curcumin treatment led to a decrease in TNF-α expression in the ovaries (Mohammadi, Kayedpoor, Karimzadeh-Bardei, & Nabiuni, 2017). Administration of curcumin at a dose of 500 mg/d twice a day resulted in decreasing the serum insulin and abnormal lipid profile in women with PCOS (Sohaei et al., 2019). Similarly, in another recent clinical trial curcumin at a dose of 500 mg/d thrice a day ameliorated PCOS-associated hyperandrogenemia and hyperglycemia. Curcumin's ameliorative effect in patients with PCOS is likely due to its ability to enhance hormonal profiles by mitigating inflammation and oxidative stress while improving ovarian function (Heshmati et al., 2021). In women with PCOS, administration of curcumin for a duration of 12 weeks resulted in notable decreases in body weight and enhancements in glycemic control, and reductions in serum lipid levels (with the exception of triglycerides and VLDL-cholesterol). Moreover, curcumin treatment was associated with downregulation of PPAR-g and LDLR gene expression (Jamilian et al., 2020). Letrozole (1 mg/kg) in combination with curcumin (100 mg/kg and 200 mg/kg for was given to PCOS patients for 15 days. Administration of letrozole led to disturbances in serum sex steroid and lipid profiles, HbA1c and antioxidant activity depletion. However curcumin alternatively demonstrated its protective effect by normalizing these parameters and eliminating ovarian cysts (Reddy et al., 2016).

Role of cinnamon in Polycystic Ovarian Syndrome

Preliminary data of a study suggested that taking cinnamon supplements for 6 months can increase menstrual cycles and may be a useful treatment option woman with PCOS. However, further research may be necessary to confirm these findings (Kort & Lobo, 2014). Another study involved 84 obese women with PCOS who were given cinnamon capsules for 8 weeks. The results showed that cinnamon significantly improved the antioxidant capacity of the blood and reduced a harmful compound called malondialdehyde. It also improved the levels of total cholesterol, LDL cholesterol, and HDL cholesterol. However, there was no noteworthy effect on TG. The study concludes that cinnamon supplementation may be beneficial for reducing the risk factors associated with PCOS (Borzoei et al., 2018).

Low Glycemic index foods in Polycystic Ovarian Syndrome

Low Glycemic index (GI) diet is characterized as those foods that primarily derive their carbohydrates from sources with a low glycemic index. Low-GI foods are considered to be those with carbohydrates that undergo slow digestion, absorption, and metabolism in the body (Augustin et al., 2015).

Elevated postprandial glycaemia is linked to an elevated risk of chronic lifestyle-related diseases, and this mechanism is universally associated with different diseases. Carbohydrates are the primary dietary component that influences insulin secretion and postprandial glucose. Higher glycemic index is widely acknowledged to hold clinical and public health significance, as it leads to higher blood glucose levels and greater insulin demand when consuming the same amount of carbohydrate. It is important to note that high glycemic index (GI diets) may directly contribute to insulin resistance by affecting glycemia, free fatty acids, and hormone secretion. This implies that the GI of the carbohydrate-rich foods we consume is crucial, regardless of the overall carbohydrate intake level (Barclay et al., 2008). Both registered dietitians and patients are increasingly embracing low-GI diets as a valuable approach in managing PCOS. Patients with the classic PCOS phenotype tend to have higher dietary GI levels, which are associated with a less favorable anthropometric and metabolic profile.

PCOS patients have been found to exhibit lower levels of glutathione peroxidase compared to healthy women. A study by Szczuko et al. (Szczuko, Zapalowska-Chwyć, & Drozd, 2019) proposed that incorporating a low-GI diet can reduce inflammation in women with PCOS. This dietary intervention achieves this effect by elevating the levels of uric acid and enhancing the activity of glutathione peroxidase. Moreover, making short-term adjustments to the diet by adopting a low-GI approach may result in a minor improvement in insulin sensitivity among women with PCOS. Additionally, a low-GI diet has been shown to be more effective than a normal glycemic index diet in improving ovulation cycles for patients with PCOS and anovulation (Sordia-Hernández et al., 2016). A preliminary study indicated that adopting a low-GI diet could potentially lower the risk of endometrial cancer in women with PCOS. This risk reduction is attributed to the diet's ability to decrease endometrial thickness and increase the number of menstrual cycles (Atiomo et al., 2009). For women who are overweight or obese, the combination of a low-GI diet with a hypocaloric (calorie-restricted) diet appears to offer greater benefits. Hypocaloric low-GI diets have been found to result in reduced BMI, body fat percentage, and leptin concentrations. Additionally, these diets have shown improvements in oocyte development and fertility rates (Becker, Passos, & Moulin, 2015). A recent study highlighted that low-GI diets are considered an excellent dietary option for women with PCOS due to their high adherence rates and effectiveness in addressing various common clinical manifestations of PCOS. These manifestations include insulin resistance, hyperandrogenism, hirsutism, acne, and menstrual irregularities. Furthermore, research indicated that a low-GI diet has equally positive effects on both anthropometric and metabolic characteristics in overweight women, regardless of whether they have PCOS or not (Shishehgar, Mirmiran, Rahmati, Tohidi, & Tehrani, 2019).

Therefore based on the findings of these investigations, it is logical to deduce that women with PCOS tend to follow a dietary pattern that involves a higher intake of high-GI foods in general. This observation further strengthens the idea that low-GI diets hold a significant and beneficial role in the management of PCOS. As researchers continue to identify low-GI foods, it will facilitate the adoption of low-GI diets, making them more accessible and applicable to a broader range of individuals. Pulses, including lentils, chickpeas, split peas, and dry beans, possess several beneficial nutritional qualities. They are rich in fiber and have low-fat content, while also providing high-quality protein and complex carbohydrates with a low GI (Mudryj, Yu, & Aukema, 2014). Additionally, pulses serve as a notable source of essential vitamins and minerals, such as iron, zinc, folate, calcium, magnesium, and potassium Research has demonstrated that incorporating pulses into the diet can lead to improvements in cardiometabolic disease risk factors among women with PCOS (Kazemi et al., 2018). Even more noteworthy is the fact that pulses contain essential phytochemicals, saponins, and tannins, which exhibit substantial anticancer properties. Moreover, maintaining sufficient folate intake can help lower the risk of endometrial carcinoma. It is important to consider this, especially because women with PCOS face an increased risk of endometrial carcinoma, ranging from 2 to 6 times higher than average (Charalampakis, Tahrani, Helmy, Gupta, & Singhal, 2016).

Role of green tea in Polycystic Ovarian Syndrome

Recently, there has been a significant attention in the use of natural herbal medicines and functional foods for treating various diseases, and one such extensively researched herbal remedy is green tea (Haghighatdoost, Nobakht, Gh, & Hariri, 2017). Green tea comprises a mixture of polyphenolic flavonoids (catechin) and caffeine, which are very useful for weight loss and weight maintenance. Besides beneficial effects on fat metabolism, green tea is also effective on glucose tolerance and insulin resistance (Maki et al., 2009). The consumption of green tea has a notable impact on fasting insulin levels in individuals who are overweight or obese and have PCOS (Hininger-Favier, Benaraba, Coves, Anderson, & Roussel, 2009). A clinical trial was structured to evaluate and contrast the impacts of green tea and metformin therapies on the physical measurements of women diagnosed with PCOS. The study summed up that green tea is suggested as a complementary therapy for patients with PCOS, as it has the potential to yield positive effects on obesity management (Farhadian, Barati, Mahmoodi, Mosleh, & Yavangui, 2020). Ghafurniya et al. conducted a study where they observed a significant reduction in the thickness of the theca cell layer and the number of follicular cysts in PCOS model rats following the administration of green tea injections (Ghafurniyan, Nabiuni, & Karimzadeh, 2014). In a different animal study conducted by Sadoughi et al., the administration of green tea extract for 24 days resulted in significant reductions in serum levels of LH, β-estradiol, and testosterone in PCOS model rats. Moreover, the study observed improved ovarian function, with a notable increase in the number of preantral, antral, prehierarchical, and corpus luteum follicles, along with a significant decrease in the number of cystic follicles. The study also reported decreases in FSH and progesterone levels (Sadoughi & Rahbarian, 2017).

The administration of green tea extract at a dose of 500 mg per day for a duration of 12 weeks had a positive impact on reproductive outcomes, particularly in reducing serum-free testosterone levels in obese individuals with PCOS (Maleki et al., 2021). Furthermore, the patients who were given a daily dose of 500mg of green tea extract experienced a significant decrease in free testosterone levels when compared to individuals who received a placebo (Tehrani, Allahdadian, Zarre, Ranjbar, & Allahdadian, 2017). Contrarily, in another study, the administration of 1.5 cups of Lung Chen tea for a period of 3 months did not result in significant changes in hormonal profiles, which included testosterone, SHBG, free androgen index, DHEA-S, FSH, and LH (Chan et al., 2006). Ghafurniyan et al. observed significant reductions in IL-6 and CRP biomarkers in PCOS model rats after a 14-day treatment of green tea extract (GTE) through injections (P < 0.05) (Maki et al., 2009). Similarly, in a clinical trial involving PCOS patients, it was observed that the supplementation of 500 mg of green tea extract per day for a period of 6 weeks did not result in statistically significant changes in the levels of inflammatory factors, including IL-6, hs-CRP, and TNF-α. (Mombaini, Jafarirad, Husain, Haghighizadeh, & Padfar, 2017). On the other hand, a conducted study in PCOS model rats, showed that the ingestion of green tea extract (GTE) for 24 days resulted in a statistically significant increase in serum levels of TNF-α, IL-1β, MDA (malondialdehyde), and IL-6. Additionally, the study also reported an increase in the levels of antioxidant enzymes such as SOD (superoxide dismutase), CAT (catalase), and GPX (glutathione peroxidase) in ovarian tissue (P < 0.05)

Based on the available evidence, green tea extract supplementation shows potential beneficial effects on PCOS. While human studies on ovarian histology are lacking, animal studies support the positive impact of green tea extract on improving ovarian function and histology. Additionally, green tea extract may contribute to better glycemic control in PCOS patients and has the potential to reduce body weight, LH, and androgen levels in these individuals. However, the evidence regarding the effects of green tea extract on inflammation appears to be contradictory. At present, there is a limited number of randomized controlled trials or definitive studies to draw strong conclusions about the impact of green tea extract on oxidative stress in PCOS. As such, further research is required to provide more robust evidence on the effects of green tea extract in the context of PCOS (Maleki et al., 2021).

Role of flaxseeds in Polycystic Ovarian Syndrome

Flaxseed, scientifically known as Linum usitatissimum, contains a variety of bioactive substances, such as α-Linolenic Acid (ALA), phytosterogenic lignans (secoisolariciresinol diglycoside-SDG), and dietary fiber. These compounds are abundant in flaxseed and offer various health benefits (Yari et al., 2016), (Farzana et al., 2015). Previous research has shown that consuming foods rich in lignans can lead to an increase in testosterone excretion by binding it to the enterohepatic circulation (Haidari, Banaei-Jahromi, Zakerkish, & Ahmadi, 2020). Additionally, lignans may decrease the availability of free testosterone by raising SHBG (sex hormone-binding globulin) levels. In one of study, flaxseed powder supplementation along with lifestyle modifications resulted in significant improvements in metabolic and anthropometric parameters in PCOS patients, compared to those who only underwent lifestyle modifications. Flaxseed showed beneficial effects on insulin resistance, lipid profile, and inflammation markers (Haidari et al., 2020). In other study, the hydroalcoholic extract of flaxseed had a positive impact on reducing PCOS symptoms in rats. Although the rat model used did not fully replicate human PCOS, the treated rats showed improvements in sex-steroid hormonal levels and ovarian histomorphometric characteristics (Jelodar, Masoomi, & Rahmanifar, 2018). In one of the clinical study conducted, earlier the effect of administration of flaxseed supplementation (30 g/day) on hormonal levels in a woman with PCOS was examined. The results showed a significant decrease in androgen levels and hirsutism, indicating a potential benefit of flaxseed supplementation in PCOS management, warranting further research (Nowak, Snyder, Brown, & Demark-Wahnefried, 2007).

Role of omega-3 fatty acids in Polycystic Ovarian Syndrome

Omega-3 fatty acids are well known for their potential health benefits, including supporting heart health, brain function, and reducing inflammation. Many health organizations recommend including fatty fish in the diet regularly to ensure an adequate intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for overall well-being. For individuals who do not consume fish or seafood, there are also plant-based sources of omega-3 fatty acids like flaxseeds, chia seeds, walnuts, and algae-based supplements that provide an alternative way to get these essential nutrients. Role of omega 3 fatty acids to treat polycystic ovarian syndrome is given in Table 4.

PCOS is characterized by elevated androgens, anovulation, and often occurs with insulin resistance. Insulin resistance can contribute to increased androgen production and ovarian dysfunction (Oner & Muderris, 2013). Lifestyle modification, with a focus on achieving substantial weight loss, is a key approach in effectively managing obesity and its associated health conditions (Albracht-Schulte et al., 2018). Natural bioactive compounds, such as n-3 PUFA, possess few side effects and can be considered a safe approach in comparison to other modalities of treatment. Omega-3 fatty acids can enhance insulin sensitivity by promoting the production and release of anti-inflammatory adipokines like adiponectin. Additionally, they may help to decrease inflammation and proinflammatory cytokines, further contributing to improved insulin sensitivity (Mohammadi, Rafraf, Farzadi, Asghari-Jafarabadi, & Sabour, 2012). Numerous potential mechanisms exist through which n-3 PUFA, specifically EPA and DHA, might enhance body composition, regulate energy metabolism, and decrease body weight (Albracht-Schulte et al., 2018). Despite claims of the beneficial impact of omega-3 fatty acids on insulin resistance, multiple studies have reported conflicting findings and results. Research conducted on mice has demonstrated that omega-3 fatty acids can protect against insulin resistance through the activation of PPARα, diminishing inflammation, and reducing fat accumulation in insulin-sensitive tissues (Kabir et al., 2007). This dietary supplement may potentially be utilized to enhance folliculogenesis disorder caused by excessive oxidative stress and reduce hyperinsulinemia in women with PCOS (Ruder, Hartman, Blumberg, & Goldman, 2008). The supplementation of omega-3 fatty acids has a positive impact on certain cardiometabolic risk factors in women with PCOS (Cussons, Watts, Mori, & Stuckey, 2009). This effect is achieved by competitively inhibiting cyclooxygenase 2 (COX-2), which reduces the synthesis of prostaglandins, and also by enhancing the activity of antioxidant enzymes (Sarbolouki et al., 2010). According to the study conducted by Oner and Muderris in 2013, the consumption of omega-3 for a duration of 6 months led to a notable reduction in insulin levels. However, there were no significant reported changes in glucose levels and HOMA index (Oner & Muderris, 2013). In a another clinical trial, 30 participants were given a daily dose of 2 g fish oil containing omega-3 fatty acids for 12 weeks. After the intervention, there was a notable rise in insulin sensitivity, and serum insulin levels (Amini et al., 2020).

Considering the evidence supporting the positive effects of omega-3 supplementation on inflammation and cardiometabolic issues, it may not be necessary to universally administer omega-3 fatty acids to all women with PCOS irrespective of their age and health status. Instead, omega-3 supplementation should be targeted specifically to those PCOS women who are already experiencing symptoms related to inflammation and cardiovascular problems, which typically become more prominent between the ages of 40 and 45 (Tosatti et al., 2021). Furthermore, research on the cardiovascular and anti-inflammatory effects of omega-3 fatty acids in adults has suggested that the minimum recommended daily dose for a combination of EPA and DHA administration is 500 mg. However, in individuals with recent myocardial infarction or those with abnormal triglyceride levels, the recommended dosage may be higher, ranging from 2000 to 4000 mg per day (Calder, 2018). Omega-3 fatty acids contain more calories than other dietary supplements, and their usage in overweight or obese individuals should be approached with caution to prevent any negative effects on metabolic imbalances, which are often present in women with PCOS. It is essential for individuals, especially those with PCOS or during pregnancy, to consult with their healthcare providers before starting omega-3 supplementation to ensure there are no potential side effects or interactions with other medications (Iervolino et al., 2021). Additionally, it is important to take into account potential side effects associated with supplementing omega-3 fatty acids. These may encompass mild digestive discomfort, intestinal gas (particularly when sourced from fish oil), feelings of nausea, diarrhea, and headaches (Iervolino et al., 2021).

Role of Rutin in Polycystic Ovarian Syndrome

Rutin, a type of flavonoid also known as 3,4,5,7 tetrahydroxyflavone 3-rutinoside has showed as an effective agent in the controlling of PCOS via biochemical and controlling the hormonal disturbance in the rats (Jahan et al., 2016). Now days PCOS is prevalent across the globe, rutin played crucial health benefits in PCOS. Rutin has potent ability to reduce the apoptosis of follicles formation showed by in vitro studies via inhibition of PI3K pathway, helps in the reduction of PCOS (Lins et al., 2021). In one of the earlier conducted research it was demonstrated that rutin, boosted the activity of brown adipose tissue (BAT) and prompted the creation of beige fat cells within white adipose tissue (WAT). This contributed to improving obesity and insulin resistance in obese mice (Hu et al., 2017). Research has indicated that administering rutin orally during PCOS reduces blood glucose levels. This effect is attributed to rutin's anti-hyperglycemic activity, which aids in lowering glycemic levels by enhancing insulin secretion in the pancreatic beta cells. This, in turn, supports the uptake of glucose by cells (Rani et al., 2022). Another study find when rutin was administered at a dose of (100 mg/kg) p.o in female Sprague-Dawley rats for fifteen days exhibits improved antioxidant and lipids profile than control (PCOS) group (Jahan et al., 2016). Moreover the rutin treated group showed significant reduction in cystic follicles by histopathological evaluation. The in vivo studies of rutin on the cell line of osteoblast showed dose of (0.01 to 0.05 mmo/L) evaluation from western blot and RT-PCR exhibits enhanced the protein expression Bcl-2 , caspase-3, rutin can easily bind with AHR which help in PCOS management (Liang et al., 2022).

Iervolino et al. (2021) conducted a review that highlighted rutin's capacity to activate brown adipose tissue (BAT) and stimulate the development of adipocytes in white adipose tissue. This activation of BAT was observed to contribute to the improvement of infertility, potentially reducing the risk further (Iervolino et al., 2021). Rutin demonstrates comparable effects to metformin, exhibiting a significant impact on potentially reducing the formation of cystic follicles. This effect is attributed to its ability to improve lipid profiles, enhance antioxidant activity, and reduce C-reactive protein levels (CRP) (Patel, 2018).