Polycystic Ovary Syndrome Symptoms

### **Chapter 1**

## Genetics and Epigenetics of Polycystic Ovary Syndrome

*Surya Prakash Goud Ponnam and Adity Paul*

### **Abstract**

Polycystic ovary syndrome (PCOS) is one of the most common endocrinological and reproductive disorders in women of reproductive age with a global prevalence rate of 5–20%. It is a clinically and genetically heterogeneous disorder. There have been multiple reports from independent research groups from different ethnicities that a variety of factors, including genetics and epigenetics, significantly contribute to the etiopathogenesis of PCOS. GWAS, twin studies, and genotype-phenotype association studies have resulted in the identification of more than a dozen candidate genes/loci with PCOS. In the proposed book chapter, we aim to provide insight and discuss the role of various genetic and epigenetic elements that are responsible for PCOS globally and in India. This book chapter should serve as a reference to all the basic researchers and healthcare professionals on the genetics and epigenetics of PCOS.

**Keywords:** PCOS, genetics, epigenetics, prevalence, classification

### **1. Introduction**

Stein and Leventhal were the first to describe women with amenorrhea, hirsutism, obesity, and ovaries that appeared to be polycystic in seven independent cases [1] and termed it as Stein-Leventhal syndrome which was subsequently referred to as polycystic ovary syndrome (PCOS). PCOS is a complex reproductive and endocrinological disorder in women of the reproductive age group across the globe. PCOS is characterized by the presence of hyperandrogenism (HA), ovulatory dysfunction (OD), and/or the presence of unilateral or bilateral polycystic ovarian morphology (PCOM).

PCOS is a multifactorial disorder with complex aetiopathophysiology. Several factors including genetic, epigenetic, lifestyle, nutrition, ethnicity, and environment are known to contribute to PCOS [2]. However, the quantum of each factor contributing to the overall phenotype is not yet ascertained. PCOS is one of the major causes of anovulatory infertility and these patients are predicted to have a high risk of developing endometrial cancer [3].

### **2. Clinical signs and symptoms**

The three main clinical signs and symptoms of PCOS include hyperandrogenism (clinical/biochemical), menstrual irregularities (oligomenorrhoea, amenorrhoea,

and/or followed by prolonged or heavy periods), and polycystic ovarian morphology (PCOM) [4].

Firstly, clinical hyperandrogenism presents itself as acne, hirsutism, alopecia, and acanthosis nigricans, and biological hyperandrogenism as excess of androgen production. Secondly, hormonal imbalance such as elevated levels of luteinizing hormone, disrupted ratio of luteinizing hormone to follicle-stimulating hormone (LH: FSH), increased Amh (anti-mullerian hormone) levels, etc. results in the development of cysts in the ovary and leads to irregular menstruation that includes anovulation and amenorrhea/oligomenorrhea [4], further leading to PCOS. Lastly, the PCOM refers to the presence of 12 or more follicles in the ovary with a diameter of 2–9 mm and an ovarian volume of around 10 ml or greater [5–7].

Various cardio-metabolic disorders are also associated with PCOS that include hyperlipidemia, insulin resistance, hypertension, type 2 diabetes mellitus, cardiovascular disease, etc. [8]. PCOS patients have also been reported to have increased neonatal complications such as pre-eclampsia, preterm birth, gestational diabetes, early pregnancy loss, etc. [9].

### **3. Prevalence**

The global prevalence rate of PCOS was reported to be between 5 and 20% of women of reproductive age [10]. A study by Liu and co-workers analyzed the burden of PCOS to be approximately one and a half million globally, after analyzing the data in women of reproductive age ranging between 15 and 49years across 194 counties [11]. The World Health Organization (2021) reported that approximately 116 million women (3.4%) suffer from PCOS globally [12]. Few independent research groups have reported different symptoms and prevalence rates of PCOS among different ethnicities [13, 14]. The wide difference in the prevalence rates across the globe is due to multiple reasons that include the different criteria being followed for diagnosis, ethnicity, time of publication, survey populations, etc. [15–20].

The prevalence rate of PCOS in India is reported to be ranging between 3.7% and 22.5% among women of the reproductive age group [19, 20]. A systematic review and meta-analysis by Bharali et al. reported the pooled prevalence of PCOS in Indian women to be 5.8% as per the NIH criteria and 10% as per the Rotterdam's criteria and AES criteria respectively [21].

### **4. Diagnosis and grading of the severity of PCOS**

The definition and the diagnostic criteria for PCOS were initially laid down by The National Institute for Child Health and Human Development (NICHD), USA conference in the year 1990. As per this conference, diagnostic characteristics for PCOS included clinical and/or biochemical hyperandrogenism and menstrual irregularities [22]. The American Society for Reproductive Medicine (ASRM), European Society of Human Reproduction and Embryology (ESHRE) presented the Rotterdam criteria in 2003. According to this, at least two out of three criteria are mandatory (oligo-ovulation or anovulation, clinical or biochemical hyperandrogenism, and/or the presence of polycystic ovarian morphology), for a patient to be diagnosed with PCOS [23]. The Androgen Excess and PCOS Society, considered PCOS as primarily a hyperandrogenic disorder and defined PCOS as the presence of clinical and/or

*Genetics and Epigenetics of Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.113187*

biochemical hyperandrogenism accompanied by either oligo-ovulation or polycystic ovarian morphology [24].

Rotterdam criteria is one of the widely accepted criteria for diagnosing PCOS. As per this classification, PCOS patients have been sub-grouped into four different phenotypes, namely, phenotype A (Frank or Classic polycystic type) with HA + OD + PCOM, phenotype B (Classic non-cystic type) with HA + OD, phenotype C (Non classic ovulatory type) with HA + PCOM, and phenotype D (Non classic mild or normo-androgenic type) with OD + PCOM symptoms [25].

### **5. Genetics of PCOS**

The role of genetics in PCOS was first proposed by Cooper et al. on chromosomal analysis of 18 families of American origin and had reported an autosomal dominant mode of inheritance and decreased penetrance [26]. Wilroy and coworkers [27] observed that the male relatives of PCOS patients were diagnosed with oligospermia and increased LH secretion, suggesting an X-linked mode of inheritance. The same study also reported the association of PCOS with metabolic co-morbidities like diabetes mellitus, dyslipidaemia, hypertension, and arteriosclerosis [27]. An increase in the incidence of infertility, oligomenorrhea, and hirsutism in first-degree relatives of PCOS patients and an increased degree of baldness in male relatives was reported by Ferriman and Purdie [28]. Twin studies have suggested PCOS to be a polygenic disorder influenced by both intrauterine and extrauterine environmental factors [29, 30].

### **6. Few candidate genes associated with PCOS**

To date, independent studies from different ethnicities and research groups have reported more than a dozen candidate genes/loci for PCOS. Majority of these candidate genes have been broadly classified into the six major pathways/groups. A few important genes in each category/pathway have been mentioned below:

i.Ovarian and adrenal steroidogenesis pathway (*CYP11A*, *CYP17*, *CYP19*)

ii.Gonadotropin action and regulation pathway (*LHCGR*, *AMH*, *FSHR*)


### **6.1** *CYP11A* **(cytochrome P450 family 11 subfamily A) gene**

The locus for the *CYP11A* gene (Ensembl ID: ENSG00000140459) is 15q24.1. The *CYP11A* gene is approximately 20 kb in size and has 9 exons. *CYP11A* gene codes for a total of nine mRNA transcripts out of which only six codes for the functional protein. The largest transcript (ENST00000268053.11) is 1837 bp and encodes for the cholesterol side-chain cleavage enzyme (cytochrome P450scc) with 521 amino acids and an approximate molecular weight of 60 kDa.

The cholesterol side-chain cleavage enzyme (cytochrome P450scc) initiates steroidogenesis and converts cholesterol to pregnenolone. *Cyp11a* is expressed in the adrenal cortex, ovaries, testis, and placenta in humans [31]. Pathogenic mutations in the *CYP11A* gene have been reported in multiple diseases such as P450scc insufficiency, XY sex reversal and adrenal insufficiency, Adrenal hyperplasia, Adrenal hypospadias, etc. [31].

Gharani et al. [32] and Diamanti-Kandarakis and co-workers [33] reported a significant correlation between the alleles of the *CYP11A* gene with a 5′ untranslated region (UTR) consisting of repeats of a (tttta)n pentanucleotide and serum testosterone levels in PCOS patients. Wang et al. reported that the allele of (tttta)n microsatellite polymorphism in the promoter of the *CYP11A* gene has a higher frequency and is associated with increased BMI in the Chinese population with PCOS [34]. Zhang and co-workers reported that the SNP rs4077582 in *CYP11A1* is positively correlated to PCOS susceptibility and affects testosterone levels by regulating LH [35].

Pusalkar and coworkers found that variations in the promoter region of *CYP11A1* and *CYP17* were associated with testosterone levels in PCOS patients in the Indian population [36]. Further, this polymorphism was suggested as a potential molecular marker for PCOS by Reddy et al. in the South Indian population [37]. On the contrary, Gaasenbeek et al. studied the polymorphisms of the *CYP11A* promoter region in PCOS patients from the United Kingdom and Finland and found no significant correlation [38].

### **6.2** *CYP17* **(cytochrome P450 family 17) gene**

The locus for the human *CYP17* gene (Ensembl ID: ENSG00000148795) is 10q24.32. This gene codes for a total of 8 mRNA transcripts out of which five codes for a functional protein. The largest transcript (ENST00000369887.4) is 1750 bp and encodes for cytochrome P450 17α-hydroxylase protein with 508 amino acids and an approximate molecular weight of 57.4 kDa. Cytochrome P450 17α-hydroxylase enzyme is primarily located in the endoplasmic reticulum in humans and has hydroxylase and lyase activity. It converts progesterone and pregnenolone into 17-hydroxyprogesterone and 17-hydroxypregnenolone respectively and subsequently to 4-androstenedione and dehydroepiandrosterone [39].

Escobar-Morreale et al. reported an increased P450c17*α* activity in PCOS women with hyperandrogenism in the adrenal cortex and ovaries [40]. Two independent reports by Wickenheisser and co-workers have concluded that there is higher transactivation of *CYP17* promoter in ovarian theca cells and dysregulation in the expression of *CYP17* at the mRNA level [41, 42]. A T/C SNP in the promoter region was found to be associated with PCOS in the Caucasian and Greek populations by Carey et al. [43] and Diamanti-Kandarakis et al. [44] respectively. The *CYP17* gene is primarily responsible for the development of insulin resistance and a hyperandrogenic phenotype in PCOS patients [45, 46].

Kaur et al. reported a − 34 T > C polymorphism in *CYP17A1* that was found to be associated with PCOS in the north Indian population [47]. Few studies have reported a negative correlation between *CYP17* polymorphisms and PCOS [48–51].

Besides PCOS, mutations in the *CYP17* gene have also been reported in 17-alphahydroxylase/17, 20-lyase deficiency, Steroid-17 alpha-hydroxylase deficiency, Pseudohermaphroditism, etc. [31].

### **6.3** *CYP19* **(cytochrome P450 family 19) gene**

The locus for the *CYP19* gene (Ensembl ID: ENSG00000137869) is 15q21. The size of this gene is approximately 70 kb and has 10 exons. *CYP19* gene codes for 19 transcripts, out of which only 12 codes for a functional protein. The largest transcript (ENST00000396402.6) codes for Aromatase (P450arom) or estrogen synthetase enzyme, which is 4403 bp and with 503 amino acids and has a molecular weight of approximately 53 kDa. The estrogen synthetase enzyme catalyzes the tranformation of the C19 testosterone androstenedione, and androgens, to the C18 estradiol, estrone and estrogens, respectively [46]. In humans, the expression of P450arom is in the bone, adipose stromal cells, ovary, placenta, and few foetal tissues [52].

Petry et al. [53] and Medeiros et al. [54] identified a deficiency of aromatase activity in patients with PCOS and hyperandrogenism in the British and Brazilian populations respectively [53, 54]. Yu et al. reported reduced *CYP19A1* expression in ovaries due to hypermethylation of its promoter region in PCOS patients from China [55]. Chen et al. reported a significant decrease in the activity of P450arom in both lean and obese women with PCOS [56]. In a multicentric study, the SNP (rs2414096) was reported to have a positive association between reduced aromatase activity, increased estradiol to testosterone ratio (E2/T), and PCOS development in Caucasian and African patients [57]. These findings were further corroborated by independent research groups in the Chinese [58] and Iranian [59] populations. Few studies have reported that a tetranucleotide repeat (TTTA)*n* in the *CYP19* gene with short alleles results in the inhibition of the aromatase activity and hyperandrogenism along with a high LH: FSH ratio [60, 61].

Ashraf et al. reported a SNP (rs2414096) of the *CYP19* gene to be associated the PCOS susceptibility and hyperandrogenism in patients from Kashmir, India [62].

### **6.4** *LHCGR* **(luteinizing hormone/choriogonadotropin receptor) gene**

The locus for the *LHCGR* gene (ENSG00000138039) is on chromosome 2p16.3 and has a size of approximately 80kbp. This gene codes for a total of six mRNA transcripts, out of which only five code for the functional protein, luteinizing hormone (LH)/ choriogonadotropin receptor. The largest transcript (ENST00000294954.12) is 3076 bp with 699 amino acids with an approximate molecular weight of 33 kDa.

The *LHCGR* gene, which is crucial for ovulation in response to the mid-cycle LH surge, is mostly expressed in the granulosa cells of preovulatory follicles in females [63]. The luteinizing hormone is a member of the G protein-coupled receptors (GPCR) subfamily N and is characterized by the presence of a large N-terminal extracellular domain with leucine-rich repeats (LRR).

Elevated LH levels are a common characteristic in PCOS patients, and are related to anovulation, as luteinizing hormone has a negative effect on the development of eggs [64]. Furui et al. reported two missense pathogenic mutations (Trp8Arg and Ilg15Thr) in the gene coding for the beta-subunit of the luteinizing hormone in PCOS patients [65]. On the contrary, a multinational and multicentric study by Nilsson et al. reported these changes in the normal population also [66]. Takahashi and co-workers reported many SNPs in the promoter site of the *LH* gene that were common to patients with PCOS and other ovulatory disorders [67]. GWAS studies have identified the 2p16.3 region containing *LHCGR* loci to be associated with PCOS in Han Chinese [68] and European populations [69]. An SNP (rs2293275) that induces an amino acid substitution (S312N) was reported in the Sardinian population with PCOS [70].

Thathapudi and co-workers reported the SNP (rs2293275) in the *LHCGR* gene to be associated with PCOS from Southern India [71]. Singh et al. suggested that a mutant allele (C) of rs12470652 and mutant genotype (AA) and mutant allele (A) of rs2293275 conferred a high risk of PCOS progression in the North Indian population [72].

Genetic analysis of 150 PCOS families of European and Caribbean origin for pathogenic mutations, in a total of 37 potential candidate genes, resulted in no significant correlation between the LH gene and PCOS [73].

### **6.5** *FSHR* **(follicle-stimulating hormone receptor) gene**

The locus for the *FSHR* gene (ENSG00000170820) is 2p21 and it is approximately 54 kbp in size. This gene codes for a total of five mRNA transcripts, out of which only three code for the functional protein- follicle-stimulating hormone (FSH). The largest transcript (ENST00000406846.7) is 2762 bp with 695 amino acids with an approximate molecular weight of 30 kDa. FSH promotes oogenesis, follicle development, and gametogenesis, which results in follicular maturation and granulosa cell proliferation [74].

Mutations in *FSHR* gene have been associated with ovarian hyperstimulation syndrome, ovarian cancer, premature ovarian insufficiency with resistant ovary syndrome, etc. Hypogonadotropic hypogonadism is caused by an inactivating mutation in the *FSHR* gene, which also causes arrests of the preantral stage of follicle development [75].

GWAS study in Han Chinese population by Shi et al. reported the association of the *FSHR* gene with PCOS [76]. Two SNPs, Thr307Ala and Asn680Ser in exon 10 of the *FSHR* gene have been found to be associated with PCOS from Italian [77] and South Korean populations [78]. While the SNP (rs2268361) was reported to be associated with PCOS in the Chinese population [79] it was not in the Dutch population [80].

### **6.6** *AMH* **(anti-Mullerian hormone) gene**

The locus for the *AMH* gene (ENSG00000104899) is 19p13.3. *AMH* gene codes for a total of three transcripts out of which only one transcript (ENST00000221496.5) encodes the functional protein-Anti-mullerian hormone (AMH). The size of the gene is 2.8 kbp with 5 exons. The AMH protein is a homo-dimeric precursor protein and has a molecular weight of approximately 140 kDa. The two-polypeptide chains contain a large N-terminal prodomain and a small C-terminal mature domain. The Sertoli and granulosa cells contain the major transcription initiation site, located 10 bp upstream of the ATG codon.

Amh protein has been found to suppress the release of estradiol (E2) and limit the development of ovarian follicles in response to serum FSH in the cells [81]. It regulates the early change from primordial follicles that are at rest, to developing follicles in females. Studies have reported that AMH−/+gene null mice recruit more primordial follicles as compared to wild-type mice but also show an early depletion of their primordial follicles stock [82]. The primary pathophysiologic circumstance for the start of PCOS is follicular arrest, which is caused by Amh's interference with follicular development and recruitment. Amh also suppresses FSH-induced aromatase activity, which promotes the development of other PCOS-related clinical symptoms such as excess androgen and insulin resistance [83].

Zheng et al. reported that *AMH* gene polymorphism (rs10407022) is linked to insulin resistance in PCOS patients from China [84]. An unbiased WGS analysis of 80 PCOS patients by Gorsic et al. resulted in identifying a total of 24 rare variants in patients of European ancestry [85].

Kevenaar and co-workers reported that genetic variants in the *AMH* and *AMHR2* genes did not influence PCOS susceptibility in Dutch Caucasian patients, however, they found that AMH Ile49Ser polymorphism had a positive correlation with follicle number and androgen levels [86].

### **6.7** *AR* **(androgen receptor) gene**

The locus for the *AR* gene (ENSG00000169083) is Xq12 and it has a size of 90 kbp. This gene has a total of eight transcripts out of which only three codes for the proteinandrogen receptor protein.

The AR protein has three major domains, the N-terminal domain, the DNAbinding domain, and the androgen-binding domain. It belongs to a family of nuclear transcription factors. In humans, AR is present in theca interna cells and granulosa cells of preantral follicles, antral follicles, and dominant follicles. The first exon of the AR gene embeds a VNTR polymorphism consisting of CAG repeats those codes for a polyglutamine chain in the N-terminal transactivation domain.

A study by Hickey et al. reported a significantly higher frequency of alleles with longer CAG repeats (>22 repeats) in PCOS patients with infertility compared to fertile Caucasian women from Australian [87]. However, Mifsud et al. found no significant differences between the anovulatory PCOS patients and controls in the distribution of the CAG repeats [88]. Xia et al. reported that shorter alleles of the (CAG)n in the first exon of *AR* gene enhanced the PCOS susceptibility either by upregulating AR activity or resulting in hyperandrogenism in the PCOS patients from China [89] and these findings were also corroborated in the Caucasian population [90]. Rajender et al. reported that CAG bi-allelic mean length and allele distribution did not differ between controls and cases in PCOS cases from India [91].

At least two separate studies from the Chinese population have reported an association between higher serum testosterone levels in PCOS with CAG repeat length [92, 93]. Peng and coworkers reported that the SNP (rs6152G/A) leads to significantly higher susceptibility to polycystic ovary syndrome in Chinese patients [94]. Yuan et al. reported a positive correlation between GGN repeat polymorphism in the *AR* gene and PCOS in the Han Chinese population [95].

### **6.8** *SHBG* **(sex hormone binding globulin) gene**

The locus of the *SHBG* gene (ENSG00000129214) is 17p13. This gene codes for a total of 21 mRNA transcripts out of which only seventeen codes for the functional protein-sex hormone-binding globulin or sex steroid-binding globulin protein. The largest transcript (ENST00000380450.9) is 1267 bp long and has 402 amino acids with an approximate molecular weight of 90 kDa.

SHBG controls the level of sex hormones by binding to androgens, mainly with testosterone and estrogens. It is primarily synthesized by hepatocytes and controlled by multiple metabolic factors, such as androgens and insulin. The SHBG receptors are expressed in human sex-steroid-dependent cells and a wide range of tissues that include hypothalamus, colon, ovaries, prostate, etc. [96]. Concentrations of SHBG are lower in females with PCOS, due to the inhibitory effect of hyperinsulinemia

on SHBG synthesis [97]. Low serum SHBG levels in PCOS women also result in hyperandrogenic symptoms such as hirsutism, acne, androgenic alopecia, and virilization [98, 99].

Hogeveen et al. reported two novel mutations, firstly, Pro156Leu, associated with abnormal glycosylation and low SHBG secretion, and a frameshift mutation in exon 8 (E326) which resulted in truncated SHBG synthesis, in a PCOS patient from France [100]. Xita et al. reported that longer allele genotypes showed a positive association with lower SHBG levels in PCOS women from Greece [101]. The same group had further reported that the combination of long *SHBG* alleles with short *CYP19* alleles results in increased testosterone levels, elevated levels of Free androgen index (FAI), Dehydroepiandrosterone-sulphate hormone (DHEAS), T/E2 ratios and low SHBG levels [102]. An independent study on PCOS women from Bahrain by Abu-Hijleh and co-workers reported that specific *SHBG* variants and haplotypes spanning six polymorphisms were linked to increased or decreased PCOS susceptibility [103].

### **6.9** *INS* **(insulin) gene**

The locus for the *INS* gene (ENSG00000254647) is 11p15.5. This gene codes for a total of 5 transcripts out of which only four codes for a functional protein. The largest transcript (ENST00000381330.5) is 465 bp long with 110 amino acids and codes for the Insulin protein. It has a variable tandem repeat (VNTR) embedded at its 5′ regulatory region ranging between 26 and 200 in number. The VNTR polymorphism in the *INS* gene has three size classes. Class-I, II and III comprises of an average length of 40, 80 and an average of 157 repeats respectively [9].

Waterworth et al. [104] reported an association of PCOS with allelic variations in the INS VNTR locus. They had observed that the class III alleles were associated with anovulatory PCOS in populations from the UK. The transmission of these allelic variations was more commonly from fathers than from mothers to affected daughters. The same study also observed that the geometric mean of fasting serum insulin concentrations was significantly higher in families with evidence of linkage [104]. Michelmore et al. demonstrated that women with polycystic ovarian morphology had increased insulin sensitivity and leptin resistance, related to insulin gene VNTR class III alleles [105].

Multiple independent studies of *INS* VNTR polymorphisms with PCOS found no signification association in Spanish [106], Czech women [107], United Kingdom, and Finland populations [108].

### **6.10** *INSR* **(insulin receptor) gene**

The locus for the *INSR* gene (ENSG00000171105) is 19p13.2. This gene has 7 available transcripts out of which only three code for the protein, insulin receptor. The largest transcript (ENST00000302850.10) is 9463 bp long with 1382 amino acids. It is a hetero-tetrameric glycoprotein composed of two *α* and two *β*-subunits and plays a significant role in insulin metabolism. The significance of the insulin signaling in PCOS is substantiated by the HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans) [109]. Insulin resistance results in pituitary LH hypersecretion, increased testosterone production in theca cells, increased P450scc activity in granulosa cells, and disruption of follicular maturation, all of which contribute to PCOS susceptibility [110].

*Genetics and Epigenetics of Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.113187*

Two independent research groups have reported that the C/T SNP at His1058 in the seventeen exon of the *INSR* gene is associated with PCOS in the Caucasian and Chinese populations [111, 112]. Jin et al. reported a novel T/C polymorphism at Cys1008 resulting in decreased insulin sensitivity in Chinese PCOS women [113]. A microsatellite marker D19S884, located on chromosome 19p13.2, close to the *INSR* gene has been reported to be associated with PCOS in the Caucasian [114] and European population [115].

Mukherjee et al. found a significant association of C/T polymorphism at His1058 of the *INSR* gene in lean PCOS women while not in obese PCOS patients from Maharashtra, India [116].

### **6.11** *PPARG* **(peroxisome proliferator-activated receptor-gamma) gene**

The locus for the *PPARG* gene (ENSG00000132170) is 3p25.2. The size of the gene is approximately 100 kb with 9 exons. *PPARG* gene has a total of 34 transcripts and only twenty-two codes for the functional protein, peroxisome proliferator-activated receptor-γ. PPARG is primarily found in adipose tissue and large intestine and intermediate levels are found in the kidney, liver, and small intestine in humans and is involved in energy metabolism and adipogenesis pathway. Mutations in this gene have been linked to Partial lipodystrophy, type 2 diabetes, and dyslipidemia [117].

Hahn et al. [118] and Shaikh et al. [119] reported that a Pro12Ala polymorphism (rs1801282) of the PPARG gene in PCOS women is associated with lower hirsutism scores and increased insulin sensitivity in German and Indian population respectively. Studies by Korhonen et al. [120] and Yilmaz et al. [121] have also reported the role of this SNP in the pathogenesis of PCOS and supported its role as a protective factor against the development of diabetes mellitus in first-degree relatives of PCOS patients. Zhang et al. performed a metanalysis and reported the rs1801282 C > G polymorphism to be a protective factor in PCOS susceptibility [122].

### **7. Epigenetics of PCOS**

The term "epigenetics" is used to describe variations that are not encoded by changes in DNA sequence and refer to several cellular elements and processes that are involved in the regulation of transcription that includes DNA modifications, noncoding RNAs, chromatin structure, and nuclear architecture. The epigenetic changes are usually transient and are heritable in daughter cells post division [123].

Wang et al. [124] reported 7929 differentially methylated CpG sites and 650 differential transcripts by combining DNA methylation profile and transcriptome analysis, in the ovaries of PCOS patients of Chinese origin. In the same study, they identified 54 genes with methylated levels correlating with gene transcription in PCOS. They also found increased hypomethylated sites and less hypermethylated sites, residing in CpG islands and N\_Shore in PCOS [124]. Yu et al. [125] observed that the level of methylation was significantly higher in CpG island shores and lower within the gene bodies in Chinese cohort of PCOS patients. This study also reported that high CpG content promoters were frequently hypermethylated in PCOS ovaries but were hypomethylated in case controls [125]. Jones and coworkers identified increased methylation in the *INSR* locus and reduced methylation in the *LHCGR* locus in PCOS patients from the USA [126]. Kokosar et al. identified 440 sites with differential CpG methylation in the adipose tissue of PCOS patients [127]. Xu and

coworkers [128] reported that DNA methylation altered the PCOS granulosa cells while hydroxymethylation did not have any significant effect. They identified 6936 differentially methylated CpG sites between the control and PCOS-obesity patients and 12,245 differentially methylated CpG sites were identified between the control and PCOS-nonobesity group [128]. Nillson et al. [129] found 85 differentially expressed transcripts in the skeletal muscles of PCOS patients but only two CpG sites exhibited differential DNA methylation after multiple testing. In the same study, they also reported that PCOS has epigenetic and transcriptional changes in skeletal muscle that can explain the metabolic abnormalities seen in these patients [129]. Sagvekar et al. reported that intrinsic changes in the transcriptional control of TETs and DNMT3A may contribute to DNA methylation modifications in CGCs of PCOS women in India [130].

### **8. Conclusion**

PCOS is a serious multifactorial disorder of women in the reproductive age group resulting primarily in infertility and other gynecological issues. The etiopathology of PCOS is poorly understood. This disease presents itself differently in different ethnic groups, with few characteristics showing more in one population, and other sets of characteristics in another. While different medical organizations/associations have proposed the diagnostic criteria for PCOS based on the different clinical signs and symptoms, there is still a gray area; none of these classifications consider any molecular genetics aspects.

The role of genetic and epigenetic factors in PCOS has been widely substantiated by extensive research findings from different parts of the world in the literature. In the current book chapter, we have provided insight into the genetic and epigenetic factors that are associated with PCOS.

The results of the molecular studies along with the clinical data/ current diagnostic parameters might help in the identification of novel molecular markers to detect all PCOS phenotypes, grading the severity and in better understanding of the etiopathology of PCOS patients and thereby aiding in better clinical management.

### **Acknowledgements**

Ms. Adity Paul acknowledges the financial support received in the form of a fellowship from Tezpur University.

### **Conflict of interest**

The authors declare no conflict of interest.

*Genetics and Epigenetics of Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.113187*

### **Author details**

Surya Prakash Goud Ponnam\* and Adity Paul Department of Molecular Biology and Biotechnology, School of Sciences, Tezpur University, Sonitpur, Assam, India

\*Address all correspondence to: surya\_p@tezu.ac.in

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. American Journal of Obstetrics and Gynecology. 1935;**29**(2):181-191. DOI: 10.1016/S0002-9378(15)30642-6

[2] Sadeghi HM, Adeli I, Calina D, et al. Polycystic ovary syndrome: A comprehensive review of pathogenesis, management, and drug repurposing. International Journal of Molecular Sciences. 2022;**23**(2):583. DOI: 10.3390/ ijms23020583

[3] Ding DC, Chen W, Wang JH, Lin SZ. Association between polycystic ovarian syndrome and endometrial, ovarian, and breast cancer: A population-based cohort study in Taiwan. Medicine (Baltimore). 2018;**97**(39):e12608. DOI: 10.1097/ MD.0000000000012608

[4] Zehra B, Khursheed AA. Polycystic ovarian syndrome: Symptoms, treatment and diagnosis: A review. Journal of Pharmacognosy and Phytochemistry. 2018;**7**(6):875-880

[5] Jonard S, Dewailly D. The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest. Human Reproduction Update. 2004;**10**(2):107-117. DOI: 10.1093/ humupd/dmh010

[6] Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: International consensus definitions. Human Reproduction Update. 2003;**9**(6):505- 514. DOI: 10.1093/humupd/dmg044

[7] Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management

of polycystic ovary syndrome. Human Reproduction. 2018;**33**(9):1602-1618

[8] Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: A systematic review and meta-analysis. Human Reproduction Update. 2010;**16**(4):347-363. DOI: 10.1093/ humupd/dmq001

[9] Ataie-Ashtiani S, Forbes B. A review of the biosynthesis and structural implications of insulin gene mutations linked to human disease. Cell. 2023;**12**(7):1008. DOI: 10.3390/ cells12071008

[10] Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nature Reviews. Disease Primers. 2016;**2**:16057. DOI: 10.1038/nrdp.2016.57

[11] Liu J, Wu Q, Hao Y, et al. Measuring the global disease burden of polycystic ovary syndrome in 194 countries: Global burden of disease study 2017. Human Reproduction. 2021;**36**(4):1108-1119. DOI: 10.1093/humrep/deaa371

[12] Bulsara J, Patel P, Soni A, Acharya A. A review: Brief insight into polycystic ovarian syndrome. Endocrine and Metabolic Science. 2021;**3**:100085

[13] Ding T, Hardiman PJ, Petersen I, et al. The prevalence of polycystic ovary syndrome in reproductive-aged women of different ethnicity: A systematic review and meta-analysis. Oncotarget. 2017;**8**(56):96351-96358. DOI: 10.18632/ oncotarget.19180

[14] Zhao Y, Qiao J. Ethnic differences in the phenotypic expression of polycystic ovary syndrome. Steroids.

*Genetics and Epigenetics of Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.113187*

2013;**78**(8):755-760. DOI: 10.1016/j. steroids.2013.04.006

[15] Okoroh EM, Hooper WC, Atrash HK, et al. Prevalence of polycystic ovary syndrome among the privately insured, United States, 2003-2008. American Journal of Obstetrics and Gynecology. 2012;**207**(4):299.e1-299.e7. DOI: 10.1016/j. ajog.2012.07.023

[16] Kumarapeli V, Seneviratne Rde A, Wijeyaratne CN, et al. A simple screening approach for assessing community prevalence and phenotype of polycystic ovary syndrome in a semi-urban population in Sri Lanka. American Journal of Epidemiology. 2008;**168**(3):321-328. DOI: 10.1093/aje/ kwn137

[17] Tehrani FR, Simbar M, Tohidi M, et al. The prevalence of polycystic ovary syndrome in a community sample of Iranian population: Iranian PCOS prevalence study. Reproductive Biology and Endocrinology. 2011;**9**:39. DOI: 10.1186/1477-7827-9-39

[18] Yang R, Li Q, Zhou Z, et al. Changes in the prevalence of polycystic ovary syndrome in China over the past decade. Lancet Regional Health – Western Pacific. 2022;**25**:100494. DOI: 10.1016/j. lanwpc.2022.100494

[19] Gill H, Tiwari P, Dabadghao P. Prevalence of polycystic ovary syndrome in young women from North India: A community-based study. Indian Journal of Endocrinology and Metabolism. 2012;**16**(Suppl 2):S389-S392. DOI: 10.4103/2230-8210.104104

[20] Joshi B, Mukherjee S, Patil A, et al. A cross-sectional study of polycystic ovarian syndrome among adolescent and young girls in Mumbai, India. Indian Journal of Endocrinology and

Metabolism. 2014;**18**(3):317-324. DOI: 10.4103/2230-8210.131162

[21] Bharali MD, Rajendran R, Goswami J, et al. Prevalence of polycystic ovarian syndrome in India: A systematic review and meta-analysis. Cureus. 2022;**14**(12):e32351. DOI: 10.7759/ cureus.32351

[22] Dumesic DA, Oberfield SE, Stener-Victorin E, et al. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocrine Reviews. 2015;**36**(5):487-525. DOI: 10.1210/ er.2015-1018

[23] Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and Sterility. 2004;**81**(1):19-25. DOI: 10.1016/j.fertnstert.2003.10.004

[24] Azziz R, Carmina E, Dewailly D, et al. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: The complete task force report. Fertility and Sterility. 2009;**91**(2):456-488. DOI: 10.1016/j. fertnstert.2008.06.035

[25] Clark NM, Podolski AJ, Brooks ED, et al. Prevalence of polycystic ovary syndrome phenotypes using updated criteria for polycystic ovarian morphology: An assessment of over 100 consecutive women self-reporting features of polycystic ovary syndrome. Reproductive Sciences. 2014;**21**(8):1034- 1043. DOI: 10.1177/1933719114522525

[26] Cooper HE, Spellacy WN, Prem KA, Cohen WD. Hereditary factors in the Stein-Leventhal syndrome. American Journal of Obstetrics and Gynecology.

1968;**100**(3):371-387. DOI: 10.1016/ s0002-9378(15)33704-2

[27] Wilroy RS Jr, Givens JR, Wiser WL, et al. Hyperthecosis: An inheritable form of polycystic ovarian disease. Birth Defects Original Article Series. 1975;**11**(4):81-85

[28] Ferriman D, Purdie AW. The inheritance of polycystic ovarian disease and a possible relationship to premature balding. Clinical Endocrinology. 1979;**11**(3):291-300. DOI: 10.1111/j.1365- 2265.1979.tb03077.x

[29] Jahanfar S, Eden JA, Warren P, et al. A twin study of polycystic ovary syndrome. Fertility and Sterility. 1995;**63**(3):478-486

[30] Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twinfamily study. The Journal of Clinical Endocrinology and Metabolism. 2006;**91**(6):2100-2104. DOI: 10.1210/ jc.2005-1494

[31] Heidarzadehpilehrood R, Pirhoushiaran M, Abdollahzadeh R, et al. A review on *CYP11A1*, *CYP17A1*, and *CYP19A1* polymorphism studies: Candidate susceptibility genes for polycystic ovary syndrome (PCOS) and infertility. Genes (Basel). 2022;**13**(2):302. DOI: 10.3390/genes13020302

[32] Gharani N, Waterworth DM, Batty S, et al. Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Human Molecular Genetics. 1997;**6**(3):397-402. DOI: 10.1093/ hmg/6.3.397

[33] Diamanti-Kandarakis E, Bartzis MI, Bergiele AT, et al. Microsatellite polymorphism (tttta)(n) at −528 base pairs of gene CYP11alpha

influences hyperandrogenemia in patients with polycystic ovary syndrome. Fertility and Sterility. 2000;**73**(4):735-741. DOI: 10.1016/ s0015-0282(99)00628-7

[34] Wang Y, Wu XK, Cao YX, et al. Microsatellite polymorphism of (tttta) n in the promoter of CYP11a gene in Chinese women with polycystic ovary syndrome. Zhonghua Yi Xue Za Zhi. 2005;**85**(48):3396-3400

[35] Zhang CW, Zhang XL, Xia YJ, et al. Association between polymorphisms of the CYP11A1 gene and polycystic ovary syndrome in Chinese women. Molecular Biology Reports. 2012;**39**(8):8379-8385. DOI: 10.1007/s11033-012-1688-7

[36] Pusalkar M, Meherji P, Gokral J, et al. CYP11A1 and CYP17 promoter polymorphisms associate with hyperandrogenemia in polycystic ovary syndrome. Fertility and Sterility. 2009;**92**(2):653-659. DOI: 10.1016/j. fertnstert.2008.07.016

[37] Reddy KR, Deepika ML, Supriya K, et al. CYP11A1 microsatellite (tttta) n polymorphism in PCOS women from South India. Journal of Assisted Reproduction and Genetics. 2014;**31**(7):857-863. DOI: 10.1007/ s10815-014-0236-x

[38] Gaasenbeek M, Powell BL, Sovio U, et al. Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone. The Journal of Clinical Endocrinology and Metabolism. 2004;**89**(5):2408-2413. DOI: 10.1210/ jc.2003-031640

[39] Gilling-Smith C, Willis DS, Beard RW, Franks S. Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. The Journal of Clinical Endocrinology and Metabolism. *Genetics and Epigenetics of Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.113187*

1994;**79**(4):1158-1165. DOI: 10.1210/ jcem.79.4.7962289

[40] Escobar-Morreale H, Pazos F, Potau N, et al. Ovarian suppression with triptorelin and adrenal stimulation with adrenocorticotropin in functional hyperadrogenism: Role of adrenal and ovarian cytochrome P450c17 alpha. Fertility and Sterility. 1994;**62**(3):521-530. DOI: 10.1016/ s0015-0282(16)56940-4

[41] Wickenheisser JK,

Nelson-DeGrave VL, Quinn PG, McAllister JM. Increased cytochrome P450 17alpha-hydroxylase promoter function in theca cells isolated from patients with polycystic ovary syndrome involves nuclear factor-1. Molecular Endocrinology. 2004;**18**(3):588-605. DOI: 10.1210/me.2003-0090

[42] Wickenheisser JK,

Nelson-Degrave VL, McAllister JM. Dysregulation of cytochrome P450 17alpha-hydroxylase messenger ribonucleic acid stability in theca cells isolated from women with polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 2005;**90**(3):1720-1727. DOI: 10.1210/ jc.2004-1860

[43] Carey AH, Waterworth D, Patel K, et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Human Molecular Genetics. 1994;**3**(10):1873-1876. DOI: 10.1093/ hmg/3.10.1873

[44] Diamanti-Kandarakis E, Bartzis MI, Zapanti ED, et al. Polymorphism T-->C (−34 bp) of gene CYP17 promoter in Greek patients with polycystic ovary syndrome. Fertility and Sterility. 1999;**71**(3):431-435. DOI: 10.1016/ s0015-0282(98)00512-3

[45] Li Y, Liu F, Luo S, et al. Polymorphism T→C of gene CYP17 promoter and polycystic ovary syndrome risk: A meta-analysis. Gene. 2012;**495**(1):16-22. DOI: 10.1016/j. gene.2011.12.048

[46] Pérez MS, Cerrone GE, Benencia H, et al. Polymorphism in CYP11alpha and CYP17 genes and the etiology of hyperandrogenism in patients with polycystic ovary syndrome. Medicina (B Aires). 2008;**68**(2):129-134

[47] Kaur R, Kaur T, Kaur A. Genetic association study from North India to analyze association of CYP19A1 and CYP17A1 with polycystic ovary syndrome. Journal of Assisted Reproduction and Genetics. 2018;**35**(6):1123-1129. DOI: 10.1007/ s10815-018-1162-0

[48] Gharani N, Waterworth DM, Williamson R, Franks S. 5′ polymorphism of the CYP17 gene is not associated with serum testosterone levels in women with polycystic ovaries. The Journal of Clinical Endocrinology and Metabolism. 1996;**81**(11):4174. DOI: 10.1210/ jcem.81.11.8923880

[49] Marszalek B, Laciński M, Babych N, et al. Investigations on the genetic polymorphism in the region of CYP17 gene encoding 5'-UTR in patients with polycystic ovarian syndrome. Gynecological Endocrinology. 2001;**15**(2):123-128. DOI: 10.1080/ gye.15.2.123.128

[50] Kahsar-Miller M, Boots LR, Bartolucci A, Azziz R. Role of a CYP17 polymorphism in the regulation of circulating dehydroepiandrosterone sulfate levels in women with polycystic ovary syndrome. Fertility and Sterility. 2004;**82**(4):973-975. DOI: 10.1016/j. fertnstert.2004.05.068

[51] Unsal T, Konac E, Yesilkaya E, et al. Genetic polymorphisms of FSHR, CYP17, CYP1A1, CAPN10, INSR, SERPINE1 genes in adolescent girls with polycystic ovary syndrome. Journal of Assisted Reproduction and Genetics. 2009;**26**(4):205-216. DOI: 10.1007/ s10815-009-9308-8

[52] Simpson ER, Clyne C, Rubin G, et al. Aromatase--A brief overview. Annual Review of Physiology. 2002;**64**:93-127. DOI: 10.1146/annurev. physiol.64.081601.142703

[53] Medeiros SF, Barbosa JS, Yamamoto MM. Comparison of steroidogenic pathways among normoandrogenic and hyperandrogenic polycystic ovary syndrome patients and normal cycling women. The Journal of Obstetrics and Gynaecology Research. 2015;**41**(2):254-263. DOI: 10.1111/ jog.12524

[54] Petry CJ, Ong KK, Michelmore KF, et al. Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women. Human Reproduction. 2005;**20**(7):1837-1843. DOI: 10.1093/ humrep/deh900

[55] Yu YY, Sun CX, Liu YK, et al. Promoter methylation of CYP19A1 gene in Chinese polycystic ovary syndrome patients. Gynecologic and Obstetric Investigation. 2013;**76**(4):209-213. DOI: 10.1159/000355314

[56] Chen J, Shen S, Tan Y, et al. The correlation of aromatase activity and obesity in women with or without polycystic ovary syndrome. Journal of Ovarian Research. 2015;**8**:11. DOI: 10.1186/s13048-015-0139-1

[57] Sowers MR, Wilson AL, Kardia SR, et al. Aromatase gene (CYP 19) polymorphisms and endogenous

androgen concentrations in a multiracial/ multiethnic, multisite study of women at midlife. The American Journal of Medicine. 2006;**119**(9 Suppl 1):S23-S30. DOI: 10.1016/j.amjmed.2006.07.003

[58] Jin JL, Sun J, Ge HJ, et al. Association between CYP19 gene SNP rs2414096 polymorphism and polycystic ovary syndrome in Chinese women. BMC Medical Genetics. 2009;**10**:139. DOI: 10.1186/1471-2350-10-139

[59] Mehdizadeh A, Kalantar SM, Sheikhha MH, et al. Association of SNP rs.2414096 CYP19 gene with polycystic ovarian syndrome in Iranian women. International Journal of Reproductive BioMedicine. 2017;**15**(8):491-496

[60] Hao CF, Zhang N, Qu Q, et al. Evaluation of the association between the CYP19 tetranucleotide (TTTA)n polymorphism and polycystic ovarian syndrome(PCOS) in Han Chinese women. Neuro Endocrinology Letters. 2010;**31**(3):370-374

[61] Lazaros L, Xita N, Hatzi E, et al. CYP19 gene variants affect the assisted reproduction outcome of women with polycystic ovary syndrome. Gynecological Endocrinology. 2013;**29**(5):478-482. DOI: 10.3109/09513590.2013.774359

[62] Ashraf S, Rasool SUA, Nabi M, et al. Impact of rs2414096 polymorphism of CYP19 gene on susceptibility of polycystic ovary syndrome and hyperandrogenism in Kashmiri women. Scientific Reports. 2021;**11**(1):12942. DOI: 10.1038/s41598-021-92265-1

[63] Dufau ML. The luteinizing hormone receptor. Annual Review of Physiology. 1998;**60**:461-496. DOI: 10.1146/annurev. physiol.60.1.461

*Genetics and Epigenetics of Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.113187*

[64] Balen AH. Hypersecretion of luteinizing hormone and the polycystic ovary syndrome. Human Reproduction. 1993;**8**(Suppl 2):123-128. DOI: 10.1093/ humrep/8.suppl\_2.123

[65] Furui K, Suganuma N, Tsukahara S, et al. Identification of two point mutations in the gene coding luteinizing hormone (LH) beta-subunit, associated with immunologically anomalous LH variants. The Journal of Clinical Endocrinology and Metabolism. 1994;**78**(1):107-113. DOI: 10.1210/ jcem.78.1.7904610

[66] Nilsson C, Pettersson K, Millar RP, et al. Worldwide frequency of a common genetic variant of luteinizing hormone: An international collaborative research. International Collaborative Research Group. Fertility and Sterility. 1997;**67**(6):998-1004. DOI: 10.1016/ s0015-0282(97)81430-6

[67] Takahashi K, Karino K, Kanasaki H, et al. Influence of missense mutation and silent mutation of LHbeta-subunit gene in Japanese patients with ovulatory disorders. European Journal of Human Genetics. 2003;**11**(5):402-408. DOI: 10.1038/sj.ejhg.5200968

[68] Chen ZJ, Zhao H, He L, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nature Genetics. 2011;**43**(1):55-59. DOI: 10.1038/ng.732

[69] Mutharasan P, Galdones E, Peñalver Bernabé B, et al. Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry. The Journal of Clinical Endocrinology and Metabolism. 2013;**98**(1):E185-E190. DOI: 10.1210/jc.2012-2471

[70] Capalbo A, Sagnella F, Apa R, et al. The 312N variant of the luteinizing

hormone/choriogonadotropin receptor gene (LHCGR) confers up to 2·7-fold increased risk of polycystic ovary syndrome in a Sardinian population. Clinical Endocrinology. 2012;**77**(1):113-119. DOI: 10.1111/j.1365-2265.2012.04372.x

[71] Thathapudi S, Kodati V, Erukkambattu J, et al. Association of luteinizing hormone chorionic gonadotropin receptor gene polymorphism (rs2293275) with polycystic ovarian syndrome. Genetic Testing and Molecular Biomarkers. 2015;**19**(3):128-132. DOI: 10.1089/ gtmb.2014.0249

[72] Singh S, Kaur M, Kaur R, et al. Association analysis of LHCGR variants and polycystic ovary syndrome in Punjab: A case-control approach. BMC Endocrine Disorders. 2022;**22**(1):335. DOI: 10.1186/s12902-022-01251-9

[73] Urbanek M, Legro RS, Driscoll DA, et al. Thirty-seven candidate genes for polycystic ovary syndrome: Strongest evidence for linkage is with follistatin. Proceedings of the National Academy of Sciences of the United States of America. 1999;**96**(15):8573-8578. DOI: 10.1073/ pnas.96.15.8573

[74] Gromoll J, Simoni M. Genetic complexity of FSH receptor function. Trends in Endocrinology and Metabolism. 2005;**16**(8):368-373. DOI: 10.1016/j.tem.2005.05.011

[75] Huhtaniemi I. The Parkes lecture. Mutations of gonadotrophin and gonadotrophin receptor genes: What do they teach us about reproductive physiology? Journal of Reproduction and Fertility. 2000;**119**(2):173-186. DOI: 10.1530/jrf.0.1190173

[76] Shi Y, Zhao H, Shi Y, et al. Genomewide association study identifies

eight new risk loci for polycystic ovary syndrome. Nature Genetics. 2012;**44**(9):1020-1025. DOI: 10.1038/ ng.2384

[77] Dolfin E, Guani B, Lussiana C, et al. FSH-receptor Ala307Thr polymorphism is associated to polycystic ovary syndrome and to a higher responsiveness to exogenous FSH in Italian women. Journal of Assisted Reproduction and Genetics. 2011;**28**(10):925-930. DOI: 10.1007/s10815-011-9619-4

[78] Gu BH, Park JM, Baek KH. Genetic variations of follicle stimulating hormone receptor are associated with polycystic ovary syndrome. International Journal of Molecular Medicine. 2010;**26**(1):107-112. DOI: 10.3892/ijmm\_00000441

[79] Du J, Zhang W, Guo L, et al. Two FSHR variants, haplotypes and meta-analysis in Chinese women with premature ovarian failure and polycystic ovary syndrome. Molecular Genetics and Metabolism. 2010;**100**(3):292-295. DOI: 10.1016/j.ymgme.2010.03.018

[80] Louwers YV, Stolk L, Uitterlinden AG, Laven JS. Cross-ethnic meta-analysis of genetic variants for polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 2013;**98**(12):E2006-E2012. DOI: 10.1210/jc.2013-2495

[81] Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Mullerian hormone in women. Human Reproduction Update. 2014;**20**(3):370-385. DOI: 10.1093/ humupd/dmt062

[82] Durlinger AL, Kramer P, Karels B, et al. Control of primordial follicle recruitment by anti-Müllerian hormone in the mouse ovary. Endocrinology. 1999;**140**(12):5789-5796. DOI: 10.1210/endo.140.12.7204

[83] Bhattacharya K, Saha I, Sen D, et al. Role of anti-Mullerian hormone in polycystic ovary syndrome. Middle East Fertility Society Journal. 2022;**27**:32. DOI: 10.1186/s43043-022-00123-5

[84] Zheng MX, Li Y, Hu R, et al. Anti-Müllerian hormone gene polymorphism is associated with androgen levels in Chinese polycystic ovary syndrome patients with insulin resistance. Journal of Assisted Reproduction and Genetics. 2016;**33**(2):199-205. DOI: 10.1007/ s10815-015-0641-9

[85] Gorsic LK, Kosova G, Werstein B, et al. Pathogenic anti-Müllerian hormone variants in polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 2017;**102**(8):2862-2872. DOI: 10.1210/jc.2017-00612

[86] Kevenaar ME, Laven JS, Fong SL, et al. A functional anti-mullerian hormone gene polymorphism is associated with follicle number and androgen levels in polycystic ovary syndrome patients. The Journal of Clinical Endocrinology and Metabolism. 2008;**93**(4):1310-1316. DOI: 10.1210/ jc.2007-2205

[87] Hickey T, Chandy A, Norman RJ. The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 2002;**87**(1):161-165. DOI: 10.1210/jcem.87.1.8137

[88] Mifsud A, Ramirez S, Yong EL. Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. The Journal of Clinical Endocrinology and Metabolism. 2000;**85**(9):3484-3488. DOI: 10.1210/jcem.85.9.6832

*Genetics and Epigenetics of Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.113187*

[89] Xia Y, Che Y, Zhang X, et al. Polymorphic CAG repeat in the androgen receptor gene in polycystic ovary syndrome patients. Molecular Medicine Reports. 2012;**5**(5):1330-1334. DOI: 10.3892/mmr.2012.789

[90] Lin LH, Baracat MC, Maciel GA, et al. Androgen receptor gene polymorphism and polycystic ovary syndrome. International Journal of Gynaecology and Obstetrics. 2013;**120**(2):115-118. DOI: 10.1016/j. ijgo.2012.08.016

[91] Rajender S, Carlus SJ, Bansal SK, et al. Androgen receptor CAG repeats length polymorphism and the risk of polycystic ovarian syndrome (PCOS). PLoS One. 2013;**8**(10):e75709. DOI: 10.1371/journal.pone.0075709

[92] Kim JJ, Choung SH, Choi YM, et al. Androgen receptor gene CAG repeat polymorphism in women with polycystic ovary syndrome. Fertility and Sterility. 2008;**90**(6):2318-2323. DOI: 10.1016/j. fertnstert.2007.10.030

[93] Peng CY, Xie HJ, Guo ZF, et al. The association between androgen receptor gene CAG polymorphism and polycystic ovary syndrome: A casecontrol study and meta-analysis. Journal of Assisted Reproduction and Genetics. 2014;**31**(9):1211-1219. DOI: 10.1007/ s10815-014-0286-0

[94] Peng CY, Long XY, Lu GX. Association of AR rs6152G/a gene polymorphism with susceptibility to polycystic ovary syndrome in Chinese women. Reproduction, Fertility, and Development. 2010;**22**(5):881-885. DOI: 10.1071/RD09190

[95] Yuan C, Gao C, Qian Y, et al. Polymorphism of CAG and GGN repeats of androgen receptor gene in women with polycystic ovary syndrome. Reproductive Biomedicine Online. 2015;**31**(6):790-798. DOI: 10.1016/j. rbmo.2015.09.007

[96] Rosner W, Hryb DJ, Kahn SM, et al. Interactions of sex hormone-binding globulin with target cells. Molecular and Cellular Endocrinology. 2010;**316**(1):79- 85. DOI: 10.1016/j.mce.2009.08.009

[97] Nestler JE, Powers LP, Matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 1991;**72**(1):83-89. DOI: 10.1210/ jcem-72-1-83

[98] Rannevik G, Jeppsson S, Johnell O, et al. A longitudinal study of the perimenopausal transition: Altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas. 1995;**21**(2):103-113. DOI: 10.1016/0378-5122(94)00869-9

[99] Burger HG, Dudley EC, Cui J, et al. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. The Journal of Clinical Endocrinology and Metabolism. 2000;**85**(8):2832-2838. DOI: 10.1210/ jcem.85.8.6740

[100] Hogeveen KN, Cousin P, Pugeat M, et al. Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction. The Journal of Clinical Investigation. 2002;**109**(7):973-981. DOI: 10.1172/JCI14060

[101] Xita N, Tsatsoulis A, Chatzikyriakidou A, Georgiou I. Association of the (TAAAA)n repeat polymorphism in the sex hormone-binding globulin (SHBG) gene with polycystic ovary

syndrome and relation to SHBG serum levels. The Journal of Clinical Endocrinology and Metabolism. 2003;**88**(12):5976-5980. DOI: 10.1210/ jc.2003-030197

[102] Xita N, Georgiou I, Lazaros L, et al. The synergistic effect of sex hormonebinding globulin and aromatase genes on polycystic ovary syndrome phenotype. European Journal of Endocrinology. 2008;**158**(6):861-865. DOI: 10.1530/ EJE-07-0905

[103] Abu-Hijleh TM, Gammoh E, Al-Busaidi AS, et al. Common variants in the sex hormone-binding globulin (SHBG) gene influence SHBG levels in women with polycystic ovary syndrome. Annals of Nutrition & Metabolism. 2016;**68**(1):66-74. DOI: 10.1159/000441570

[104] Waterworth DM, Bennett ST, Gharani N, et al. Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet. 1997;**349**(9057):986-990. DOI: 10.1016/ S0140-6736(96)08368-7

[105] Michelmore K, Ong K, Mason S, et al. Clinical features in women with polycystic ovaries: Relationships to insulin sensitivity, insulin gene VNTR and birth weight. Clinical Endocrinology. 2001;**55**(4):439-446. DOI: 10.1046/j.1365-2265.2001.01375.x

[106] Calvo RM, Tellería D, Sancho J, et al. Insulin gene variable number of tandem repeats regulatory polymorphism is not associated with hyperandrogenism in Spanish women. Fertility and Sterility. 2002;**77**(4):666-668. DOI: 10.1016/ s0015-0282(01)03238-1

[107] Vanková M, Vrbíková J, Hill M, et al. Association of insulin gene VNTR polymorphism with polycystic ovary

syndrome. Annals of the New York Academy of Sciences. 2002;**967**:558-565. DOI: 10.1111/j.1749-6632.2002.tb04317.x

[108] Powell BL, Haddad L, Bennett A, et al. Analysis of multiple data sets reveals no association between the insulin gene variable number tandem repeat element and polycystic ovary syndrome or related traits. The Journal of Clinical Endocrinology and Metabolism. 2005;**90**(5):2988-2993. DOI: 10.1210/ jc.2004-2485

[109] Rager KM, Omar HA. Androgen excess disorders in women: The severe insulin-resistant hyperandrogenic syndrome, HAIR-AN. Scientific World Journal. 2006;**6**:116-121. DOI: 10.1100/ tsw.2006.23

[110] Diamanti-Kandarakis E, Papavassiliou AG. Molecular mechanisms of insulin resistance in polycystic ovary syndrome. Trends in Molecular Medicine. 2006;**12**(7):324-332. DOI: 10.1016/j.molmed.2006.05.006

[111] Siegel S, Futterweit W, Davies TF, et al. A C/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovary syndrome. Fertility and Sterility. 2002;**78**(6):1240-1243. DOI: 10.1016/ s0015-0282(02)04241-3

[112] Chen ZJ, Shi YH, Zhao YR, et al. Correlation between single nucleotide polymorphism of insulin receptor gene with polycystic ovary syndrome. Zhonghua Fu Chan Ke Za Zhi. 2004;**39**(9):582-585

[113] Jin L, Zhu XM, Luo Q, et al. A novel SNP at exon 17 of INSR is associated with decreased insulin sensitivity in Chinese women with PCOS. Molecular Human Reproduction. 2006;**12**(3):151-155. DOI: 10.1093/molehr/gal022

*Genetics and Epigenetics of Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.113187*

[114] Tucci S, Futterweit W, Concepcion ES, et al. Evidence for association of polycystic ovary syndrome in caucasian women with a marker at the insulin receptor gene locus. The Journal of Clinical Endocrinology and Metabolism. 2001;**86**(1):446-449. DOI: 10.1210/jcem.86.1.7274

[115] Urbanek M, Woodroffe A, Ewens KG, et al. Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2. The Journal of Clinical Endocrinology and Metabolism. 2005;**90**(12):6623-6629. DOI: 10.1210/ jc.2005-0622

[116] Mukherjee S, Shaikh N, Khavale S, et al. Genetic variation in exon 17 of INSR is associated with insulin resistance and hyperandrogenemia among lean Indian women with polycystic ovary syndrome. European Journal of Endocrinology. 2009;**160**(5):855-862. DOI: 10.1530/EJE-08-0932

[117] Janani C, Ranjitha Kumari BD. PPAR gamma gene--a review. Diabetes and Metabolic Syndrome: Clinical Research and Reviews. 2015;**9**(1):46-50. DOI: 10.1016/j.dsx.2014.09.015

[118] Hahn S, Fingerhut A, Khomtsiv U, et al. The peroxisome proliferator activated receptor gamma Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome. Clinical Endocrinology. 2005;**62**(5):573- 579. DOI: 10.1111/j.1365-2265.2005.02261

[119] Shaikh N, Mukherjee A, Shah N, et al. Peroxisome proliferator activated receptor gamma gene variants influence susceptibility and insulin related traits in Indian women with polycystic ovary syndrome. Journal of Assisted Reproduction and Genetics. 2013;**30**(7):913-921. DOI: 10.1007/ s10815-013-0025-y

[120] Korhonen S, Heinonen S, Hiltunen M, et al. Polymorphism in the peroxisome proliferator-activated receptor-gamma gene in women with polycystic ovary syndrome. Human Reproduction. 2003;**18**(3):540-543. DOI: 10.1093/humrep/deg128

[121] Yilmaz M, Ergün MA, Karakoç A, et al. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma gene in first-degree relatives of subjects with polycystic ovary syndrome. Gynecological Endocrinology. 2005;**21**(4):206-210. DOI: 10.1080/09513590500231593

[122] Zhang S, Wang Y, Jiang H, et al. Peroxisome proliferator-activated receptor gamma rs1801282 C>G polymorphism is associated with polycystic ovary syndrome susceptibility: A meta-analysis involving 7,069 subjects. International Journal of Clinical and Experimental Medicine. 2015;**8**(10):17418-17429

[123] Stener-Victorin E, Deng Q. Epigenetic inheritance of polycystic ovary syndrome — Challenges and opportunities for treatment. Nature Reviews. Endocrinology. 2021;**17**:521-533. DOI: 10.1038/s41574-021-00517

[124] Wang XX, Wei JZ, Jiao J, et al. Genome-wide DNA methylation and gene expression patterns provide insight into polycystic ovary syndrome development. Oncotarget. 2014;**5**(16):6603-6610. DOI: 10.18632/ oncotarget.2224

[125] Yu YY, Sun CX, Liu YK, et al. Genome-wide screen of ovary-specific DNA methylation in polycystic ovary syndrome. Fertility and Sterility. 2015;**104**(1):145-53.e6. DOI: 10.1016/j. fertnstert.2015.04.005

[126] Jones MR, Brower MA, Xu N, et al. Systems genetics reveals the functional

context of PCOS loci and identifies genetic and molecular mechanisms of disease heterogeneity. PLoS Genetics. 2015;**11**(8):e1005455. DOI: 10.1371/ journal.pgen.1005455

[127] Kokosar M, Benrick A, Perfilyev A, et al. Epigenetic and transcriptional alterations in human adipose tissue of polycystic ovary syndrome. Scientific Reports. 2016;**6**:22883. DOI: 10.1038/ srep22883

[128] Xu J, Bao X, Peng Z, et al. Comprehensive analysis of genomewide DNA methylation across human polycystic ovary syndrome ovary granulosa cell. Oncotarget. 2016;**7**(19):27899-27909. DOI: 10.18632/ oncotarget.8544

[129] Nilsson E, Benrick A, Kokosar M, et al. Transcriptional and epigenetic changes influencing skeletal muscle metabolism in women with polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism. 2018;**103**(12):4465-4477. DOI: 10.1210/ jc.2018-00935

[130] Sagvekar P, Shinde G, Mangoli V, et al. Evidence for TET-mediated DNA demethylation as an epigenetic alteration in cumulus granulosa cells of women with polycystic ovary syndrome. Molecular Human Reproduction. 2022;**28**(7):gaac019. DOI: 10.1093/ molehr/gaac019

### **Chapter 2**

## Optimizing Nutrition for PCOS Management: A Comprehensive Guide

*Madan Pandey and Kritee Niroula*

### **Abstract**

This chapter aims to provide a comprehensive guide to optimizing nutrition for the management of polycystic ovary syndrome (PCOS), a hormonal disorder affecting reproductive-aged women that are associated with various metabolic and reproductive complications. It explores the critical role of nutrition in PCOS management, focusing on evidence-based dietary strategies to alleviate symptoms, promote hormonal balance, and enhance overall health outcomes. Beginning with the pathophysiology of PCOS, the chapter highlights the impact of insulin resistance, inflammation, and hormonal imbalances on the condition. The chapter provides practical guidelines for optimizing macronutrient intake, including recommendations for carbohydrate quality, protein sources, and fat composition. Additionally, it explores the potential benefits of dietary supplements and herbal remedies in PCOS management. It addresses key lifestyle factors—physical activity, stress management, and adequate sleep—which synergistically enhance nutrition in optimizing PCOS management. This valuable resource is tailored for healthcare professionals, nutritionists, and individuals with PCOS seeking evidence-based guidance on effectively managing this complex condition through optimized nutrition.

**Keywords:** polycystic ovary syndrome, endocrine-metabolic disorder, nutrition in PCOS, dietary therapy, dietary supplements

### **1. Introduction**

Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder affecting women of reproductive age [1]. It is a heterogeneous endocrine condition characterized by elevated androgen levels and endocrine variation, menstrual irregularities, and anovulation and/or small cysts on one or both ovaries that severely impact the life of a woman [2–4]. PCOS, marked by enlarged ovaries and amenorrhea, was characterized in 1935 by Stein and Leventhal. Extensive research since then aims to understand its molecular mechanisms and improve management. PCOS involves a complex interplay of genetic and environmental factors [5]. PCOS, known for reproductive issues, also poses metabolic risks like obesity, diabetes, and cardiovascular diseases. It adversely affects mental health, reducing quality of life. Weight reduction through lifestyle changes is crucial for managing and improving the reproductive, metabolic,

and psychological aspects of PCOS. Thus, lifestyle changes should be the primary management approach for PCOS [6].

### **2. Polycystic ovarian (PCO) physiology**

The ovarian follicles are functional units of the mammalian ovary, which are roughly spheroid cellular aggregations consisting of an oocyte (germ cell) surrounded by granulosa cells forming intercellular connections and further surrounded by theca cells [7, 8]. There are approximately 295,000 primordial follicles in the ovarian reserve per ovary of a female human child at birth [9, 10]. Follicular growth is coordinated, usually resulting in the selection of a single follicle for maturation and ovulation sequentially. Over time, the continual recruitment of more primordial follicles from this pool is a dynamic process. The regulation of the rate at which primordial follicles enter the growing pool has a crucial role in maintaining the ovarian reserve and safeguarding fertility. However, during PCOS, due to a potential dysregulation in the recruitment mechanism of primordial follicles for growth, a greater number of small antral follicles (2–9 mm in diameter) are formed than in the normal ovary. During a normal menstrual cycle, the luteinizing hormone (LH) response is limited to the dominant follicle, usually when it attains a diameter of around 10 mm. However, in individuals with PCOS, the LH response occurs unusually in smaller follicles. Consequently, a significant proportion of antral follicles undergo terminal differentiation before the appropriate time. As the antral follicles produce steroids (estrogen) and inhibin B, the presence of a large number of these follicles results in an increased production of a higher amount of steroids (estrogen) and inhibin B. They have negative feedback on the production of follicle-stimulating hormone (FSH). As FSH has a role in the maturation of the follicles and the release of the ovum, its imbalance leads to the arrest of follicular growth and the ovum is not released, creating a large number of cysts-like structures containing immature ovum [11–13]. PCOS is distinguished by an elevated count of follicles across all developmental stages, with a notable increase observed in the pre-antral and small antral follicles [14].

### **3. Pathophysiology of PCOS**

PCOS is a complex endocrine disorder involving genetics, environment, obesity, ovarian dysfunction, and hormonal imbalances like elevated androgens and hyperinsulinemia. It disrupts the hypothalamic-pituitary-ovarian (HPO) axis and leads to symptoms of excess androgens and irregular ovulation [6, 15]. Hyperandrogenism, often characterized by elevated levels of unbound (free) testosterone in the blood, is the prevailing anomaly in this syndrome and plays a significant role in perpetuating the irregular hormonal factors contributing to the pathophysiology of PCOS. PCOS is complex, with disruptions in the menstrual cycle, hyperandrogenism, and obesity. Ovarian dysfunction is crucial to its pathophysiology, involving multiple factors and genes [16]. Here are some of the complications of PCOS:

### **3.1 Hyperandrogenism**

Clinical and biochemical hyperandrogenism are major features of PCOS. Disruptions in hypothalamic-pituitary feedback, excessive LH secretion, premature luteinization of granulosa cells, irregular oocyte maturation, and premature arrest of activated primary follicles are associated with persistent hyperandrogenism [15]. Excessive ovarian androgen production is the result of a combination of intrinsic ovarian factors, such as alterations in steroidogenesis, and external factors, such as hyperinsulinemia [15].

### **3.2 Polycystic ovaries, ovulatory dysfunction**

A well-coordinated interaction of reproductive, metabolic, and intraovarian processes is necessary for ovulation. Follicle development is disrupted by ovarian hyperandrogenism, hyperinsulinemia due to insulin resistance (IR), and altered intraovarian paracrine signaling during PCOS. This disruption leads to follicular arrest, resulting in menstrual irregularities, anovulatory subfertility, and the accumulation of small antral follicles in the ovarian periphery, which imparts a polycystic morphology to the ovary [17].

### **3.3 Insulin resistance (IR), impaired lipid metabolism, obesity**

Excessive levels of androgens influence where fat is stored in the body. The pattern of fat accumulation is altered in hyperandrogenic women with PCOS [18]. Testosterone promotes visceral fat accumulation and IR [19]. Hyperinsulinemia then further exacerbates androgen generation. The anabolic effect of hyperinsulinemia on fat metabolism via the adipogenesis process results in an elevated uptake of glucose into adipocytes and the subsequent production of triglycerides, contributing to obesity [20]. Central obesity is a distinctive feature of PCOS, as evidenced by an elevated waist-to-hip ratio in these patients compared to obese women without PCOS. Hyperinsulinemia may contribute to the development of central adiposity, further exacerbating underlying or latent IR [21].

### **4. Complications and symptoms**

### **4.1 Menstrual abnormalities**

Chronic anovulation often manifests as various forms of menstrual irregularities such as secondary amenorrhea, oligomenorrhea, and dysfunctional uterine bleeding [21]. In PCOS, irregular menstrual cycles begin at menarche or shortly after, often progressing to oligomenorrhea or amenorrhea. Menstrual dysfunction, marked by anovulation and unpredictable bleeding, correlates with IR severity. Longer cycles, beyond 3 months, indicate higher IR. Amenorrhea in PCOS exacerbates IR. Prolonged anovulation results in irregular bleeding resembling regular periods. Chronic anovulation, especially in obesity, leads to atypical endometrial thickening, a precursor to endometrial cancer [20].

### **4.2 Hirsutism, acne, and male pattern alopecia**

Hirsutism, acne, and male pattern alopecia are manifestations of hyperandrogenism. Hirsutism, the growth of coarse pigmented hairs in androgen-dependent areas, including the face, chest, back, and lower abdomen, is driven by testosterone and dihydrotestosterone [20, 21].

Androgenic alopecia, a form of hair loss, is a less well-studied marker for androgen excess [16]. The balding pattern primarily affects the frontal and parietal scalp zones, with the occipital area maintaining a higher hair density [20].

In PCOS, acne is exacerbated because sebaceous glands, influenced by androgens, are sensitive structures that contribute to acne and seborrhoea intensified by sebaceous gland sensitivity [16, 20]. Androgens stimulate the proliferation of sebocytes and the secretion of sebum, which comprises lipids such as glycerides, squalene, free fatty acids (FFA), and cholesterol.

### **4.3 Dyslipidaemia**

The majority of PCOS patients exhibit dyslipidaemia, driven by factors like insulin, estrogen, and androgens influencing lipoprotein lipid metabolism. Elevated hepatic lipase activity, stimulated by insulin, plays a role in lipid alterations. Hyperandrogenism is linked to adverse lipid profiles, particularly testosterone's negative impact on lipids. The typical lipid profile in PCOS features elevated low-density lipoprotein (LDL) cholesterol, increased very low-density lipoprotein (VLDL) cholesterol, higher triglycerides, and reduced high-density lipoprotein (HDL) cholesterol. These lipid issues worsen in PCOS women with glucose intolerance [20].

### **4.4 Non-alcoholic fatty liver disease (NFALD)**

Common pathophysiological factors linking NAFLD and PCOS include obesity and IR. Elevated liver enzymes and IR are associated with both conditions. NAFLD worsens IR, aggravating it in PCOS. Conversely, IR leads to lipolysis, increasing hepatic fat accumulation and collagen production. Hyperandrogenism is linked to IR and affects NAFLD independently of it. Hyperandrogenic women with PCOS tend to have a higher liver fat [22].

### **4.5 Chronic inflammation, endothelial function, and atherosclerosis**

Chronic inflammation, endothelial dysfunction, and atherosclerosis are key considerations in understanding cardiovascular implications of PCOS. Endothelial injury is an early indication of cardiovascular issues. Testosterone levels in hyperandrogenic insulin-resistant women correlate with abnormal endothelial function. Mechanisms include reduced nitric oxide synthesis, enhanced inactivation, increased vasoconstrictor synthesis, and insulin's direct effects. Obesity exacerbates endothelial dysfunction and reduced adiponectin in PCOS further contributes. PCOS, a proinflammatory state, links chronic inflammation to metabolic and ovarian dysfunction. Elevated C-reactive protein promotes atherosclerosis and endothelial cell inflammation, raising cardiovascular risk [20].

### **4.6 Gestational diabetes mellitus (GDM) and diabetes mellitus (DM)**

In a typical pregnancy, maternal carbohydrate metabolism changes, including pancreatic β-cell hyperplasia and increased insulin sensitivity, followed by the development of insulin resistance (IR). Women with PCOS, already predisposed to IR, face a higher risk of gestational diabetes mellitus (GDM) due to these changes. The pathophysiology involves IR and abnormalities in β-cell glucose sensitivity, resulting in inadequate insulin response. Pregnancy-related IR, combined with pre-existing IR in

PCOS, heightens the risk. PCOS women with GDM also face an increased likelihood of impaired glucose tolerance post-delivery. Their heightened risk of progressing to impaired glucose metabolism and type II diabetes (T2D) is influenced by a prevalent family history of T2D. Diabetes may contribute more significantly to mortality rates in PCOS women compared to the general population [20].

### **4.7 Infertility and recurrent pregnancy loss (RPL)**

PCOS often leads to anovulatory infertility, but some women with PCOS can conceive, though with longer conception times. In cases of infertility, overweight is common among PCOS-affected women. RPL occurs in PCOS, with uncertain reasons like uterine dysfunction, disrupted cell-embryo interaction, or insulin-related factors. PCOS mainly affects fertility through oligo-ovulation or anovulation. High LH concentrations during the follicular phase can reduce conception rates and cause early pregnancy loss. LH hypersecretion in PCOS may trigger premature oocyte maturation and impact folliculogenesis, leading to endometrial receptivity issues. Hyperinsulinemia in PCOS might hinder preimplantation conditions and affect embryo-endometrial interaction, contributing to pregnancy loss [20, 21].

### **5. Etiology, causes and associated factors**

PCOS is a complex polygenic disorder resulting from the interplay of various genetic, environmental, and intrauterine influences, with an estimated heritability of about 70% [13, 23]. Several susceptible genes have been identified as contributors to the pathophysiology of the. Additionally, the environment plays a major role in the expression of these genes and the development and progression of the disease. The most common environmental factors include obesity and IR [24–27]. Some factors that can lead to PCOS are:

### **5.1 Heredity and genetic linkages**

PCOS often runs in families, showing a dominant trait inheritance pattern. Twin studies highlight family factors in PCOS. Maternal PCOS, PCOM (polycystic ovarian morphology), hyperandrogenaemia, and metabolic syndrome are heritable risk factors. Daughters of PCOS women exhibit elevated AMH in infancy, larger ovaries, and increased insulin responses in childhood. Post-menarche, they may have higher testosterone. PCOM tends to follow an inherited pattern, with sisters having a higher risk of PCOM, hirsutism, and irregular periods. Parental factors and defective insulin secretion contribute, leading to increased adiposity, abnormal glucose tolerance, and diabetes in relatives. Gene variants are associated with PCOS [28].

### **5.2 Intrauterine environment**

There is growing evidence that developmental exposure to a distorted environment can induce enduring alterations in the epigenome. These modifications subsequently contribute to altered gene expression and an elevated susceptibility to adult-onset diseases. Factors such as congenital virilization and intrauterine nutrition have been recognized as potential contributors to the risk of developing PCOS [28].

### **5.3 Postnatal environment**

Postnatal environmental factors can trigger latent, congenitally programmed susceptibility traits to surface as PCOS symptoms. Key factors include:

*Insulin resistance:* PCOS is linked to extreme IR, with high insulin levels contributing to anovulation. Weight loss and improved insulin sensitivity enhance ovulation and menstrual cyclicity [28].

*Hyperandrogenism:* postnatal androgen excess, observed in some animal models and conditions like congenital adrenal virilizing disorders, contributes to ovarian hyperandrogenism [28].

*Obesity:* obesity, independently and by exacerbating PCOS, increases reproductive features—hyperandrogenism, hirsutism, infertility and pregnancy complications. Additionally, obesity amplifies the risk factors associated with PCOS, such as impaired glucose tolerance, T2D, and cardiovascular disease (CVD) [29].

### **6. Nutrition in PCOS**

Some evolutionary biologists posit that numerous genetic and hormonal predispositions contributing to PCOS may have originated during the transition from a pre-agrarian age diet to a contemporary diet. This hypothesis is substantiated by the concurrent increase in rates of diabetes, heart disease, and PCOS, aligning with the swift changes in the modern human diet. For all women diagnosed with PCOS, the inclusion of dietary therapy and regular exercise offers noteworthy benefits. Indeed, dietary and lifestyle interventions are regarded as primary strategies for managing PCOS. While there is not a specific "PCOS diet" that can completely reverse the syndrome, several dietary principles should be followed to ameliorate its symptoms [30].

A growing body of evidence indicates that various dietary strategies might yield positive effects on PCOS features, even without resulting in weight loss. Here, the impact of different nutrients and other dietary modifications according to diet strategies will be discussed.

### **6.1 Different nutrients in PCOS**

### *6.1.1 Dietary carbohydrates*

There is no optimum amount of carbohydrate intake for women with PCOS, and, therefore, any range (about 40–55%) of dietary carbohydrates can be adopted, according to the individuals' dietary assessment, metabolic goals, dietary habits and preferences. However, a beneficial strategy might involve consuming a larger portion of carbohydrates during lunchtime. Another appropriate approach would be to evenly spread carbohydrates across meals throughout the day. It would be better to avoid having a high-carbohydrate breakfast. While limited, studies have been done incorporating low-glycaemic index (GI) foods that might offer slight additional benefits for certain PCOS outcomes [31].

### *6.1.2 Protein*

Studies have found a diet higher in protein may yield several positive health outcomes, including increased weight loss, preservation of lean mass during weight

### *Optimizing Nutrition for PCOS Management: A Comprehensive Guide DOI: http://dx.doi.org/10.5772/intechopen.114149*

loss and maintenance, improved glycaemic control, and mitigation of other CVD risk factors such as blood pressure. However, it remains unclear whether these effects are primarily attributable to the higher protein intake or a reduction in carbohydrate intake. Some factors like increased thermogenesis and enhanced satiety have been proposed. Adding 7–15 g of dietary protein to meals and snacks might offer health benefits for women with PCOS, particularly regarding insulin sensitivity and postprandial glucose levels [31].

### *6.1.3 Fat*

It has been found that low-fat hypocaloric diets can help reduce body weight and composition compared to high-fat hypocaloric diets. Moderately low-carbohydrate, high-fat diets can help to decrease fasting insulin, increase insulin sensitivity, and improve metabolic parameters in women with PCOS. Furthermore, a diet moderately low in carbohydrates (43%) but rich in unsaturated fatty acids may lead to a significant decline in fasting insulin levels A diet rich in fat and moderately limited in carbohydrates (~41% carbohydrate, 19% protein, 40% fat) may significantly reduce in basal β-cell response, fasting insulin, fasting glucose, and IR and decrease testosterone levels, in conjunction with declines in blood lipid levels and adipose tissue mass [31].

### *6.1.4 Micronutrients*

Women with PCOS often have imbalanced diets with deficiencies in essential nutrients such as fiber, Ω-3 fatty acids, calcium, magnesium, zinc, and vitamins (folic acid, vitamin C, vitamin B12, and vitamin D). There is also an excess intake of certain nutrients like sucrose, sodium, total fats, saturated fatty acids, and cholesterol. Balancing deficiencies with a calorie-reduced diet with a low GI can positively influence water-soluble vitamins [32]. While most B vitamins respond well to increased dietary supply, a study has shown that such an effect may not be observed for vitamins B3, B2 and thiamine [33]. Women with PCOS are treated with metformin, but its chronic intake may lead to deficiencies in thiamine and cobalamin [34]. So, these vitamin supplementations may be necessary.

Micronutrients like selenium, chromium, zinc, carotenoids, and vitamin E can have potential benefits in the metabolic condition of PCOS patients and deficiency in these nutrients might contribute to the exacerbation of metabolic disturbances in PCOS patients with metabolic syndromes [35]. Supplementation of micronutrients like zinc, selenium, chromium, and folate may positively impact fasting glucose, insulin, IR, blood lipid levels, and inflammatory and oxidative stress biomarkers in PCOS individuals. Despite potential benefits, recommending micronutrient supplements for PCOS management is considered premature based on current evidence [31, 36]. Thus, the consumption of micronutrient-rich foods on a daily basis becomes important.

### **6.2 Dietary strategies**

### *6.2.1 Negative energy balance and weight reduction*

Calorie restriction diets (1000–1500 kcal/day) can help in weight loss and improvements in hirsutism, IR, and androgen levels [37]. Modest weight loss (5–10%) in PCOS shows positive impacts on cardiovascular and diabetes risk, hormone levels, and PCOS outcomes. Weight reduction yields improved insulin sensitivity and lipid

profiles, alleviating hyperandrogenism, increased Sex hormone Binding Globulin (SHBG), reduced Free Androgen Index (FAI) and testosterone, and normalizing menstrual cycles. Weight loss benefits overweight PCOS women by reducing IR and hyperandrogenism and enhancing ovarian health, menstrual function, and ovulation. Effects on LH vary, while hirsutism may improve. The extent of the caloric deficit should be tailored to individual needs, including dietary preferences, habits, cultural factors, metabolic objectives, and physical activity levels [31].

### *6.2.2 Glycaemic index and glycaemic load*

From different studies, it has been found that low-GI diets are helpful for successful weight loss, increase insulin sensitivity, and reduce IR, fasting insulin, LDL cholesterol, triglycerides, waist circumference, total testosterone and maintaining menstrual regularity when compared to high GI diets. A low to medium glycaemic load (GL) diet containing high-protein, moderately low-carb can also be helpful for improvement in IR, and inflammation markers. Low-GI foods, however, have similar effects as conventional diets on fasting glucose, HDL cholesterol, free androgen, inflammation, and quality of life [31, 32].

### *6.2.3 Meal frequency*

Meal frequency and timing are important considerations in lifestyle changes for PCOS management, although there is limited specific data for women with PCOS. There are contrasting viewpoints on the effects of meal frequency on body composition and glycaemic control. Some argue that frequent meals might lead to weight gain due to increased fat deposition after meals or higher energy intake. Others suggest that increased meal frequency could spread nutrient load, leading to lower postprandial insulin levels, reduced hunger, and improved glucose clearance. In a study, a sixmeal pattern showed improved post-oral glucose tolerance test insulin sensitivity and reduced subjective hunger in women with PCOS compared to a three-meal pattern. Another study showed that consuming a high-energy breakfast instead of a highenergy dinner improved insulin sensitivity and reproductive markers in lean women with PCOS. Meal timing has also gained attention. Eating late in the day has been linked to decreased energy expenditure, impaired glucose tolerance, and disrupted circadian rhythms. People with prediabetes who prefer evening meals might have a higher risk of developing T2D. The American Heart Association suggests that meal frequency and timing could be crucial in managing chronic diseases and reducing cardiometabolic risk factors [31].

### *6.2.4 Dietary modification*

Multiple dietary compositions show promise in treating obesity and its associated conditions in PCOS [29]. Implementing low-GI diets, exercise, and omega-3 supplementation leads to increased HDL, SHBG synthesis, and reduced body fat. Studies support the efficacy and safety of the low-GI diet in relieving IR, and proper professional dietary advice should be provided for PCOS patients [32].

The DASH diet, which is low-GI and high in complex carbohydrates, demonstrated positive effects on weight loss, insulin metabolism, and inflammation markers in women with PCOS. Adherence to the DASH diet led to significant reductions in body weight, insulin levels, IR, high-sensitivity C-reactive protein, and triglycerides,

*Optimizing Nutrition for PCOS Management: A Comprehensive Guide DOI: http://dx.doi.org/10.5772/intechopen.114149*

encouraging healthy dietary patterns like DASH or Mediterranean-style diets, rich in fiber, antioxidants, and anti-inflammatory nutrients, could be beneficial for women with PCOS due to their satiety, anti-hyperlipidaemic, antihypertensive, and antidiabetic properties [31].

Low-carbohydrate diets (<30% of energy) contribute to weight loss and metabolic enhancements. Specifically, long-term low-carb diets, including low-fat/low-carb variations, are recommended to reduce BMI, address PCOS with IR, prevent high LDL-C, increase FSH and SHBG levels, and decrease total testosterone. Controlled carbohydrate intake positively affects PCOS aspects, presenting a significant intervention for symptom improvement [37, 38]. Studies suggest that a high-protein, lowcarb diet may aid weight loss and improve metabolic and reproductive parameters in PCOS. Carbohydrate restriction, especially with a low glycaemic index (GI), is proposed for satiety and cardiovascular health, though sustaining long-term adherence proves challenging (**Table 1**) [29].

### **6.3 Dietary supplements in PCOS management**

### *6.3.1 Omega-3 fatty acids*

Omega-3 fatty acids, often lacking in PCOS diets, enhance reproductive performance by affecting hormone secretion and ovarian functions [32]. Omega-3 fatty acids, specifically EPA and DHA, offer various positive effects, such as antioxidant, anti-inflammatory, anti-obesity, and insulin-sensitizing properties. They enhance insulin sensitivity by reducing inflammatory cytokines and boosting anti-inflammatory adiponectin secretion in PCOS women, which is evident through decreased

	- Low-fat dairy (two to three servings/day)
	- Whole-grain/low-GI bread and cereals (at least three servings/day)
	- Fruit (at least two servings/day)
	- Vegetables (at least two cups/day)
	- Lean meat, chicken, fish (one to two serves/day)
	- Low-saturated fat fats/oils (three to four teaspoons or nuts/seeds)

### **Table 1.**

*Dietary recommendations for PCOS [39].*

high-sensitivity C-reactive protein and increased adiponectin levels. However, the impact of omega-3 supplementation on PCOS remains debated, with mixed study results on waist circumference, lipid profiles, and menstrual regularity. Studies indicate that n-3 PUFA supplementation may reduce total testosterone levels, while further research is required to explore the potential antiandrogenic effects of longchain n-3 PUFAs, including EPA and DHA [31].

### *6.3.2 Vitamin D*

The complex interplay between vitamin D and Polycystic Ovary Syndrome (PCOS) reveals significant implications. Vitamin D deficiency, prevalent in PCOS, is closely tied to symptoms such as central obesity, IR, infertility, and hirsutism. Functioning as a steroid hormone with progesterone-like activity, vitamin D is pivotal in insulin synthesis, receptor expression, and glucose transport, normalizing calcium and parathyroid levels [31, 32, 40–42].

Supplementation studies suggest potential relief for PCOS symptoms, with observed reductions in total testosterone levels. Combining calcium and vitamin D enhances insulin levels, reduces resistance, and improves lipid profiles. A combination of metformin, calcium, and vitamin D exhibits positive impacts on weight loss, menstrual regularity, and hyperandrogenism in PCOS-associated infertility, with a noteworthy dose of 20,000 IU cholecalciferol weekly showcasing improvements in carbohydrate metabolism and menstrual frequency [31, 32, 41–43].

### *6.3.3 Zinc*

Zinc is crucial for corpus luteum formation, supporting progesterone production essential for implantation [44]. Studies link zinc supplementation to elevated progesterone, while deficiency inhibits LH and estrogen, impacting luteal function [45–48]. Zinc supplementation is linked to enhanced lipid and glucose metabolism [32]. In an 8-week trial among PCOS women, zinc supplementation (50 mg elemental zinc/ day) increased serum zinc and reduced IR, total cholesterol, LDL-C, triglycerides, testosterone, and TG/HDL-C ratio [49]. A study among PCOS subjects revealed that twice-daily co-supplementation of 250 mg magnesium oxide and 220 mg zinc sulphate (50 mg elemental zinc) notably decreased inflammation and oxidative stress markers [50]. These findings suggest potential benefits of at least 50 mg zinc/day for 8 weeks in PCOS management.

### *6.3.4 Selenium*

As an antioxidant, selenium intake in PCOS may offer benefits by reducing oxidative stress along with IR, and hyperandrogenism, with its levels correlating with estrogen changes during the menstrual cycle [32, 51–57].

A rat model suggests that combined selenium nanoparticles and metformin therapy improve insulin sensitivity, lipid profile, inflammation, oxidative stress, and mitochondrial functions [51]. In different randomized trials, 200 μg daily selenium supplementation for 8–12 weeks in PCOS women showed improved pregnancy rates, reduced alopecia, acne, and lowered inflammatory markers [52–54]. Hence, a daily dose of 200 μg selenium for at least 8 weeks may benefit individuals with PCOS, suggesting potential advantages for hormonal and metabolic aspects, but it warrants further exploration.

### *6.3.5 Vitamin C*

Vitamin C exhibits antioxidant properties and is involved in ovarian regulation and endometrial health. Vitamin C levels modulate throughout the menstrual cycle, affecting ovulation and progesterone production. Vitamin C levels decline immediately before ovulation and increase again after post-ovulation temperature rises. Ascorbic acid stimulates progesterone and oxytocin production. Vitamin C may play a role in regulating menstrual cycle irregularities in PCOS women, but further research is needed [40].

### *6.3.6 Vitamin E*

Vitamin E, a crucial antioxidant, shows potential in counteracting reproductive system oxidative stress, impacting oocyte quality and countering pregnancyrelated diseases [58]. It might positively affect endometrial thickness and overall ovarian function. Vitamin E supplementation, combined with coenzyme Q10, can increase SHBG levels and reduce free plasma testosterone concentrations in PCOS patients [40].

In a clinical trial with PCOS women, a 100 mg/day short-term vitamin E supplementation demonstrated the potential to diminish oxidative stress, resulting in reduced markers. Vitamin E can reduce oxidative stress, consequently reducing the exogenous human menopausal gonadotropin (HMG) dosage. The study revealed improved endometrial thickness and estrogen levels. However, this supplementation had no significant impact on pregnancy rates, regardless of initiation in the follicular or luteal phase [40, 58].

### *6.3.7 Inositol*

Inositol represents a cyclic carbohydrate with six hydroxyl groups, one on each of the ring carbons. Nine stereoisomers of inositol exist, with myo-inositol (MI) and D-chiro-inositol (DCI) being the two primary stereoisomers found in the human body [40, 59, 60].

In the ovary, DCI plays a role in insulin-driven testosterone production, whereas MI is involved in FSH signaling. The insulin-dependent epimerase activity controls the ratio of MI to DCI, and it is noteworthy that ovaries do not develop IR, unlike muscles and the liver. This suggests that in PCOS, there could be an increased conversion of MI to DCI within the ovary due to insulin overproduction, resulting in excessive DCI levels and MI deficiency, disrupting hormonal balance [61].

### *6.3.8 Berberine*

Berberine is a quaternary ammonium salt found in various medicinal plants like *Berberis and Hydrastis canadensis.* It belongs to the protoberberine group of isoquinoline alkaloids [62, 63]. Among PCOS patients, berberine positively impacts lipid profile, enhances insulin sensitivity, and increases ovulation rates, promoting fertility. It is considered safe for premenopausal women with minimal side effects [64]. It is efficient against IR and obesity, particularly targeting visceral adipose tissue [64], and if associated with a healthy lifestyle, improves women's body composition and causes androgen reduction [65]. Berberine may benefit PCOS management by improving metabolic, hormonal, and anthropometric parameters.

### *6.3.9 Polyphenols*

Polyphenols, diverse secondary plant metabolites, are polyhydroxyphenols with multiple phenolic rings, often conjugated with sugars lacking nitrogen-based functional groups. Derived from shikimate and acetate pathways, they include phenolic acids, stilbenes, flavonoids, and lignans [66–68].

Resveratrol, a polyphenol found in grapes and berries, has anti-inflammatory and antioxidant properties. Initially considered for infertility treatment, caution is urged during pregnancy and the luteal phase due to potential adverse effects. Despite limitations, resveratrol inhibits proinflammatory cytokines, emphasizing the need for further PCOS research [40]. Various clinical trials using 800–1500 mg/day of resveratrol at least 40 days to 3 months have demonstrated positive effects on ovarian morphology, dominant follicle incidence, and androgen levels, anti-inflammatory effects and ER stress modulation, improved menstrual cyclicity and reduced hair loss in PCOS women [69–72]. Thus, resveratrol supplementation among PCOS women at doses up to 1500 mg/day for at least 40 days can be beneficial.

Naringenin, a key flavonoid in human diets, imparts color and a bitter-sour taste to foods. Found in grapefruit, sour orange, cherries, tomatoes, citrus fruits, and Greek oregano, it is also present in smaller amounts in bergamot, beans, fenugreek, milk thistle, tea, coffee, cocoa, and red wine naringenin's potential in PCOS treatment involves the AKT pathway, steroidogenesis, and gut microbiota modulation [73–75]. This indicates the supplementation of naringenin among PCOS women may be beneficial, but further study is required.

Quercetin, a flavonoid in fruits and vegetables, demonstrated therapeutic effects in PCOS treatment [76]. Administered at varying doses (15–150 mg/kg) for 3–10 weeks in rat models, it alleviated obesity, diabetes, and infertility. Quercetin enhanced antioxidants, reduced weight gain, normalized hormone levels, and inhibited PI3 kinase, showcasing multifaceted benefits in PCOS management [77–79]. A 40-day study with 500 mg quercetin supplementation among women daily reduced LH, TNF-alpha, and IL-6 levels, improved oocyte and embryo grades and increased pregnancy rates [80]. Thus, at least 500 mg/day supplementation of quercetin can be beneficial.

Individualized approach: supplementation needs vary among individuals, requiring consultation and active participation for optimal outcomes. A balanced diet and healthy lifestyle remain fundamental in PCOS therapy.

### **6.4 Herbs supporting treatment for PCOS**

A balanced diet is vital in managing PCOS, and herbal extracts like Aloe vera, cinnamon, green tea, chamomile, and white mulberry complement this therapy. Certain herbs can influence lipid profiles, blood glucose, and IR, benefiting all PCOS phenotypes. Some herbs, such as green tea and marjoram, possess endocrine properties, improving hormonal levels, ovarian health, insulin sensitivity, and reducing inflammation. Green mint and liquorice root are recommended for women with elevated androgen levels. They have antiandrogen effects and reduce excess testosterone. Flaxseed lignans, turmeric, nettle, milk thistle, artichoke, dandelion, and black cumin offer various therapeutic benefits for PCOS, including antioxidant, anti-inflammatory, and hepatoprotective properties [32].

### *6.4.1 Flaxseed*

Flaxseed, a nutrient-rich seed encompasses omega-3 fatty acids, lignans, fiber, niacin, vitamin E (39.5–50 mg/100 g), minerals, proteins, and peptides. With 37–45% lipid content, it is a prime omega-3 source. Rich in lignans and phenolic compounds, it offers diverse health benefits, including cardiovascular and anti-inflammatory effects [81, 82]. Flaxseed lignans stand out as well-studied dietary phytoestrogens. They can influence key enzymes involved in estrogen synthesis, shaping sex hormone levels [32]. A 4-month study on PCOS, patients taking 30 g/day of flaxseed exhibited reduced BMI, testosterone, insulin levels, and hirsutism [83]. In a 12-week study on women with PCOS, twice-daily supplementation of flaxseed oil omega-3 fatty acids (1000 mg capsule) significantly improved insulin levels, IR, hirsutism, triglycerides, VLDL-cholesterol, and CRP levels, demonstrating positive effects on insulin metabolism and specific metabolic markers [84]. Thus flaxseed (at least 20 g/day) or flaxseed oil flaxseed oil omega-3 fatty acids (1000 mg) for a minimum of 3 months can be beneficial for PCOS women.

### *6.4.2 Curcumin*

Curcumin, found in turmeric, possesses strong antioxidant properties, reducing oxidative stress in PCOS patients. It also modulates proangiogenic and proinflammatory factors, suggesting potential pharmacologic benefits for PCOS [32, 85]. Turmeric extract exhibits promising effects in treating PCOS in albino rats, showing improvements in hormone and lipid profiles, antioxidant and glycaemic status, and ovarian morphology compared to metformin [85]. Additionally, in a mouse model, curcumin protects granulosa cells from apoptosis in PCOS rats by inhibiting the ER stress-related IRE1α-XBP1 pathway and activating the PI3K/AKT signaling pathway, suggesting its potential as a beneficial supplement for PCOS patients [86].

In a 12-week double-blind trial, curcumin intake (500 mg thrice daily) by women with PCOS demonstrated significant reductions in blood sugar and dehydroepiandrosterone, along with a potential increase in oestradiol [87]. Similarly, another study for 12 weeks found intake of 500 mg of curcumin per day can have beneficial effects on body weight, glycaemic control, and serum lipids except triglycerides and VLDL-cholesterol levels [88]. Most of the clinical trials using curcumin extract have used about 500–1500 mg of curcumin per day for 6–12 weeks has shown beneficial effects on PCOS patients [87–89].

### *6.4.3 Cinnamon*

Cinnamon, valued for its fragrance, has diverse uses. Its essential oil, containing cinnamaldehyde, and the bark, with antioxidants like procyanidins, provide various biological benefits. The bark, rich in cinnamaldehyde, eugenol, and linalool, plays a significant role in its effects. With an abundance of phytochemicals, cinnamon exhibits potential health benefits, including anti-inflammatory, antimicrobial, antioxidant, and cardioprotective effects [90, 91].

A study done in mice found cinnamon (10 mg/100 g body weight) could restore oestrous cyclicity, normalize hormone levels, and improve ovarian morphology [92]. A 12-week study among women with PCOS using cinnamon powder capsules (1.5 g/ day in three doses) showed significant reductions in fasting insulin and IR, with a decrease in low-density lipoprotein levels [93]. Thus, about 1.5 g of cinnamon powder consumption can be beneficial for PCOS women.

### **7. Lifestyle in PCOS management**

### **7.1 Exercise and physical activity in PCOS management**

Exercise offers metabolic benefits beyond weight management, particularly relevant to PCOS-related risk factors like hypertension, IR, elevated blood glucose, and endothelial dysfunction. Research demonstrates that increased physical activity and fitness, regardless of weight loss, can ameliorate these factors. Endurance training has been shown to reduce IR and improve metabolic profiles in overweight PCOS women. Combining aerobic and resistance training proves effective in reducing IR and body fat, and resistance training maintains basal metabolic rate and enhances muscle strength, facilitating regular physical activity [29].

Exercise reduces IR by two mechanisms as below [30]:


It has been shown that exercise improves menstrual abnormalities and restores ovulation in obese patients with PCOS, and its benefit on reproductive function is greater than the benefit of a low-calorie diet only. Exercise exerts its beneficial effects on body composition with greater reduction in fat mass and better preservation of fat-free mass [30]. Collectively, the evidence underscores the health advantages of exercise, both for weight management and metabolic well-being in PCOS and beyond [29].

Exercise is increasingly recognized as a vital element in managing PCOS, enhancing insulin sensitivity through optimized glucose transport and metabolism. Recent research emphasizes the importance of exercise intensity for health improvements. Meta-analysis and systematic reviews highlight the significant impact of vigorous intensity exercise on factors like cardiorespiratory fitness, IR, and body composition. Studies using metrics like HOMA-IR and BMI show substantial decreases in IR, supporting the benefits of physical activity. Engaging in a minimum of 120 minutes of aerobic activity per week is recommended for optimal results in managing PCOSrelated concerns [32].

Public health recommendations advise overweight and obese individuals, including those with PCOS, to gradually increase physical activity to 200–300 minutes per week of moderate exercise, like brisk walking, to prevent unhealthy weight regain and promote long-term weight maintenance. This evidence highlights the importance of incorporating adequate physical activity into PCOS weight management programmes [29]. At the moment, there are no guidelines for the type, intensity, frequency, and duration of exercise in patients with PCOS, but physical activities as of a normal adult should performed regularly as below [30]:


*Optimizing Nutrition for PCOS Management: A Comprehensive Guide DOI: http://dx.doi.org/10.5772/intechopen.114149*


### **7.2 Lifestyle modification**

Lifestyle intervention (diet and physical activity) leading to a 5–10% weight loss has shown significant improvements in IR, ovulation, menstrual regularity, and other PCOS symptoms. Women with PCOS adopt both healthy and non-healthy practices for weight management. Despite its benefits, many PCOS patients do not receive lifestyle advice from healthcare providers. Lifestyle programmes combine diet, exercise, and cognitive strategies. They have been effective in preventing diabetes and improving PCOS-related factors like weight, hormones, and metabolic issues. Studies support their impact on BMI, blood glucose, and hormonal balance. While positive effects are seen, clinical reproductive outcomes and quality of life need further study. Combining lifestyle changes with treatments like metformin can enhance results. In overweight PCOS women, lifestyle changes led to better menstrual regularity and insulin sensitivity. Lifestyle interventions should be the primary approach for PCOS management, but maintaining healthy habits longterm remains a challenge. A team-based approach could offer better results for comprehensive PCOS care [31].

	- *Frequency*: engage in physical activity 3–5 days per week, emphasizing the establishment of a consistent exercise routine before advancing frequency.
	- *Intensity*: initiate with low to moderate intensity, gradually increasing over weeks, prioritizing duration for optimal energy expenditure, emphasizing prolonged activity over intensity.
	- *Time*: 30–60 min, using a gradual progression (can be accumulated in multiple short bouts of at least 10 min that may promote greater adherence).
	- *Type*: choose low-impact activities such as walking, cycling, or low-impact aerobics, ensuring convenience and enjoyment.

*Adapted from: Refs. [30, 39].*

### **Table 2.**

*Exercise and lifestyle modification guidelines.*

Exercise is a vital component of successful lifestyle modifications for weight management in PCOS. Studies show that physical activity is associated with sustained weight loss and that combining exercise with diet enhances weight reduction compared to diet alone. Research suggests that highly active individuals have the greatest success in maintaining weight loss [29].

Lifestyle adjustments play a crucial role in managing PCOS in women, complementing medical treatments. This encompasses regular behavioral adjustments, social support, and psychological adaptations. Essential modifications include maintaining regular physical activity and exercise, long-term weight management strategy, adhering to a balanced diet, behavior therapies, and avoiding tobacco—a comprehensive approach aligned with clinical guidelines to prevent and treat metabolic issues. Prioritizing overall well-being and mental health is a personal choice, offering valuable steps toward a more fulfilling life [29, 32].

### **8. Conclusion**

Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder affecting women, marked by hormonal imbalances, menstrual irregularities, and ovarian cysts. Its pathophysiology involves genetic, environmental, and hormonal factors, disrupting the HPO axis and contributing to reproductive and metabolic complexities. Hyperandrogenism, ovarian dysfunction, insulin resistance, and obesity amplify PCOS's intricacy, elevating the risk of metabolic syndrome and cardiovascular diseases. The interplay of genetic predisposition and an "obesogenic" environment remains to be fully elucidated. PCOS complications encompass menstrual irregularities, hirsutism, acne, alopecia, acanthosis nigricans, dyslipidaemia, fatty liver disease, inflammation, obstructive sleep apnoea, gestational diabetes, type II diabetes, infertility, and recurrent pregnancy loss.

PCOS management includes supplementation with vitamin D, zinc, selenium, omega-3 fatty acids, vitamin C, vitamin E, chromium, inositol, and berberine. These supplements address deficiencies, reduce inflammation, improve hormonal balance, enhance insulin sensitivity, and mitigate metabolic abnormalities in PCOS patients. An individualized approach, considering diverse needs and factors, is essential for optimal outcomes, emphasizing the importance of a balanced diet and a healthy lifestyle in PCOS therapy. Further research is needed to establish precise dosages and guidelines for supplementation in PCOS management.

Polyphenols like resveratrol, naringenin, and rutin show antioxidant benefits. Herbs such as flaxseed, turmeric, nettle, and traditional remedies offer diverse therapeutic support for PCOS management. Exercise, particularly aerobic and resistance training, plays a crucial role in managing PCOS. It improves insulin sensitivity, reproductive function, and overall health, promoting lasting lifestyle changes.

Personalized, sustainable lifestyle adjustments, including 5–10% weight loss, significantly improve PCOS symptoms, enhancing IR, ovulation, and menstrual regularity. A team-based approach could offer better results for comprehensive PCOS care. A holistic approach to PCOS management involves medical treatments complemented by lifestyle modification, which integrates exercise, dietary adjustments, and prioritizing psychological well-being for comprehensive women's health.

*Optimizing Nutrition for PCOS Management: A Comprehensive Guide DOI: http://dx.doi.org/10.5772/intechopen.114149*

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Madan Pandey1 \* and Kritee Niroula2

1 Metro Kathmandu Hospital, Kathmandu, Nepal

2 Central Campus of Technology, Tribhuvan University, Dharan, Nepal

\*Address all correspondence to: cumyps23@gmail.com

© 2024 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Rosenberg SL. The relationship between PCOS and obesity: Which comes first? The Science Journal of the Lander College of Arts and Sciences. 2019;**13**(1):5

[2] Ndefo UA, Eaton A, Green MR. Polycystic ovary syndrome: A review of treatment options with a focus on pharmacological approaches. P & T: A Peer-reviewed Journal for Formulary Management. 2013;**38**(6):336-355

[3] Stracquadanio M, Ciotta L. Introduction. In: Stracquadanio M, Ciotta L, editors. Metabolic Aspects of PCOS: Treatment with Insulin Sensitizers. Cham: Springer International Publishing; 2015. pp. 1-4

[4] Zeng X, Xie Y-j, Liu Y-t, Long S-l, Mo Z-c. Polycystic ovarian syndrome: Correlation between hyperandrogenism, insulin resistance and obesity. Clinica Chimica Acta. 2020;**502**:214-221

[5] Di Pietro M, Pascuali N, Parborell F, Abramovich D. Ovarian angiogenesis in polycystic ovary syndrome. Reproduction. 2018;**155**(5):R199-R209

[6] Teede HJ, Misso ML, Deeks AA, Moran LJ, Stuckey BGA, Wong JLA, et al. Assessment and management of polycystic ovary syndrome: Summary of an evidence-based guideline. Medical Journal of Australia. 2011;**195**(S6):S65-S112

[7] McGee EA, Hsueh AJW. Initial and cyclic recruitment of ovarian follicles\*. Endocrine Reviews. 2000;**21**(2):200-214

[8] Luderer U. Ovarian toxicity from reactive oxygen species. Vitamins and Hormones. 2014;**94**:99-127

[9] Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One. 2010;**5**(1):e8772

[10] Findlay JK, Hutt KJ, Hickey M, Anderson RA. How is the number of primordial follicles in the ovarian reserve established? Biology of Reproduction. 2015;**93**(5):1-7

[11] Dumont A, Robin G, Catteau-Jonard S, Dewailly D. Role of anti-Müllerian hormone in pathophysiology, diagnosis and treatment of polycystic ovary syndrome: A review. Reproductive Biology and Endocrinology. 2015;**13**(1):137

[12] Ibáñez L, Oberfield Sharon E, Witchel S, Auchus Richard J, Chang RJ, Codner E, et al. An international consortium update: Pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Hormone Research in Paediatrics. 2017;**88**(6):371-395

[13] Stracquadanio M, Ciotta L. Etiopathogenesis. In: Stracquadanio M, Ciotta L, editors. Metabolic Aspects of PCOS: Treatment with Insulin Sensitizers. Cham: Springer International Publishing; 2015. pp. 5-20

[14] Rudnicka E, Kunicki M, Calik-Ksepka A, Suchta K, Duszewska A, Smolarczyk K, et al. Anti-Müllerian hormone in pathogenesis, diagnostic and treatment of PCOS. International Journal of Molecular Sciences. 2021;**22**(22):12507

[15] Witchel SF, Oberfield SE, Peña AS. Polycystic ovary syndrome: Pathophysiology, presentation, and treatment with emphasis on adolescent girls. Journal of the Endocrine Society. 2019;**3**(8):1545-1573

### *Optimizing Nutrition for PCOS Management: A Comprehensive Guide DOI: http://dx.doi.org/10.5772/intechopen.114149*

[16] Balen A. The pathophysiology of polycystic ovary syndrome: Trying to understand PCOS and its endocrinology. Best Practice & Research Clinical Obstetrics & Gynaecology. 2004;**18**(5):685-706

[17] Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: Etiology, pathogenesis and diagnosis. Nature Reviews Endocrinology. 2011;**7**(4):219-231

[18] Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies. Molecular Metabolism. 2020;**35**:100937

[19] Glueck CJ, Goldenberg N. Characteristics of obesity in polycystic ovary syndrome: Etiology, treatment, and genetics. Metabolism. 2019;**92**:108-120

[20] Stracquadanio M, Ciotta L. Clinical features. In: Stracquadanio M, Ciotta L, editors. Metabolic Aspects of PCOS: Treatment with Insulin Sensitizers. Cham: Springer International Publishing; 2015. pp. 21-62

[21] Johnston-MacAnanny EB, Berga SL. Polycystic ovary syndrome. In: Falcone T, Hurd WW, editors. Clinical reproductive medicine and surgery: A practical guide. Cham: Springer International Publishing; 2017. pp. 123-137

[22] Paschou SA, Polyzos SA, Anagnostis P, Goulis DG, Kanaka-Gantenbein C, Lambrinoudaki I, et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Endocrine. 2020;**67**(1):1-8

[23] de Melo AS, Dias SV, Cavalli RC, Cardoso VC, Bettiol H, Barbieri MA, et al. Pathogenesis of polycystic ovary syndrome: Multifactorial assessment from the foetal stage to menopause. Reproduction. 2015;**150**(1):R11-R24

[24] Puttabyatappa M, Padmanabhan V. Ovarian and extra-ovarian mediators in the development of polycystic ovary syndrome. Journal of Molecular Endocrinology. 2018;**61**(4):R161-RR84

[25] Goyal A, Ganie MA. Idiopathic hyperprolactinemia presenting as polycystic ovary syndrome in identical twin sisters: A case report and literature review. Cureus. 2018;**10**(7):e3004

[26] Spinedi E, Cardinali DP. The polycystic ovary syndrome and the metabolic syndrome: A possible chronobiotic-cytoprotective adjuvant therapy. International Journal of Endocrinology. 2018;**2018**:1349868

[27] Albu D, Albu A. The relationship between anti-Müllerian hormone serum level and body mass index in a large cohort of infertile patients. Endocrine. 2019;**63**(1):157-163

[28] Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocrine Reviews. 2016;**37**(5):467-520

[29] Moran LJ, Brinkworth GD, Norman RJ. Dietary therapy in polycystic ovary syndrome. Seminars in Reproductive Medicine. 2008;**26**(01):085-092

[30] Stracquadanio M, Ciotta L. PCOS therapy. In: Stracquadanio M, Ciotta L, editors. Metabolic Aspects of PCOS: Treatment with Insulin Sensitizers. Cham: Springer International Publishing; 2015. pp. 89-137

[31] Papavasiliou K, Papakonstantinou E. Nutritional support and dietary

interventions for women with polycystic ovary syndrome. Nutrition and Dietary Supplements. 2017;**9**:63-85

[32] Szczuko M, Kikut J, Szczuko U, Szydłowska I, Nawrocka-Rutkowska J, Ziętek M, et al. Nutrition strategy and life style in polycystic ovary syndrome—Narrative review. Nutrients. 2021;**13**(7):2452

[33] Szczuko M, Szydłowska I, Nawrocka-Rutkowska J. A properly balanced reduction diet and/or supplementation solve the problem with the deficiency of these vitamins soluble in water in patients with PCOS. Nutrients. 2021;**13**(3):2-10

[34] Esmaeilzadeh S, Gholinezhad-Chari M, Ghadimi R. The effect of metformin treatment on the serum levels of homocysteine, folic acid, and vitamin B12 in patients with polycystic ovary syndrome. Journal of Human Reproductive Sciences. 2017;**10**(2):95-101

[35] Zaeemzadeh N, Jahanian Sadatmahalleh S, Ziaei S, Kazemnejad A, Movahedinejad M, Mottaghi A, et al. Comparison of dietary micronutrient intake in PCOS patients with and without metabolic syndrome. Journal of Ovarian Research. 2021;**14**(1):10

[36] Tripathi S, Singh M, Jain M, Khatoon S. Nutritional perspective of polycystic ovarian syndrome: A review study. Current Medicine Research and Practice. 2020;**10**(2):65-69

[37] Neves LPP, Marcondes RR, Maffazioli GDN, Simões RS, Maciel GAR, Soares JM, et al. Nutritional and dietary aspects in polycystic ovary syndrome: Insights into the biology of nutritional interventions. Gynecological Endocrinology. 2020;**36**(12):1047-1050

[38] Zhang X, Zheng Y, Guo Y, Lai Z. The effect of low carbohydrate diet on polycystic ovary syndrome: A metaanalysis of randomized controlled trials. International Journal of Endocrinology. 2019;**2019**:4386401

[39] Moran LJ, Brinkworth G, Noakes M, Norman RJ. Effects of lifestyle modification in polycystic ovarian syndrome. Reproductive Biomedicine Online. 2006;**12**(5):569-578

[40] Iervolino M, Lepore E, Forte G, Laganà AS, Buzzaccarini G, Unfer V. Natural molecules in the Management of Polycystic Ovary Syndrome (PCOS): An analytical review. Nutrients. 2021;**13**(5):1677

[41] Teegarden D, Donkin SS. Vitamin D: Emerging new roles in insulin sensitivity. Nutrition Research Reviews. 2009;**22**(1):82-92

[42] He C, Lin Z, Robb SW, Ezeamama AE. Serum vitamin D levels and polycystic ovary syndrome: A systematic review and meta-analysis. Nutrients. 2015;**7**(6):4555-4577

[43] Wehr E, Pieber TR, Obermayer-Pietsch B. Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: A pilot study. Journal of Endocrinological Investigation. 2011;**34**(10):757-763

[44] Sunar F, Baltaci AK, Ergene N, Mogulkoc R. Zinc deficiency and supplementation in ovariectomized rats: Their effect on serum estrogen and progesterone levels and their relation to calcium and phosphorus. Pakistan Journal of Pharmaceutical Sciences. 2009;**22**(2):150-154

[45] Kechrid Z, Amamra S, Bouzerna N. The effect of zinc deficiency on zinc

### *Optimizing Nutrition for PCOS Management: A Comprehensive Guide DOI: http://dx.doi.org/10.5772/intechopen.114149*

status, carbohydrate metabolism and progesterone level in pregnant rats. Turkish Journal of Medical Sciences. 2006;**36**(6):337-342

[46] Om AS, Chung KW. Dietary zinc deficiency alters 5 alpha-reduction and aromatization of testosterone and androgen and estrogen receptors in rat liver. The Journal of Nutrition. 1996;**126**(4):842-848

[47] Humeny A, Bökenkamp D, Thole HH. The HDQVH-motif in domain E of the estradiol receptor alpha is responsible for zinc-binding and zinc-induced hormone release. Molecular and Cellular Endocrinology. 1999;**153**(1-2):71-78

[48] Noda Y, Ota K, Shirasawa T, Shimizu T. Copper/zinc superoxide dismutase insufficiency impairs progesterone secretion and fertility in female Mice1. Biology of Reproduction. 2012;**86**(1):1-8

[49] Pourteymourfard TF, Alipour B, Mehrzad SM, Ostad RA. Effect of zinc supplementation on cardiometabolic risk factors in women with polycystic ovary syndrome. Journal of Cardiovascular and Thoracic Research. 2010;**2**(2):11-20

[50] Afshar Ebrahimi F, Foroozanfard F, Aghadavod E, Bahmani F, Asemi Z. The effects of magnesium and zinc co-supplementation on biomarkers of inflammation and oxidative stress, and gene expression related to inflammation in polycystic ovary syndrome: A randomized controlled clinical trial. Biological Trace Element Research. 2018;**184**(2):300-307

[51] Rabah HM, Mohamed DA, Mariah RA, Abd El-Khalik SR, Khattab HA, AbuoHashish NA, et al. Novel insights into the synergistic effects of selenium nanoparticles and metformin treatment

of letrozole-induced polycystic ovarian syndrome: Targeting PI3K/Akt signalling pathway, redox status and mitochondrial dysfunction in ovarian tissue. Redox Report. 2023;**28**(1):2160569

[52] Razavi M, Jamilian M, Kashan ZF, Heidar Z, Mohseni M, Ghandi Y, et al. Selenium supplementation and the effects on reproductive outcomes, biomarkers of inflammation, and oxidative stress in women with polycystic ovary syndrome. Horm Metab Res = Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2016;**48**(3):185-190

[53] Jamilian M, Razavi M, Fakhrie Kashan Z, Ghandi Y, Bagherian T, Asemi Z. Metabolic response to selenium supplementation in women with polycystic ovary syndrome: A randomized, double-blind, placebocontrolled trial. Clinical Endocrinology. 2015;**82**(6):885-891

[54] Rashidi BH, Mohammad Hosseinzadeh F, Alipoor E, Asghari S, Yekaninejad MS, Hosseinzadeh-Attar MJ. Effects of selenium supplementation on asymmetric dimethylarginine and cardiometabolic risk factors in patients with polycystic ovary syndrome. Biological Trace Element Research. 2020;**196**(2):430-437

[55] Zhao J, Dong L, Lin Z, Sui X, Wang Y, Li L, et al. Effects of selenium supplementation on polycystic ovarian syndrome: A systematic review and meta-analysis on randomized clinical trials. BMC Endocrine Disorders. 2023;**23**(1):33

[56] Hajizadeh-Sharafabad F, Moludi J, Tutunchi H, Taheri E, Izadi A, Maleki V. Selenium and polycystic ovary syndrome; current knowledge and future directions: A systematic review.

Hormone and Metabolism Research. 2019;**51**(05):279-287

[57] Pieczyńska J, Grajeta H. The role of selenium in human conception and pregnancy. Journal of Trace Elements in Medicine and Biology. 2015;**29**:31-38

[58] Chen J, Guo Q, Pei YH, Ren QL, Chi L, Hu RK, et al. Effect of a shortterm vitamin E supplementation on oxidative stress in infertile PCOS women under ovulation induction: A retrospective cohort study. BMC Women's Health. 2020;**20**(1):69

[59] Caputo M, Bona E, Leone I, Samà MT, Nuzzo A, Ferrero A, et al. Inositols and metabolic disorders: From farm to bedside. Journal of Traditional and Complementary Medicine. 2020;**10**(3):252-259

[60] Murthy PPN. Structure and nomenclature of inositol phosphates, phosphoinositides, and glycosylphosphatidylinositols. In: Majumder AL, Biswas BB, editors. Biology of Inositols and Phosphoinositides: Subcellular Biochemistry. Boston, MA: Springer US; 2006. pp. 1-19

[61] Facchinetti F, Bizzarri M, Benvenga S, D'Anna R, Lanzone A, Soulage C, et al. Results from the international consensus conference on Myo-inositol and d-chiroinositol in obstetrics and gynecology: The link between metabolic syndrome and PCOS. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2015;**195**:72-76

[62] Zhang S-w, Zhou J, Gober H-J, Leung WT, Wang L. Effect and mechanism of berberine against polycystic ovary syndrome. Biomedicine & Pharmacotherapy. 2021;**138**:111468

[63] Cicero AFG, Baggioni A. Berberine and its role in chronic disease. In: Gupta SC, Prasad S, Aggarwal BB, editors. Anti-Inflammatory Nutraceuticals and Chronic Diseases. Cham: Springer International Publishing; 2016. pp. 27-45

[64] Rondanelli M, Infantino V, Riva A, Petrangolini G, Faliva MA, Peroni G, et al. Polycystic ovary syndrome management: A review of the possible amazing role of berberine. Archives of Gynecology and Obstetrics. 2020;**301**(1):53-60

[65] Saleem F, Rizvi SW. New therapeutic approaches in obesity and metabolic syndrome associated with polycystic ovary syndrome. Cureus. 2017;**9**(11):e1844

[66] Quideau S, Deffieux D, Douat-Casassus C, Pouységu L. Plant polyphenols: Chemical properties, biological activities, and synthesis. Angewandte Chemie, International Edition. 2011;**50**(3):586-621

[67] Bravo L. Polyphenols: Chemistry, dietary sources, metabolism, and nutritional significance. Nutrition Reviews. 1998;**56**(11):317-333

[68] Spencer JPE, Abd El Mohsen MM, Minihane A-M, Mathers JC. Biomarkers of the intake of dietary polyphenols: Strengths, limitations and application in nutrition research. British Journal of Nutrition. 2008;**99**(1):12-22

[69] Hashemi Taheri AP, Moradi B, Radmard AR, Sanginabadi M, Qorbani M, Mohajeri-Tehrani MR, et al. Effect of resveratrol administration on ovarian morphology, determined by transvaginal ultrasound for the women with polycystic ovary syndrome (PCOS). British Journal of Nutrition. 2022;**128**(2):211-216

[70] Banaszewska B, Wrotyńska-Barczyńska J, Spaczynski RZ,

### *Optimizing Nutrition for PCOS Management: A Comprehensive Guide DOI: http://dx.doi.org/10.5772/intechopen.114149*

Pawelczyk L, Duleba AJ. Effects of resveratrol on polycystic ovary syndrome: A double-blind, randomized, placebo-controlled trial. The Journal of Clinical Endocrinology & Metabolism. 2016;**101**(11):4322-4328

[71] Brenjian S, Moini A, Yamini N, Kashani L, Faridmojtahedi M, Bahramrezaie M, et al. Resveratrol treatment in patients with polycystic ovary syndrome decreased proinflammatory and endoplasmic reticulum stress markers. American Journal of Reproductive Immunology (NewYork, NY : 1989). 2020;**83**(1):e13186

[72] Mansour A, Samadi M, Sanginabadi M, Gerami H, Karimi S, Hosseini S, et al. Effect of resveratrol on menstrual cyclicity, hyperandrogenism and metabolic profile in women with PCOS. Clinical Nutrition (Edinburgh, Scotland). 2021;**40**(6):4106-4112

[73] Hong Y, Yin Y, Tan Y, Hong K, Zhou H. The flavanone, naringenin, modifies antioxidant and steroidogenic enzyme activity in a rat model of letrozole-induced polycystic ovary syndrome. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2019;**25**:395-401

[74] Wu Y-X, Yang X-Y, Han B-S, Hu Y-Y, An T, Lv B-H, et al. Naringenin regulates gut microbiota and SIRT1/ PGC-1ɑ signaling pathway in rats with letrozoleinduced polycystic ovary syndrome. Biomedicine & Pharmacotherapy. 2022;**153**:113286

[75] Rashid R, Tripathi R, Singh A, Sarkar S, Kawale A, Bader GN, et al. Naringenin improves ovarian health by reducing the serum androgen and eliminating follicular cysts in letrozoleinduced polycystic ovary syndrome in the Sprague Dawley rats. Phytotherapy Research. 2023;**37**(9):4018-4041

[76] Luo E-D, Jiang H-M, Chen W, Wang Y, Tang M, Guo W-M, et al. Advancements in lead therapeutic phytochemicals polycystic ovary syndrome: A review. Frontiers in Pharmacology. 2023;**13**:1-21

[77] Jafari Khorchani M, Zal F, Neisy A. The phytoestrogen, quercetin, in serum, uterus and ovary as a potential treatment for dehydroepiandrosterone-induced polycystic ovary syndrome in the rat. Reproduction, Fertility, and Development. 2020;**32**(3):313-321

[78] Hong Y, Yin Y, Tan Y, Hong K, Jiang F, Wang Y. Effect of quercetin on biochemical parameters in letrozoleinduced polycystic ovary syndrome in rats. Tropical Journal of Pharmaceutical Research. 2018;**17**(9):1783-1788

[79] Shah KN, Patel SS. Phosphatidylinositide 3-kinase inhibition: A new potential target for the treatment of polycystic ovarian syndrome. Pharmaceutical Biology. 2016;**54**(6):975-983

[80] Vaez S, Parivr K, Amidi F, Rudbari NH, Moini A, Amini N. Quercetin and polycystic ovary syndrome; inflammation, hormonal parameters and pregnancy outcome: A randomized clinical trial. American Journal of Reproductive Immunology (New York, NY : 1989). 2023;**89**(3):e13644

[81] Nowak W, Jeziorek M. The Role of Flaxseed in Improving Human Health. Healthcare (Basel, Switzerland). 2023;11(3):1-20

[82] Kajla P, Sharma A, Sood DR. Flaxseed-a potential functional food source. Journal of Food Science and Technology. 2015;**52**(4):1857-1871

[83] Nowak DA, Snyder DC, Brown AJ, Demark-Wahnefried W. The effect of flaxseed supplementation on hormonal levels associated with polycystic ovarian syndrome: A case study. Current Topics in Nutraceutical Research. 2007;**5**(4):177-181

[84] Mirmasoumi G, Fazilati M, Foroozanfard F, Vahedpoor Z, Mahmoodi S, Taghizadeh M, et al. The effects of flaxseed oil Omega-3 fatty acids supplementation on metabolic status of patients with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial. Experimental and Clinical Endocrinology & Diabetes: Official Journal, German Society of Endocrinology [and] German Diabetes Association. 2018;**126**(4):222-228

[85] Shah MZH, Shrivastava VK. Turmeric extract alleviates endocrinemetabolic disturbances in letrozoleinduced PCOS by increasing adiponectin circulation: A comparison with metformin. Metabolism Open. 2022;**13**:100160

[86] Zhang Y, Wang L, Weng Y, Wang D, Wang R, Wang H, et al. Curcumin inhibits hyperandrogeninduced IRE1α-XBP1 pathway activation by activating the PI3K/AKT signaling in ovarian granulosa cells of PCOS model rats. Oxidative Medicine and Cellular Longevity. 2022;**2022**:20

[87] Heshmati J, Moini A, Sepidarkish M, Morvaridzadeh M, Salehi M, Palmowski A, et al. Effects of curcumin supplementation on blood glucose, insulin resistance and androgens in patients with polycystic ovary syndrome: A randomized doubleblind placebo-controlled clinical trial. Phytomedicine. 2021;**80**:153395

[88] Jamilian M, Foroozanfard F, Kavossian E, Aghadavod E, Shafabakhsh R, Hoseini A, et al. Effects of curcumin on body weight, glycemic control and serum lipids in women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial. Clinical Nutrition ESPEN. 2020;**36**:128-133

[89] Jabczyk M, Nowak J, Hudzik B, Zubelewicz-Szkodzińska B. Curcumin in metabolic health and disease. Nutrients. 2021;**13**(12):4440

[90] Rao PV, Gan SH. Cinnamon: A multifaceted medicinal plant. Evidence-Based Complementary and Alternative Medicine. 2014;**2014**:642942

[91] Gruenwald J, Freder J, Armbruester N. Cinnamon and health. Critical Reviews in Food Science and Nutrition. 2010;**50**(9):822-834

[92] Dou L, Zheng Y, Li L, Gui X, Chen Y, Yu M, et al. The effect of cinnamon on polycystic ovary syndrome in a mouse model. Reproductive Biology and Endocrinology: RB&E. 2018;**16**(1):99

[93] Hajimonfarednejad M, Nimrouzi M, Heydari M, Zarshenas MM, Raee MJ, Jahromi BN. Insulin resistance improvement by cinnamon powder in polycystic ovary syndrome: A randomized double-blind placebo controlled clinical trial. Phytotherapy Research. 2018;**32**(2):276-283

### Section 2
