158 1 REPRODUCTIONREVIEW DNA methylation in the pathogenesis of polycystic ovary syndrome Edgar Ricardo Vázquez-Martínez1, Yadira Inés Gómez-Viais1, Elizabeth García-Gómez2, Christian Reyes-Mayoral3, Enrique Reyes-Muñoz4, Ignacio Camacho-Arroyo1 and Marco Cerbón1 1Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, México, 2Unidad de Investigación en Reproducción Humana, Consejo Nacional de Ciencia y Tecnología (CONACyT)-Instituto Nacional de Perinatología, Ciudad de México, México, 3Subdirección de Reproducción Humana, Instituto Nacional de Perinatología ‘Isidro Espinosa de los Reyes’, Ciudad de México, México and 4Coordinación de Endocrinología Ginecológica y Perinatal, Instituto Nacional de Perinatología ‘Isidro Espinosa de los Reyes’, Ciudad de México, México Correspondence should be addressed to E R Vázquez-Martínez; Email: [email protected] Abstract Polycystic ovary syndrome (PCOS) is the leading endocrine and metabolic disorder in premenopausal women characterized by hyperandrogenism and abnormal development of ovarian follicles. To date, the PCOS etiology remains unclear and has been related to insulin resistance, obesity, type 2 diabetes mellitus, cardiovascular disease and infertility, among other morbidities. Substantial evidence illustrates the impact of genetic, intrauterine and environmental factors on the PCOS etiology. Lately, epigenetic factors have garnered considerable attention in the pathogenesis of PCOS considering that changes in the content of DNA methylation, histone acetylation and noncoding RNAs have been reported in various tissues of women with this disease. DNA methylation is changed in the peripheral and umbilical cord blood, as well as in ovarian and adipose tissue of women with PCOS, suggesting the involvement of this epigenetic modification in the pathogenesis of the disease. Perhaps, these defects in DNA methylation promote the deregulation of genes involved in inflammation, hormone synthesis and signaling and glucose and lipid metabolism. Research on the role of DNA methylation in the pathogenesis of PCOS is just beginning, and several issues await investigation. This review aims to provide an overview of current research focused on DNA methylation and PCOS, as well as discuss the perspectives regarding this topic. Reproduction (2019) 158 R27–R40 Introduction hyperplasia and prenatally androgenized animals, correlates with a decline in the negative feedback effect Polycystic ovary syndrome (PCOS) is an endocrine of estradiol and progesterone in the GnRH-mediated and metabolic dysfunction characterized by release of LH, which is a typical characteristic in women hyperandrogenism and incomplete development of with PCOS (Blank et al. 2006). A study recently proposed ovarian follicles that result in an anovulatory state that prenatal exposure to androgens results in aberrant (Dumesic & Richards 2013, Trikudanathan 2015, Patel fetal programming in GnRH neurons that impairs their 2018). Alteration of the hypothalamic–pituitary–ovarian response to the steroid hormones negative feedback in (HPO) axis is one major dysfunction observed in PCOS; mice (Silva et al. 2018). this modification is because of an increase in the Substantial evidence demonstrates that fetal pulse frequency release of the gonadotropin-releasing programming with prenatal testosterone treatment hormone (GnRH) from the hypothalamus, which, in results in a phenotype similar to PCOS during adulthood turn, favors the synthesis and secretion of luteinizing in models of sheep and monkeys (Padmanabhan & hormone (LH) instead of follicle-stimulating hormone Veiga-Lopez 2013, Rae et al. 2013, Abbott et al. 2016, (FSH) by the pituitary gland. An elevation in serum Ramaswamy et al. 2016). In addition, prenatal exposure levels of LH results in a high LH/FSH ratio (higher than to elevated levels of anti-Müllerian hormone (elevated in 2:1) that promotes androgen production in the ovarian pregnant women with PCOS) in pregnant mice programs theca cells (Trikudanathan 2015). female offspring to develop a PCOS phenotype during Remarkably, exposure to elevated androgens early adulthood; however, this functional correlation has not in life, such as in women with congenital adrenal been established in humans (Tata et al. 2018). © 2019 Society for Reproduction and Fertility https://doi.org/10.1530/REP -18-0449 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via https://rep.bioscientifica.com Downloaded from Bioscientifica.com at 10/01/2021 10:57:58PM via free access -18-0449 R28 E R Vázquez-Martínez and others Anovulation in women with PCOS is accompanied probably altered by this epigenetic modification Fig. 1( ) by menstrual dysfunction such as oligomenorrhea and because of its participation in the regulation of (menstrual periods occurring >35 days apart) gene expression and chromatin structure (Andersen & or amenorrhea (absence of menstruation for, at Tost 2018). However, further investigation is warranted least, 3 months), hyperandrogenism (evidenced by to establish the functional role of DNA methylation in hirsutism, acne and alopecia), infertility and metabolic patients with PCOS because of a lack of cause and effect dysfunctions (Trikudanathan 2015, McCartney & studies. Hence, this review aims to provide an overview Marshall 2016). Recently, the updated diagnosis criteria of current research focused on DNA methylation and and the international guidelines for the assessment and PCOS, as well as discuss the perspectives regarding management of women with PCOS have been published this topic. (Neven et al. 2018, Teede et al. 2018). Although PCOS is one of the leading endocrine and DNA methylation in PCOS metabolic disorders in premenopausal women (range: 6–20% worldwide), its etiology remains unclear to DNA methylation is referred as an enzymatic reaction date (Teede et al. 2010, Goodarzi et al. 2011, Barber consisting of the addition of a methyl group generally at et al. 2015, Escobar-Morreale 2018a). PCOS is a the carbon in the 5′ position of the pyrimidine ring of a chronic disease that directly affects the quality of life cytosine followed by a guanine, called CpG dinucleotides of reproductive age women as it is related to insulin (Illingworth et al. 2008). In addition, DNA methylation resistance (60–70% of cases), obesity, type 2 diabetes is involved in essential processes such as transcriptional mellitus, cardiovascular disease and mood disorders regulation, X chromosome inactivation, imprinting, (primarily depression), among others morbidities and gametogenesis, development and differentiation, among is the leading cause of anovulatory infertility (Brassard others (Senner 2011). Alterations in DNA methylation et al. 2008, Teede et al. 2010, Sirmans & Pate 2013, are related to the pathogenesis of several diseases such Reyes-Muñoz et al. 2016). The ovary is not the only as type 2 diabetes mellitus, neurodegenerative diseases, affected tissue in the disease, as women with PCOS also cardiovascular disease and cancer (Berson et al. 2018, exhibit adipose tissue dysfunction (Cortón et al. 2007, Nebbioso et al. 2018, Rosa-Garrido et al. 2018, Zhou Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus et al. 2018). Workshop Group 2008, Martínez-García et al. 2013, The interest in the role of DNA methylation in the Montes-Nieto et al. 2013), insulin resistance in the PCOS pathogenesis began, at least, 10 years ago; skeletal muscle (Silva Dantas et al. 2013), elevated however, a growing body of evidence reveals that women serum levels of inflammatory markers (Orio et al. 2005, with PCOS have an altered epigenetic program due, in Diamanti-Kandarakis et al. 2006a, Escobar-Morreale part, to this covalent modification Fig. 1( and Table 1). et al. 2011) and endometrial alterations (Piltonen 2016). In addition, alterations in DNA methylation have been Several studies have demonstrated the impact of genetic noted in the peripheral and umbilical cord blood, and environmental factors on the PCOS etiology (Abbott suggesting a correlation between the PCOS phenotype et al. 2005, Diamanti-Kandarakis et al. 2006b, Azziz and epigenetic changes in cells from systemic and fetal et al. 2016, Mykhalchenko et al. 2017). Lately, epigenetic circulation. Remarkably, changes in DNA methylation factors have garnered considerable attention in the study have also been reported in tissues affected in the disease, of the PCOS pathogenesis, considering that intrauterine including the ovary, adipose tissue and skeletal muscle and environmental insults, as well as lifestyle factors, (Table 1). Table 1 summarizes the studies that report DNA might predispose to the disease development (Escobar- methylation changes related to PCOS, which includes Morreale 2018b, Patel 2018, Smyka et al. 2018, Tata observed changes in the gene expression, ontology et al. 2018). Some studies have revealed alterations in the terms obtained with the g:Profiler software Reimand( content of miRNAs and long noncoding RNAs in tissues et al. 2016), and correlations reported between DNA affected by PCOS (Sørensen et al. 2016, Concha et al. methylation and clinical or functional findings observed 2017, Liu et al. 2017, Sagvekar et al. 2018). In addition, in PCOS. Moreover, recent studies have highlighted the other studies have indicated that modifications in plasticity of DNA methylation observed across age and histone acetylation could be involved in the acquisition through therapeutic