Review Article

PCOS and Its Correlation to Insulin Resistance and Dyslipidemia

Sukhmani Batra K¹ and Jay Shubrook H²*

¹College of Osteopathic Medicine at Touro University California, Vallejo, CA, USA

²Department of Clinical Sciences and Community Health, College of Osteopathic Medicine at Touro University California, Vallejo, CA, USA

Submission: February 09, 2024; Published: January 20, 2024

*Corresponding author: Jay Shubrook, Department of Clinical Sciences and Community Health, College of Osteopathic Medicine at Touro University California, Vallejo, CA, USA, Email: jshubroo@touro.edu

How to cite this article: Sukhmani Batra K and Jay Shubrook H*. PCOS and Its Correlation to Insulin Resistance and Dyslipidemia. Curre Res Diabetes & Obes J 2024; 17(2): 555960.DOI: 10.19080/CRDOJ.2024.17.555960

Abstract

Context: Polycystic Ovarian Syndrome (PCOS) is a common endocrine disorder associated with significant metabolic complications. Many people with PCOS often only consider the reproductive implications. Insulpatientse (IR) and dyslipidemia are two distinct metabolic markers found in PCOS patients but remain relatively unaddressed in-patient care.

Objectives: To analyze the correlation between polycystic ovarian syndrome and metabolic markers, including IR and free fatty acid metabolism impairment.

Methods: PubMed was searched using the terms PCOS, IR, biomarkers, genetics, lifestyle modification, free fatty acid metabolism, and dyslipidemia. A total of 2600 articles were identified. After removing duplicates and non-full text articles, 340 articles remained, which were assessed for eligibility. Articles were excluded due to a lack of focus on IR, impaired free fatty acid metabolism, or dyslipidemia in PCOS patients. Articles that described genetic predisposition, biomarkers, or lifestyle modifications in PCOS patients without a specific focus on their association with IR were also excluded. Identification, screening, and selection of articles were conducted by one reviewer (SKB).

Results: A total of 68 articles were reviewed to analyze the prevalence and association of IR and dyslipidemia in PCOS patients. Genetic susceptibility, biomarkers, and lifestyle modification indicated that IR plays a crucial role in the pathophysiology of PCOS. Dyslipidemia was also found to be closely associated with PCOS.

Conclusion: PCOS has profound metabolic complications that are associated with the presence of IR and dyslipidemia in PCOS patients. IR and dyslipidemia should be addressed as a part of PCOS treatment.

Keywords: Insulin resistance; polycystic ovarian syndrome; Clinical implications; DNA methylation; Reproductive disorder

Abbreviation: PCOS: Polycystic Ovarian Syndrome; IR: Insulin Resistance; CVD: Cardiovascular Disease; AMH: Anti-Mullerian Hormone; CEBPS: CCAAT/Enhancer-Binding Protein; LMNA; Lamin A; miRNAs: microRNAs; OxLDLs: Oxidized LDLs; NEFAs: Non-Esterified Fatty Acids; OA: Oleic Acid

Introduction

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder that impacts 3-15% of all women [1]. It is often diagnosed using the Rotterdam criteria, which requires two of the following symptoms: abnormal ovulation, hyperandrogenism, and polycystic ovaries [1]. PCOS can often manifest through hormonal, reproductive, and mental health presentations. With hyperandrogenism, PCOS patients will likely experience hirsutism and acne due to an altered hormonal profile [2]. Menstrual complications are common in PCOS and can lead to infertility complaints [1]. Studies have also shown a correlation between PCOS and depression, eating disorders, and anxiety [2]. While commonly characterized by its gynecologic features, PCOS has significant endocrine and metabolic implications. Often accompanied by metabolic abnormalities, including IR and impaired lipid metabolism [3], PCOS has been identified as a precursor to metabolic syndrome, which increases the risk of type 2 diabetes and cardiovascular disease (CVD) [1]. Due to serious clinical implications, recent research has focused on the metabolic implications of PCOS. This systematic review examines the genetic mechanisms, biomarkers, and effect of lifestyle modification on IR in PCOS patients, as well as dyslipidemia’s involvement in the pathophysiology and treatment of PCOS.

Methods

PubMed was searched from inception, including terms - PCOS, IR, biomarkers, genetics, lifestyle modification, free fatty acid metabolism, and dyslipidemia. Articles were restricted using PubMed’s filters for “Free Full Text.” All article types were included except “Books and Documents.” Duplicate and non-English articles were excluded. The identified studies were screened with the title and abstract. Studies that discussed IR or dyslipidemia were eligible for inclusion. Studies that analyzed biomarkers, genetics, and lifestyle modification and their association with IR in PCOS patients were included. Studies were excluded if the study discussed IR or dyslipidemia without a specific focus on PCOS patients. Studies were also excluded if free fatty acid metabolism or dyslipidemia were analyzed without a particular emphasis on PCOS patients. Searches, screening, and selection were conducted by one reviewer (SKB) from February 21, 2023, to July 14, 2023(Figure 1).

Results

Insulin Resistance (IR)

Recent research has shown a high prevalence of IR in PCOS patients. While the etiology of IR in PCOS is unclear, there are several proposed mechanisms. One mechanism is intrauterine growth restriction, which leads to changes in adipose tissue development at the fetal stage, which can promote IR in adulthood [5]. Changes in insulin function and the hormonal profile may be another mechanism of IR in PCOS patients [5]. In some PCOS patients, auto-phosphorylation of receptors is abnormal, while in other PCOS patients, there are defects in post-binding receptor events [5]. Both mechanisms contribute to insulin function changes, leading to IR [5]. Moreover, hyperandrogenism can change insulin sensitivity by modifying visceral fat or secretion of adiponectin, resulting in hyperandrogenemia-induced IR [5].

Genetics

PCOS and IR correlations can be identified through several genetic mechanisms. Many genes involved in insulin signaling or metabolic regulation are altered in people with PCOS [5]. Many of these genes are also identified as risk genes for diabetes and other metabolic disorders (Table 1) [5-18]. While genetic polymorphisms have been heavily studied, epigenetic theories about IR in PCOS patients are now being explored. Fetal development is an area of focus for epigenetics in PCOS and IR. One theory is that a fetus’ exposure to excess androgens may increase susceptibility to PCOS due to the known correlation between androgens and the polycystic morphology of ovaries, hyperandrogenism, and IR [2]. Several animal studies have shown consistent results to support this theory [2]. Another theory focuses on the anti-Mullerian hormone (AMH), which is responsible for fetal sex differentiation [2]. An increase in AMH can lead to a reduction in estradiol, which may contribute to both the polycystic morphology and the rise in testosterone, as seen in animal studies [2]. The increase in testosterone may lead to metabolic abnormalities seen in PCOS patients, including IR [2].

However, some research has found that maternal AMH is not present until 36 weeks of gestation, which suggests that AMH may not be a contributing factor during fetal development [2]. With both theories, the excess androgens that result are expected to have an epigenetic effect on developing ovaries, increasing susceptibility to IR [2]. DNA methylation is another epigenetic mechanism closely associated with PCOS and its metabolic effects [19]. Researchers detected changes in DNA methylation in 78 genes when comparing PCOS patients with IR to those without [19]. Significant alterations have been found in DNA methylation in the CCAAT/enhancer-binding protein (CEBPS) gene, which can also indirectly regulate the ODC1 gene [19]. Both genes are known to contribute to IR when modified. Lamin A (LMNA) gene mutations and hypermethylation have also been shown to cause IR and other metabolic abnormalities in PCOS patients [19]. DNA methylation of insulin signaling pathway genes, like INSR, has also been implicated in the development of IR in PCOS patients [19].

Biomarkers

IR in PCOS patients can be identified through the presence of several biomarkers. Several hormones [20,21], proteins and peptides [22-25] have been implicated in PCOS and IR. Additionally, PCOS has been associated with chronic inflammation primarily due to excess adipose tissue, so inflammatory biomarkers have been an essential area of research [26]. Moreover microRNAs (miRNAs), small RNAs that regulate gene expression posttranscriptionally, have been found in the blood, serum, plasma, and follicular fluid of PCOS patients and are being investigated as potential biomarkers of IR in PCOS [27]. Also, vitamin D deficiency is a common feature in PCOS and may be a potential biomarker for IR in PCOS (Table 2) [21-39].

Lifestyle Modification

Lifestyle modification, a common treatment for PCOS patients, has improved both IR and other non-related symptoms of PCOS. Key recommendations for lifestyle changes include weight reduction, diet, and exercise [40,41]. Weight reduction is often recommended to PCOS patients as a therapeutic option. It has been shown that weight loss may decrease the magnitude of hyperinsulinemia and help scale down menstrual irregularities and infertility [41]. Weight reduction may specifically benefit obese PCOS women by decreasing adiposity, reducing androgen and insulin levels, improving ovulatory function, increasing fertility, and decreasing the risk of metabolic complications like CVD [41]. It has been reported that a minor weight reduction of 5-10% could significantly improve metabolic and reproductive dysfunction in PCOS patients [42-45]. Nutritional interventions have also been assessed as a treatment for PCOS. With PCOS’ association with IR and other metabolic complications, a low glycemic index diet has been considered [41,46]. One meta-analysis showed improved menstrual irregularities and decreased IR with a low glycemic diet [41]. Another meta-analysis showed that a low glycemic diet decreased androgen levels and reduced IR [47]. Some research has also looked at low or reduced carbohydrate diets and found beneficial metabolic effects, including weight reduction, decreased adiposity, decreased insulin levels, improvement in fertility, and normalization of the hormonal profile [41]. A ketogenic Mediterranean diet reduced serum insulin, blood glucose levels, and weight [41]. Low-calorie diets improved insulin sensitivity and promoted weight loss in PCOS patients [46]. A pulse-based diet has also improved insulin sensitivity and lipid profiles in PCOS patients [43].

Additionally, increasing intake of fiber-rich food can help regulate insulin levels and promote weight loss [46]. Plant-based foods, which promote glycemic control, also have phytochemicals that can reduce hyperglycemia and improve insulin sensitivity and acute insulin response [46]. Limiting simple sugar, salt, and processed food intake can also help improve insulin sensitivity and reduce the risk of PCOS’s metabolic complications [46]. Saturated fat has been found to worsen IR, and unsaturated fatty acids have been found to improve IR [46]. Omega-3 fatty acids have also been found to enhance insulin sensitivity in PCOS patients [46]. Physical activity is another therapeutic option for PCOS patients. Benefits of exercise include weight loss, reduced IR, decreased androgen concentrations, and restored fertility [46]. Moderate-intensity aerobic exercise was found to reduce menstrual dysfunction and contribute to weight loss and reduced IR in PCOS patients [41]. Vigorous aerobic exercise decreased IR significantly in PCOS patients [45]. Some research has found that vigorous aerobic exercise and resistance training improve insulin sensitivity and androgen concentrations in PCOS patients [45]. Moreover, it has been reported that a reduction in insulin levels can improve hirsutism, acne, and the menstrual cycle, all of which are symptoms of PCOS [44]. Yoga has been found to be effective in improving ovarian morphology, mood, and hormonal profiles but is ineffective in regulating IR [44].

Other lifestyle modifications have been shown to have positive effects. Sleep deprivation has been found to increase risk of IR, obesity, and type 2 diabetes in PCOS patients, so sufficient, highquality sleep is essential for PCOS patients [15,45]. Additionally, IR is independently associated with depression in PCOS, so psychological care is another key therapeutic option for PCOS patients [15]. Avoidance of smoking is essential in PCOS patients because smoking can decrease insulin sensitivity and increase the risk of CVD in PCOS patients [48]. The gut microbiome has also been studied for its connection to PCOS and IR. It has been established that PCOS patients have an altered gut microbiome [49,50]. It has been found that alterations in the gut microbiome are more distinct in PCOS patients with IR than those without [49]. It is believed that altered gut microbiota may contribute to the development of IR in PCOS patients [49]. It is proposed that an imbalance of gut microbiota can activate chronic low-grade inflammation, disrupting that insulin signaling pathway leading to IR [49]. This mechanism has been supported through preliminary studies [49]. Another plausible mechanism suggests that increased Bacteroides species in the gut microbiome decrease ghrelin and peptide YY levels, leading to IR [49]. It is known that diet, probiotics, and prebiotics can change the gut microbiome, so these may be potential targeted therapeutic options for PCOS patients [49,50]. Several studies have looked at the benefits of lifestyle modification and medication as combined therapy, but data remains inconclusive [51,52].

Dyslipidemia

In addition to IR, dyslipidemia, an imbalance of lipids, is another common metabolic abnormality in PCOS patients [53]. Dyslipidemia is seen in both obese and non-obese PCOS patients [54]. One meta-analysis has found an increased prevalence of dyslipidemia in mothers and fathers of PCOS patients, which suggests there may be a partial genetic causality for dyslipidemia in PCOS patients [55]. The typical lipid profile of a PCOS patient consists of an increase in VLDL, LDL-C, and triglycerides and a decrease in HDL-C [1,53,56]. The most common pattern of dyslipidemia in PCOS patients is reported to be classic atherogenic dyslipidemia (increased triglycerides, increased LDL-C, and low HDL-C) which is linked to IR, while the elevated LDL-C is suggested to be due to the excess of androgens in PCOS patients [56]. Moreover, apolipoprotein concentrations were found to be modified in PCOS patients. Apo-AI levels are significantly reduced in PCOS patients, with no difference in Apo-B levels, due to obesity and hyperandrogenism [53]. It has also been reported that Apo-CI levels are increased in both lean and obese PCOS patients and may be early indicators of lipid abnormalities in PCOS patients [53]. Levels of lipoprotein a, an independent risk factor for CVD, were also significantly higher in some PCOS phenotypes and may be a focus of future research [53].

Recent studies have found a correlation between dyslipidemia and hyperandrogenism in PCOS patients. One study found that liver fat was strongly associated with hyperandrogenism [3]. It has also been reported that hyperandrogenism is related to fat distribution, specifically intra-abdominal fat deposition [3]. Additionally, the reduced Apo-AI levels in the granulosa cells of PCOS patients could hamper the conversion of testosterone to estradiol, which may account for the elevated testosterone concentrations observed in PCOS patients [3]. Dyslipidemia has also been associated with anovulation in PCOS patients. It has been reported that anovulatory PCOS patients have higher total cholesterol, triglycerides, and LDL-C levels and lower HDL-C levels than ovulatory PCOS patients [3]. It has also been found that high levels of triglycerides, free fatty acids, and oxidized LDLs (oxLDLs) result in mitochondrial dysfunction, which increases ROS, leading to ovarian damage and follicular atresia [3]. Additionally, oxLDLs can activate receptors, which cause apoptosis of granulosa cells and impaired ovulation [3]. Specific lipid abnormalities have also been investigated for their association with PCOS. A few studies found that concentrations of prostaglandins and metabolites of arachidonic acid, via the COX pathway, were elevated in the ovarian tissue of the PCOS group compared to the control group [57,58]. In humans, a significant increase was found in concentrations of 9-HODE and 13-HODE, both derivatives of linoleic acid [58].

Non-esterified fatty acids (NEFAs), associated with lipotoxic effects, have also been associated with PCOS [59]. Increased mitochondrial NEFA β-oxidation has been shown to increase serine phosphorylation of insulin receptors in PCOS skin fibroblasts [59]. Additionally, TNF-α, a NEFA metabolite, has been associated with PCOS [59]. Moreover, palmitate, a saturated fatty acid, increases androgen biosynthesis in animal models, which may model lipids promoting androgen overproduction in PCOS patients (59). It was also found that PPAR-y activation reduces androgen hyperresponsiveness in PCOS by upregulating genes that decrease circulating NEFA concentrations [59]. Unsaturated fatty acids are also implicated in PCOS pathophysiology. Elevated concentrations of oleic acid (OA) have been found in the follicular fluid of PCOS patients and are thought to contribute to adverse pregnancy outcomes [57]. OA also regulates transcriptional factors necessary for synthesizing female hormones, which may contribute to excess androgens [57]. Dyslipidemia is also believed to increase the risk of CVD in PCOS patients [60-63]. Dyslipidemia is an important factor in intensifying atherosclerosis, leading to cardiovascular events. While PCOS is linked to vascular impairment and cardiovascular risk [62, 64], data connecting dyslipidemia to CVD in PCOS patients is limited and unclear [60,65].

Treatments for dyslipidemia have shown positive effects in treating PCOS [66]. In addition to improving the lipid profile, simvastatin was found to reduce testosterone, with a proposed mechanism of inhibiting cholesterol production, which is needed for testosterone synthesis [3,66]. It also improved hirsutism, acne, and the hormonal profile [3,66]. Moreover, simvastatin was seen to be cardioprotective, with lower pro-inflammatory markers [66]. Atorvastatin has also been found to improve the lipid profile, decrease hyperandrogenism, and reduce IR in PCOS patients. Other treatments have also been investigated for their potential as a therapeutic option for dyslipidemia in PCOS patients. Omega-3 fatty acid supplementation has improved serum adiponectin levels, IR, serum lipids, the overall lipid profile [3,67], and other metabolic dysfunction [68] in PCOS patients. One study found that vitamin D supplementation resulted in significant improvement in total cholesterol, triglycerides, LDL-C, and VLDL-C [69], while other research found no therapeutic effect on the lipid profile [39]. Additionally, metformin has shown improvement in lipid profiles and IR, but data is inconsistent due to several confounding factors [64].

Discussion

IR and dyslipidemia are integral metabolic manifestations of PCOS that require a greater clinical focus and should be regularly assessed in all PCOS patients. Dyslipidemia profoundly affects PCOS pathogenesis, prognosis, and treatment and should be monitored regularly. PCOS’ status as a precursor to metabolic syndrome highlights a critical need to gain further insight into PCOS as a metabolic disorder, especially for patient awareness. Further studies should include greater emphasis on biomarkers of IR and dyslipidemia in PCOS and their clinical applicability. Additionally, research should focus on treatment options that target IR and dyslipidemia in addition to the symptoms of PCOS. More research is needed to determine dyslipidemia’s role in PCOS pathogenesis and cardiovascular risk. There are several limitations in the literature review. Only one database, PubMed, was searched for relevant articles, which may reduce the available research. One reviewer identified, screened, and selected articles, which may have introduced selection bias. Articles were screened at the title and abstract level, which may have brought selection bias.

Conclusion

PCOS is often identified as a reproductive disorder, but its metabolic and endocrine significance is too important to ignore. PCOS has profound metabolic effects, including IR and dyslipidemia, which lead to significant metabolic complications. It is important to recognize the relationship between PCOS, IR, and dyslipidemia as they are vital to treating PCOS and managing patient care.

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