Polycystic ovarian syndrome a risk factor for non-communicable diseases: insights into recent research and prevention approaches

Abstract

Polycystic Ovarian Syndrome (PCOS) is a prevalent and complex endocrine disorder affecting 8–13% of women of reproductive age worldwide. It manifests as a spectrum of clinical symptoms, including irregular menstrual cycles, acne, hirsutism, hyperandrogenism, infertility, ovarian cysts, obesity, and metabolic dysfunction. Women with PCOS are at a significantly higher risk of developing chronic conditions, such as insulin resistance, gestational diabetes, endometrial cancer, cardiovascular diseases, hypertension, and infertility. The etiology of PCOS is multifactorial, with unhealthy dietary patterns, environmental factors, genetic predispositions, and hormonal imbalances being recognized as critical contributors to its pathogenesis. This review provides a comprehensive examination of the intricate association between PCOS and non-communicable diseases, including dyslipidemia, depression, obesity, cardiovascular disease, insulin resistance, hypertension, nonalcoholic fatty liver disease, and diabetes. It also explored the underlying mechanisms linking these conditions to PCOS, offering a detailed perspective on the systemic impact of the disorder. Furthermore, we discuss recent advancements in PCOS management, highlighting the role of lifestyle modifications in dietary interventions and emerging therapeutic strategies. By integrating these insights, this review aimed to provide a holistic understanding of PCOS and its management to improve clinical outcomes and enhance the quality of life of affected individuals.

Highlights

• Association of PCOS with non-communicable diseases have been discussed.

• Dietary factors contributing to PCOS have been elaborated.

• Dietary factors triggering the syndrome has been elucidated.

• PCOS management with Lifestyle and dietary interventions have been explored.

Introduction

Polycystic Ovarian Syndrome (PCOS) is among the widely reported endocrine disorders across all races of women of reproductive age group (RAG) around the globe in recent years. The syndrome is characterized by various clinical features, including hormonal imbalances, ovarian dysfunction, and disturbed metabolic functions [1]. In addition, irregular menstrual cycles, elevated androgen levels, and ovarian cystic degeneration are among the significant symptoms of the syndrome, which collectively impair ovulation and cause infertility [2].

Extensive research on POCS contributing factors highlighted obesity, elevated testosterone levels, fasting insulin levels, reduced sex hormone-binding globulin (SHBG), menopausal timing, and depression as the main contributors [3]. Furthermore, studies have also revealed that females with PCOS have a 2.7-fold increased risk of developing endometrial cancer [4]. These issues affect the psychological and metabolic pathways in women with PCOS [5]. Globally, up to 70% of women with PCOS remain undiagnosed, with the syndrome affecting 8–13% of females worldwide (WHO, 2023). The prevalence of PCOS in the Middle East and North Africa has increased drastically over the last three decades, reaching 37.9% in recent estimations [6, 7]. The association of PCOS with insulin resistance, genetic predisposition, and hormonal dysregulation has also been reported [8, 9].

Moreover, some studies have highlighted oxidative stress (OS) as a key contributor to PCOS pathophysiology. OS results from an imbalance in producing and removing reactive oxygen species (ROS) and reactive nitrogen species. OS can cause cellular and DNA damage, and women with PCOS exhibit higher OS levels than healthy women [10, 11]. Bisphenol-A (BPA) and phthalates are among the 800 environmental endocrine disruptors that lead to PCOS [12]. BPA is used in plastic bottles and food containers, and numerous investigations (14 out of 16 studies) have established a direct correlation between BPA exposure and PCOS in several countries [13]. A human-based study reported Increased BPA levels in diabetic women with PCOS [12]. Likewise, phthalates, such as diethylhexyl phthalate (DEHP), benzyl butyl phthalate (BBP), di-n-butyl phthalate (DBP), and di-isononyl phthalate (DiNP) are used as plasticizers and building materials. The leading widespread human exposure to toxins harms reproductive health in both males and females (particularly affecting ovarian function and contributing to PCOS-like symptoms) [14]. The European Union has classified these compounds as reproductive toxicants [15].

In addition to environmental factors, some contributors to PCOS are also formed through dietary intake. For instance, advanced glycation end products (AGEs) are highly reactive molecules produced by dietary intake and are by-products of metabolic pathways, causing the pathology of PCOS [16]. High-fat foods can elevate AGE production, whereas a diet low in AGEs can improve nutrient absorption by the body. AGEs have a direct correlation with serum testosterone levels and are associated with an increased risk of cardiovascular disease (CVD) in women with PCOS compared to healthy women. Additionally, obese women with PCOS are more likely to synthesize AGEs owing to higher fat deposition in their bodies [17]. Likewise, consuming processed foods, irregular sleep patterns, and an inactive lifestyle exacerbate the disease [18, 19]. Women with PCOS are vitamin D deficient, with prevalence rates ranging from 67 to 85% [20].

In recent years, significant efforts have been made to explore various aspects of PCOS, including advancements in diagnostic criteria for PCOS [21], the role of insulin resistance, and elevated androgen levels under these conditions [22]. A few studies have also examined the potential link between PCOS and artificial intelligence applications [23] and the preventive role of vitamin D in managing the syndrome [24]. Additionally, researchers have investigated the etiology, genetics, and immunology of PCOS [25].

Despite these efforts, no review papers have focused on understanding the relationship between PCOS and non-communicable diseases (NCDs). This study highlights the intricate associations between the syndrome and obesity, CVDs, hypertension, nonalcoholic fatty liver disease, dyslipidemia, depression, and diabetes. This study also elucidates the mechanisms linking PCOS to these conditions and underscores the need for enhanced therapeutic strategies.

PCOS etiology

PCOS is linked to androgen secretion, with studies indicating that environmental, metabolic, and lifestyle factors may disrupt metabolic pathways regulating androgen levels [26]. PCOS often leads to obesity, which contributes to comorbidities, such as CVDs, hypertension, menstrual irregularities, and infertility (Fig. 1). According to the World Health Organization, 43% of adults aged 18 years and above are overweight, and 16% are obese (WHO, 2022). Similarly, insulin resistance, abdominal fat accumulation, and hyperandrogenism are significant contributors to PCOS. Approximately 80% of obese women with PCOS exhibit insulin resistance and elevated insulin levels, compared to 30–40% of lean women [22]. Moreover, Asian women have a higher predisposition to insulin resistance than their European counterparts [27]. Women with PCOS are highly susceptible to myocardial infarction, hypertension, diabetes mellitus, elevated serum LDL and triglyceride levels, and inflammatory markers. The incidence of ischemic heart disease and mental health disorders, such as depression and anxiety, is higher in patients with PCOS [2, 28]. Depression and anxiety rates among PCOS patients are documented at 56.9% and 61.8% in Pakistan, respectively, which are much higher than the global average, indicating higher chances of PCOS and associated health issues [28].

Fig. 1.

Association of PCOS with other ailments

A healthy gut microbial population and diversity aids in proper metabolism. However, inflammation in the gut contributes to serious health issues such as PCOS (due to endotoxins) in females. Furthermore, imbalances in the gut microbiome interrupt energy production, detoxification, and vitamin synthesis [29, 30]. Lower alpha and beta diversities in obese females with PCOS and a lower population of beneficial bacteria (Ruminococcaceae and Clostridium) have been documented. In contrast, Proteobacteria, Salmonella, and Lactobacillus concentrations increase, leading to gut inflammation and consequences in PCOS [30]. Moreover, investigation of Bacteroidetes showed its association with luteinizing hormone and thyroid-stimulating hormone; both were at lower concentrations in stool samples of PCOS patients [31].

Studies on granulosa cells have shown that increased testosterone levels are associated with increased production and accumulation of AGEs by inducing endoplasmic reticulum stress. The process contributes to PCOS pathology [32]. However, the effects of dietary interventions on AGEs in PCOS females revealed that those adhering to a low AGEs diet exhibited reduced levels of serum AGEs, testosterone, oxidative stress, and insulin compared to women following a high-AGE diet [33]. Moreover, the production of ROS is triggered by the interaction between AGEs and their receptor RAGE, which enhances the production of pro-inflammatory markers (tumour necrosis factor). Increased concentrations of these markers have been reported in women with PCOS [34]. Additionally, the excessive production of ROS creates a vicious cycle that further exacerbates inflammation and oxidative stress, contributing to the syndrome [10, 11].

Likewise, endocrine-disturbing BPA and phthalates are reported to exhibit estrogenic activity by binding to estrogen and androgen receptors. Such an attachment may interfere with healthy biological endocrine function directly or through its derivatives [35]. A study estimated higher values for both environmental toxins in 62 girls (12–18 years of age) with PCOS [36]. Another study found that the association of phthalates (DEHP) with insulin resistance and dyslipidemia suggests a direct or indirect effect on energy metabolism. This association was stronger in the PCOS group than in the control group. Interestingly, after adjusting for BMI in the PCOS group, the correlations of both DEHP and MEHP with insulin resistance indices and serum triglycerides remained significant [37, 38]. The association between other environmental pollutants and PCOS is shown in Fig. 2.

Fig. 2.

Association of environmental pollutant with PCOS

Furthermore, females with chronic kidney disease (CKD) are also associated with PCOS. A report by [39] confirmed that a reduced glomerular filtration rate of < 60 mL/min for > three months, with proteinuria, shows a significant correlation with PCOS. Moreover, increased androgen levels (in PCOS patients) contribute to upper urinary tract infections, increased urinary citrate and sodium excretion, and renal tubular injury. Elevated serum testosterone levels in PCOS patients are also linked to fibrotic changes in renal tubular cells [40, 41].

Common symptoms and diagnostic methods of PCOS

PCOS affects approximately 40% of RAG, disrupting normal metabolic function, reproductive health, and psychological well-being [42]. Extensive studies on PCOS have shown several symptoms, such as absent or irregular periods, infertility, obesity, and oligomenorrhea (infrequent menstruation) [6]. Moreover, ovarian cysts (typically 8 −10 mm in diameter), abdominal fat deposits, acne, hair loss, hirsutism (excess hair growth), and voice deepening are other observed indicators. Typically, the menstrual cycle is regulated by gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormones (FSH). In PCOS, increased androgen and prolactin levels and impaired ovulation occur due to abnormal GnRH secretion, resulting in the syndrome arises [43]. Another notable feature of PCOS is hyperandrogenism, which can be observed through increased testosterone concentrations. This hormonal imbalance leads to sleep apnea, mood swings, ovarian cysts, and other significant symptoms of PCOS, affecting ovulation [44].

The presence of ovarian cysts was the first diagnostic criterion set by the National Institutes of Health in the United States. The European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine established the Rotterdam diagnostic criteria. These collective efforts enable more comprehensive insights into PCOS diagnosis [45]. According to the Rotterdam criteria, PCOS diagnosis requires at least two of the following three features: hyperandrogenism (clinical or biochemical signs of elevated androgen levels), irregular menstrual cycles (anovulation or oligo-ovulation) or PCO morphology observed on ultrasound analysis [45, 46].

Based on the presence of these diagnostic criteria, four distinct PCOS phenotypes were identified. Phenotype A is the first type characterized by hyperandrogenism, ovulatory dysfunction, and PCO morphology. Phenotype B involves hyperandrogenism and ovulatory dysfunction, whereas Phenotype C involves hyperandrogenism and PCO morphology. Finally, Phenotype D involves ovulatory dysfunction and PCO morphology. Various proposed methods for classifying PCOS show the syndrome’s complexity, thereby requiring a healthy diet and a modified lifestyle for its prevention [26, 47]. Among the various classification systems, the EGOI-PCOS scientific society stands out for incorporating insulin resistance as a diagnostic criterion, recognizing its pivotal role in developing hyperandrogenic phenotypes. For this reason, the EGOI-PCOS proposes to distinguish hyperandrogenic patients (previously classified as phenotypes A, B and C) into three subtypes of endocrine-metabolic syndrome: type 1, 2, and 3, while redefining non-hyperandrogenic patients, the phenotype D, as true PCOS without metabolic alteration. So, rather than being driven by systemic insulin resistance or hyperinsulinemia, phenotype D may result from intrinsic ovarian dysfunction of ovaries or abnormalities in folliculogenesis. Notably, high IGF-1 (insulin-like growth factor 1) levels lead to the arrest of follicle maturation, as shown by Dai, Zhang [48]. Therefore, high IGF-1 levels may be a potential underlying cause of phenotype D [49–52].

Global prevalence of PCOS

Four different diagnostic approaches have been used to determine the prevalence of PCOS worldwide. Among them, the National Institutes of Health diagnostic method showed 5.5%, Advanced Encryption presented 7.1%, and the self-reported subgroup recorded an 11% prevalence rate. A study showed that African females had the highest prevalence rates of approximately 16.4% compared to other continents [53], whereas caucasian and black races had 4% identified cases. Collaborative work between Oxford University and health care estimated 8% of PCOS patients, with China having 5.6% and India having 9.13% of the patients. The survey also showed that South Asian females had the highest prevalence ratio as compared to Caucasian women, including Pakistani females, where 40% of females were infertile [54].

Moreover, the Rotterdam criteria were applied to 500 women (18–45 years of age) in India, which showed 18.2% PCOS cases. Among the associated symptoms, irregular menstrual periods (79.1%), ovarian cysts (91.2%), metabolic syndrome (28.6%), type 2 diabetes mellitus (15.4%), hypertension (19.8%), depression (18.7%), and anxiety (17.6%) were examined. In addition, 30.8% of women were infertile, whereas only 17.6% received fertility treatment [55].

Another study comprising 560 unmarried women (24 years old) showed the highest PCOS prevalence rate of 74.4% in both developed (28.2%) (America and China) and developing (71.8%) (Pakistan) parts of the world [56].

Furthermore, a cross-sectional study examining PCOS prevalence from 1990 to 2019 demonstrated a significant increase in annual cases from 1.4 million to 2.1 million [29].

Non-communicable diseases and PCOS

PCOS and insulin resistance

In PCOS, consistently elevated gonadotropin-releasing hormone levels increase luteinizing hormone levels while reducing follicle-stimulating hormone levels. These hormonal changes lead to increased androgen production and ovarian dysfunction, which results in PCOS. Elevated androgen levels are strongly associated with insulin resistance and hyperinsulinemia. Indeed, during systemic insulin resistance, the ovaries remain responsive to insulin signaling, a phenomenon known as the “ovarian paradox” [57]. This occurs because insulin receptors are on the theca cell, allowing insulin to stimulate ovarian steroidogenesis and promote testosterone biosynthesis. As a result, hyperinsulinemia can disrupt androgen production, contributing to hormonal imbalances [58]. An increase in androgen levels increases the risk of infertility, CVDs, and endometrial cancer [22, 59].

Studies also indicate that 35–80% of women with PCOS experience insulin resistance, confirmed by blood glucose testing and insulin sensitivity assessments with the hyperinsulinemic euglycemic clamp technique [60, 61]. Additionally, insulin resistance gene variants (rs2059807 and rs1799817) are strongly associated with insulin resistance in women with PCOS. Additionally, the Gly972Arg polymorphism in insulin receptor substrate 1 increases fasting glucose levels and is a risk factor for PCOS development. Women with both PCOS and insulin resistance face an increased risk of type 2 diabetes, cardiovascular disease, metabolic disorders, and adverse pregnancy outcomes [8].

Globally, approximately 17 million women with PCOS experience pregnancy-related complications that negatively affect both maternal and fetal health. These women face an increased risk of miscarriage, gestational hypertension, preeclampsia, and cesarean delivery. Additionally, they often experience increased maternal BMI, while their infants are more likely to have preterm delivery, reduced height and head circumference, and low birth weight [62].

A Tianjin Medical University General Hospital study involved 277 participants (18–44 age), comprising 144 PCOS patients and 133 non-PCOS patients. Women were categorized into the insulin-resistant and non-insulin-resistant groups. The former group demonstrated significantly higher values for BMI, higher ratio of waist-to-hip ratio, waist circumference, waist-to-height ratio, cardiometabolic index, body roundness index, triglyceride, LDL, visceral adiposity index, and lipid aggregation products [63].

PCOS and dyslipidemia

Dyslipidemia includes high levels of total cholesterol, LDL, and triglycerides and lower levels of HDL, affecting 70% of women with PCOS. Researchers have found a correlation between androgen and elevated total cholesterol levels and decreased HDL levels, facilitating atherosclerosis and CVDs in women with PCOS females [64].

Numerous researchers have established the association between PCOS and dyslipidemia. For example, to determine the prevalence of dyslipidemia in PCOS, 286 participants (18–35 age) were categorized based on age and BMI. Examination showed that 24.13% of the participants had abnormal lipid profile levels, and the group aged 18–27 and BMI of 21–23 kg/m² were more susceptible to dyslipidemia with PCOS. Patients also demonstrated abnormal lipid profiles and elevated blood pressure, indicating a higher risk of CVDs independent of BMI [65].

A comparison of obese PCOS participants with lean subjects revealed lower HDL/LDL ratios and estradiol and HDL levels in the PCOS group. In non-obese PCOS patients, compared to non-obese controls, higher values for serum triglyceride/HDL ratio, FSH, LH, testosterone, and progesterone were estimated [66]. Likewise, elevated triglycerides and total cholesterol levels, while those with subclinical hypothyroidism demonstrate significantly higher HDL cholesterol and triglyceride levels [67, 68].

A comparative study involving 40 PCOS patients and 20 healthy controls investigated the relationship between total cholesterol, insulin resistance, and androgen levels. Investigation to find PCOS association with obesity and insulin resistance exhibited higher levels of testosterone, free androgen, an increased triglycerides/LDL ratio, and reduced sex hormone-binding globulin than healthy controls. This research further supported previous findings that obese women with PCOS have an increased risk of developing dyslipidemia [69].

PCOS and depression

A recent study assessed mental health, ways of coping with stress, and self-esteem in women with PCOS (n = 42) with central obesity and levels of androgen and insulin resistance. Elevated tension, depression, and severity of hirsutism were inversely related to emotional induction levels, and increased testosterone levels were directly associated with emotional attention. Stress holders were more susceptible to alcohol consumption and waist circumference. Insulin resistance showed no significant association with physiological measures compared with non-PCOS (n = 39) [70].

Another study comprising 74 participants (Islamabad, Pakistan) showed that 57 women had irregular menstrual periods, 50 experienced weight gain, 41 faced hair growth issues, and 20 reported a genetic history of depression and anxiety. There is a strong association of depression with BMI, education, income, and anxiety interconnection with job status and pregnancy [28]. In another study, 204 females were diagnosed with PCOS, and 150 patients enrolled in the control group had a higher incidence of depression (56.9%), anxiety (61.8%), and sleep apnea (35.3%) than the control group [71]. Research has revealed that only 5% of women with PCOS undergo professional psychotherapy [42].

A study was designed to explore the mental health and resilience of working and non-working women with PCOS (n = 200) using a non-probability sampling technique. The findings indicate a prominent association between mental health and resilience (r = 0.85, p < 0.001). Non-working PCOS women experienced poor mental health (Mean ± SD 85.37 ± 9.91) and resilience relative to (Mean ± SD 65.06 ± 8.71) working women [71].

Furthermore, a validated body esteem scale and a quick inventory of depressive symptomatology self-reports were employed to examine body image perception (BIP) and depression. Outcomes revealed that 55% of participants with PCOS (n = 60) had depression compared to non-PCOS (n = 30). The conclusion was that PCOS participants were 2.27 times more susceptible to developing depression, and 96% of normal participants experienced less negative BIP compared to PCOS participants [72].

PCOS and obesity

Obesity and insulin resistance trigger androgen levels, leading to the development of PCOS. Excess androgen production impairs the function of ovaries and granulosa cells and steroid secretion, leading to obesity, acne, and hair problems [73]. Obese women are more vulnerable to PCOS, hypertension, type 2 diabetes mellitus, CVD, cancer, sleep apnea, and visceral fat related to others [74].

Research has also established strong associations between hormonal imbalance, PCOS, and infertility, particularly abdominal obesity [75]. Adipose tissue plays a crucial role in steroid metabolism through its aromatase activity, which converts androgens to estrogen. The resulting elevated levels of estrogen and leptin can lead to menstrual irregularities and infertility. Another study in Europe and China identified an association between PCOS and obesity. This study showed that SNPs are linked with BMI and are associated with an increased possibility of PCOS [76].

Women with PCOS are approximately 11 times more likely to develop ovarian cancer, menstrual irregularities, anxiety, stress, eating disorders, nonalcoholic fatty liver disease, and adverse pregnancy outcomes such as premature birth, gestational diabetes, gestational hypertension, fetal death, and miscarriage [75, 77]. Similar to Dyslipidemia, obese females with PCOS also show increased insulin resistance, elevated insulin levels, and decreased sex hormone-binding globulin production. This mechanism promotes free androgen circulation, which inhibits follicular formation and leads to irregular menstrual cycles [78].

PCOS and cardiovascular disease (CVDs)

In addition to reproductive dysfunction, PCOS increases the risk of myocardial infarction, ischemic heart disease, and stroke. In PCOS patients, endothelial problems occur because of increased levels of homocysteine, decreased levels of superoxide dismutase activity, and elevated levels of C-reactive protein, critical indicators of CVD risk [79]. CVD remains a leading cause of global mortality, with a particularly concerning trend among PCOS patients. From 1990 to 2019, the burden of CVD in PCOS patients increased dramatically from 1.02 to 3.2 million cases across all age groups, with South Asia experiencing notably higher rates [80]. The impact on women’s health is substantial, with CVD accounting for approximately 35% of the female mortality. PCOS patients are 1.51- and 1.37-fold more prone to CVD risk than non-PCOS women in their 10–54-year range [81].

The pathophysiological relationship between PCOS and CVDs risk is multifaceted. Key risk factors include hyperandrogenism, hyperinsulinemia, menstrual irregularities, and amenorrhea. These factors collectively contribute to cardiometabolic dysfunction, primarily through their adverse effects on dyslipidemia and the development of metabolic syndrome in women with PCOS [82]. Recent meta-analyses have quantified these increased risks, demonstrating significant associations between PCOS and various cardiovascular conditions: overall CVD (OR 1.66, 95% CI 1.32–2.08), myocardial infarction (OR 2.57, 95% CI 1.37–4.82), ischemic heart disease (OR 2.77, 95% CI 2.12–3.61), and stroke (OR 1.96, 95% CI 1.56–2.47) [83].

PCOS and hypertension

The pathophysiology underlying hypertension in patients with PCOS involves several complex mechanisms. These include activation of the renin-angiotensin system due to hyperaldosteronism, insulin resistance with compensatory hyperinsulinemia, hyperandrogenism, sympathetic nervous system activation, and insufficient nitric oxide release [84].

The relationship between PCOS and hypertension is significant during pregnancy. Hyperinsulinemia activates insulin-sensitive vascular endothelial cells, which decrease prostaglandin production [85]. This reduction increases the peripheral vascular resistance and subsequently elevates the blood pressure. Additionally, vascular lumen stenosis and endothelial dysfunction lead to hypertension in women with syndromes [86].

Moreover, the role of androgens in hypertension demonstrated interesting sex-specific patterns. In males, its deficiency increases blood pressure, whereas higher values in females result in hypertension. However, testosterone is listed as the primary androgenic contributor, making patients more susceptible to both hypertension and atherosclerosis [85, 87]. A study conducted in Northern California between 2013 and 2019 also revealed a 7.2% higher prevalence of hypertension in PCOS patients (13–17 age) than in the general population [88]. Furthermore, PCOS women with obesity face a 37% higher risk of developing hypertension compared to healthy women [83]. Demographic variations were also notable, with Bengali Hindu or Muslim women residing in Kolkata, India. Studies showed a higher number of cases in Hindus (24.5%) than in Muslim women (22.2%) [89]. Among different approaches, international PCOS guidelines recommended regularly monitoring blood pressure and haemoglobin levels during treatment, with annual check-ups for all patients [90].

PCOS and Metabolic Dysfunction-Associated Liver Disease or (MAFLD)

The first documented significant relationship between nonalcoholic fatty liver disease (NAFLD), now referred to as metabolic-associated fatty liver disease (MAFLD), and PCOS was established in 2005 through patient biopsies. MAFLD encompasses a spectrum of liver conditions, ranging from simple hepatic steatosis to advanced liver damage, primarily characterized by excessive fat accumulation in the liver tissue [91]. The prevalence of MAFLD in PCOS patients is notable, affecting up to 39% of lean patients [92]. The contributing risks of MAFLD development include insulin resistance, central obesity, hyperandrogenemia (HA), hormonal imbalances, and other irregular metabolic symptoms of PCOS [93, 94].

The pathophysiological connection between PCOS and MAFLD is also evident in the roles of HA and hepatic triglyceride (TG) metabolism. HA is a major endocrine disruptor that affects approximately 80% of the patients. The mechanism is characterized by increased androgen hormones interacting with their specific receptors, which results in elevated hepatic steatosis risk, which is regarded as the initial stage of MAFLD [92, 95]. Similarly, the impact of androgens on TG metabolism is equally essential. Androgens enhance hepatic TG synthesis and worsen hepatic steatosis via multiple mechanisms. For instance, the upregulation of key proteins, such as Fas, SCD, ACC 1, ACC 2, and SREBP1 in hepatocytes. Furthermore, they strengthen SREBP cleavage-activating protein (SCAP)-SREBP1 interactions, which are closely associated with developing both hepatic steatosis and MAFLD [96].

PCOS and diabetes

Gestational diabetes mellitus and PCOS represent significant metabolic disorders that affect women with RAG. Both conditions increase the risk of type 2 diabetes through similar pathophysiological mechanisms [97]. In such situations, primarily beta cell dysfunction, characterized by decreased insulin secretion and reduced proliferation, leads to insulin resistance due to impaired insulin signaling [98]. The underlying mechanisms involve multiple hormonal imbalances, including elevated insulin levels, decreased growth hormone production, and increased ghrelin secretion, all contributing to increased diabetes risk [32].

PCOS significantly reduces insulin sensitivity, leading to an increased prevalence of glucose intolerance and diabetes in women with RAG. This risk is quantifiably higher in PCOS patients than in non-PCOS (OR = 2.87, 95% CI 1.44–5.72) [99]. Research shows that there is an increased risk of diabetes progression in women with a history [97]. This elevated risk highlights the importance of careful monitoring and management of glucose metabolism in PCOS patients, particularly during pregnancy. Figure 3 shows the significant factors contributing to the disease and consequent development of NCDs.

Fig. 3.

Major risk factor and consequences of PCOS

Recent advancements in PCOS management

Dietary management

Studies have shown that diet approaches to stop hypertension (DASH) and calorie-restricted diets help in the management of insulin resistance and weight in women with PCOS. The DASH diet comprises fruits, vegetables, nuts, fiber, legumes, whole grains, low-fat dairy products, low saturated fats, and sweets. Diets with a lower glycemic index (less than 50) can help manage bold sugar levels in PCOS patients [100]. Eating healthy foods, weight management, herbal medication, and skipping junk food with aerobic exercise and yoga can help recover from PCOS by improving insulin response and androgen production [101].

Moreover, lower to medium glycemic index foods (high protein and low carbon) and calorie-restricted diets introduce some favorable regulations, preventing PCOS. Among them, reduction in body weight, enhancement of insulin sensitivity, reduction of triglycerides and cholesterol, regulation of testosterone, and cycle regularity are noteworthy. Interestingly, diets rich in protein content are reported to suppress androgen levels and reduce insulin and dehydroepidiandrosteone stimulation significantly compared to high-carbohydrate diets in PCOS patients [102]. Feeding high-fibre food, low dairy products, omega 3 fatty acids, zinc, selenium, vitamins B and C, flux seed, curcumin, cinnamon, and reduced refined or simple carbohydrates help manage PCOS [103].

A significant role of Vitamin D in stabilizing AMH production, supporting follicular development, and regulating menstruation has recently been established. Clinical trials have indicated that sufficient Vitamin D intake improves fertility, balances hormonal levels, and aids in managing PCOS by regulating reproductive hormones (estradiol, estrogen, and progesterone) both in vitro and in vivo [104, 105]. Table 1 depicts recent studies revealing foods or nutrients that positively impact PCOS.

Table 1.

Recent studies focusing on foods/nutrients beneficial in PCOS management

Food/Nutrients	Result	Model	References
Zinc and selenium	Improved metabolic profile, insulin function, and lipid profile in PCOS patients	Human	[106]
Vitamin D	Help in menstrual cycle regulation and follicular development in PCOS patients	Human	[106]
Omega 3 fatty acid, curcumin, and berberine	Improved the metabolic and reproductive abnormalities by reducing PCOS risks	Mendelian Randomization	[107]
Vitamin D	Deficiency of vitamin D can increase the risk of oxidative stress hyperandrogenism, which causes PCOS	Rat model	[108]
Herbal Tea	decreases in weight, body mass index, and fasting blood glucose, increased follicle-stimulating hormone concentration	Human and rat	[109]
Low carbohydrates and low fats	Low carbohydrate intake helps increase Sex hormone binding protein (SHBP) and ovarian function, reducing BMI and androgen levels in PCOS patients	Human model	[110]
Curcumin	showing improvements in hormone and lipid profiles, antioxidant and glycemic status, and ovarian morphology compared to metformin in rats	Rat model	[111]
Canola oil	Canola oil reduced serum levels of TG (P = 0.002) and TC/HDL (P = 0.021), LDL/HDL (P = 0.047), and TG/HDL (P = 0.001) ratio in PCOS women	Human	[112]
Selenium	In combination with nanoparticles and metformin therapy, Selenium improves insulin sensitivity, lipid profile, inflammation, oxidative stress, and mitochondrial functions	Rat	[113]
Pomegranate juice	Improved lipid profile, oxidative stress, inflammation, and blood pressure	Human	[114]
Fennel essential oil and flaxseed oil	Both oils showed anti-diabetic effects and antioxidative properties, helping improve the BMI, serum glucose, insulin and progesterone concentration, and HOMA-IR, HOMA-β, and QUICKI indices in PCOS rats	Rat	[115]
Clove oil and gonadectomy	Regulate and inhibit excessive autophagy	Rat	[116]
Vitamin C	Ascorbic acid stimulates progesterone and oxytocin production. Vitamin C may play a role in regulating menstrual cycle irregularities in PCOS women	Human	[103]
Anise, fennel, and celery seed extracts	LH levels, serum testosterone, and FSH levels significantly decreased. Estradiol and progesterone levels significantly increased. Overall, the herbal extracts improved serum levels of sex hormones and recovered the ovarian morphology in PCOS-induced rats	Rat	[117]
Ginger supplementation + exercise	The method showed reduced LH (p < 0.05), testosterone (p < 0.05), and insulin (p < 0.05) levels. At the same time, FSH (p < 0.05) and SHBG (p < 0.05) indices in the PCOS groups were significantly increased	Human	[118]
Concentrated pomegranate juice	Positive impact on blood pressure, serum concentrations of TG and HDL-C, and TG/HDL-C ratio in women with PCOS	Human	[119]

TG Serum triglyceride and TG/high-density lipoprotein cholesterol (HDL-C), LH luteinizing hormone, FSH follicle-stimulating hormone

In addition to selecting a nutritious diet, maintaining a consistent eating pattern plays a crucial role in PCOS management. Research indicates that consuming smaller, more frequent daily meals helps regulate blood sugar levels and improves metabolic function [120, 121]. Furthermore, eating a larger breakfast and lighter dinner enhances insulin sensitivity and reduces androgen levels in PCOS patients [122]. These findings highlight the detrimental effects of irregular eating patterns, such as skipping meals or eating at inconsistent times, on PCOS symptom management.

Non-dietary lifestyle interventions

Physical activity and lifestyle modifications

Notable improvements in metabolic and physical parameters in women with PCOS include reduced fasting insulin (FINS), TC, LDL, TAG, and insulin resistance measured by homeostatic model assessment (HOMA-IR). Exercise also enhances body composition by reducing body fat percentage and waist circumference (WC) and improves aerobic fitness (VO_{2 max}) [90, 123].

The 2018 PCOS guidelines recommended at least 150 min of moderate-intensity exercise or 75 min of vigorous-intensity exercise per week to prevent weight gain. For weight loss or regain prevention, 250 min of moderate-intensity exercise or 150 min of vigorous-intensity exercise weekly was suggested. An active lifestyle and incorporating strength training exercises at least twice per week are also emphasized [124, 125].

Specific exercise modalities further highlight the diverse benefits of physical activity in PCOS management. Aerobic exercise improves BMI, WC, body fat percentage, FINS, HOMA-IR, TC, TAG, and VO_2max [126]. It also improves body composition, including reducing BMI and WC, while boosting cardiorespiratory fitness. High-intensity interval training has also demonstrated promise as an effective intervention for improving insulin resistance and BMI, making it a valuable addition to patient exercise regimens [127].

A study aimed to identify the association between physical activity and dietary patterns between PCOS (n = 100) and non-PCOS (n = 100) adolescents revealed a strong link between fatty food (p < 0.05) and physical activity (p < 0.05), except for girls with PCOS who regularly run (Salih and Al- Ogaili, 2024). A comparative study of PCOS’s dietary patterns and physical activity (49) and healthy females (66) aged 18–45 years was performed. Significant differences in physical activity level and nutrient intake (vitamins and polyunsaturated fatty acids) between the groups and food low in glycemic index and glycemic load can improve PCOS [128]. These findings show the importance of integrating a healthy diet with physical activity to prevent serious issues such as PCOS.

Medical treatment

Metabolic medications

Modern evidence-based methods such as combined oral contraceptive pills (COCP), anti-androgens such as spironolactone, and laser or mechanical light therapy for treating hirsutism are among the hot topics. Additionally, PCOS-associated fertility problems are managed by recommending metformin, letrozole, gonadotropin therapy, laparoscopic ovarian drilling, ovulation induction medication, and IVF [90].

Metformin, an insulin activator and non-hormonal treatment, efficiently regulates the menstrual cycle and reduces hyperandrogenism. Metformin also optimizes BMI, testosterone, fasting glucose, and LDL levels in women with a higher BMI (> 25). In obese PCOS females, it improves endocrine and metabolic function, enhances insulin regulation, lowers lipid levels, significantly reduces weight, serves as an insulin sensitizer, and aids in proper ovarian function [129]. Combining metformin with simvastatin enhances hormone function, blood sugar regulation, and lipid profiles [64]. According to the WHO, combining 35 μg estrogen with cyproterone acetate or COCP with metformin presents positive outcomes. Clomiphene citrate and letrozole also improve ovulation and fertility in mothers and fetuses. Moreover, semaglutide and tirzepatide have shown promise in reducing body weight and improving insulin sensitivity in PCOS patients [130]. Likewise, inositols–natural insulin-sensitizing compounds that act as second messenger of insulin, enhance insulin sensitivity, decrease BMI, reduce FSH levels and regulate cycles more effectively than placebo [131]. Similarly, recombinant FSH is increasingly used for follicular development, whereas letrozole is preferred for regulating irregular periods, ovulation, and fertility [132].

Metabolic medications concerns

In addition to PCOS management, some medications can cause health problems in patients. For example, metformin and thiazolidinediones may cause gastrointestinal issues and weight gain, whereas clomiphene citrate and laparoscopic ovarian drilling may be involved in gestational diabetes, hypertension, and preeclampsia. IVF has shown limited efficacy in PCOS treatment [133]. Moreover, spironolactone may cause congenital disabilities, and clomiphene citrate is associated with a higher risk of multiple births [134].

Nutritional supplementation

Inositol carbohydrate-based supplements have emerged as promising experimental therapies for PCOS management. The two primary forms, myo-inositol (MI) and D-chiro-inositol (DCI), have been shown to enhance insulin signal transduction [135]. In particular, MI promotes glucose uptake by translocating GLUT4 transporters to the cell surface, while DCI supports glucose storage by activating glycogen synthesis. In the serum, MI and DCI are present in a 40:1 physiological ratio; however, each organ regulates its intracellular balance based on epimerase activity, an insulin-dependent enzyme that converts MI into DCI. Epimerase activity is disrupted in insulin-resistant conditions, leading to an imbalance in the MI:DCI ratio. Specifically, insulin-resistant tissues exhibit an increased MI:DCI ratio, whereas, in ovarian theca and granulosa cells, epimerase activity is upregulated, resulting in MI deficiency and excessive DCI accumulation [136]. Elevated DCI levels in the ovary negatively impact hormone regulation, as DCI inhibits aromatase, the enzyme responsible for converting androgens into estrogens, ultimately increasing testosterone production [137]. For this reason, supplementation with MI alone or MI and DCI in a 40:1 ratio is effective in managing hyperandrogenic and insulin-resistant PCOS patients [138]. MI functions as a key endocrine regulator, demonstrating its ability to improve metabolic profiles and reduce hyperandrogenism, while DCI supports MI in metabolic health, particularly in overweight and obese PCOS patients (BMI ≥ 25 kg/m²) [139]. Clinical studies have documented that inositol supplementation can significantly improve ovulation rates, menstrual cycles, and hormonal profiles [135, 140]. However, DCI supplementation alone may not be optimal in treating PCOS, as long-term high-dose DCI intake has been associated with increased androgen levels and menstrual cycle disruption [141].

Among the different supplements, vitamin D, resveratrol, alpha-lipoic acid, omega-3 fatty acids, berberine, and folic acid have shown promising results against syndrome symptoms [142, 143]. Additionally, pharmaceutical interventions such as atorvastatin have demonstrated efficacy in addressing insulin resistance, elevated cholesterol levels, hyperandrogenism, and ovarian dysfunction [144]. These therapeutic advances underscore the importance of implementing a comprehensive, individualized approach to PCOS treatment that may combine both nutritional supplementation and pharmaceutical interventions as a useful approach. These advancements emphasize the importance of a multifaceted and individualized approach for PCOS treatment.

Conclusions

PCOS is a global health concern intricately linked to metabolic, cardiovascular, and psychological comorbidities, including obesity, insulin resistance, hypertension, and depression. Its pathophysiology arises from interconnected hormonal, metabolic, and environmental factors, such as insulin resistance, obesity, and exposure to endocrine-disrupting chemicals. Current Diagnosis relies on phenotypic categorization (A-D), while management prioritizes lifestyle interventions targeting modifiable risks: reducing processed foods, refined sugars, and environmental toxins (e.g., phthalates) while promoting antioxidant-rich diets, physical activity, and sleep hygiene. Public health strategies, including education and early intervention programs, are critical to mitigate PCOS-related complications and long-term health burdens.

Authors’ contributions

Iqra Naeem, Ayman Zehra, Faiza Rehman: writing-original draft. Abid Hussain, Nisar Hussain: Conceptualization, supervision, review and editing. Azhar Hussain, Muhammad Waseem, Reem Mohammed Alqahtani, Ghalia Shamlan, Isam A. Mohamed Ahmed, Muhammad Faisal Manzoor, Muhammed Adem Abdullahi: Investigation, review and editing.

Funding

This work received no financial support or funding from institutions, organizations, or external sources.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.