Therapeutic Role Of Omega-3 Fatty Acids In Improving PCOS And PCOS Related Complications

To our insight, despite a few preliminaries investigating the helpful impact of n-3 polyunsaturated unsaturated fats (PUFA) on Polycystic Ovarian Syndrome (PCOS), not many studies are done to examine the impacts of n-3 PUFA utilization on PCOS inconveniences. In this manner, our point was to write a review to explore the potential impact of omega 3 and related components. Data base search was conducted through PubMed, Googlescholar, Scopus, EMBASE. Omega-3 fatty PUFAs were explored for their effects on PCOS, mechanisms regulating these pathologies and associated consequences. Omega 3 PUFA helps in management of PCOS by causing weight reduction, maintaining glycemic and hormonal balance and enhancing the endothelial capacity. Patients are observed to show improvements in symptoms of PCOS after using Omega 3 PUFAs. They have various positive impacts on these patients which will be discussed in detail in this review. Accordingly, more preliminaries are justified to examine attractive instruments for explaining the metabolic and hormonal impacts of these specialists in PCOS. __________________________________________________________________________________________


INTRODUCTION
Polycystic Ovarian Syndrome (PCOS) is viewed as one of the most well-known female endocrine issues with a prevalence of 5-10 % globally [1]. Omega-3 PUFAs may apply advantageous consequences for PCOS, including the upgrade of endothelial capacity, helps in reducing weight, improving glycemic load and hormonal homeostasis, and reducing inflammation. Past investigations have shown that an eating regime containing omega-3 PUFAs, particularly long-chain PUFAs, altogether worked on the clinical appearances of dyslipidemia, vascular endothelial functioning, and insulin obstruction in patients with PCOS. Komal et al. discovered that fish oil contains EPA and DHA that lowers body weight and metabolic inconsistencies in an animal model. One meta-investigation including 591 PCOS patients from nine randomized controlled preliminaries (RCTs) showed that supplementation with omega-3 PUFAs further improved HOMA-IR and adiponectin levels and lipid profiles [2]. The logic behind the phenomenon of PCOS is not buttoned-down; even with this, a mixture of specifications, involving genetics or epigenetics, ecological components, and disclosure to elevated leveled androgen prenatally are studied to supposedly showcase a part in the outbreak of the disease. Previously it has been studied that ecological components might serve as central components in the prevalence and cure of the disease. In the ecological components, dietary modifications are one of the essential and administrable components [3]. For the analysis of PCOS, the most common criteria which should be examined are FSH, LH, and androgen levels. Elevated LH level drives to an elevation in androgen amount, which raises the evolution of PCOS [3]. Remedial choices of PCOS bounds from pharmacological to surgical. Oral contraceptive pills (OCP) prescribed for half a year alleviates hyperandrogenism and normalize menstruation [4]. It also decreases the serum 25 hydroxyvitamin D level, which can alter bone health. Metformin, an insulin sharpener, upgrades the condition of women suffering from PCOS by reducing the increased criteria as insulin, androgen, rotating free T levels, at the same time elevating sex hormone-binding globulin and insulin-like growth factor-binding protein [5,6]. Metformin medication during and before the IVF or sperm injection in females with PCOS restrains from the danger of OHSS [7]. Whereas the negative consequences of metformin are lactic acidosis, tiredness, severe drowsiness, cold skin, muscle ache, labored breathing, slow/irregular heartbeat, stomach ache, nausea, vomiting, and diarrhea [9], Steroid hormonal mediations are one more form to cure PCOS. Antiandrogens are administrated to deal with androgenism. N acetylcysteine and some others are administrated to deal with the resistivity of insulin. These remedies are useful to some degree, but not completely. These remedial methods are also not free from negative effects. The importance and danger of medicine lean on the host elements. The use of these hormone controllers for a longer period of time can become a reason for obesity, cancer, psychiatric problems, along with some other issues [11]. Alteration of lifestyle, like eating habits, nutritional products, workout, and psychological remedies, must be the go-to medication for PCOS as they have no harmful effects [10]. Around the world, pervasiveness assessment of PCOS is greatly fluctuating, starting from 2.2 percent to as above as 26 percent. It is also linked with cognitive deterioration in addition to stress and some other mood swings. Many females with PCOS also suffer from overweight or obesity, boosting up androgen release while decreasing function of reproduction and most probably facilitating the expansion of PCOS. Metabolic irregularities like dyslipidemia, insulin resistance, then disorders like diabetes, obesity, cancer, infertility, along with coronary heart diseases, could be identified with PCOS [11]. Sensitive oxygen breeds and antioxidants stay stable in an ordinary person, but as soon as this balance is interrupted, oxidative stress evolves that might drive to multiple diseases. Elevated oxidative stress adds up to the hazards of CVD in females having PCOS [12]. Though excellent medication for PCOS is not completely found, a number of ways are desirable, along with a mixture of one or more of the greatest compelling mediational design, like change in eating pattern and living style, numerous professionals consider exercise and diet to be the initial step in treating PCOS [13,14]. For example, digestible fats like PUFA along with ω− 3 and ω-6 fats are considered in relationship to PCOS. Food origins of n-3 PUFA are confined compared to n-6 PUFA origin. Alpha-linolenic acid ALA is rich in plant sources and is rich in products like flaxseeds [14].
Omega-3 PUFA is affirmed to apply its beneficial properties in signaling pathways and inaction of transcription. Gene expression is one illustration of the desirable system of n-3 PUFA utilization is certainly affecting wellbeing indicators. Utilization of PUFA foods lowers the danger of recurring disorders, which is exceptionally correct regarding the dangerous aspects of the metabolic diseases in patients suffering from PCOS, dyslipidemia, damaged endothelial function, and insulin resistance [16,17]. Nutritional mediation serves as an encouraging approach for the medication of PCOS, PUFAs have health benefits such as anti-inflammatory, insulin sensitivity, cellular discrimination, and ovulation [18,19].

Mechanism of omega -3 fatty acids:
There are many mechanisms for how omega 3 fatty acids work in our bodies ( Figure 1). 1. Omega-3 PUFAs upgrade endothelial function by decreasing the development of plaque in the blood vessel and improving endothelial-subordinate vasodilation. 2. Omega-3 PUFAs, particularly DHA, activate mRNA levels of adipocyte protein, CCAAT/enhancerrestricting proteins (C/EBPs), and peroxisome proliferator-actuated receptor γ (PPAR-γ), and these two unique groups control fat biosynthesis. 3. Omega-3 PUFAs improve insulin sensitivity by reducing the stress of the endoplasmic reticulum, increasing β-oxidation of mitochondrial unsaturated fats and mitochondrial uncoupling, decreasing lipid stores, and developing ROS; hence this process improves insulin responsiveness. 4. EPA and DHA work as lowering inflammation in the body by decreasing the TNF-α, IL-6, and IL-1β, which are produced by the process of lipopolysaccharide (LPS) as well as downregulating the outflow of the outer layer of monocytes and endothelial cells [20]

Obesity and omega 3
Approximately 40 %-50 % of patients with PCOS are observed to be overweight and is viewed as a significant factor for PCOS. The fatter in the body can prompt fat tissue dysfunction, which is associated with the pathological mechanisms of MetS and disturbed insulin obstruction in the liver and skeletal muscle. It is found that teenagers with a higher waist circumference and increased BMI are deficient in n-3 PUFA, especially DHA. Functioning of an endocrine organ is done by adipose tissues, which can emit a few adipokines and chemicals, for example, leptin and adiponectin, and cytokines, for example, interleukin-6 (IL-6) [21].
Obesity can be treated with an active lifestyle and dietary modifications. Regular bioactive mixtures, such as n-3 PUFA, are considered safe in contrast with different treatment modalities. There are many studies that showed that n-3 PUFA, especially EPA and DHA, increase the metabolism of the body, improves body composition, and decreases body weight [21]. Few investigations have detailed great results of omega-3 utilization on obesity. For example, BMI diminished fundamentally day by day with the oral organization of 1,500 mg omega-3 for quite a long time [22][23][24].

3.improves insulin senstivity
Reduces endoplasmic stress increases Beta oxidation of mitochondrial fatty acids reduces lipid deposits and process of Reactive oxygen spiecies

DHA and EPA reduces inflammation
reduces formation of TNF-a, IL-6 ,IL-1B

Insulin Resistance
Insulin resistance is the response of peripheral tissue to decreased insulin. This disease appears particularly in the lean muscle and liver, with multiple drawbacks in glucose metabolism associated with the abnormal adjustment in GLUT4. Skeletal muscle plays a considerable part in IR. gluconeogenesis, glycogenolysis are not regulated properly due to insulin resistance, leading to abnormal glucose output [25]. IR has been recorded in thirty percent of skinny and seventy-five percent of obese people with PCOS while insulin resistance is greater in overweight and older people [26]. Obesity leads to insulin resistivity IR, which is responsible for metabolic syndrome [21]. IR plays its part in hyperandrogenism in PCOS in 2 noticeable ways: 1) stimulant of androgen cells with luteinizing hormone LH and elevated androgen cells leads to excessive man-like hair growth low fertility in females.
2) Elimination of sex hormone constricting globulin fusion from the liver [27]. Sex hormone-binding globulin is a plasma protein of androgen or estrogen, so all reductions in sex hormone-binding globulin levels can lead to hyperandrogenism in PCOS patients. There are few findings that display the properties of n-3 on insulin resistance. Oner and Muderris found that levels of insulin were automatically reduced by taking n-3 for six months, contrarily no changes were observed in glucose level and Homeostatic model assessment index. Another study was conducted in which 30 people took 2 grams of fish oil for about twelve weeks; serum insulin levels were improved respectively [28]. Mirmasoumi et al. recorded a decline in insulin levels after distributing 1 gram of flaxseed oil n-3 fatty acid daily for twelve weeks [29]. Furthermore, insulin decline was seen after twelve weeks of supplementation with omega 3 acids and vitamin [10].

Inflammation
Constant low-grade inflammation is common in obesity. White blood cells in the adipose tissue can raise IR in type 2 diabetes and obesity. PCOS devotes itself to a proinflammatory state, and a link between inflammation and IR has been recorded. Furthermore, inflammatory modulators increase PCOS that is escorted by glucose stimulation of proatherogenic routes [30]. Omega 3 PUFA controls multiple inflammatory markers like adhesion molecules and cytokines, TNF α, IL6, and interleukin1β. Many studies have recorded that EPA and DHA reduce the TNFα, interleukin 6, and interleukin-1β. While other research has demonstrated that EPA and DHA might result in elevation of the cytokines IL-10 absorption, which is anti-inflammatory [31]. There are multiple records proposing that PUFAs can lessen inflammation of patients with PCOS [32]. Three grams of fish oil or 5000 IU of cholecalciferol daily automatically declined CRP and IL-1 [33]. One more research says that flaxseed oil supplementation declined high sensitivity C-reactive protein. At the same time, Rahmani indicated that taking 1 gram of fish oil daily for twelve weeks regulated PPARγ and lowered gene expression of Interleukin 1 and 8 [10]. Undoubtedly, a lot of earlier research has affirmed the effectiveness of omega 3-PUFA in PCOS.

Adipokines
Adjustments of adipokines are examined as a particular problem of PCOS; still it is not completely accepted that either this dysregulation is insignificant to PCOS problems like obesity, hyperinsulinemia, and hyperandrogenism, or is precisely associated with PCOS [34]. Adiponectin or leptin is present in the adipokines, which are excreted from adipocytes [34]. Anti-inflammatory adipokines are declined in obese people, while inflammatory adipokine is increased in comparison with slim individuals [35]. The greater leptin absorption in the obese individual is because of resistance of leptin which is linked to more inflammation, that includes TNFα and C-reactive protein. In inclusion to the inflammatory feedbacks of adipokines, adiponectin and leptin can balance hunger and energy consumption, which concludes that alterations in these can bring insulin sensitivity in the body. Omega 3 PUFA taken from plant and marine origins has positive effects in modulating the anti-inflammation of adipokines [36]. An increase of adiponectin and depletion of leptin was recorded by omega 3 PUFAs control in former research [37], which is linked with improvised functioning of skeletal muscles mitochondria and, therefore, elevated glucose levels.
There are multiple researches linked with n-3 and adipokines, and research recorded an elevation of adiponectin by n-3 fatty acids supplements of eight weeks. According to Mejia-Montilla, when patients with PCOS were given n-3 FA for twelve weeks, elevated adiponectin levels were seen. In addition to that, research was followed in PCOS patients, who were given