Understanding polycystic ovary syndrome in light of associated key genes
Egyptian Journal of Medical Human Genetics volume 24, Article number: 38 (2023)
Polycystic ovary syndrome (PCOS) is an endocrinopathy affecting women of reproductive age group at a global level. According to many community-based studies, the prevalence of PCOS in India ranges from 3.7 to 22.5% due to the country's enormous population. Upon ultrasound, it shows multiple cysts arranged in a bead of necklace-like appearance causing irregular menstrual cycles and infertility in most cases. It is manifested with abnormally raised testosterone and insulin levels and increased luteinizing hormone (LH)-to-follicle-stimulating hormone (FSH) ratio. Phenotypically, it is presented as obesity, hirsutism, acne and male pattern baldness, which impacts the self-esteem of young girls leading to depression and compromised quality of life.
Numerous potential genes have been shown to contribute to PCOS, and the genetic linkage of PCOS has been investigated in many studies. In this study we are looking into the candidate genes, the variants, and other responsible factors behind the genesis of PCOS. This will help in better understanding of its pathogenesis and, as a result, deciphering the mechanism by proper medication.
Method of the study
We comprehensively searched for publications including PCOS-relevant keywords in different areas in five different electronic databases: PubMed, Google Scholars, Elsevier, Springer Link and Science Direct up to March 2023 focusing on the new ones. We excluded non-English articles, conference papers and studies that were overlapping. Chosen articles were carefully read and further articles that were retrieved from their references were also reviewed so as to make the search complete with the inclusion criterion.
This review summarizes PCOS as an polygenic and a multifactorial complex disease in which a vast array of genetic and environmental factors are involved. Genes that affect steroidogenesis (ovarian and adrenal), gonadotropin action and regulation, insulin action and secretion, body mass index and chronic inflammation are directly or indirectly associated with PCOS.
In this study, research of the genetic propensity to PCOS was made, though not in-depth. With the acquired knowledge of array of genes involved, targeted efforts can be made for the potential therapeutic management of the PCOS patients via the novel discovered routes. Moreover, understanding more about PCOS would be beneficial in prevention of the associated metabolic disorders, life-threatening morbidities, restoring fertility and raising the self-esteem of the young women.
Polycystic ovarian syndrome, also referred as Stein Leventhal Syndrome, is a multifactorial disease with a complex pathophysiology, affecting 5–15% of premenopausal women globally. It is characterized by metabolic disturbances, endocrine imbalances and life-threatening co-morbidities [1, 2]. Menstrual dysfunction affects an estimated one in five to six women owing to stress, obesity and hormonal fluctuations [3, 4]. The three most common factors associated with PCOS include irregular ovulation, elevated androgen levels and cystic ovaries on ultrasound. During the manifestation of PCOS, the observable ovarian phenotypic changes include thickened capsule layer and a drastic increase in the number of small antral follicles arrested at the stage of the cell cycle wherein the dominant follicles are undergoing the selection process. In comparison to normal ovulatory follicles, these cystic follicles demonstrate a decreased number of granulosa cell layers and elevated levels of the number of steroidogenic cells in theca interna, suggesting a strong correlation between abnormalities in proliferation and differentiation in PCOS’s theca interna and granulosa layers. It results in changed hormonal mileu in transformed ovaries of PCOS females leading to the development of cysts in the ovarian stroma .
Earlier literature reported the association of genetic predisposition to PCOS development; however, no uniform consensus has been reached till now on established genetic marker for PCOS. As depicted in Fig. 1, PCOS progression is regulated by various environmental and genetic factors that affect ovaries directly or indirectly,. Several genes have a crucial role in the manifestation of this syndrome in females; these genes block and regulate the activity of various metabolic/hormonal pathways. The abnormal gene regulation at the genetic level leads to various post-translational modifications in the protein products, which causes the development of PCOS. The environmental or occupational factors such as sedentary lifestyle and dietary habits cause deterioration of the reproductive cycle by irregular menstruation, loss of physical activity, obesity, impairment of the menstrual cycle, etc., which contribute to the prevalence and modulation of PCOS. Throughout evolution, PCOS manifestation has occurred that can be demonstrated by the presence of 2–3 times increase in Anti-Mullerian hormone (AMH) in PCOS females, which serves as a diagnostic biomarker for monitoring the pathophysiology of PCOS [6,7,8].
This review presents a brief overview of pathophysiology of PCOS in light of vast array of genes involved in disruption of biochemical pathways—ovarian and adrenal steroidogenesis, gonadotropin action and regulation, insulin action and secretion, energy homeostasis and chronic inflammation.
Etiology of PCOS
The etiology of this syndrome is a combination of hereditary and environmental factors. Unhealthy eating habits, lifestyle choices and infectious agents further contribute to disease severity and progression [9, 10]. Hayes et al. in his study emphasized the association of PCOS with genetic components, candidate genes and single-nucleotide polymorphism (SNPs). As per the database, 241 gene variants have a direct implication in the etiology of PCOS manifestation [11,12,13]. The abnormal transcriptional activity of a gene due to polymorphisms or nucleotide mutations, results in PCOS . Several polymorphisms have been identified as contributing to PCOS including steroidogenic acute regulatory (StAR) polymorphs, follicle-stimulating hormone receptor (FSHR) polymorphs, FTO alpha-ketoglutarate-dependent dioxygenase (FTO) polymorphs, vitamin D receptor (VDR) polymorphs, insulin resistance (IR) and insulin receptor substrate (IRS) polymorphs and gonadotropin-releasing hormone receptor (Gn-RHR) polymorphs. An ovary becomes dysfunctional due to a gene defect that disrupts the biochemical pathway. Mainly the genes encoding for hormone receptors such as androgen, LH, FSH, insulin and leptin are accountable . With the increase in insulin secretion, ovarian theca cells respond by elevating the androgen level (androstenedione) that leads to anovulation. Unlike the normal ovary that metabolizes the androstenedione produced by the theca cells to estrone in peripheral tissues and estradiol in the granulosa cells, polycystic ovaries do not express the high aromatase activity thereby accumulating majority of androstenedione. The condition lowers the hepatic biosynthesis of sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein-1 (IGFBP-1) produced in the liver. The stimulation of visceral adipose tissue (VAT) by increasing androgen levels leads to the production of free fatty acids (FFAs), which further contribute to insulin resistance . An imbalanced secretion pattern of the gonadotropin-releasing hormone (GnRH) in PCOS contributes in the relative increase in LH-to-FSH ratio. As a result of this deranged ratio, ovulation does not occur in PCOS patients [17, 18].
Genetic predisposition and PCOS
There is a strong tie between the genetic predisposition and PCOS, which is demonstrated by the expression of different genes in different locations, illustrating other functions, as shown in Table 1. Expression of altered patterns of these genes is highly indicative of deranged signal transduction pathways involved in a cluster of a family of genes rather than a single gene. An overview of the genetic paradigm of PCOS is depicted in Table 1, and their roles in PCOS are discussed below in detail.
Genes involved in steroid hormone effect
Androgen receptor gene (AR)
This gene, which has 11 exons and is located on chromosome Xq12, codes for a protein-90 kb long and consists of 3 functional domains . PCOS and androgen receptor AR are related. The androgen signaling pathway is disturbed and increased by X inactivation. A single copy of the X chromosome can affect the entire pathway of gene regulation of AR, an X-linked gene. Genome-wide association studies for PCOS can be used to find novel mutations and other genetic variations linked to the etiology of this condition .
Sex hormone-binding globulin gene (SHBG)
Sex steroid-binding globulin (SSBG), also known as sex hormone-binding globulin (SHBG), is a glycoprotein that binds to androgens and estrogens, located on chromosome 17p13-p12. It is also known as an androgen-binding protein when it is generated by Sertoli cells in the seminiferous tubules of the testis (ABP). Generally, SHBG gene polymorphism is associated with PCOS. Down-expression of this gene often serves as a potential biomarker of insulin resistance, abnormal glucose and lipid metabolism in PCOS patients.
Genes involved in gonadotropin action and regulation
Follicular-stimulating hormone receptor (FSHR)
The FSHR gene has 14 exons and is located on chromosome 2p16.3. This gene produces the G-coupled receptors protein, which is essential for the growth of the gonads . Hormonal imbalances have an impact on the reproductive endocrine system. In addition to other hormone imbalances, FSH level is also accountable for the severity of PCOS. Follicular-stimulating hormone receptor is responsible for encoding FSH. Any aberration in the FSHR causes disturbances in follicular and ovarian function. Studies have reported a crystal-clear distinction between individuals of two cohorts—healthy and affected in the North of Iraq, by statistical analysis and RFLP using the Eam11051 restriction enzyme .
Anti-Müllerian hormone (AMH)
Polycystic ovaries produce many follicles—pre-antral and antral, which further up regulate the production of AMH, a member of the growth factor β family [23, 24]. The AMH gene is located on the long arm of chromosome 19 at cytogenetic location 13.3. Hence, elevated AMH levels are helpful for estimating ovarian volume in women with PCOS [25, 26]. The serum AMH levels are proposed as a diagnostic test for PCOS [27, 28]. The role of AMH in PCOS etiology has been reported, which mainly focuses on the AMH gene and its Type II Receptor (AMHR2). Kevenaar et al. studied the role of AMH SNPrs10407022 (Ile49Ser) and the AMHR2 polymorphism rs2002555 with the PCOS . GATA4, FOXL2 and steroidogenic factor 1 are some transcription factors (TFs) that have been newly discovered genes that control AMH production in the ovary. There is an increase in the number of follicles, elevated expression of AMH levels per follicle as well as increased expression of AMH and AMHR2 in PCOS women, in contrast normal ovulatory females showed the absence of AMH gene expression after the follicle maturation [30,31,32,33].
Genes involved in insulin action and secretion
Insulin gene (INS)
Insulin is produced by the androgen receptors in the theca cells, which is also activated through the pathway (phosphoinositide 3-kinase/protein kinase B) in PCOS theca cells. Increased production of insulin corresponds to increased androgen synthesis, similarly to LH. The transcriptional activity of INS and IGF-II is often regulated by these VNTR polymorphisms which is associated with PCOS [34, 35].
Calcium-dependent cysteine protease (CAPN)
The calcium-dependent cysteine protease CAPN10 is often referred to as Caplain10. There are 12 exons in it, which are located on chromosome 2q37.3, a heterodimer protein associated with type 2 diabetes. It is located in a region where type 1 non-insulin-dependent diabetes mellitus is prevalent . Calpain 10 is a cysteine protease encoded by the chromosomal region CAPN10. Calpain 10 has been identified to be involved in the action and secretion of insulin. Since insulin resistance and type 2 diabetes are linked to PCOS, genetic polymorphisms in CAPN10 result in PCOS, hence serving as an ideal candidate gene for PCOS .
Genes involved in insulin sensitivity and BMI
Fat mass obesity (FTO)
Alpha-ketoglutarate-dependent dioxygenase is another name for the FTO gene, which is located on chromosome 16q12.2 and contains 14 exons. Many investigations have demonstrated a link between FTO and type 2 diabetes, obesity and BMI . A study carried out in Pakistan indicates the reported evidence of genetic polymorphism in the FTO gene among PCOS females. Patients with PCOS had the intronic variation of the rs9939609 SNP. The considerable BMI difference between affected patients and healthy persons has been found through genetic and statistical analyses. FTO genes (rs9939609 and rs1421085) in Saudi women suffering from PCOS shows increased obesity and provide likely a connection between FTO and PCOS susceptibility.
Tumor necrosis factor (TNF)
The TNF super family, which includes several transmembrane proteins with a homologous TNF domain, includes TNF-α as a member. The TNF-α is an adipokine and cytokine that causes insulin resistance and is linked to type 2 diabetes brought on by fat . TNF-α is involved in chronic inflammation in PCOS females, but a direct association of polymorphism of TNF-α is not yet reported. But studies indicate that PCOS phenotypic traits are modified by TNF- gene polymorphism .
Genes involved in ovarian steroidogenesis and gametogenesis
Leptin is acknowledged as a peripheral signal and a potential regulator of a variety of reproductive processes, including ovarian steroidogenesis and gametogenesis. Leptin is thought to be a link between diet and reproduction . The hypothalamus–pituitary–ovarian (HPO) axis contains the leptin receptor and mRNA [41, 42] Leptin mRNA and protein production is also established in granulosa cells, oocytes and early cleavage-stage embryos. . Leptin regulates ovarian folliculogenesis by leptin receptors in granulosa cells, and glucocorticoids regulate steroidogenesis . It modulates the side chain cleavage enzyme and 17α-hydroxylase  and LH-stimulated estradiol production  in the ovary. Also, it serves as a potential marker in PCOS patients. Generally, PCOS individuals have elevated leptin levels than normal ovulatory females [47,48,49].
Aromatase, a member of the intricate Cytochrome P450 family, plays a crucial part in steroid conversion, and the conversion of testosterone into estrogen is one of the enzymes involved in steroidogenesis. A malfunction in the route caused by an aromatase deficit prevents its conversion . Due to the lack of C19 to C18 conversion, this defect will disrupt ovarian function and boost androgen levels. Aromatase genes associated with PCOS are CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP1A1, CYP21A2 and CYP3A7 listed in Table 1. Cytochrome P450 abnormality is associated with an increased risk of PCOS manifestation and progression.
CYPA1A gene: The etiology of PCOS has been linked to the CYPA1A gene, which is also recognized as a candidate gene. Cytochrome P450 family 1, subfamily A, member 1 is the acronym for this gene, which is present on chromosome 15q24.1. There are seven exons in all. Polycyclic aromatic hydrocarbons (PAHs) have a significant role in inducing the expression of this gene, which encodes the Cytochrome P450 proteins found in the endoplasmic reticulum . In a study of PCOS patients and healthy people, the ratio of isoleucine to valine in PCOS patients was higher than in healthy people. It was also determined through statistical analysis that PCOS patients have the genotype for valine and that isoleucine is replaced by valine in this condition. As a result, they concluded that the isoleucine/valine CYP1A1 genotype was 7.8 times more common than the valine genotype, which was 7.4 times more common . Increased toxification and detoxification may result from polymorphism in phase 1 and 2 enzymes. Any change in such enzymes causes aberrant ovarian function and cyst development. Strong correlations exist between PCOS susceptibility and the genetic variant T6235C in the CYP1A1-encoded phase 1 enzyme. Because of the disruption to the enzymatic route caused by this mutant gene, PCOS propensity and advancement are at risk .
CYP11A1 gene: CYP11A1 is a member of the Cytochrome P450 family 11, subfamily A. The super family of cytochrome p450 is encoded. It is present in the inner membrane of mitochondria. Pregnenolone is produced primarily by the catalysis of cholesterol. In the pathway for steroid production, it is also essential. The ten exons that make up this gene are found on chromosome 15q24.1 . The promotor pentanucleotide (TTTTA)n polymorphism is another genetic predisposition factor for PCOS. According to reports, CYP11A1 polymorphism is a molecular risk marker for PCOS. An interplay between hereditary and environmental variables raised the risk. Approximately 15 allele variations, with the most prevalent having eight repetitions, was found in a study of the South Indian population, generally ranging between 2–16 repeats. The occurrence of > 8 repeat alleles in PCOS-affected females was also examined in this study, which implies a threefold increased risk of PCOS predisposition compared to controls . Case–control research conducted in China showed that polymorphism in CYP11A1 is thought to be the primary cause of PCOS. SNP rs4077582 in CYP11A1 is strongly linked to PCOS and increases androgen levels by regulating luteinizing hormones in different genotypes .
CYP11b2 gene: Cytochrome P450, family 11, subfamily B and member 2 is its short form. Nine exons make up this gene, which is found on chromosome 8q24.3. Its job is to transmit instructions for the adrenal gland aldosterone synthetases to create new molecules . According to reports, this additional gene is in charge of the developing of PCOS. According to the results of a case–control study, the etiology of PCOS is due to polymorphism in the aldosterone synthetase promoter area. When compared to people without PCOS, the frequency of polymorphism was significantly high. Since PCOS-affected individuals also had significantly higher levels of aldosterone and testosterone, the likelihood of developing PCOS was enhanced .
CYP17A1 gene: Another monooxygenase involved in steroidogenesis is Cytochrome P450, Family 17, Subfamily A and Member 1. It has eight exons and is located on chromosome 10q24.32 . According to reports, the pathophysiology of PCOS involves the gene CYP17. According to a study done on the population of Chile, the CYP17 polymorphism C>T causes PCOS to progress. Through hormonal and clinical evidence, the comparison of polymorphism with body weight and insulin resistance was also made. Furthermore, an increase in body weight, insulin resistance and excessive lipid are caused by the polymorphism in CYP17 and the gene defect discovered by RFLP PCR. As a result, it is linked to PCOS and metabolic pathways . Another study found that the Chinese population has T/C polymorphism in the CYP17A1 gene. The genotypes of TC, TT and CC, which were 43.71%, 49.69% and 6.6%, were shown by the clinical and genetic criteria. In comparison to those who have the TT and TC genotypes, affected females with the CC genotype showed higher testosterone levels. Furthermore, T/C polymorphism might not be directly related to PCOS . When there is increased insulin resistance and testosterone levels, the association may be based on polymorphism. Among Indian women with PCOS, Pusalkar et al. reported that the frequency of the C allele rises, which could have an influence on their hyperandrogenic phenotype . However, this correlation was not found by Xing et al., suggesting the role of CYP17A1 rs7435721 polymorphisms as protective factors for PCOS .
CYP21A2 gene: Another gene implicated in the development and progression of PCOS is Cytochrome P450, Family 21, Subfamily A, Member 2. It has ten exons and is located on chromosome 6p21.33 . A heterozygous mutation in CYP21A2 may be involved in the etiology of PCOS. For the advancement of PCOS, about 14 molecular abnormalities in CYP21A2 have been documented. 5.9% and 7.6% of afflicted and control individuals had mutations, respectively. In the case of CYP21A2, however, it still isn't an acceptable response .
CYP3A7 gene: Cytochrome P450, Family 3, Subfamily A, Member 7 is another name for CYP3A7. It predominantly manifests in the liver. It has 13 exons located at chromosome 7q22.1 . According to reports, females with abnormal levels of androgen have inherited them. DHEAS metabolism is helped by CYP3A7. The CYP3A7 promoter variant allele lowers the activity of the metabolic pathway. In a study, the variant's overall frequency was 2.7%. It was 2.2% in the affected person and 3.6% in control. As a result, it is proven that females with PCOS have decreased DHEAS due to a mutant mutation in CYP3A7. The androgen metabolic pathway is affected by polymorphism, which can also lessen the severity of increased androgen levels and the PCOS phenotype .
CYP19A1 gene: It is also mentioned that the SNP rs2414096 discovered in the CYP19 gene in the Chinese population contributes to hyperandrogenism. In PCOS patients compared to controls, the genotype for rs2414096 was expressible different (AG, AA, GG), suggesting that the CYP19 SNP may also be linked to PCOS risk . PCOS development is also caused by a gene called CYP19A1 that encodes aromatase. Cytochrome P450, Family 19, Subfamily A, Polypeptide 1 is called CYP19A1. The manufacture of lipids, steroids and cholesterol is carried out by monooxygenase. It is found in the endoplasmic reticulum and is essential for the estrogen production. The CYP19A1 gene, located on chromosome 15q21.2 and contains a total of 18 exons and 17 introns , can exhibit abnormalities that disrupt the estrogen pathway and aromatase activity. The exon part of this gene contains the SNP rs700519(C/T), and the intronic part contains rs710059(C/T) . The regulatory part of CYP19A1 is 93 kb long, whereas the coding region is 30 kb long . Due to CYP19A1 gene polymorphism, there is additional evidence that PCOS advancement increases the risk of endometrial cancer, breast cancer and prostate cancer . The identification of SNPs, which are determined to be crucial in the disruption of the estrogen pathway, is also seen in the Korean population. Nineteen variants, found in 10 introns, four exons, 1 SNP in the 30 UTR and 6 SNP in the 50 untranslated part, have been identified . The SNPs rs700519 at the exon region and rs2414096 and rs60271534 at the intronic region were also discovered in the South Indian population. These variations are what give rise to PCOS. The exon region Arg264Cys shows a substantial correlation with variance, according to statistical research. While the in-silico study revealed that the structure of the aromatase substrate recognition site 3 was destabilized, resulting in decreased enzymatic activity.
Genes involved in chronic inflammation
Plasminogen activator inhibitor-1 (PAI-1)
Cardiovascular disease is known to be associated with abnormalities in the fibrinolytic and coagulation pathways among patients with PCOS, with the possibility of involvement of associated candidate genes for PCOS . Plasminogen activator inhibitor-1 (PAI-1) is one of the gene involved in chronic inflammation. PCOS women develop increasing amounts of PAI-1, and the 4G allele in the PAI-1 promoter is expressed, which enhances its expression .
Interleukin 6 (IL-6)
Several studies have demonstrated a correlation between PCOS women's chronic low-grade inflammation and hyperandrogenism. With conflicting existing literature, the involvement of IL-6 in insulin sensitivity is less established. It has been hypothesized that the influence of IL-6 on insulin metabolism fluctuates according to the type of tissue, the physiological status and the duration of IL-6 elevation (transient or chronic) . During exercise, a transient surge of IL-6 has both an anti-inflammatory response and stimulated absorption of glucose in the skeletal muscle . IL-6 also induces insulin sensitivity in fatty tissue and the liver by over-expressing the protein suppressor of cytokine signaling 3 (SOCS3), which binds to the insulin receptor and inhibits it. It also suppresses the transcription and phosphorylation of IRS-1 [78,79,80]. IL-1β has a major role in various stages of implantation that induced the secretion of urokinase plasminogen activator (uPA), PAL-1 and PAL-2. IL-1β-511C/T polymorphism has a positive correlation with PCOS pathogenesis along with recurrent spontaneous abortion (RSA) in Chinese and Saudi populations whereas no such effect was observed in Korean, Indian, Caucasian and Iranian Azeri individuals [81,82,83,84,85]. Similarly, IL-6-174G/C and TNF-α-1031 T/C polymorphisms showed significant disease pathogenesis and also reflected chemical characteristics of RSA with PCOS women in Saudi women [86, 87].
Transforming growth factor-beta (TGF)
TGF-β1 is a multifunctional cytokine which is associated with the maintenance of ovarian functions, from granulosa cells differentiation, regulating progesterone production, maintaining corpus luteum to inducing follicular atresia . It is also associated with tissue fibrosis, wound healing and embryonic development. TGF-1 levels in PCOS patients' serum and ovaries were found to be elevated than in non-PCOS women, making it a major therapeutic target for PCOS pathophysiology . TGF-1 gene SNPs and haplotypes were linked to PCOS in Chinese women . The TGF-1 gene polymorphism (rs1800469C/T) is linked to the emergence of PCOS and metabolic problems, which are more common among Koreans .
Role of oxidative stress in PCOS
Inflammation and oxidative stress (OS) are an essential parameter in PCOS pathogenesis. Studies have reported elevated levels of markers in the oxidative circulation, demonstrated by Fig. 2 [92, 93]. Reactive oxygen species (ROS) acts as secondary redox messenger and helps in the development and progression of cancer, diabetes and cardiovascular diseases. ROS modulates gene expression by regulating cell growth, differentiation and apoptosis. It has been found that different phenotypes impact oxidative stress, but the mechanism remains open to investigation in the future. ROS are often associated with mitochondrial dysfunction since mitochondria are the energy currency of the cell, and also the primary source of ROS generation, which is a by-product of nutrient translation . An increase in ROS may induce mitochondrial DNA damage (mt-DNA), proteins and lipids and can cause apoptosis . Two factors demonstrate the correlation of ROS with PCOS: first studies have shown a decrease in mt-DNA copy number in PCOS females, which is essential for ROS generation . Secondly, mitochondrial gene mutations such as single-point mutations of genes encoding mt-tRNA cause PCOS complications such as diabetes and hypertension [97, 98]. Mutations in mt-DNA displacement loop (D-loop) potentially disrupt mt-DNA replication and transcription, altering ETC and enhancing cellular ROS production and oxidative stress (OS). Many human disorders, including PCOS, have been linked to sequence variations in the mt-DNA D-loop. Hence, the development of PCOS is closely related to mitochondrial oxidative metabolism. Variations in the genes for antioxidant enzymes may make patients more susceptible to oxidative stress and hence aid in the etiology of PCOS [99,100,101].
Also, the effect of oxidative stress is impaired on glucose uptake, mainly in the muscle and adipose tissues. Also, insulin secretion by pancreatic cells is reduced. Hyperinsulinemia prevents nitric oxide (NO) secretion from the vascular endothelium, which leads to a series of events, thereby resulting in endothelial dysfunction, caused mainly by the decrease in endothelial fluid and increase in intracellular calcium levels. Thus, endothelial dysfunction may occur in PCOS patients which is also an early symptom of atherosclerosis. Oxidative stress is further maintained and regulated by other features of PCOS, such as abdominal adiposity, insulin resistance, obesity and androgen excess . A cumulative increase in oxidative stress may also facilitate the development of Atherosclerotic heart disease (AHD) .
Diet-induced ROS-related oxidative stress (OS) causes an inflammatory response that activates an over-expression of Nuclear Factor Kappa B (NFKB) [104, 105]. It triggers the action of TNF and IL-6 from monocytes which are altered in PCOS. The ROS generation also causes increased expression of the p47 (phok) protein which is translocated from cytosol to membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and causes superoxide generation . Hence, diet-induced response contributes to OS.
Hormonal-induced ROS have also been studied; hand is often related to PCOS. The administration of oral androgens causes mononuclear cell (MNC) activation, which further generates ROS, activating the cascade of activation of nuclear factor kappa B (NFKB) and TNF-mRNA. Tsai-Turton studied similar results with androgen-resistant mice models, which were not treated with testosterone or dihydrotestosterone (DHT). Oxidative Stress also leads to follicular apoptosis in PCOS individuals which blocks the maturation of follicles and is inhibited by glutathione [94, 107,108,109]. PCOS-obese women also suffer from frequent pregnancy and miscarriages mediated by OS . Increased production of ROS causes antioxidant depletion and sometimes causes the abnormal distribution of mitochondria in oocytes . Therefore, increasing oxidative stress with low antioxidants and insulin resistance, as reported in PCOS patients, support the concept of the role of oxidative stress in the pathophysiology of PCOS.
Epigenetics and PCOS
Genome-wide association studies (GWAS) have identified that the susceptibility of hereditary loci in PCOS females are less than ~ 10%. In contrast, studies have reported that monozygotic twins have hereditary PCOS susceptibility loci of approximately ~ 70%. Hence, there is a strong association between epigenetic changes and PCOS. Both environmental and epigenetic mechanisms have an important role in etiology and pathophysiology of PCOS. Tissue-specific epigenetic regulations such as promoter activity, histone modifications, DNA methylation, enhancer-binding activity and transcription factor binding profiles in PCOS females have been reported. Over-expression of DENND1A (DENN/ MADD domain containing 1A) in theca cells of PCOS females has a significant role in elevated androgen and progestin synthesis . Hox A family genes identified in cumulus cells and luteinizing hormone/chorionic gonadotropic receptors (LHCGR) identified in theca and mature granulosa cells associated polymorphisms drive excess androgen production which also play a crucial role in etiology of PCOS . Over-expression of androgen receptors during prenatal life leads to DNA hypomethylation in androgenized rats at specific CpG sites from the promoter region of GATA6 (-520) and STAR (-822) genes. These genes play an essential role in steroidogenesis, which alters the epigenetic landscape and thus confers PCOS , as shown in Fig. 3. GWAS studies have reported many gene that differ in DNA methylation status in normal and PCOS females. For instance, the LHCGR gene encodes for LH receptors, FST gene for follistatin, LMNA for Lamin A/C, PRARGC1A for the proliferation the peroxisomes and EPHX1 encoding epoxide hydrolase in PCOS individuals showed modified gene expression. It is to be noted that any individual gene methylation alterations do not cause the disease, instead they encode for the fundamental physiological process such as steroidogenesis, glucose metabolism, inflammation, follicular development and insulin regulation . It is the modification in their methylation status that leads to syndromic conditions.
Histone epigenetic modifications such as acetylation, methylation, phosphorylation and ubiquitination are versatile alterations closely linked to disease pathophysiology and development such as PCOS. Hosseini et al. reported the CYP19A1 in ovarian cumulus cells when compared to control showed a direct pathophysiological link between histone acetylation and PCOS. Low cytochrome p450 aromatase activity was caused due to upregulation of serum levels of histone H3 acetylation and methylation of H3K9 in PCOS individuals which downregulated the CYP19A1 expression [116, 117].
Another aspect of epigenetic modifications that influence gene expression involves the microRNA (miRNA); these are non-coding single-stranded RNA that modulated the activity of two enzymes—DNA methyltransferases and histone deacetylases . Numerous miRNAs have been reported that influence PCOS pathogenesis  and serve as potential biomarkers. For instance, the expression of miR-182 and miR-15a was downregulated in PCOS rat models which is essential for the maintenance of granulosa cell (GC) in the ovaries ; hence, similar studies were conducted on PCOS women and by targeting a particular pathway helps decipher the exact role of a certain miRNA that aids in the understanding of metabolic consequences and diagnosis of PCOS . There are diverse functions of miRNAs such as in steroidogenesis by regulating development and maturation of oocytes, in glucose metabolism via GLUT-4, insulin signaling system, cholesterol homeostasis, lipid metabolism, BMI, adipogenesis, etc. The miR-222 and miR-93 are known to regulate insulin metabolism . These miRNAs are the major contributors of PCOS pathophysiology since miR-93 over-expression causes decreased expression of GLUT4, the major insulin mediated glucose transporter into adiposities and miR-222 over-expression is linked with elevated serum levels . Various other miRNAs reported in adipose generation and inflammation are miR-132, miR-103, miR-27b, miR-9, miR-18b, miR-21, miR-135a and miR-320 and in androgen regulation are miR-155, miR-146a and miR-222 [124, 125]. Deswal et al. demonstrated various expression levels of miRNAs in PCOS as shown in Fig. 4, corresponding upregulation levels of miR-518-3p, miR-27b, miR-301a-3p, miR-93, miR-21, miR-19b, miR-24, miR-93, miR-222, miR-223, miR-93, miR-27a-3p, miR-27a-5p, miR-23a, miR-24-2, miR-25, miR-106, miR-509-3p, let-7i-3p, miR-5706, miR-4463, miR-3665, miR-638, miR-502-3p, miR-200c, miR-1, hsa-let-7g, miR-32, miR-513-3p, miR-508-3p, miR-513b, miR-144, miR-146a, miR-30c, miR-16, miR-200a-3p, miR-10b-3p, miR-200b-3p, miR-29c-3p, miR-99a-3p, miR-125a-5p and miR-424, whereas downregulation levels of miR-24-3p, miR-29a -5p, miR-151-3p, miR-574-3p, miR-155, miR-4522, miR-324-3p, miR-9, miR-18b, miR-32, miR-34c, miR-26a-5p, miR-135a, miR-23a, miR-23b, miR-105-3p, miR-19a, miR-186, miR-320, miR-128 and let-7c in PCOS women. Among these, miR-29a-5p and miR-320 can be potentially used for PCOS diagnosis as biomarkers .
Furthermore, the circular RNAs (circRNAs) are non-coding RNAs that form a covalently closed-loop due to back-splicing of exons, hence excluding 5′-end cap and 3′-end poly (A) tails. CircRNAs function in protein sequestration, elevated parental gene expression, translation leading to polypeptides, and miRNA sponges. These circular molecules are more abundant and specialized than other types of RNA. They are therefore referred to as possible biomarkers for various disorders . Interactions between miRNAs and circRNAs could influence the miRNAs' downstream targets, resulting to the hormonal imbalance as reported by the interactions between miR-139-5p and five circRNAs have sponging effects, mainly hsa_circ_0063309, hsa_circ_0054275, hsa_circ_0056196, hsa_circ_0018108 and hsa_circ_007098 . Zhang et al. identified miR-217-RUNX2 upregulation in the cumulus cells of PCOS women, whereas when silenced, it causes estradiol biosynthesis by over-expression of CYP11A1 and CYP19A1 genes .
Potential miRNA-based therapeutics are being developed that can either restore or inhibit the function of miRNA by using miRNA mimics and inhibitors (anti-miRNAs) such as small interfering RNA (siRNA), anti-miRNA oligonucleotides and miRNA mimics. This may explain the reason behind heterogeneity in PCOS women. Therefore, further studies need to be conducted for understanding the involvement of non-coding RNAs in the etiology of PCOS that might lead to new insights and treatments.
Polycystic ovary syndrome (PCOS) has a significant genetic, epigenetic and deranged lifestyle basis involving interplay of individual genes, genetic polymorphism and altered genes’ environmental conditions. Numerous genes, including the sex hormone-binding globulin gene (SHBG), androgen receptor gene (AR), follicular-stimulating hormone receptor (FSHR), fat mass obesity (FTO), calcium-dependent cysteine protease (CAPN), leptin and anti-Müllerian hormone (AMH), have been proposed as playing a role in the etiopathogenesis of PCOS. Affected women have hyper-synthesis of androgens owing to altered expression of critical enzymes involved in the steroid hormone biosynthesis pathway chiefly Cytochrome P450 enzymes: CYP17, CYP21, CYP19 and CYP11A. Hypothalamic–pituitary–adrenal axis impairment, ovarian dysfunctions and ovarian expression of certain genes (mainly of inflammatory origin) contribute in the pathophysiology of PCOS. Due to complexity and heterogeneity of PCOS, there is a difference in genetic basis of PCOS between families and within families. An estimate of 20–40% of the first-degree female family members of PCOS patients are also diagnosed with the syndrome, and the heritability is estimated to be around 65% indicating that genetic factors chiefly determine PCOS susceptibility. Thus, we can say that PCOS is a complicated multisystem disorder, where numerous genetic, epigenetic and environmental factors contribute to its pathophysiology. Small genetic effects taken together increase disease risk and modulate the phenotype of any specific patient.
PCOS is a multifactorial, polygenic and complex infertility disorder with overlapping symptoms. The current review has summarized the influence of several factors that contribute to PCOS progression; including altered metabolic pathways caused by a genetic abnormality that result in ovarian dysfunction. Genes involved in steroidogenesis, obesity, inflammation, gonadotropin action, insulin production and resistance along with the epigenetic factors are central to manifestation of PCOS. The proper preventative measures, such as losing weight, eating a nutritious diet and taking prescribed medications, can assist in alleviating the critical symptoms of PCOS and minimize the psycho-social trauma and severity associated with it. With better understanding of the pathogenesis of PCOS and by shedding light on the genetics of PCOS, we can do earlier intervention in controlling the co-morbidities that would allow treatment to be tailored with more personalized care.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Polycystic ovary syndrome
Short tandem repeat polymorphisms
Fat mass obesity
Sex hormone-binding globulin gene
Calcium-dependent cysteine protease
Androgen receptor gene
Follicular-stimulating hormone receptor
Tumor necrosis factor
Plasminogen activator inhibitor-1
Genome-wide association studies
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We would like to thank Principal, Kirori Mal College, University of Delhi, Prof. Dinesh Khattar for allowing us to conduct this research.
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Bhimwal, T., Puneet & Priyadarshani, A. Understanding polycystic ovary syndrome in light of associated key genes. Egypt J Med Hum Genet 24, 38 (2023). https://doi.org/10.1186/s43042-023-00418-w