A SYSTEMATIC REVIEW ON CURRENT TREATMENT OPTIONS FOR INSULIN RESISTANCE IN POLYCYSTIC OVARY SYNDROME

A SYSTEMATIC REVIEW ON CURRENT TREATMENT OPTIONS FOR INSULIN RESISTANCE IN POLYCYSTIC OVARY SYNDROME

B. Dharani * and A. Suba

A. C. S. Medical College and Hospital, Dr. M. G. R. Educational and Research Institute, Chennai, Tamil Nadu, India.

ABSTRACT: Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age. It is characterized by symptoms such as elevated androgen levels, the presence of multiple cysts on the ovaries, irregular or absent ovulation and various metabolic disturbances. Women with PCOS commonly experience metabolic dysfunction, obesity and infertility. They also face a higher risk of pregnancy complications and long-term cardiovascular disease. About 75% of individuals with PCOS have Insulin Resistance (IR). IR can trigger symptoms of PCOS, but hyperandrogenemia related to PCOS can also worsen IR. This review aims to summarize the current treatment options for managing IR in PCOS and to prevent the long-term complications associated with it. Current treatment strategies include lifestyle modifications, which remain foundational for improving metabolic health, alongside pharmacological interventions such as Metformin, Thiazolidinediones, GLP-1 Receptor Agonists (GLP-1 RA) and SGLT-2 (Sodium Glucose Co-transport) inhibitors. These established therapies offer significant benefits in managing IR and associated symptoms. Additionally, Inositol has gained recognition for its role in supporting metabolic and reproductive outcomes. Emerging treatments also show promise, including Alpha-Lipoic Acid (ALA), Probiotics, Green Tea Extracts (GTE), L-Carnitine, Astaxanthin (ASX), Resveratrol, N-Acetylcysteine (NAC), L-Arginine, Berberine, Vitamin D, Omega-3 fatty acid, Chromium and Magnesium. As our understanding of PCOS and IR continues to advance, integrating both current and emerging therapies will be key to improving patient outcomes and quality of life.

Keywords: Polycystic ovary syndrome, PCOS, Insulin resistance, PCOS current treatment, PCOS review, Treatment of Insulin Resistance

INTRODUCTION: Polycystic Ovary Syndrome (PCOS) is a reproductive age disorder affecting women, that is marked by high level of androgen, the existence of multiple cysts on the ovaries, irregular or absent ovulation and various metabolic disturbances ¹. The global prevalence of PCOS is approximately 9.2%, with the highest rate observed in Africa, where it reaches 16.4% ².

Obesity and being overweight are commonly linked with PCOS, with observational studies indicating that 33% to 88% of women with PCOS are affected by these conditions ^{3, 4}. Diagnosis is advised using the 2003 Rotterdam criteria, which require meeting at least any two of this presentation: hyperandrogenism, Polycystic Ovary Morphology (PCOM) and irregular menstrual cycle ⁵.

PCOS is usually accompanied by obesity, metabolic dysfunction and infertility. They are also at risk of developing complications during pregnancy and early cardiovascular disease ^6-11. It greatly affects quality of life and causes Non-Alcoholic Fatty Liver Disease (NAFLD), metabolic diseases and Type 2 Diabetes Mellitus (T2DM) ^12-14. Central obesity is particularly important due to its association with hyperandrogenism and Insulin Resistance (IR) ¹⁵.

The patient frequently has IR and diminished amount of sex hormone-binding globulin (SHBG). SHBG is normally formed by liver, which binds to sex hormones like testosterone and estradiol. When SHBG levels are low, there are higher amounts of free testosterone, leading to hyperandrogenemia. Low SHBG levels are seen as a marker of metabolic abnormalities and are linked to IR because high insulin levels reduce SHBG production in the liver ¹⁶. About 75% of individuals with PCOS have IR ¹⁷. IR can trigger symptoms of PCOS, but hyperandrogenemia related to PCOS can also worsen IR. Women with PCOS are frequently exposed to traditional cardiovascular disease (CVD) risk factors over the long term, as they often exhibit obesity, IR, impaired glucose metabolism, dyslipidemia and elevated Blood Pressure (BP) from a young age or even during adolescence ¹⁸.

This review aims to summarize the current treatment options for managing IR in PCOS and to prevent the long-term complications associated with it.

MATERIAL AND METHODS:

Study Design: This systematic review aimed to evaluate the current treatment options for IR in PCOS. The review was written as per the PRISMA guidelines, to ensure proper methodology and comprehensiveness. All included studies were assessed based on their design, sample size, treatment interventions, outcome measures and quality.

Inclusion and Exclusion Criteria: Studies investigating treatment strategies for IR in PCOS, including pharmacological and non-pharmacological therapies. Studies published in English, Studies that assessed clinical and/or biochemical outcomes of IR in PCOS, such as insulin sensitivity indices, fasting glucose, HbA1c, and lipid profiles were included.

Those studies focusing on PCOS without assessing IR, non-original research articles, such as letters and editorials, studies that did not report specific data on IR outcomes, studies with incomplete data or insufficient information on treatments were excluded.

Search Strategy: A thorough probe of the literature was performed using the electronic databases like PubMed, Cochrane Library, EMBASE and google scholar. The search for the current article was done for studies published from the period of January 2000 and January 2025. The search strategy included the following key terms and their combinations:"Polycystic Ovary Syndrome" or "PCOS", "Insulin resistance" or "IR", "Treatment options" or "Management" or "Therapies", "Pharmacological treatment" or "non-pharmacological treatment", "Metformin", "Insulin sensitizers", "Vitamin D", "Omega-3", "Chromium", "Curcumin".

Relevant articles were screened using the abstracts and the titles. Also, the entire article text was reviewed for potentially eligible studies to ensure compliance with inclusion criteria and exclusion criteria.

Extraction of Data: With the help of standardized form for data extraction, data so collected were extracted independently.

Synthesis and Analysis of Data: The collected data from all the studies, were qualitatively synthesized. The effectiveness of each treatment modality was assessed in terms of improvements in insulin sensitivity, metabolic outcomes and hormonal regulation.

RESULTS & DISCUSSION:

Mechanism of Insulin Resistance (IR) in PCOS: Recent studies have suggested that PCOS is influenced by multiple determinants like environmental changes, epigenetic changes, oxidative stress, genetics, mitochondrial derangement and chronic low-grade inflammation, all of which can disrupt normal ovarian function ^19-26. IR and compensatory hyperinsulinemia are regarded as key factors in the pathophysiology of PCOS. They contribute to the advancement of hyperandrogenemia and subsequent reproductive complications through multiple processes ²⁷. IR is the most common type of PCOS phenotype ²⁸. PCOS is linked to gene mutations especially in the genes that control steroid production, signalling of insulin and development of follicles in ovary. It was also found to affect multiple proteins like activators of LH/HCG receptor, transcription factors, insulin receptors, and cell traffic proteins ^{29, 30}. Further it is complicated by high serine phosphorylation and low tyrosine phosphorylation of insulin receptors, that affect the action of insulin. This results in defective transduction of insulin after binding, thereby contributing to defective action of insulin ³¹.

IR is characterized by reduced sensitivity of target organs such as the liver, skeletal muscle, and adipose tissue to insulin, leading to decreased effectiveness of insulin in facilitating glucose uptake and utilization. To compensate, the body increases insulin production, resulting in hyperinsulinemia to stabilize blood sugar levels. Persistent hyperinsulinemia is a hallmark feature often observed before the onset of PCOS. In 1980, Burghen first suggested that IR act as a crucial component in the formation of PCOS. Later studies confirmed that it is a fundamental initiating factor for the development of PCOS ³². Moreover, factors such as excessive androgens, lipid accumulation, inflammatory cytokines and other systemic elements also contribute to IR in peripheral tissues ³³.

Because of IR, patients with PCOS are at greater risk of developing negative outcome during pregnancy as well as chronic conditions like T2DM, CVD and metabolic syndrome. These related issues add to the social burden for women of childbearing age ^34-38.

FIG. 1: MECHANISM OF INSULIN RESISTANCE IN PCOS

Treatment Options for Insulin Resistance in PCOS: The management of PCOS should consider not just the patient needs but also any associated comorbidities. IR and hyperandrogenism are key characteristics of the syndrome in PCOS individuals ³⁹. IR is a primary focus of treatment along with Combined Oral Contraceptives (COC) ⁴⁰.

Current Treatment Options:

Lifestyle Change: The initial approach to managing IR involves making lifestyle changes, which are fundamental for improving the associated metabolic disorders and endocrine changes in women with PCOS ⁴¹. This is possible by a change in diet and by adopting an exercise regimen ⁴². Exercise enhances insulin sensitivity through its effects on increasing the transport of glucose and thereby enhancing metabolism. This is said to be the prime important aspect of PCOS treatment. Both moderate and high-intensity aerobic exercise are effective in treating IR. The recommended exercise regimen consists of exercising at least 30 minutes per day for around 3 to 5 times a week. Even a single exercise session can boost insulin sensitivity for up to 2-72 hours afterward. Regular exercise not only improves insulin sensitivity and glycemic control but also helps reduce abdominal fat, making it a valuable strategy for managing IR in women with PCOS ⁴³. Research has demonstrated that the Mediterranean diet which focuses on including large quantities of mixed vegetables, seafood, nuts, fruits, and whole grains. It also includes a diet rich in low-carbohydrate that is combined with vegetable oils. This can positively impact menstrual cycles in PCOS patients, especially who are overweight ⁴⁴. Sleep deprivation is linked to a higher risk developing overweight, IR and T2DM in PCOS. Consequently, managing sleep must be included as a component of lifestyle modifications for these women ⁴⁵.

Metformin: Metformin is the one of the commonly used medications because of its proven efficiency in PCOS and safety profile. Its positive effects are becoming more apparent, particularly when used alongside lifestyle changes. Metformin helps address the underlying mechanisms of PCOS, restores function of ovaries and enhances the metabolic status, notably improving the sensitivity of insulin. In contrast to COCs, it positively affects lipid levels ⁴⁶. Recent research on Metformin shows that it decreases the ongoing inflammation in PCOS both directly and indirectly, because of its anti-inflammatory properties. Its effect appears to control the balance of T-cell, as observed in mice ⁴⁷. During Metformin treatment, serum IL-6 levels decreased in conjunction with improvements in IR ⁴⁸.

The typical doses for PCOS studied and prescribed are 500 mg given for three times daily or 850 mg given twice a day. It is usually started at a lower dose to prevent any gastrointestinal discomfort and then its dose is slowly increased to achieve the target dose. Previous study on 360 young patients with PCOS and normal kidney function, showed no instances of developing lactic acidosis ⁴⁹.

Thiazolidinediones: Thiazolidinediones (TZD) are known as an effective sensitizer of insulin. TZDs can serve as an alternative treatment for metabolic and reproductive issues related to PCOS who either doesn’t tolerate Metformin or shows poor response to it ^50-52. The TZDs such as Rosiglitazone and Rosiglitazone were linked to notable increases in the BMI when compared in studies to placebo or Metformin. Pioglitazone notably lowered fasting levels of insulin and triglycerides when evaluated against a placebo. Rosiglitazone, was found to decrease LH levels when evaluated against Metformin ⁵³. Moreover, they help regulate menstrual cycle irregularities, stimulate the ovulation process and lower the level of androgen PCOS ^{54, 55}. But, clinically its use is limited because of several known side effects like peripheral edema, weight gain and heart failure ⁵⁶.

Glucagon like Peptide-1 Receptor Agonist (GLP-1 RA): GLP-1, a type of in cretin hormone, can promote release of insulin as a response to levels of glucose. GLP-1 receptor agonist mimics this effect, as they also attach to the GLP-1 receptor and stimulate the secretion of insulin from islets of pancreas in a way of glucose-dependent manner. Besides this primary action, GLP-1 analogues help slow down gastric transit and reduce secretion of the hormone glucagon from alpha cells of pancreas ⁵⁷.

In a randomized trial, PCOS patients with obesity, who was treated with the drug Metformin were given either Liraglutide at a dose of 1.2mg daily or Metformin at a dose of 1000mg twice daily. The results showed that Liraglutide led to greater reductions in BMI, with a decrease of 1.1 ± 1.26 kg/m² compared to Metformin. Additionally, Liraglutide was found to decrease the area of visceral adipose tissue ⁵⁸.

In a study, on 72 PCOS patients with overweight were given with either 1.8 mg per day of Liraglutide or a placebo over a period of 26 weeks. The results indicated that the drug Liraglutide significantly decreased body weight, liver fat, visceral adipose tissueand free testosterone levels ⁵⁹.

Liraglutide treatment, which was associated with weight loss, significantly reduced levels of Procollagen type 3 amino-terminal Peptide (PIIINP). This peptide is said to be an indicator of cirrhosis of liver, especially in obese patients with PCOS. This finding adds a new dimension to the evaluation of Liraglutide's use in women with PCOS, obesity and NAFLD ⁶⁰. GLP-1 RAs have shown a great reduction in fasting blood glucose, IR, total cholesterol and triglycerides level. In a clinical trial involving 150 patients with PCOS who had impaired glucose and fasting tolerance, it was found that 32% had remission of prediabetes with Metformin, 56 % had remission with Exenatide alone and around 64% had remission by using combined treatment ⁶¹. Combining GLP-1 RA with Metformin appears to be more effective than using either medication alone ^{62, 63}.

Inositol: As insulin sensitizers, Inositol was found to enhance both metabolic and endocrine parameters of PCOS. Previous studies have proven its benefits by improving hyperandrogenic parameter in PCOS. The two most common forms of inositol in humans are D-chiro-inositol (DCI) and Myo-inositol (MYO), which are primarily obtained from dietary sources. MYO was converted into its another form DCI in the presence of an enzyme called epimerase, which is stimulated by insulin. This conversion helps regulate the DCI/MYO ratio across different organs and tissues, that are involved in mediated various processes in body like remodelling of cytoskeleton, developmental mechanism, permeability of ion channel, signal transduction in endocrine process and stress mechanism.

Research has confirmed that MYO and DCI are known as insulin sensitizers mediating oxidative balance and enhancing metabolic role ⁶⁴. MYO is involved in enhancing the FSH signalling by acting as a second messenger in ovaries. Thereby, it controls the process of ovulation and menstrual cycle. As a result, it improves the production and quality of oocyte. Also, it was found that taking DCI supplementation without MYO can lead to increased insulin dependent androgen production, causing poor fertility outcome in PCOS.

Combining DCI and MYO in a ratio of 1:40 closely resembles the normal ratio found in plasma of a women. It was proven to benefit IR in PCOS, as it enhances the metabolic parameter and function of ovary ⁶⁵. Additionally, combining this with COC or Metformin exerts a synergistic effect and thereby decrease the potential side effects ⁶⁶.

Sodium-Glucose Co-transporter 2 Inhibitors: Sodium-Glucose co-transporter 2 inhibitors (SGLT-2 Inhibitors) act by attaching to SGLT-2 receptors which are found in the proximal convoluted tubule of the kidney, thereby inhibiting the reabsorption of glucose and sodium.

This results in lower blood glucose levels, increased glucose in the urine (glucosuria) and enhanced sodium excretion (natriuresis), which helps reduce BP. They promote glucose excretion at a rate of 60-80 grams per day, leading to an average weight loss of around 1.7 kg in a person. The effectiveness of SGLT-2 inhibitors is independent of IR, beta-cell function and insulin secretion. Additionally, it further lower levels of blood glucose by enhancing sensitivity of insulin, boosting uptake of glucose in muscles, reducing gluconeogenesis process in the liver and enhancing the initial stage of insulin release from the beta-cells of pancreas ^{67, 68}. Research indicates that SGLT-2 inhibitors may help preserve function of beta cell indirectly by decreasing insulin secretion while enhancing glucagon release. This process contributes to increased lipolysis and reduced fat in the liver and visceral adipose tissue ⁶⁹.

TABLE 1: CURRENT TREATMENT OPTIONS FOR INSULIN RESISTANCE IN PCOS

Emerging Treatment Options:

Alpha-Lipoic Acid: Alpha-lipoic acid (ALA) is a known biological compound having strong antioxidant properties, found in various vegetables like spinach, broccoli and potatoes, as well as in red and organ meats such as the liver and heart.

Genazzani et al. administered 400 mg/day of ALA to obese women with PCOS for 12 weeks and observed significant improvements in several parameters, including insulin levels, glucose level, BMI, insulin response to OGTT, the HOMA index and maximal insulin response ⁷⁰. It reduces IR and oxidative damage in PCOS.

Probiotics: Numerous studies have found the association between PCOS and alterations in gut microbiota. Studies have shown a notable difference in gut microbiome composition between patients with PCOS and healthy individuals ⁷¹. For instance, Singh et al. found that diets high in proteins of animal origin were linked to increased levels of Alistipes, Bacteroides and Bilophila, along with decreased amount of Bifidobacterium adolescentis, a microbiota that was associated with a higher risk of developing cardiovascular disease ⁷². PCOS is a state of inflammation contributing to dysfunction of pancreatic beta-cell, IR and process of atherogenesis.

It was found that a 12-week regimen combining a mixture of probiotic consisting of Lactobacillus reuteri, Lactobacillus acidophilus, Bifidobacterium bifidum and Lactobacillus fermentum with a daily supplementation selenium in a dose of 200 mg leads to improvements in serum total testosterone levels, hs-CRP, hirsutism, total antioxidant capacity, mental health and malondialdehyde levels ⁷³.

Green Tea Extracts: Studies on Green Tea Extracts (GTE) have shown that IR can be improved through increased representation of glucose transporter 4 (GLUT-4) in adipocytes ⁷⁴. GTE enhances both basal and insulin mediated uptake of glucose in adipocytes, thereby decreasing glucose absorption in the small intestine ⁷⁵. It was found to decrease insulin resistance in obese and overweight women with PCOS following GTE consumption. Tehrani et al. demonstrated that a daily supplementation in a dose of 500 mg for 3 months reduced fasting insulin, blood glucose and free testosterone levels in overweight PCOS patients ⁷⁶. Similarly, Allahdadian et al. found that GTE when given for 3 months significantly reduced serum insulin and FBS levels.

It is important to recognize that while green tea has beneficial effects, over consumption may lead to adverse effect. It was found that the effect of green tea catechins might differ among individuals. For example, Epigallocatechin Gallate (EGCG) may act as cytotoxic and frequent intake of green tea leads to acute cytotoxicity in liver cells. Additionally, another research has shown that EGCG can act as a pro-oxidant in pancreatic beta cell. Consequently, patients should be cautioned against excessive and unregulated use of green tea, particularly its extracts ^{77, 78}.

L-Carnitine: Carnitines are quaternary amines that can be either ingested through intake or produced in the body. It functions as vitamin like compounds and exist in two forms which are L-carnitine, the important active form needed for cellular energy production and D-carnitine, which is inactive and might be toxic. Previous studies have found that L-carnitine can lower levels of insulin and enhance serum adiponectin levels. Treatment with L-carnitine was associated with a reduction in HOMA-IR, as well as notable improvements in testosterone, FSH, and LH levels ⁷⁹. However, a clinical trial of 12-week found that L-carnitine had no significant impact onlipid profile and SHBG ⁸⁰. Additionally, targeting the kisspeptin and neurokinin B (NKB) pathways may become a promising novel therapy for tackling hyperandrogenic symptoms of PCOS ⁸¹.

Astaxanthin: Astaxanthin (ASX) is a known carotenoid that is found naturally numerous seafood and microorganisms. Previous studies have found that ASX when consumed for 8 weeks has resulted in decrease of HOMA-IR, Fasting blood glucose, FI, LDL, MDA, and TC/HDL-C. Conversely, it has prominently elevated HDL-C, TAC and QUICKI ⁸². On the other hand, ASX lowered serum levels of pro-inflammatory markers, including IL-18, IL-6, TNF-α and CRP, in patients with PCOS ⁸³. Multiple studies have explored various therapeutic approaches that show promise in alleviating symptoms associated with PCOS, such as infertility, menstrual cycle irregularity, BMI, IR and hirsutism ^{84, 85}.

Resveratrol: Resveratrol is a natural polyphenol found in various fruits, including grape skins, peanuts and red wine, as well as in several plant-based medicinal sources ^{86, 87}. In a study, the effect of Resveratrol in a dose of 800 mg/day for around 40 days on the levels of serum inflammatory markers in PCOS was determined ⁸⁸. The treatment led to reductions in serum levels of IL-6, IL-1beta, TNF-alpha, IL-1beta, IL-18, CRP and NFkB. Another study by Ghowsi et al.  investigated the effects of Resveratrol when injected intraperitoneally at a dose of 10 mg/kg in PCOS-induced Wistar rats, which exhibited enhanced peroxidation of lipid and IR ⁸⁹. Resveratrol improved these conditions and the levels of two inflammatory markers in adipocytes were found to be significantly reduced in the PCOS rats treated with Resveratrol compared to untreated ones. These markers were like those in control rats, indicating that Resveratrol treatment potentially normalized inflammatory marker levels and reduced inflammation associated with PCOS. A study indicated that Resveratrol supplementation could be beneficial in managing PCOS-related symptoms by decreasing IR, improving dyslipidemia, enhancing morphology of ovaries and anthropometric measurements, controlling hormones of reproductive system, reducing inflammation and related oxidative stress through various biological pathways. This evidence suggests that Resveratrol may help alleviate PCOS complications ⁹⁰.

N-Acetyl Cysteine & L-Arginine: N-acetyl-L-cysteine (NAC) is widely prescribed as a mucolytic drug and to treat toxicity of acetaminophen. At greater doses, it boosts the reduced glutathione (GSH) at cellular levels and neutralizes formed free radicals such as superoxide and hydrogen peroxide, functioning as an essential antioxidant. Arginine serves as the substrate for Nitric Oxide Synthase (NOS) during the synthesis of Nitric Oxide (NO). Masha et al. showed that administering N-Acetyl Cysteine at a dose of 1200 mg and L-Arginine at a dose of 1600 mg for a period of six months has resulted in an increased frequency of menstrual cycles and improved insulin sensitivity, as evidenced by a reduced HOMA index in PCOS. These findings further prove the hypothesis that L-Arginine and NAC enhance ovarian function by increasing nitric oxide (NO) availability ⁹¹.

Berberine: Berberine was known as an isoquinoline alkaloid found in various herbal products, has a history of been used in Chinese and Ayurvedic medicine. It is recognized for its strong antimicrobial properties, effective against fungi, bacteria, protozoa, helminths, virusesand chlamydia. In women with PCOS, berberine can influence various metabolic factors by reducing IR and increasing the active phosphorylation of insulin receptors and alsoinsulin receptor substrate-1 (IRS1) in adipocytes ⁹².

Chromium: Chromium plays a role in fat and carbohydrate metabolism and has been found to improve IR in PCOS by enhancing insulin receptor expression and activating proteins like Akt and GLUT4, which are involved in insulin signaling. It also exerts anti-inflammatory effects, improving insulin sensitivity. Studies have shown that chromium can help with weight management and reduce androgen levels in PCOS patients. It is been commonly administered in form of chromium polynicotinate and chromium picolinate.

While generally considered safe, high doses may cause gastrointestinal side effects. Hence, it should be used as a complementary therapy ^93-96.

Omega-3 Fatty Acids: Omega-3 fatty acids used as supplementation are DHA and EPA, have shown favorable effects in treating IR in PCOS by exhibiting anti-inflammatory properties, enhancing insulin receptor signaling and improving lipid profiles. Studies have indicated that they can enhance insulin sensitivity and reduce androgen levels. They are commonly administered in the form of Fish oil supplements. At high doses, they may result in gastrointestinal side effects ^97-101.

Vitamin D: Vitamin D is a crucial vitamin needed for immune health and bone density and has proven benefits in improving insulin sensitivity in patients with PCOS. It works by helping maintain calcium homeostasis and exhibiting anti-inflammatory effects. Studies have observed that administering vitamin D has resulted in decreased androgen levels and thereby attenuates IR in PCOS. The most used vitamin D forms are Vitamin D2 (ergocalciferol) and Vitamin D3 (cholecalciferol). While generally safe, high doses may lead to hypercalcemia and interactions with medications like calcium channel blockers and thiazide diuretics ^102-107.

Curcumin: Curcumin, derived from turmeric, is known for its anti-inflammatory and antioxidant properties. In PCOS, it has been found to decrease androgen levels and improve insulin sensitivity. Common forms of curcumin used in supplements include curcuminoids and curcumin phytosome, the latter improving bioavailability. They might cause mild gastrointestinal side effects in some patients ^108-113.

Magnesium: Magnesium is involved in insulin signalling and glucose metabolism. It helps improve pancreatic beta-cell function, modulate inflammation and regulate insulin tyrosine kinase activity. It was found that administering Magnesium as supplements might enhance insulin sensitivity in PCOS. The most used Magnesium forms are Magnesium citrate and Magnesium oxide, with the latter being better absorbed. At higher doses, it can lead to diarrhoea ^114-118.

TABLE 2: EMERGING TREATMENT OPTIONS FOR INSULIN RESISTANCE IN PCOS

Future Direction to Treat IR in PCOS: The future strategies for treatment option of IR in PCOS must focus on personalized medicine to be tailored for individual needs. A combination therapy in the form of combination pill must be used widely to improve compliance. Stem cell therapy can play a role in cure of this condition in future. Use of AI in integrating nutrition and exercise with routine treatment can play a significant role. Continued research into the genetic, metabolic, hormonal, and inflammatory pathways will offer exciting opportunities for improving treatment outcomes and addressing the root causes of insulin resistance in PCOS.

CONCLUSION: In conclusion, the management of IR in PCOS has evolved with a diverse array of treatment options, reflecting the complexity of this condition. The current treatment strategies include lifestyle modifications, which remain foundational for improving metabolic health, alongside pharmacological interventions such as Metformin, TZD, GLP-1 RA and SGLT2 inhibitors. These established therapies offer significant benefits in managing insulin resistance and associated symptoms. Additionally, Inositol has gained recognition for its role in supporting metabolic and reproductive outcomes.

Emerging treatments also show promise, including ALA, Probiotics, GTE, L-Carnitine, ASX, Resveratrol, NAC, L-Arginine, Berberine, Chromium, Vitamin D, Omege-3 Fatty Acid, Curcumin and Magnesium. While these options are still under investigation, preliminary findings suggest they may provide additional benefits by targeting IR and enhancing overall metabolic function.

The combination of well-established and emerging therapies offers a comprehensive approach to managing insulin resistance in PCOS. Future research will be crucial in combining these emerging treatments and optimizing personalized treatment plans. As our understanding of PCOS and IR continues to advance, integrating both current and novel therapies will be crucial in enhancing quality of life.

Author Contribution: In this review paper, the author contribution is crucial in compiling an extensive overview of current research and applications related to treatment options for insulin resistance in T2DM. The author has carefully examined and analysed a wide range of scientific literature, offering a thorough evaluation of both current and investigational treatment options available. By systematically assessing recent developments and ongoing discussions in the field, the authors have created a detailed narrative that underscores both well-established knowledge and emerging trends. Additionally, the author has reviewed and approved the final manuscript.

ACKNOWLEDGEMENT: I would like to express my sincere gratitude to all those who have supported me throughout the preparation of this systematic review on the current treatment options for insulin resistance in Polycystic Ovary Syndrome (PCOS). I would like to thank the researchers, clinicians, and experts whose valuable studies and publications have significantly contributed to the foundation of this review. Their work has deepened the understanding of insulin resistance in PCOS and the available treatment strategies. A special thank you to my peers and mentors for their constructive feedback, encouragement, and support during the research process. Their insights have greatly enhanced the quality of this work.

Finally, I would like to acknowledge the unwavering support of my family and loved ones. Their patience, understanding and encouragement have been essential throughout this endeavor. This work is dedicated to the women living with PCOS, with the hope that it contributes to improved treatment options and better management of the condition.

Funding: No financial support, grants, or other assistance was obtained.

Human and Animal Rights and Informed Consent: This article does not include any research involving human or animal subjects conducted by the author.

CONFLICTS OF INTEREST: The author declares no conflicts of interest.

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     Dharani B and Suba A: A systematic review on current treatment options for insulin resistance in polycystic ovary syndrome. Int J Pharm Sci & Res 2025; 16(7): 1774-88. doi: 10.13040/IJPSR.0975-8232.16(7).1774-88.

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