Beyond Metformin: Emerging Insulin Sensitizers, Combination Therapies, and Clinical Perspectives in Polycystic Ovary Syndrome.

With a prevalence of between 4–12%, polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine illnesses affecting women of reproductive age. Amenorrhea, hirsutism, infertility, and enlarged polycystic ovaries were the hallmarks of Stein-Leventhal syndrome, which was originally identified in 1935^[3]. The name PCOS is currently recommended since it reflects both ovarian and systemic metabolic involvement rather than being a disease exclusive to the ovaries, as knowledge of this condition has grown over time. It is now known that PCOS is a complex condition that includes problems related to both metabolism and reproduction. PCOS is increasingly recognized as a chronic illness with serious metabolic effects in addition to reproductive abnormalities ^[2,5]. Insulin resistance, type 2 diabetes, metabolic syndrome, and cardiovascular illnesses are all more common in women with PCOS ^[6,7]. A key factor in the pathophysiology of PCOS is insulin resistance, which is characterized as a decreased cellular responsiveness to normal insulin levels. This exacerbates the situation by causing compensatory hyperinsulinemia ^[7]. Increased levels of insulin either directly or indirectly boost the production of androgens by lowering sex hormone-binding globulin (SHBG), which raises the levels of free androgens in the blood ^[12,13]. Clinical symptoms like hirsutism, acne, and irregular menstruation are caused by this hyperandrogenism ^[4]. Metformin has long been the only biguanide medication used to treat type 2 diabetes ^[26]. Bailey and Turner (1996) state that metformin lowers blood insulin levels by increasing peripheral tissue's sensitivity to insulin thereby improving metabolic and reproductive outcomes in PCOS ^[26]. PCOS is largely caused by insulin resistance (IR) and hyperinsulinemia, or elevated insulin levels. One of the main characteristics of this disorder is the increased synthesis of androgens, or male hormones, which is directly associated with them. Research has indicated that when insulin-sensitizing medications are administered to women with PCOS, their insulin levels fall. At the same time, ovarian function improves and androgen levels decrease. The brain-ovary hormonal system (hypothalamus–pituitary–ovary axis) is one significant impact of elevated insulin levels. GnRH and LH hormone secretion can be enhanced by insulin. Consequently, the production of ovarian hormones, particularly androgens, increases when LH levels rise ^[13]. In recent years, several emerging insulin sensitizers have gained attention for their potential role in PCOS management. These include inositol isomers (myo-inositol and D-chiro-inositol), thiazolidinediones (such as pioglitazone), glucagon-like peptide-1 (GLP-1) receptor agonists, sodium–glucose co-transporter-2 (SGLT2) inhibitors, and other novel agents targeting metabolic pathways ^[52]. These agents act through diverse mechanisms, such as enhancing insulin signaling pathways, improving glucose uptake, modulating adipokine release, reducing inflammation, and promoting weight loss. With a focus on their mechanisms of action, clinical advantages, and possible role in enhancing both metabolic and reproductive outcomes, this review attempts to investigate new insulin sensitizers that go beyond metformin in the treatment of PCOS. Additionally, the study aims to highlight these novel medicines' potential for use in individualized PCOS treatment plans and compare them with traditional therapy. The review's objective is to investigate how various insulin sensitizers, aside than metformin, can be used to treat polycystic ovarian syndrome.

• Limitations of Metformin:

Nausea, diarrhoea, gas, bloating, loss of appetite, a metallic taste in the mouth, and abdominal pain are among the major stomach-related adverse effects of metformin ^[28]. Although these symptoms can differ from person to person, they frequently get better on their own over time. Metformin is often begun at a low dose and increased gradually to lessen these negative effects ^[28]. For instance, 500 mg taken once day with a large meal for one to two weeks can be the starting point for treatment. Depending on the patient's tolerance, the dose can thereafter be increased by 500 mg every one to two weeks, up to a daily maximum of about 2500 mg. It is preferable to maintain the same dosage for a while until the body adjusts if adverse effects worsen after raising the dosage. These adverse effects can also be lessened by taking metformin in a slow-release (extended-release) version.
Another crucial aspect is that metformin may cause some people to absorb less vitamin B12, particularly if they take it for an extended period of time, take larger dosages ^[28]. Rarely, metformin may result in lactic acidosis, a potentially fatal illness. However, if the medication is taken as directed and people with illnesses like kidney disease are excluded, this risk is extremely minimal ^[26].

• Pathophysiology of Insulin Resistance:

Samuel and Shulman claim that the buildup of extra fat in non-adipose tissues including the liver and skeletal muscle is the primary cause of insulin resistance ^[8,9]. A sedentary lifestyle, and elevated levels of free fatty acids in the blood are typically the causes of this. These fatty acids are not fully oxidized when they reach cells; instead, they are transformed into lipid intermediates such ceramides and diacylglycerol (DAG), which are important in interfering with the action of insulin ^[8]. A class of enzymes known as protein kinase C (PKC), specifically PKC in muscle and PKC in the liver, is activated by DAG ^[8]. By generating aberrant (serine) phosphorylation of insulin receptor substrate (IRS) proteins rather than the typical tyrosine phosphorylation, these enzymes disrupt normal insulin signaling ^[8,9]. As a result, the downstream insulin signaling cascade including PI3K and Akt is compromised, which lowers insulin's efficacy ^[8].
Ceramides also exacerbate the disease by directly blocking Akt, a crucial protein needed for the uptake and metabolism of glucose. Insulin is unable to carry out its regular tasks effectively as a result of this combined effect ^[9].

Figure 1: Core Mechanism Of Insulin Resistance And Its Metabolic Consequence

This results in decreased GLUT-4 transporter translocation to the cell membrane in skeletal muscle and adipose tissue, which lowers glucose absorption and utilization ^[8]. Insulin is unable to inhibit the liver's synthesis of glucose, which increases gluconeogenesis and the amount of glucose released into the blood ^[9].
Hyperinsulinemia results from the pancreas secreting more insulin in response to rising blood glucose levels. Nevertheless, this does not solve the issue; rather, it feeds a vicious cycle in which elevated insulin levels exacerbate fat buildup and metabolic disorders ^[7]. Therefore, intracellular lipid buildup, which interferes with insulin signaling pathways and results in decreased glucose utilization and increased glucose synthesis, might be considered the primary cause of insulin resistance.

• Chronic low-grade inflammation:

According to Shoelson, a chronic, low-grade inflammatory process that primarily begins in situations like obesity and long-term excess nutrition can account for the development of insulin resistance ^[10]. Adipose (fat) tissue grows when there is an excess of energy consumed. Adipocytes, or fat cells, experience stress and begin to behave differently as they increase. They start releasing pro-inflammatory cytokines like TNF-α and IL-6 instead of just accumulating fat. Adipose tissue also draws immune cells, particularly macrophages. These macrophages build up in the spaces between fat cells, which further boosts the generation of inflammatory mediators ^[10]. As a result, the tissue develops a chronic inflammatory environment.

Figure 2: Obesity-Induced Inflammation And Its Role In Insulin Resistance And Atherosclerosis

Unlike infections, inflammation is low and chronic, yet it nevertheless has a constant impact on metabolic pathways. Adipose tissue releases inflammatory signals that can extend throughout the body to other organs like the liver and skeletal muscle ^[10]. These pathways serve as a conduit between metabolism and inflammation. They disrupt insulin signaling once they are active. Insulin normally attaches to its receptor and tyrosine phosphorylates IRS proteins, activating the PI3K–Akt pathway for glucose absorption and metabolism. However, IRS proteins experience serine phosphorylation rather than tyrosine phosphorylation as a result of JNK and IKK activation, which diminishes their capacity to convey the insulin signal ^[10]. Due to this flaw, GLUT-4 does not go to the cell surface as effectively, which reduces glucose absorption in muscle. More glucose is released into the bloodstream when insulin is unable to inhibit the liver's synthesis of glucose ^[10]. The issue is made worse by the disruption of normal metabolic control of adipose tissue, which may lead to an increase in fat breakdown.
Additionally, Shoelson emphasizes that although these inflammatory pathways are a normal element of the body's defensive mechanism, obesity causes them to become overactive and chronic, which has detrimental metabolic implications ^[10]. In conclusion, immune cell activation and adipose tissue dysfunction-induced chronic inflammation activate the JNK and IKK pathways, which hinder insulin signaling at the IRS level and ultimately result in insulin   resistance.

• Multi-organ Involvement:

According to DeFronzo (2009), type 2 diabetes is caused by several issues occurring simultaneously in various organs rather than a single flaw. It was once referred to as the trio, which had three primary flaws:
1. The pancreas secretes less insulin.
2. The liver produces more glucose.
3. Lower muscular absorption of glucose.
DeFronzo, however, extended this idea to the frightening octet, demonstrating that type 2 diabetes is caused by eight distinct processes ^[11].
First, over time, the beta cells in the pancreas are unable to produce enough insulin. Alpha cells also begin to release more glucagon, which raises blood glucose levels even further. Insulin is unable to inhibit the synthesis of glucose because insulin resistance develops in the liver. Consequently, even when glucose is not required, the liver continues to release it into the blood ^[11].
Insulin resistance causes skeletal muscle to absorb less glucose, which keeps glucose in the circulation rather than being used as fuel.
Increased lipolysis, or the breakdown of fat, occurs in adipose tissue, releasing more free fatty acids into the blood. In other organs, these fatty acids exacerbate insulin resistance ^[11].
Reduced incretin effects (like GLP-1), which often aid in insulin secretion after meals, are another way the gastrointestinal system contributes. The insulin response weakens when this impact is diminished. Increased glucose reabsorption, or the return of more glucose to the circulation rather than its excretion in urine, is one way the kidneys help. Insulin resistance has an impact on metabolism and appetite control in the brain, which exacerbates the imbalance in glucose regulation ^[11]. All things considered, DeFronzo's frightening octet demonstrates that type 2 diabetes is a complex illness affecting numerous organs rather than simply one or two. This knowledge is crucial because it clarifies why therapy should target several pathways rather of just one.

• Hyperinsulinemia and ovarian androgen excess:

Hyperinsulinemia, or elevated insulin levels, is a major factor in the overproduction of androgens by the ovaries in PCOS ^[12,13]. Insulin can affect reproductive function in addition to being a metabolic hormone. Insulin functions similarly to a co-gonadotropin. This indicates that insulin stimulates the ovarian theca cells in conjunction with luteinizing hormone (LH). High insulin levels amplify the effects of LH, increasing the synthesis of androgens like testosterone ^[12].
Additionally, hyperinsulinemia indirectly raises androgen levels. It lowers the liver's production of sex hormone-binding globulin (SHBG). A drop in SHBG causes more free (active) testosterone in the blood since SHBG typically binds to androgens and keeps them inactive ^[13]. Furthermore, insulin may increase the activity of several ovarian enzymes (such as those that produce steroids), which further encourages the synthesis of androgens. Women with PCOS frequently exhibit both high insulin and high androgen levels concurrently due to these combined effects.

Figure 3: Hyperinsulinemia And Ovarian Androgen Excess In Pcos

The study also links this illness to acanthosis nigricans, a skin alteration that some patients experience and is thought to be a clinical indicator of severe insulin resistance and hyperinsulinemia.
Overall, research shows that hyperinsulinemia, which acts both directly on the ovary and indirectly through modifications in hormone-binding proteins, is a significant contributing factor to ovarian androgen excess in PCOS ^[13]. This idea is crucial because it clarifies how insulin-lowering medications, such as metformin, can lower androgen levels and alleviate PCOS symptoms.

• Limitations of Conventional Therapies:

Because it reduces insulin resistance, one of the primary issues with PCOS, metformin is beneficial for the condition ^[7,26,28]. Improved insulin levels can also help lower levels of the male hormone, or androgen, and make periods more regular ^[12,13,26]. As a result, some women particularly those who are overweight or have high blood sugar may also experience improved ovulation and a minor boost in fertility ^[21,27]. Metformin is not, however, the recommended treatment for conditions including weight loss, ovulation induction, or the treatment of symptoms like acne and excessive hair growth ^[1,27]. Physicians typically advise it in conjunction with dietary and exercise modifications, or as a backup plan in certain situations like infertility or glucose intolerance ^[1,21]. According to research, metformin is generally safe during pregnancy and may help lower risks such as preterm delivery, early miscarriage, and excessive weight gain ^[28]. For certain women, it may also lessen the requirement for insulin ^[28]. However, the outcomes are inconsistent for disorders like high blood pressure during pregnancy or gestational diabetes ^[28]. Furthermore, the long-term impacts on children are still unclear ^[28]. The fact that different studies employ various populations, criteria, and techniques is a significant problem in research ^[1,5]. It's not always possible to effectively regulate factors including body weight, lifestyle, other ailments, and drugs ^[5,21]. As a result, outcomes might differ greatly and are occasionally challenging to generalize to all PCOS patients ^[1,5]. Therefore, higher-quality research with appropriate study design and long-term follow-up is required ^[1]. To determine which PCOS patients benefit most from metformin, future research should concentrate on particular patient groups ^[1].
To sum up, metformin helps manage PCOS, particularly with regard to menstrual periods and insulin-related issues ^[26,28]. However, it shouldn't be the primary treatment for every condition ^[1]. More study is required to properly understand its benefits, particularly during pregnancy, and its use should be more focused ^[1,28].

• Emerging Insulin Sensitizers:

1. Inositol

Myo-inositol (MI) and D-chiro-inositol (DCI) in particular have drawn a lot of interest as potential insulin sensitizers for the treatment of polycystic ovarian syndrome (PCOS) ^[33,35,39]. By serving as secondary messengers in insulin signaling pathways, these substances aid in restoring metabolic balance and enhancing insulin sensitivity ^[33,35]. Inositol supplementation has been demonstrated to lower circulating insulin levels, which in turn lowers ovarian androgen production in PCOS, where insulin resistance plays a major role ^[33,36,37].
In the treatment of PCOS, the idea of the ideal ratio of myo-inositol (MI) to D-chiro-inositol (DCI) is crucial ^[33,34]. These two types of inositol are found in a particular ratio in a healthy, normal body. In blood, and particularly in ovarian tissue, the typical physiological ratio is approximately 40:1 (MI:DCI) ^[34]. Because both forms play distinct roles in the body, this balance is essential ^[34,35].
Myo-inositol mostly supports ovarian function. Follicle-stimulating hormone (FSH), which is critical for follicle formation and ovulation, is enhanced by it ^[33,34]. Additionally, it aids in enhancing oocyte (egg) quality, which is crucial for conception ^[36,38]. D-chiro-inositol, on the other hand, aids in lowering insulin resistance and is more engaged in insulin signaling ^[33,35]. This natural equilibrium is upset with PCOS ^[34]. The body turns too much MI into DCI, particularly in the ovaries, as a result of elevated insulin levels ^[34]. Because of this, there is less MI accessible where it is truly needed, which may have a detrimental effect on ovulation and egg quality ^[34,38]. Simultaneously, an excess of DCI in the ovaries may lead to a rise in androgen production, exacerbating symptoms such as irregular periods and infertility ^[33,34].
Therefore, it is not believed to be beneficial to provide DCI alone or in big dosages ^[34,39]. In fact, several studies suggest that high dosages of DCI alone may be detrimental to ovarian function ^[34]. To help restore the body's natural balance, researchers advise a 40:1 ratio of MI to DCI ^[34].
This ratio offers two advantages: DCI reduces insulin resistance, while MI promotes ovarian health and fertility ^[33,34]. When compared to utilizing either MI or DCI alone, numerous clinical trials have demonstrated that this combination improves menstrual regularity, ovulation, and metabolic markers ^[36,37,38]. To put it simply, maintaining the proper ratio is crucial since both forms serve distinct purposes and excessive or insufficient amounts of one can interfere with regular ovarian activity ^[34]. Therefore, the 40:1 ratio is thought to be the best and most widely advised strategy for managing PCOS ^[34,38].
There are still certain restrictions, though, such as inconsistent patient responses, a lack of defined dosage guidelines, and a dearth of long-term evidence ^[38,39]. Furthermore, ovarian function and oocyte quality may be adversely affected by excessive DCI use alone, underscoring the significance of preserving a suitable MI:DCI ratio ^[34]. Overall, there is evidence that Inositol can improve the metabolic and reproductive aspects of PCOS ^[33,38].

2. Thiazolidinediones (Pioglitazone)

One medication in the thiazolidinedione (TZD) class that functions as an insulin sensitizer is pioglitazone ^[29,30]. PPAR-γ (peroxisome proliferator-activated receptor gamma), which is primarily found in adipose tissue, is activated by it ^[29]. By doing this, it increases peripheral tissues like muscle and fat's sensitivity to insulin ^[29,31].
The purpose of the study was to determine the effects of pioglitazone on women with polycystic ovarian syndrome ^[30,32]. In women of reproductive age, PCOS is a prevalent hormonal condition that is mostly linked to insulin resistance, excess androgen (male hormone), and irregular periods ^[2,7]. The goal of the study was to determine whether pioglitazone may help these individuals with their hormonal and metabolic issues (related to insulin and glucose) ^[30,32]. The participants were split into two groups at random as part of the study's randomized, placebo-controlled clinical trial methodology ^[32]. Pioglitazone was administered to one group and a placebo (a dummy medication) to the other. Because it lessens bias and produces more accurate results, this kind of study design is regarded as trustworthy ^[32]. Women with PCOS were the participants, and the treatment was administered over several months while various parameters, including insulin levels, hormone levels, and ovulation patterns, were monitored ^[30,31,32].

Table 1: Clinical Studies Evaluating Pioglitazone In Pcos Management

The study's findings demonstrated that pioglitazone significantly increased insulin sensitivity ^[29,30,32]. To put it simply, the body began reacting to insulin more effectively, which is crucial since one of the primary reasons of PCOS is insulin resistance ^[7]. The levels of circulating insulin dropped as a result of enhanced insulin action, which further assisted in lowering androgen levels ^[12,29]. Many hormonal abnormalities were resolved when androgen levels dropped, which improved ovulation and menstrual regularity in certain patients ^[30,31]. Pioglitazone primarily acts by activating a receptor known as PPAR-gamma (Peroxisome Proliferator-Activated Receptor gamma) ^[29]. This receptor is found in fat cells and is essential for controlling the metabolism of fats and carbohydrates ^[29,31]. Pioglitazone increases tissue sensitivity to insulin, decreases the liver's synthesis of glucose, and enhances fat metabolism when it activates this receptor ^[29]. Because high insulin levels often drive androgen production, this technique indirectly lowers excess androgen production from the ovaries in PCOS patients ^[12,13]. Therefore, pioglitazone helps restore hormonal balance and enhances ovarian function by lowering insulin levels ^[29,30]. Additionally, the study emphasized a number of advantages of pioglitazone for PCOS patients ^[30,31]. It was discovered to considerably reduce insulin resistance, a key underlying issue with PCOS ^[7,21]. Additionally, it assisted in lowering androgen levels, which improved hormonal balance ^[30]. Some patients reported better ovulation and menstrual periods, which may boost their chances of becoming pregnant ^[31]. Long-term health benefits also included changes in metabolic markers like blood glucose levels and cholesterol profiles ^[29,30]. Nevertheless, the study also mentioned a few negative effects of pioglitazone ^[29,32]. Weight increase was one of the most often reported side effects, which can be problematic, particularly for PCOS patients who are already overweight ^[29]. Additionally, some individuals had fluid retention, which could cause edema ^[29]. Owing to these adverse effects, pioglitazone is typically used when other medications, like as metformin, are ineffective or inappropriate rather than as a first-line treatment ^[1,29]. Long-term safety is another issue, therefore close observation is necessary ^[29]. In summary, this study shown that pioglitazone can help PCOS patients with their hormonal and metabolic problems ^[30,32]. It primarily functions by increasing insulin sensitivity, which aids in re establishing ovulation and rectifying hormonal imbalance ^[29,30]. Despite its many advantages, its use is restricted because of adverse consequences like weight gain ^[29]. As a result, it is mostly advised for specific patients under close medical supervision ^[1,29].

3. GLP-1Receptor Agonists

A more recent class of medications called GLP-1 receptor agonists (GLP-1 RAs) is being investigated for its potential impact on reproductive health, particularly in PCOS ^[44,52]. These medications function similarly to the natural hormone GLP-1, which aids in controlling hunger and blood sugar levels ^[44]. They lower glucagon levels, boost insulin production in a glucose-dependent manner, and enhance insulin sensitivity ^[44,52]. They also slow down the emptying of the stomach, which prolongs feelings of fullness and reduces appetite and weight loss ^[40,44]. These treatments indirectly aid in enhancing reproductive function because obesity and insulin resistance are major issues in PCOS ^[2,7,44]. GLP-1 RAs may operate at the ovarian level in addition to their metabolic effects ^[44]. By lowering oxidative stress and inflammation, they are thought to enhance the ovarian environment ^[44]. Additionally, they aid in reducing androgen levels, which are typically high in PCOS ^[41,44]. In addition to promoting improved follicular growth, this decrease in androgens may aid in the restoration of regular ovulation ^[41,44]. Additionally, some research indicates that these medications may affect hormonal balance, improving menstrual regularity ^[41,42]. GLP-1 RAs have demonstrated some beneficial results in IVF and other reproductive therapy settings, particularly in overweight or obese women ^[44]. Pre-treatment use of these medications may enhance ovarian responsiveness to stimulation and oocyte (egg) quality. The likelihood of a successful pregnancy and fertilization may rise as a result. To confirm these effects, more research is necessary because the results are not entirely consistent ^[44]. Significant weight loss, improved insulin resistance, improved glucose control, and decreased testosterone levels are the key advantages of GLP-1 receptor agonists in PCOS ^[40,41,42]. Improved menstrual cycles and, in certain situations, higher ovulation rates can result from these modifications ^[41,42]. They might be especially helpful for patients who don't react well to traditional therapies like metformin ^[40]. However, using them has certain disadvantages. Gastrointestinal side effects, including nausea, vomiting, and appetite loss, are the most frequent ^[40,44]. Additionally, the majority of these medications come in injectable form and are somewhat costly, which may lower patient compliance ^[44]. Another important limitation is the lack of sufficient long-term safety data, especially regarding their use in pregnancy and long-term effects on offspring. The metabolic and reproductive features of PCOS, such as ovulation and fertility outcomes, are generally improved with GLP-1 receptor agonists. However, their use should be selective, and they are not yet considered a first-line treatment. To gain a better understanding of their long-term safety and efficacy in various patient groups, more carefully planned studies are needed ^[1,44].

4. SGLT2 Inhibitors (Empagliflozin and Dapagliflozin)

Because of their impact on insulin levels and metabolism, SGLT2 inhibitors like empagliflozin and dapagliflozin are being investigated as a more recent therapy option for PCOS ^[47,48]. These medications function by inhibiting the kidneys' SGLT2 protein, which is in charge of reabsorbing glucose back into the blood, according to research like Tan S et al. (2022). Urine excretes more glucose when this protein is blocked. Without directly raising insulin secretion, this results in a decrease in blood glucose levels ^[47,48]. The body's insulin levels consequently drop, which is advantageous in PCOS because hyperinsulinemia is a key cause of insulin resistance and increased androgen production ^[7,12,47]. Benefits-wise, SGLT2 inhibitors have demonstrated encouraging outcomes in enhancing metabolic parameters in PCOS-affected patients ^[45,46,47]. They aid in the reduction of body weight, particularly visceral fat, which is strongly associated with insulin resistance ^[45,47]. Additionally, lower insulin levels indirectly aid in lowering androgen levels, which may alleviate symptoms including hirsutism, acne, and irregular periods ^[12,24]. Additionally, some research indicates that general metabolic health and insulin sensitivity have improved. These medications may also have cardiovascular advantages, which is significant as women with PCOS are more likely to experience heart-related issues ^[2,47]. SGLT2 inhibitors do have certain disadvantages, though ^[47,48]. These medications can raise the risk of vaginal and urinary tract infections because they increase the excretion of glucose in the urine. Increased urination may also put you at risk for dehydration ^[47]. Rarely, even at low blood glucose levels, a dangerous condition known as ketoacidosis can develop. Another drawback is that long-term safety and efficacy, particularly in PCOS patients, are not fully demonstrated because the use of SGLT2 inhibitors in PCOS is still relatively new ^[47,48]. In general, SGLT2 inhibitors work primarily by lowering insulin and glucose levels, which improves insulin resistance and may tangentially lessen androgen excess in PCOS. Although the findings are encouraging, further investigation is required to validate their long-term function in PCOS treatment ^[47,48]. Although there is currently no clinical data on the use of SGLT2 inhibitors in PCOS, there are encouraging metabolic advantages. According to a study by Javed et al. (2019), empagliflozin significantly reduced body weight and visceral adiposity in overweight and obese women with PCOS. It also improved metabolic metrics, though androgen levels changed only little ^[45]. In a similar vein, Elkind-Hirsch et al. (2021) examined dapagliflozin as monotherapy and in combination with exenatide in a randomized clinical study. They discovered significant improvements in glucose metabolism and reductions in body weight, with combination therapy demonstrating better efficacy ^[46]. The effect on testosterone levels and reproductive results, however, was less noticeable. The majority of the research that are now available have short durations and limited sample sizes, as noted in the review by Tan S et al. (2022) ^[47]. Consistent results indicate that weight reduction and insulin resistance are more strongly affected than hormonal markers. Overall, these findings imply that SGLT2 inhibitors, which mainly target metabolic dysfunction rather than directly treating hyperandrogenism, may be helpful as an adjuvant therapy for PCOS ^[47,48].

5.Berberine

The study found that berberine's influence on insulin resistance, which is thought to be the primary cause of PCOS in many patients, is its most significant mechanism ^[49,51]. The enzyme AMPK (adenosine monophosphate-activated protein kinase), which is essential for controlling energy and glucose metabolism, is activated by berberine ^[51]. Berberine increases the absorption of glucose by cells, decreases the synthesis of glucose in the liver, and enhances insulin sensitivity by activating AMPK ^[51]. The ovaries produce fewer androgens, or male hormones, when insulin levels drop ^[12,49]. Menstrual regularity is improved and hormonal balance is restored as a result ^[49,50]. The effects of berberine on ovarian function are also explained in the paper. It promotes ovulation and enhances follicular development. Berberine also enhances endometrial receptivity, which may raise the likelihood of a successful pregnancy implantation ^[49]. Its anti-inflammatory and antioxidant properties are another significant mechanism ^[51]. Berberine helps lower oxidative stress and inflammatory indicators, which further enhances metabolic and reproductive health because PCOS is linked to persistent low-grade inflammation ^[10,51]. Berberine may affect gut flora, which indirectly promotes improved metabolism and hormone balance, according to the study ^[51]. According to the study, berberine can considerably improve insulin resistance, lower blood glucose levels, and enhance lipid profiles by decreasing triglycerides and cholesterol ^[49,50]. For certain people, it also aids in lowering body weight and belly fat. Berberine aids in lowering androgen levels, increasing ovulation rate, and controlling menstrual cycles from a reproductive perspective. According to several of the studies that are included in the research, berberine had somewhat fewer negative effects than metformin, a medication that is frequently used to treat PCOS ^[50]. Berberine treatment improved ovulation rate, hormonal profile, and metabolic markers in some clinical trials involving PCOS-affected patients ^[49,50]. Berberine and metformin were compared in certain studies, and both exhibited comparable benefits in hormone levels and insulin sensitivity. Studies on animals that showed enhanced ovarian structure and decreased ovarian cyst formation following berberine therapy provided more evidence for its mechanism ^[51]. However, the majority of studies were brief and had small sample sizes, which weakened the conclusions ^[49,51]. The study lists several disadvantages of berberine in addition to its advantages. Its limited bioavailability, which indicates that the body absorbs very little of the medication, is one of its main drawbacks ^[51]. Mild gastrointestinal side effects, such as nausea, constipation, or diarrhoea, may occur in certain patients. It should be used carefully because there is little information on its long-term safety and impact on pregnancy outcomes ^[49]. Since many studies employ varying dosages and durations, the absence of established dosage and treatment protocols is another problem ^[49,51]. The study concludes that because of its potent effects on insulin resistance and hormonal imbalance, berberine is a viable natural substance for the treatment of PCOS. It has positive impacts on the disease's reproductive and metabolic components ^[49]. However, before it can be widely advised as a regular treatment, additional extensive and prolonged clinical trials are required to prove its safety and efficacy ^[49,51]. Adapted and summarised data from various studies:

Table 2: Comparison Of Insulin Sensitizers And Relates Therapies In Pcos

• Combination Therapies

1. Metformin + Inositol

The theory behind combination therapy with metformin and Inositol (myo-inositol and D-chiro-inositol) is that both medications reduce insulin resistance through distinct but complimentary pathways, potentially improving PCOS outcomes. While Inositol function inside the cell as second messengers in insulin signaling pathways, aiding in the restoration of a normal insulin response, metformin primarily decreases hepatic glucose synthesis and lowers circulating insulin levels ^[33,35]. Improving insulin action at the systemic and cellular levels can help lower androgen production and enhance ovarian function since hyperinsulinemia is a significant source of ovarian androgen excess ^[12,13]. Clinical research backs up this combined strategy. In comparison to either therapy alone, treatment with metformin + myo-inositol improved insulin sensitivity, hormonal balance, and ovulatory function more in a research by Genazzani et al. (2014) ^[36]. Combination therapy patients showed improved menstrual cycle regulation and decreased hyperandrogenic characteristics, indicating a synergistic impact. In a similar vein, Fruzzetti et al. (2017) found that combination therapy improved metabolic indices like insulin and glucose levels, reduced androgen levels, and increased menstrual regularity ^[37]. These results suggest that treating insulin production and insulin signaling together can result in more reliable therapeutic outcomes. Each component's role is further supported by comparative studies. Although their processes are different, the study by Pkhaladze et al. (2016) demonstrated that both metformin and myo-inositol independently alleviate insulin resistance and hormonal imbalance in PCOS ^[26,33]. Given that their effects might be additive, this offers a compelling case for combining them. Inositol supplementation improves ovulation rates, insulin sensitivity, and lowers androgen levels in women with PCOS, according to a mechanistic investigation conducted by Unfer et al. (2017) ^[33]. Additionally, utilizing myo-inositol and D-chiro-inositol at a healthy ratio of 40:1 is crucial for preserving appropriate ovarian function and maximizing therapeutic results, according to Facchinetti et al. (2020) ^[34]. In summary, these research findings indicate that metformin–inositol combination therapy improves intracellular insulin signaling (inositol impact) and lowers circulating insulin levels (metformin effect). By breaking the loop of insulin resistance and hyperandrogenism in PCOS, this dual action improves ovulation, menstrual regularity, and metabolic profile ^[33,36,37]. To completely determine long-term benefits and conventional treatment methods, more large-scale trials are still required, as the majority of research are of moderate size and length.

2. GLP-1 agonists + lifestyle intervention

Due to its effects on improving insulin resistance and reducing weight, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly liraglutide, have been investigated more and more in the treatment of PCOS. These medications reduce hunger, slow stomach emptying, and increase glucose-dependent insulin secretion, all of which result in lower calorie intake and weight loss ^[40,44]. This technique is especially helpful because obesity and insulin resistance are important components of PCOS ^[18,19]. These effects are supported by clinical research.  For instance, Jensterle et al. (2015) demonstrated that liraglutide treatment, either by alone or in conjunction with metformin, significantly reduced body weight and enhanced metabolic parameters in obese women with PCOS ^[40]. Jensterle et al. (2017) found improvements in insulin sensitivity, decreases in visceral fat, and slight improvements in hormonal imbalance ^[41]. In a similar vein, Elkind-Hirsch et al. (2018) showed that women with PCOS who received larger dosages of liraglutide (3 mg) saw significant weight loss and improved glycemic management ^[42]. A key component of managing PCOS is still lifestyle intervention, primarily food and exercise, in addition to medication. Moran et al. (2011) claim that lifestyle changes alone can improve ovulation, insulin resistance, and body weight ^[21]. However, it seems that GLP-1 receptor agonists and lifestyle modifications work better together. According to a study by Nylander et al. (2017), liraglutide plus lifestyle modification improved insulin sensitivity and weight loss more than lifestyle modification alone ^[43]. Similarly, Rasmussen et al. (2014) reported enhanced metabolic outcomes when GLP-1 receptor agonists were used along with dietary and lifestyle advice. According to current guidelines, such as those by Teede et al. (2018), the first-line treatment for PCOS should be lifestyle modification, with GLP-1 receptor agonists being considered as a backup option, particularly for obese patients ^[1]. According to the evidence that is currently available, GLP-1 receptor agonists can effectively improve the metabolic characteristics of PCOS, especially when paired with lifestyle adjustment. Their primary advantages are encouraging weight loss and enhancing insulin sensitivity, both of which tangentially lessen the intensity of PCOS symptoms.

3. Multitarget therapy approach vs monotherapy

The ailment known as polycystic ovarian syndrome (PCOS) is now recognized to be caused by a number of interrelated factors, such as increased androgen production, insulin resistance, and metabolic imbalance, which explains why a single treatment frequently only partially improves the condition ^[5,7]. According to Teede et al. (2018)'s International Evidence-Based Guideline, management should start with lifestyle modification and, if necessary, be complemented with pharmaceutical treatments to target various aspects of the disorder ^[1]. Accordingly, Escobar-Morreale (2018) characterizes PCOS as a disorder with both reproductive and metabolic components, implying that treatments targeting just one pathway could not sufficiently enhance overall results ^[2]. Combination therapy is directly supported by clinical research. According to a research by Jensterle et al. (2015), treating obese women with PCOS with liraglutide plus metformin produced superior metabolic changes and much more weight loss than either medication taken alone ^[40]. This suggests that treating insulin resistance with metformin and appetite management with GLP-1 receptor agonists yields synergistic effects. Similarly, Elkind-Hirsch et al. (2021) showed that dapagliflozin combination therapy produced more noticeable changes in metabolic parameters than monotherapy, especially in terms of glucose management and weight loss ^[46]. This strategy is also supported by data from insulin-sensitizing medications. Metformin and myo-inositol together improved insulin sensitivity, hormonal balance, and ovulatory function more successfully than either medication alone ^[36,37]. These results demonstrate that whereas Inositol improve intracellular insulin signaling, metformin mainly lowers circulating insulin levels, resulting in a more all-encompassing effect when combined ^[33,35]. Further benefits have been demonstrated when pharmaceutical therapy is combined with lifestyle modifications. According to Nylander et al. (2017), liraglutide with lifestyle intervention (diet and activity) improved body weight and insulin sensitivity more than lifestyle adjustment alone ^[43]. This validates the suggestion made by Moran et al. (2011) that while lifestyle modifications are beneficial, they can be further improved when paired with medication ^[21]. Broader metabolic considerations also reinforce the logic for such multi-target techniques. According to DeFronzo (2009), it is unlikely to obtain optimal management by focusing on a single fault because metabolic diseases include several organs and pathways ^[11]. When this idea is applied to PCOS, it becomes easier to understand why combination treatments, which target several processes at once, typically result in superior clinical outcomes.
Overall, research from these studies consistently demonstrates that, as compared to monotherapy, multi-target therapy whether by combining medications or integrating medications with lifestyle modifications offers a more thorough improvement in the metabolic and reproductive aspects of PCOS.

• Personalized medicines in PCOS

1. Phenotype-based treatment (lean vs obese PCOS)

One of the most significant clinical differences between lean and obese women with polycystic ovarian syndrome (PCOS) is that it impacts both the underlying mechanism and the response to treatment. Obesity dramatically exacerbates the metabolic characteristics of PCOS, according to studies. For instance, a significant frequency of central obesity and overweight in PCOS was noted by Lim et al. (2012), which is closely linked to elevated insulin resistance and metabolic risk ^[18]. In a similar vein, Barber et al. (2019) clarified that extra adipose tissue exacerbates the severity of the illness by increasing testosterone production and worsening insulin resistance ^[19].

However, as noted by Panidis et al. (2013), thin women with PCOS typically have less severe metabolic disturbance, albeit they may still have hormonal imbalance and hyperandrogenism ^[20]. According to Dumesic et al. (2015), insulin resistance can exist in both phenotypes, but it is more noticeable in obese people ^[3]. When choosing a course of treatment, these distinctions are crucial. Treatments that target metabolism work better in obese PCOS, where insulin resistance is a significant contributing factor. Moran et al. (2011) showed that in overweight and obese women, lifestyle treatments like diet and exercise greatly improve weight, insulin sensitivity, and reproductive outcomes ^[21]. Additionally, this group responds better to pharmaceutical treatment with insulin sensitizers like metformin. According to Palomba et al. (2008), metformin improves metabolic and reproductive parameters more effectively in obese PCOS patients than in lean people (generalized support from metformin clinical evidence) ^[26,28]. However, treatment for lean PCOS, where insulin resistance is less prevalent, frequently focuses more on hormone management and ovulation induction. Legro et al. (2007) provided support for this, demonstrating the effectiveness of ovulation induction drugs like clomiphene, especially in women without severe metabolic ^[27].

Adapted and summarized from multiple studies and guideline:

Table 3: Lean Vs Obese Pcos: Pathophysiology And Treatment