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Review

Emerging Topics in Cardiometabolic and Psychologic Sequelae, Pathogenesis, and Treatment of Polycystic Ovarian Syndrome: A Review

by
Rachana Shah
Division of Pediatric Endocrinology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, 3615 Civic Center Blvd, 802F Philadelphia, PA 19104, USA
Children 2019, 6(8), 89; https://doi.org/10.3390/children6080089
Submission received: 30 May 2019 / Revised: 18 July 2019 / Accepted: 25 July 2019 / Published: 31 July 2019
(This article belongs to the Special Issue Obesity and Metabolic Dysregulation in Childhood)
Versions Notes

Abstract

:
Polycystic ovarian syndrome (PCOS) is a common endocrine disorder, affecting 6–10% of reproductive age women and influences the reproductive, metabolic, dermatologic, and psychiatric health of affected girls and women. Despite its prevalence, the pathogenesis of the disease is largely unknown, and treatment options are limited. Thus, PCOS has been a ripe area for research in recent years, and novel etiologic pathways, diagnostic parameters, and treatment options are being explored. This review focuses on recent data suggesting pathogenic and therapeutic considerations, as well as the psychiatric and metabolic sequelae of PCOS.

1. Introduction

Polycystic ovarian syndrome (PCOS) is the most common endocrine disease in reproductive age women, with reported prevalence of 6–10% in the general population. PCOS features a combination of anovulation and hyperandrogenism, which clinically present as irregular menstrual periods and infertility, as well as hirsutism and acne. Increased awareness and screening have led to increasing diagnosis in the adolescent population. While insulin resistance, impaired gonadotropin signaling, and altered ovarian reactivity have all been implicated in the pathogenesis, the primary underlying cause of PCOS remains unknown [1]. Thus, management of the disorder is primarily focused on alleviating symptoms. Fortunately, there has been significant progress in clarifying diagnosis and management, elucidating the pathogenesis, and developing therapeutics to help the millions of women worldwide suffering from PCOS.
This review focused on providing a summary of recent advances in clarifying the comorbidities, underlying pathogenic pathways, therapeutic options, and long-term sequelae of PCOS.

2. Diagnosis and Management of PCOS

Symptoms of PCOS often emerge during adolescence, but diagnosis can occur at any time during the reproductive years. There are three commonly utilized diagnostic criteria for PCOS in adult women, all of which begin with ruling out other etiologies of symptoms. In the Rotterdam criteria, patients must meet two of the following three: clinical or biochemical hyperandrogenism (acne, hirsutism, or alopecia and/or elevated free or total testosterone), oligo-ovulation or anovulation (>35-day cycle or midluteal progesterone <2.5 ng/mL), and polycystic ovaries (>10 mL volume, or >12 2–9 mm follicles in at least one ovary). The National Institute of Health (NIH) criteria require both hyperandrogenism and menstrual dysfunction and the Androgen Excess and PCOS Society (AE-PCOS) guidelines require hyperandrogenism plus ovarian dysfunction and or polycystic ovaries (with follicle count cutoff raised to 25 due to more sensitive current imaging techniques) [2].
Recent consensus guidelines have established diagnostic criteria for adolescent PCOS to require the combination of the following in girls at least two years from menarche: (1) oligo- or anovulation (defined as <8 cycles per year or cycles <21 or >35 days in length or amenorrhea for >90 days for any one cycle or primary amenorrhea by age 15 or >3 years post thelarche); (2) hyperandrogenism, both biochemical (elevated free or bioavailable testosterone levels by sensitive assay) or clinical (hirsutism, severe acne not responsive to topical treatment) [3]. Ultrasound criteria are not utilized in adolescents due to lack of age-specific normative data and cut-off values. The adolescent guidelines for making a diagnosis of PCOS are more specific but potentially less sensitive, thus requiring careful follow up over time in girls that do not fully meet criteria at initial evaluation [4,5,6].
Once the diagnosis is established, management of PCOS should include: (1) regulation of menstrual cycles (and restoration of ovulation if fertility is desired); (2) assessment and treatment of dermatologic concerns (hirsutism, acne, androgenic alopecia) with cosmetic or pharmaceutical options; (3) screening for cardiometabolic comorbidities (e.g., insulin resistance, obstructive sleep apnea, hypertension) and counseling on lifestyle modification—calorie reduction and increased physical activity—to improve weight and metabolic parameters; and (4) screening and counseling for mental health conditions and appropriate referrals for mental health care [7].

3. Beyond Reproduction: Current Understanding of Comorbidities in PCOS

While irregular menses, infertility, acne, and hirsutism can majorly impact health and quality of life (QOL)in girls with PCOS, the risks of PCOS extend well beyond the readily assessed gynecologic and dermatologic symptoms and can have wide-ranging impacts on a women’s physical and mental health throughout her life.

3.1. Cardiometabolic Risk

PCOS is associated with significant cardiometabolic which begins to manifest in adolescence [8]. Adolescents with PCOS are more likely than age- and body mass index (BMI)-matched controls to have insulin resistance [9], dyslipidemia, and non-alcoholic fatty liver disease. Akgul et al. recently reported that 52% of adolescent girls with PCOS in their cohort met criteria for metabolic syndrome [10], which is well above the rate reported in obese non-PCOS teens. A meta-analysis of seven studies confirmed these findings, reporting odds of metabolic syndrome in PCOS as 2.69 times higher than girls without PCOS [11].
Looking beyond traditional metabolic syndrome parameters, complex determinants of cardiometabolic risk are also higher in PCOS teens than age and BMI-matched control girls. Increased carotid intima thickness (CIMT), beta thickness, and reduced arterial compliance, as well as atherogenic lipid profile, in PCOS compared to BMI-matched controls have been reported by one group [9]; however, another study showed similar rates in obese PCOS and obese-non PCOS subjects of CIMT, pulse wave velocity, and inflammatory markers [12]. Using indirect calorimetry and hyperinsulinemic-euglycemic clamps, Kim et al. determined that girls with PCOS had decreased lipid mobilization and fat oxidation, and metabolic inflexibility as a phenotype of adipose tissue dysfunction, despite similar BMI and body fat percentage as a control group [13].
Several novel biomarkers associated with adiposity and metabolic derangements have been assessed in PCOS. Irisin is a myokine expressed in muscle and adipose tissue, induced by exercise, and leads to adipose tissue browning, increased energy expenditure, and improvements in glucose homeostasis in a mouse model [14]. Its benefits on glucose tolerance has been related to increased glucose transport and decreased hepatic gluconeogenesis in an adenosine monophosphate-activated protein kinase (AMPK) pathway [15]. In PCOS, circulating levels of irisin are elevated and associated with metabolic, androgenic, and reproductive markers [16,17], with one small trial showing reduced levels with metformin treatment [18]. Conversely, levels are reduced in subjects with type 2 diabetes and gestational diabetes [19], suggesting a regulatory role that is induced by obesity and insulin resistance and compromised with beta-cell failure and further metabolic derangement.
The adipokine S100A4 has been implicated in subcutaneous adipose tissue dysfunction and insulin resistance [20]. In mice, S100A4 levels were reduced after high fat diet and S1004 deficient mice had reduced insulin signaling, increased obesity, and liver inflammation [21]. In girls with PCOS, S100A4 levels were elevated and correlated with hepato-visceral adiposity; S100A4 and hepato-visceral fat decreased further with a combination spironolactone/pioglitazone/metformin (SPIOMET) treatment than with oral contraceptives [22].
Fetuin, a glycoprotein expressed predominantly in liver and adipose tissue, has been broadly associated with obesity and cardiometabolic dysfunction [23]. In human cell lines, fetuin A blocked insulin receptor tyrosine kinase activity which is critical for insulin signaling [24]. Levels of fetuin A are higher in type 2 diabetes [25] and metabolic syndrome, and levels reduced with weight loss [26], exercise [27], and metformin [28]. Results on associations of fetuin A to PCOS have been conflicting. Several studies have reported found levels were higher compared to age and BMI-matched controls [29,30] and positively correlated with insulin, HOMA-IR, and free androgen index [31], while another found no difference [32]. In a small adolescent study, fetuin A levels were lower in PCOS and normalized with SPIOMET [33,34]. The role of fetuin in PCOS and its relationship to hormonal and metabolic markers requires further study.
The insulin-sensitizing adipokine omentin-1 is secreted by visceral adipose tissue and increases glucose-stimulated insulin secretion in adipocytes [35]. Omentin expression and secretion in adipose is down-regulated by glucose and insulin ex vivo, and circulating levels reduced by inducing hyperinsulinemia in healthy subjects [36]. Lower levels are seen in obese but otherwise healthy children [37], suggesting a role early in metabolic derangement. In PCOS, levels are reported to be reduced in both lean and obese subjects [38], with levels correlating negatively with hyperandrogenism [39] and increased after treatment with both estrogen-progestin oral contraceptives (OCP) [40] and metformin [41].

3.2. Psychiatric Co-Morbidities

In the past several years, the high rate of mood disorders in women with PCOS has come to light. Adult studies have shown increased rates of anxiety and depression when matched for BMI [42,43,44], though data in teens remains very limited. An internet-based survey conducted in Germany found that maladaptive coping behavior associated with depression and anxiety symptoms [44]. Another group reported that reduced health related QOL was predicted by self-esteem, body image, and sexual function in a cohort of women with PCOS in Iran [45] similar to a study in Poland reporting low rates of self-attractiveness that correlated with poor sexual function [46]. A small qualitative study revealed that girls with PCOS perceived lack of control, and were most concerned about menstrual issues and fertility prognosis, with lower levels of control predicting depression [47].
Notably, there appears to be a relationship between insulin resistance and depression [48,49]. In a recent pilot study of adolescent and adult PCOS, Erensoy et al. demonstrated that treatment with metformin for 90 days led to reduction in depression and anxiety scores, along with weight and insulin resistance [50], though mechanism of how metformin effects mental health—directly or indirectly—are unknown. Benefits of lifestyle modification on mental health in PCOS have also been demonstrated. Physical activity itself has been shown to decrease depression and increase QOL in PCOS [51,52]. Dokras et al. reported that both weight loss via weight loss and oral contraceptive pill use to treat hyperandrogenism led to improved depression, anxiety and QOL scores, with additive benefits in the combined treatment group [53]. Addressing psychological concerns with cognitive behavioral therapy improved QOL but also weight loss during a lifestyle intervention program in overweight or obese PCOS women highlighting the importance of identifying and treating mental in addition to physical health concerns [54].
A study evaluating efficacy of an 8-week a mindfulness program compared to placebo showed that the treatment led to improvements in mental health parameters and reduction in salivary cortisol in PCOS women [55], suggesting that multiple modalities of therapies should be explored.

4. Setting the Foundation: Proposed Pathogenic Mechanisms

Despite its prevalence, the pathogenesis of PCOS remains incompletely understood. Alterations in ovarian structure and function, adrenal steroidogenesis, pituitary gonadotropin pathways, insulin signaling, gut microbiome, environmental exposures, and genetic and epigenetic markers have all been implicated and are areas of current research focus.

4.1. Fetal Origins

Origins of ovarian dysfunction, including PCOS, likely begin early in fetal development. Germ cells migrate to the gonadal ridge and undergo mitosis until around 20 weeks of gestation, reaching maximum number of about seven million. At this point, the ovary can produce and detect androgens and estrogen, though it is unknown whether human fetal ovaries in vivo produce androgens in response to insulin [56]. Intra-uterine androgen exposure has been reported to affect programming of adrenal and pituitary pathway in human and animal models [57,58].
In the rhesus monkey, exposure to androgen excess early in gestation led to PCOS phenotype with hyperandrogenism, oligomenorrhea, LH hypersecretion, enlarged multi-follicular ovaries in addition to insulin resistance, hyperlipidemia, and increased abdominal adiposity [59].
In a clinical study of pregnant women, testosterone levels at 18 weeks correlated with early follicular AMH levels in their daughters [60]. Examination of placental tissue in women with PCOS showed higher 3β-HSD-1 activity and lower P450 aromatase activity (pathogenic of hyperandrogenism) compared to control [61].

4.2. Environmental Exposures

Exposure to endocrine-disrupting chemicals in utero or at other critical developmental periods have been hypothesized to contribute to PCOS. A “two-hit” hypothesis of genetic and environmental exposures has been suggested. Levels of bisphenol A (BPA) are higher in adolescents [62] and women with PCOS than controls, even after controlling for obesity, and correlate to testosterone levels [63,64]. BPA levels were also negatively correlated with antral follicle count, a marker of ovarian reserve [65]. Another group reported higher levels of perfluorinated compounds and lower levels of phthalate metabolites in serum and urine of PCOS women than controls [66].

4.3. Gut Microbiome

As it is become clear that sex steroids affect the gut microbiome, recent studies of animal and human models have examined the potential role of the gut microbiome in PCOS [67]. A Letrozole-induced mouse model of PCOS found lower diversity and increase in Bacteroides and Firmicutes species that were previous associated with mouse models of metabolic disease [68]. A rat model using prenatal androgen exposure also exhibited altered gut microbial composition [69] along with cardiovascular risk factors. Human studies similarly found lower alpha diversity in PCOS with both alpha and beta diversity correlated to markers of hyperandrogenism [70,71]. Results from a small pilot study suggested that gut dysbiosis was more severe in PCOS subjects with insulin resistance [72]. Another study which compared obese and non-obese PCOS, control women and control men actually found reduced alpha diversity in all women compared to men, whereas beta diversity was reduced only in obese PCOS women; overall diversity and abundance of several specific general correlated positively to testosterone levels and negatively to estradiol [73]. Of note, there is no data on gut microbiome in pediatric PCOS, and it is unclear how early these changes occur.

4.4. Genetics

Great focus has been placed on trying to identify genetic mediators of PCOS. While this work has predominantly been done in adult PCOS populations rather than adolescents, we have summarized the major areas of genetic investigation. Genome wide association studies (GWAS) have been performed in various cohorts of women with PCOS and led to identification of many candidate genes implicated in diverse pathways, including insulin signaling, gonadotropin axis, ovarian folliculogenesis, and sex steroid production [74,75,76,77,78]. Ultimately, GWAS has yielded conflicting data with significant population variation and lack of reproducibility; no clear genetic etiology can be supported nor can any genotype predict PCOS risk in the general population.
More recent studies are looking beyond genome to the epigenome, with analysis of DNA methylation. A number of such studies have found altered DNA methylation at loci identified originally via GWAS, including LHCGR, INSR, YAP1, and TOX3 [79]. Genome-wide DNA methylation analysis of human ovarian granulosa cells revealed thousands of differentially methylated CpG sites in PCOS versus controls, interestingly, there were more sites identified in the lean PCOS group versus the obese group [80]. Other studies implicate hypomethylation at specific sites in ovarian and blood cells [81,82].
Alterations in levels of specific micro-RNAs, which regulate gene expression in myriad pathways have also been explored in recent studies [83] and found to affect expression of genes involved in androgen activity, glucose metabolism, and follicular development. Micro-RNA alterations have been described in ovarian theca and granulosa cells, adipose tissue, and follicular fluid in addition to serum [84,85,86].

5. No Magic Pill: Explorative Treatment Options

Standard treatment options for PCOS include lifestyle changes, the insulin sensitizer metformin, anti-androgens, and estrogen-progestin oral contraceptive pills with a focus on restoring menstrual regularity, reducing dermatologic complications, and improving metabolic health [3,55].
As these treatment options for PCOS are mostly symptomatic and have not been shown to alter the overall course and progression of disease, identification of novel therapeutic modalities remains a priority for clinicians and scientists in the sphere.

5.1. Metabolic Modulation

Given the strong association of PCOS with insulin resistance, diabetes, and cardiometabolic disease, and the efficacy of the diabetes medication metformin, drugs designed for the treatment of diabetes are a main focus of therapeutic trials in PCOS. In an open-label study of obese and overweight women with PCOS, the glucagon-like peptide-1 (GLP-1) analog, exenatide, led to significant weight loss and improvements in menstrual cycling after 12 weeks [87]. In a cohort of overweight, insulin–resistant women with PCOS, metformin combined with exenatide improved weight loss, hormonal and metabolic parameters, and menstrual cyclicity better than either metformin or exenatide alone [88]. Another diabetes medication, the dipeptidyl peptidase-4 inhibitor saxagliptin also showed greater efficacy when combined with metformin versus either drug alone in a group of subjects with PCOS and pre-diabetes [89]. Two studies report that the β-Hydroxy β-methylglutaryl-CoA reductase inhibitor simvastatin, generally used for hyperlipidemia and protection from atherosclerotic heart disease, was found to be effective in improving ovarian morphology and cardiometabolic parameters as monotherapy [90] and in combination with metformin [91]. As statins have been linked to increased incidence of type 2 diabetes [92], further understanding of short and long-term effects on glucose metabolism in PCOS are required.
While most of these studies have been done in adult populations, one group has explored the effects of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist that was previously a common treatment for diabetes, in adolescents with PCOS. Combination of spironolactone, pioglitazone, and metformin (i.e., SPIOMET) in low doses was compared to oral contraceptive treatment for 12 months resulted in higher ovulation rates, as well as loss of visceral fat and improved insulin sensitivity despite no change in body weight [93].

5.2. Supplements

While lifestyle changes and promoting healthy dietary intake remain the foundation of PCOS treatment, the use of specific nutritional and other supplements have been studied extensively in this population.
A meta-analysis of omega-3 fatty acids in PCOS showed improvement in insulin resistance and, Homeostatic model assessment of insulin resistance (HOMA-IR), adiponectin, and expected decrease in triglyceride levels in women with PCOS, though no significant effects on androgen levels or ovulation rates were seen [94]. In contrast, an earlier meta-analysis including fewer studies, showed no difference in insulin or HOMA-IR [95].
Myo-inositol is a carbocyclic sugar found in many plants but also naturally formed in the human body from glucose; it functions as a cell signal mediator. It has been studied as a treatment for restoring hormonal and metabolic balance in PCOS, alone or in combination with its isomer D-chiro-inositol; improvements in hormonal function are proposed to be secondary to reduction in insulin resistance [96]. In fact, a metanalysis did show significant decreases in fasting insulin and HOMA-IR with trend to lower testosterone with myo-inositol supplementation [97]. In a study of adolescent girls with PCOS, myo-inositol alone led to reductions in weight, metabolic parameters, and free testosterone, whereas in combination with oral contraceptives, weight remained unchanged (compared to weight gain in OCP only group) and led to improvements in metabolic and hormonal profile [98]. At this time overall evidence is lacking to support clinical use of this therapy, but it deserves further study [3].
Vitamin D has been frequently explored for possible cardiometabolic benefits in diverse populations, including PCOS. Polymorphisms in the vitamin D receptor (VDR) gene have been found to be a risk factor for PCOS [99,100]. In one clinical trial, high dose vitamin D (4000 units daily) for 12 weeks in insulin resistant women with PCOS led to lower free androgen index compared to low dose vitamin D (1000 units) or placebo [101]. Another study by the same group, using 50,000 units vitamin D every other week for eight weeks in infertile women with PCOS showed lower AMH levels and improved insulin and lipid gene expression compared to placebo, as well as improved mental health scores [102]. In vitamin D deficient women with PCOS, high dose supplementation improved metabolic markers, including adiponectin, HOMA-B, and fasting glucose [103]. A study of low dose supplementation showed modest decreases in HOMA-IR but significant reduction in liver enzymes (a marker of fatty liver disease) [104].
The trace metal selenium has gained interest due to purported anti-oxidant and insulin-mimicking properties [105]. Supplementation with selenium combined with probiotics for 12 weeks was shown by one group to improve mental health parameters and androgen levels in women with PCOS [106]. In contrast, another study found that selenium supplementation worsened insulin resistance in PCOS [107].
Magnesium, zinc, and soy isoflavones have also been reported to have beneficial effects in women with PCOS, though all studies are short-term and have not yet been widely replicated [108,109].

6. Conclusions

PCOS is a common and complex condition with multi-faceted etiologic origins and represents a major long-term health risk for affected adolescents and women. Our understanding of the comorbidities, pathogenesis, and treatment options continues to evolve as the science advances. While progress has been made, there remain many unanswered questions and fertile areas for future scientific inquiry.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Rosenfield, R.L.; Ehrmann, D.A. The pathogenesis of polycystic ovary syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr. Rev. 2016, 37, 467–520. [Google Scholar] [CrossRef] [PubMed]
  2. Goodman, N.F.; Cobin, R.H.; Futterweit, W.; Glueck, J.S.; Legro, R.S.; Carmina, E.; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society (AES). American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and Pcos Society Disease State clinical review: Guide to the best practices in the evaluation and treatment of polycystic ovary syndrome--Part 1. Endocr. Pract. 2015, 21, 1291–1300. [Google Scholar] [CrossRef] [PubMed]
  3. Teede, H.J.; Misso, M.L.; Costello, M.F.; Dokras, A.; Laven, J.; Moran, L.; Piltonen, T.; Norman, R.J.; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum. Reprod. 2018, 33, 1602–1618. [Google Scholar] [CrossRef] [PubMed]
  4. Akgül, S.; Düzçeker, Y.; Kanbur, N.; Derman, O. Do different diagnostic criteria impact polycystic ovary syndrome diagnosis for adolescents? J. Pediatr. Adolesc. Gynecol. 2018, 31, 258–262. [Google Scholar] [CrossRef] [PubMed]
  5. Merino, P.M.; Villarroel, C.; Jesam, C.; López, P.; Codner, E. New diagnostic criteria of polycystic ovarian morphology for adolescents: Impact on prevalence and hormonal profile. Horm. Res. Paediatr. 2017, 88, 401–407. [Google Scholar] [CrossRef] [PubMed]
  6. West, S.; Lashen, H.; Bloigu, A.; Franks, S.; Puukka, K.; Ruokonen, A.; Jarvelin, M.R.; Tapanainen, J.S.; Morin-Papunen, L. Irregular menstruation and hyperandrogenaemia in adolescence are associated with polycystic ovary syndrome and infertility in later life: Northern Finland Birth Cohort 1986 study. Hum. Reprod. 2014, 29, 2339–2351. [Google Scholar] [CrossRef] [Green Version]
  7. Ibanez, L.; Oberfield, S.E.; Witchel, S.; Auchus, R.J.; Chang, R.J.; Codner, E.; Dabadghao, P.; Darendeliler, F.; Elbarbary, N.S.; Gambineri, A.; et al. An International Consortium Update: Pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm. Res. Paediatr. 2017, 88, 371–395. [Google Scholar] [CrossRef]
  8. Cooney, L.G.; Lee, I.; Sammel, M.D.; Dokras, A. High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: A systematic review and meta-analysis. Hum. Reprod. 2017, 32, 1075–1091. [Google Scholar] [CrossRef]
  9. Patel, S.S.; Truong, U.; King, M.; Ferland, A.; Moreau, K.L.; Dorosz, J.; E Hokanson, J.; Wang, H.; Kinney, G.L.; Maahs, D.M.; et al. Obese adolescents with polycystic ovarian syndrome have elevated cardiovascular disease risk markers. Vasc. Med. 2017, 22, 85–95. [Google Scholar] [CrossRef] [Green Version]
  10. Akgul, S.; Bonny, A.E. Metabolic syndrome in adolescents with polycystic ovary syndrome: Prevalence on the basis of different diagnostic criteria. J. Pediatr. Adolesc. Gynecol. 2019. [Google Scholar] [CrossRef]
  11. Fazleen, N.E.; Whittaker, M.; Mamun, A. Risk of metabolic syndrome in adolescents with polycystic ovarian syndrome: A systematic review and meta-analysis. Diabetes Metab. Syndr. Clin. Res. Rev. 2018, 12, 1083–1090. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Hughan, K.S.; Tfayli, H.; Warren-Ulanch, J.G.; Barinas-Mitchell, E.; Arslanian, S.A. Early biomarkers of subclinical atherosclerosis in obese adolescent girls with polycystic ovary syndrome. J. Pediatr. 2016, 168, 104–111. [Google Scholar] [CrossRef] [PubMed]
  13. Kim, J.Y.; Tfayli, H.; Michaliszyn, S.F.; Arslanian, S. Impaired lipolysis, diminished fat oxidation, and metabolic inflexibility in obese girls with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2018, 103, 546–554. [Google Scholar] [CrossRef]
  14. Bostrom, P.; Wu, J.; Jedrychowski, M.P.; Korde, A.; Ye, L.; Lo, J.C.; Rasbach, K.A.; Bostrom, E.A.; Choi, J.H.; Long, J.Z.; et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012, 481, 463–468. [Google Scholar] [CrossRef] [PubMed]
  15. Xin, C.; Liu, J.; Zhang, J.; Zhu, D.; Wang, H.; Xiong, L.; Lee, Y.; Ye, J.; Lian, K.; Xu, C.; et al. Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway. Int. J. Obes. 2016, 40, 443–451. [Google Scholar] [CrossRef] [PubMed]
  16. Bacopoulou, F.; Athanasopoulos, N.; Efthymiou, V.; Mantzou, A.; Aravantinos, L.; Vlahopoulos, S.; Deligeoroglou, E. Serum irisin concentrations in lean adolescents with polycystic ovary syndrome. Clin. Endocrinol. 2018, 88, 585–591. [Google Scholar] [CrossRef] [PubMed]
  17. Chang, C.L.; Huang, S.Y.; Hsu, Y.C.; Chin, T.H.; Soong, Y.K. The serum level of irisin, but not asprosin, is abnormal in polycystic ovary syndrome patients. Sci. Rep. 2019, 9, 6447. [Google Scholar] [CrossRef]
  18. Masaeli, A.; Nayeri, H.; Mirzaee, M. Effect of metformin treatment on insulin resistance markers, and circulating irisin in women with polycystic ovarian syndrome (PCOS). Horm. Metab. Res. 2019. [Google Scholar] [CrossRef]
  19. Kulhan, N.; Kulhan, M.; Turkler, C.; Ata, N.; Kiremitli, T.; Kiremitli, S. Could serum levels of irisin be used in gestational diabetes predicting. Taiwan J. Obstet. Gynecol. 2019, 58, 434–437. [Google Scholar] [CrossRef]
  20. Arner, P.; Petrus, P.; Esteve, D.; Boulomié, A.; Naslund, E.; Thorell, A.; Gao, H.; Dahlman, I.; Ryden, M. Screening of potential adipokines identifies S100A4 as a marker of pernicious adipose tissue and insulin resistance. Int. J. Obes. 2018, 42, 2047–2056. [Google Scholar] [CrossRef]
  21. Hou, S.; Jiao, Y.; Yuan, Q.; Zhai, J.; Tian, T.; Sun, K.; Chen, Z.; Wu, Z.; Zhang, J. S100A4 protects mice from high-fat diet-induced obesity and inflammation. Lab. Investig. 2018, 98, 1025–1038. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Malpique, R.; Sanchez-Infantes, D.; Garcia-Beltran, C.; Taxeras, S.D.; Lopez-Bermejo, A.; de Zegher, F.; Ibanez, L. Towards a circulating marker of hepato-visceral fat excess: S100A4 in adolescent girls with polycystic ovary syndrome - Evidence from randomized clinical trials. Pediatr. Obes. 2019, 14, e12500. [Google Scholar] [CrossRef] [PubMed]
  23. Trepanowski, J.F.; Mey, J.; Varady, K.A. Fetuin-A: A novel link between obesity and related complications. Int. J. Obes. 2015, 39, 734–741. [Google Scholar] [CrossRef] [PubMed]
  24. Ix, J.H.; Wassel, C.L.; Kanaya, A.M.; Vittinghoff, E.; Johnson, K.C.; Koster, A.; Cauley, J.A.; Harris, T.B.; Cummings, S.R.; Shlipak, M.G.; et al. Fetuin-A and incident diabetes mellitus in older persons. JAMA 2008, 300, 182–188. [Google Scholar] [CrossRef] [PubMed]
  25. Ix, J.H.; Shlipak, M.G.; Brandenburg, V.M.; Ali, S.; Ketteler, M.; Whooley, M.A. Association between human fetuin-a and the metabolic syndrome data from the heart and soul study. Circ. 2006, 113, 1760–1767. [Google Scholar] [CrossRef] [PubMed]
  26. Choi, K.M.; Han, K.A.; Ahn, H.J.; Lee, S.Y.; Hwang, S.Y.; Kim, B.H.; Hong, H.C.; Choi, H.Y.; Yang, S.J.; Yoo, H.J.; et al. The effects of caloric restriction on fetuin-A and cardiovascular risk factors in rats and humans: A randomized controlled trial. Clin. Endocrinol. 2013, 79, 356–363. [Google Scholar] [CrossRef] [PubMed]
  27. Malin, S.K.; Del Rincon, J.P.; Huang, H.; Kirwan, J.P. Exercise-induced lowering of fetuin-a may increase hepatic insulin sensitivity. Med. Sci. Sports Exerc. 2014, 46, 2085–2090. [Google Scholar] [CrossRef] [PubMed]
  28. Ismail, T.A.; Soliman, M.M.; Nassan, M.A. Molecular and immunohistochemical effects of metformin in a rat model of type 2 diabetes mellitus. Exp. Ther. Med. 2015, 9, 1921–1930. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Abali, R.; Celik, C.; Tasdemir, N.; Guzel, S.; Alpsoy, S.; Yuksel, A.; Celik, E. The serum protein alpha2-Heremans-Schmid glycoprotein/fetuin-a concentration and carotid intima-media thickness in women with polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 2013, 169, 45–49. [Google Scholar] [CrossRef] [PubMed]
  30. Sak, S.; Uyanikoglu, H.; Incebiyik, A.; Incebiyik, H.; Hilali, N.G.; Sabuncu, T.; Sak, E. Associations of serum fetuin-A and oxidative stress parameters with polycystic ovary syndrome. Clin. Exp. Reprod. Med. 2018, 45, 116–121. [Google Scholar] [CrossRef]
  31. Enli, Y.; Fenkci, S.M.; Fenkci, V.; Öztekin, Ö. Serum Fetuin-A levels, insulin resistance and oxidative stress in women with polycystic ovary syndrome. Gynecol. Endocrinol. 2013, 29, 1036–1039. [Google Scholar] [CrossRef] [PubMed]
  32. Gulhan, I.; Bozkaya, G.; Oztekin, D.; Uyar, I.; Kebapcilar, A.G.; Pamuk, B. Serum Fetuin-A levels in women with polycystic ovary syndrome. Arch. Gynecol. Obstet. 2012, 286, 1473–1476. [Google Scholar] [CrossRef] [PubMed]
  33. Díaz, M.; Gallego-Escuredo, J.M.; López-Bermejo, A.; De Zegher, F.; Villarroya, F.; Ibáñez, L. Low-dose spironolactone-pioglitazone-metformin normalizes circulating fetuin-a concentrations in adolescent girls with polycystic ovary syndrome. Int. J. Endocrinol. 2018, 2018, 1–5. [Google Scholar] [CrossRef] [PubMed]
  34. Yang, R.Z.; Lee, M.J.; Hu, H.; Pray, J.; Wu, H.B.; Hansen, B.C.; Shuldiner, A.R.; Fried, S.K.; McLenithan, J.C.; Gong, D.W. Identification of omentin as a novel depot-specific adipokine in human adipose tissue: Possible role in modulating insulin action. Am. J. Physiol. Endocrinol. Metab. 2006, 290, E1253–E1261. [Google Scholar] [CrossRef] [PubMed]
  35. Tan, B.; Adya, R.; Farhatullah, S.; Lewandowski, K.; O’Hare, P.; Lehnert, H.; Randeva, H. Omentin-1, a novel adipokine is decreased in overweight insulin resistant women with polycystic ovarian syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes 2008, 57, 801–808. [Google Scholar] [CrossRef] [PubMed]
  36. Zengi, S.; Zengi, O.; Kirankaya, A.; Kucuk, S.H.; Kutanis, E.E.; Yigit, O. Serum omentin-1 levels in obese children. J. Pediatr. Endocrinol. Metab. 2019, 32, 247–251. [Google Scholar] [CrossRef]
  37. Yang, H.-Y.; Ma, Y.; Lu, X.-H.; Liang, X.-H.; Suo, Y.-J.; Huang, Z.-X.; Lu, D.-C.; Qin, Y.-F.; Luo, Z.-J. The correlation of plasma omentin-1 with insulin resistance in non-obese polycystic ovary syndrome. Ann. d’Endocrinologie 2015, 76, 620–627. [Google Scholar] [CrossRef]
  38. Özgen, I.T.; Oruçlu, Ş.; Selek, S.; Kutlu, E.; Guzel, G.; Cesur, Y. Omentin-1 level in adolescents with polycystic ovarian syndrome. Pediatr. Int. 2019, 61, 147–151. [Google Scholar]
  39. Tan, B.; Adya, R.; Farhatullah, S.; Chen, J.; Lehnert, H.; Randeva, H. Metformin treatment may incrase omentin-1 levels in women with polycystic ovary syndrome. Diabetes 2010, 59, 3023–3031. [Google Scholar] [CrossRef]
  40. Anithasri, A.; Ananthanarayanan, P.; Veena, P. A study on omentin-1 and prostate specific antigen in women on treatment for polycystic ovary syndrome. Indian J. Clin. Biochem. 2019, 34, 108–114. [Google Scholar] [CrossRef]
  41. Brutocao, C.; Zaiem, F.; Alsawas, M.; Morrow, A.S.; Murad, M.H.; Javed, A. Psychiatric disorders in women with polycystic ovary syndrome: A systematic review and meta-analysis. Endocr. 2018, 62, 318–325. [Google Scholar] [CrossRef] [PubMed]
  42. Dokras, A. Mood and anxiety disorders in women with PCOS. Steroids 2012, 77, 338–341. [Google Scholar] [CrossRef] [PubMed]
  43. Jedel, E.; Waern, M.; Gustafson, D.; Landen, M.; Eriksson, E.; Holm, G.; Nilsson, L.; Lind, A.K.; Janson, P.O.; Stener-Victorin, E. Anxiety and depression symptoms in women with polycystic ovary syndrome compared with controls matched for body mass index. Hum. Reprod. 2010, 25, 450–456. [Google Scholar] [CrossRef] [PubMed]
  44. Benson, S.; Hahn, S.; Tan, S.; Janssen, O.E.; Schedlowski, M.; Elsenbruch, S. Maladaptive Coping with illness in women with polycystic ovary syndrome. J. Obstet. Gynecol. Neonatal Nurs. 2010, 39, 37–45. [Google Scholar] [CrossRef] [PubMed]
  45. Bazarganipour, F.; Ziaei, S.; Montazeri, A.; Foroozanfard, F.; Kazemnejad, A.; Faghihzadeh, S. Health related quality of life in patients with polycystic ovary syndrome (PCOS): A model-based study of predictive factors. J. Sex. Med. 2014, 11, 1023–1032. [Google Scholar] [CrossRef] [PubMed]
  46. Stapinska-Syniec, A.; Grabowska, K.; Szpotanska-Silorska, M.; Pietrzak, B. Depression, sexual satisfaction, and other psychological issues in women with polycystic ovary syndrome. Gynecol. Endocrinol. 2018, 34, 597–600. [Google Scholar] [CrossRef] [PubMed]
  47. Hopkins, C.S.; Kimble, L.P.; Hodges, H.F.; Koci, A.F.; Mills, B.B. A mixed-methods study of coping and depression in adolescent girls with polycystic ovary syndrome. J. Am. Assoc. Nurse Pr. 2019, 31, 189–197. [Google Scholar] [CrossRef] [Green Version]
  48. Greenwood, E.A.; Pasch, L.A.; Shinkai, K.; Cedars, M.I.; Huddleston, H.G. Putative role for insulin resistance in depression risk in polycystic ovary syndrome. Fertil. Steril. 2015, 104, 707–714. [Google Scholar] [CrossRef]
  49. Özdemir, O.; Kurdoglu, Z.; Yıldız, S.; Özdemir, P.G.; Yilmaz, E. The relationship between atypical depression and insülin resistance in patients with polycystic ovary syndrome and major depression. Psychiatry Res. 2017, 258, 171–176. [Google Scholar] [CrossRef]
  50. Erensoy, H.; Niafar, M.; Ghafarzadeh, S.; Aghamohammadzadeh, N.; Nader, N.D. A pilot trial of metformin for insulin resistance and mood disturbances in adolescent and adult women with polycystic ovary syndrome. Gynecol. Endocrinol. 2019, 35, 72–75. [Google Scholar] [CrossRef]
  51. Banting, L.K.; Gibson-Helm, M.; Polman, R.; Teede, H.J.; Stepto, N.K. Physical activity and mental health in women with polycystic ovary syndrome. BMC Women’s Health 2014, 14, 51. [Google Scholar] [CrossRef] [PubMed]
  52. Costa, E.C.; De Sá, J.C.F.; Stepto, N.K.; Costa, I.B.B.; Farias-Junior, L.F.; Moreira, S.D.N.T.; Soares, E.M.M.; Lemos, T.M.A.M.; Browne, R.A.V.; Azevedo, G.D. Aerobic training improves quality of life in women with polycystic ovary syndrome. Med. Sci. Sports Exerc. 2018, 50, 1357–1366. [Google Scholar] [CrossRef] [PubMed]
  53. Dokras, A.; Sarwer, D.; Allison, K.; Milman, L.; Kris-Etherton, P.; Kunselman, A.; Stetter, C.; Williams, N.; Gnatuk, C.; Estes, S.; et al. Weight and lowering androgens predict improvements in health-related quality of life in women with PCOS. J. Clin. Endocrinol. Metab. 2016, 101, 2966–2974. [Google Scholar] [CrossRef] [PubMed]
  54. Cooney, L.; Milman, L.; Hantsoo, L.; Kornfield, S.; Sammel, M.; Allison, K.; Epperson, C.; Dokras, A. Cognitive-behavioral therapy improves weight loss and quality of life in women with polycystic ovary syndrome: A pilot randomized clinical trial. Fertil. Steril. 2018, 110, 161–171. [Google Scholar] [CrossRef] [PubMed]
  55. Stefanaki, C.; Bacopoulou, F.; Livadas, S.; Kandaraki, A.; Karachalios, A.; Chrousos, G.; Diamanti-Kandarakis, E. Impact of a mindfulness stress management program on stress, anxiety, depression, and quality of life in women with polycystic ovary syndrome: A randomized controlled trial. Stress 2015, 18, 57–66. [Google Scholar] [CrossRef] [PubMed]
  56. Adashi, E. The Ovarian Follicular Apparatus. In Reproductive Endocrinology, Surgery, and Technology; Adashi, E.Y., Rock, J., Rosenwaks, Z., Eds.; Raven Press: Philadelphia, PA, USA, 1996; pp. 18–40. [Google Scholar]
  57. Filippou, P.; Homburg, R. Is foetal hyperexposure to androgens a cause of PCOS? Hum. Reprod. Update 2017, 23, 421–432. [Google Scholar] [CrossRef] [PubMed]
  58. Xita, N.; Tsatsoulis, A. Review: Fetal programming of polycystic ovary syndrome by androgen excess: Evidence from experimental, clinical, and genetic association studies. J. Clin. Endocrinol. Metab. 2006, 91, 1660–1666. [Google Scholar] [CrossRef]
  59. Abbott, D.; Barnett, D.; Bruns, C.; Dumesic, D. Androgen excess fetal programming of female reproduction: A developmental aetiology for polycystic ovary syndrome? Hum. Reprod. Update 2005, 11, 357–374. [Google Scholar] [CrossRef]
  60. Hart, R.; Sloboda, D.M.; Doherty, D.A.; Norman, R.J.; Atkinson, H.C.; Newnham, J.P.; Dickinson, J.E.; Hickey, M. Circulating maternal testosterone concentrations at 18 weeks of gestation predict circulating levels of antimüllerian hormone in adolescence: A prospective cohort study. Fertil. Steril. 2010, 94, 1544–1547. [Google Scholar] [CrossRef]
  61. Maliqueo, M.; Lara, H.E.; Sánchez, F.; Echiburú, B.; Crisosto, N.; Sir-Petermann, T. Placental steroidogenesis in pregnant women with polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Boil. 2013, 166, 151–155. [Google Scholar] [CrossRef]
  62. Akın, L.; Kendirci, M.; Narin, F.; Kurtoglu, S.; Saraymen, R.; Kondolot, M.; Koçak, S.; Elmalı, F.; Elmali, F. The endocrine disruptor bisphenol A may play a role in the aetiopathogenesis of polycystic ovary syndrome in adolescent girls. Acta Paediatr. 2015, 104, e171–e177. [Google Scholar] [CrossRef]
  63. Hossein Rashidi, B.; Amanlou, M.; Behrouzi Lak, T.; Ghazizadeh, M.; Haghollahi, F.; Bagheri, M.; Eslami, B. The association between bisphenol a and polycystic ovarian syndrome: A case-control study. Acta Med. Iran 2017, 55, 759–764. [Google Scholar]
  64. Konieczna, A.; Rachoń, D.; Owczarek, K.; Kubica, P.; Kowalewska, A.; Kudłak, B.; Wasik, A.; Namieśnik, J. Serum bisphenol A concentrations correlate with serum testosterone levels in women with polycystic ovary syndrome. Reprod. Toxicol. 2018, 82, 32–37. [Google Scholar] [CrossRef]
  65. Zhou, W.; Fang, F.; Zhu, W.; Chen, Z.-J.; Du, Y.; Zhang, J. Bisphenol A and ovarian reserve among infertile women with polycystic ovarian syndrome. Int. J. Environ. Res. Public Health 2016, 14, 18. [Google Scholar] [CrossRef]
  66. Vagi, S.J.; Azziz-Baumgartner, E.; Sjödin, A.; Calafat, A.M.; Dumesic, D.; González, L.; Kato, K.; Silva, M.J.; Ye, X.; Azziz, R. Exploring the potential association between brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phthalates, and bisphenol a in polycystic ovary syndrome: A case–control study. BMC Endocr. Disord. 2014, 14, 86. [Google Scholar] [CrossRef]
  67. Thackray, V.G. Sex, Microbes, and Polycystic Ovary Syndrome. Trends Endocrinol. Metab. 2019, 30, 54–65. [Google Scholar] [CrossRef]
  68. Kelley, S.T.; Skarra, D.V.; Rivera, A.J.; Thackray, V.G. The gut microbiome is altered in a letrozole-induced mouse model of polycystic ovary syndrome. PLoS ONE 2016, 11, e0146509. [Google Scholar] [CrossRef]
  69. Sherman, S.B.; Sarsour, N.; Salehi, M.; Schroering, A.; Mell, B.; Joe, B.; Hill, J.W. Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis. Gut Microbes 2018, 9, 400–421. [Google Scholar] [CrossRef]
  70. Torres, P.J.; Siakowska, M.; Banaszewska, B.; Pawelczyk, L.; Duleba, A.J.; Kelley, S.T.; Thackray, V.G. Gut microbial diversity in women with polycystic ovary syndrome correlates with hyperandrogenism. J. Clin. Endocrinol. Metab. 2018, 103, 1502–1511. [Google Scholar] [CrossRef]
  71. Lindheim, L.; Bashir, M.; Munzker, J.; Trummer, C.; Zachhuber, V.; Leber, B.; Horvath, A.; Pieber, T.R.; Gorkiewicz, G.; Stadlbauer, V.; et al. Alterations in gut microbiome composition and barrier function are associated with reproductive and metabolic defects in women with polycystic ovary syndrome (PCOS): A pilot study. PLoS ONE 2017, 12, e0168390. [Google Scholar] [CrossRef]
  72. Zeng, B.; Lai, Z.; Sun, L.; Zhang, Z.; Yang, J.; Li, Z.; Lin, J.; Zhang, Z. Structural and functional profiles of the gut microbial community in polycystic ovary syndrome with insulin resistance (IR-PCOS): A pilot study. Res. Microbiol. 2019, 170, 43–52. [Google Scholar] [CrossRef]
  73. Insenser, M.; Murri, M.; Del Campo, R.; Martinez-Garcia, M.A.; Fernandez-Duran, E.; Escobar-Morreale, H.F. Gut microbiota and the polycystic ovary syndrome: influence of sex, sex hormones, and obesity. J. Clin. Endocrinol. Metab. 2018, 103, 2552–2562. [Google Scholar] [CrossRef]
  74. Hayes, M.G.; Urbanek, M.; Ehrmann, D.A.; Armstrong, L.L.; Lee, J.Y.; Sisk, R.; Karaderi, T.; Barber, T.M.; McCarthy, M.I.; Franks, S.; et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat. Commun. 2015, 6, 7502. [Google Scholar] [CrossRef] [Green Version]
  75. Jacobsen, V.M.; Li, S.; Wang, A.; Zhu, D.; Liu, M.; Thomassen, M.; Kruse, T.; Tan, Q. Epigenetic association analysis of clinical sub-phenotypes in patients with polycystic ovary syndrome (PCOS). Gynecol. Endocrinol. 2019, 35, 691–694. [Google Scholar] [CrossRef]
  76. Lee, H.; Oh, J.-Y.; Sung, Y.-A.; Chung, H.; Kim, H.-L.; Cho, Y.S. Genome-wide association study identified new susceptibility loci for polycystic ovary syndrome. Hum. Reprod. 2015, 30, 723–731. [Google Scholar] [CrossRef]
  77. Shi, Y.; Zhao, H.; Shi, Y.; Cao, Y.; Yang, D.; Li, Z.; Zhang, B.; Liang, X.; Li, T.; Chen, J.; et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat. Genet. 2012, 44, 1020–1025. [Google Scholar] [CrossRef]
  78. McAllister, J.M.; Modi, B.; Miller, B.A.; Biegler, J.; Bruggeman, R.; Legro, R.S.; Strauss, J.F., 3rd. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc. Natl. Acad. Sci. USA 2014, 111, E1519–E1527. [Google Scholar] [CrossRef] [Green Version]
  79. Mukherjee, S. Pathomechanisms of polycystic ovary syndrome Multidimensional approaches. Front. Biosci. 2018, 10, 384–422. [Google Scholar] [CrossRef] [Green Version]
  80. Xu, J.; Bao, X.; Peng, Z.; Wang, L.; Du, L.; Niu, W.; Sun, Y. Comprehensive analysis of genome-wide DNA methylation across human polycystic ovary syndrome ovary granulosa cell. Oncotarget 2016, 7, 27899–27909. [Google Scholar] [CrossRef]
  81. Sagvekar, P.; Mangoli, V.; Desai, S.; Patil, A.; Mukherjee, S. LINE1 CpG-DNA hypomethylation in granulosa cells and blood leukocytes is associated with PCOS and related traits. J. Clin. Endocrinol. Metab. 2017, 102, 1396–1405. [Google Scholar] [CrossRef]
  82. Wang, P.; Zhao, H.; Li, T.; Zhang, W.; Wu, K.; Li, M.; Bian, Y.; Liu, H.; Ning, Y.; Li, G.; et al. Hypomethylation of the LH/choriogonadotropin receptor promoter region is a potential mechanism underlying susceptibility to polycystic ovary syndrome. Endocrinol. 2014, 155, 1445–1452. [Google Scholar] [CrossRef]
  83. Murri, M.; Insenser, M.; Fernandez-Duran, E.; San-Millan, J.L.; Escobar-Morreale, H.F. Effects of polycystic ovary syndrome (PCOS), sex hormones, and obesity on circulating miRNA-21, miRNA-27b, miRNA-103, and miRNA-155 expression. J. Clin. Endocrinol. Metab. 2013, 98, E1835–E1844. [Google Scholar] [CrossRef]
  84. Chen, B.; Xu, P.; Wang, J.; Zhang, C. The role of MiRNA in polycystic ovary syndrome (PCOS). Gene 2019, 706, 91–96. [Google Scholar] [CrossRef]
  85. Xiong, W.; Lin, Y.; Xu, L.; Tamadon, A.; Zou, S.; Tian, F.; Shao, R.; Li, X.; Feng, Y. Circulatory microRNA 23a and microRNA 23b and polycystic ovary syndrome (PCOS): The effects of body mass index and sex hormones in an Eastern Han Chinese population. J. Ovarian Res. 2017, 10, 10. [Google Scholar] [CrossRef]
  86. Sørensen, A.E.; Udesen, P.B.; Wissing, M.L.; Englund, A.L.M.; Dalgaard, L.T. MicroRNAs related to androgen metabolism and polycystic ovary syndrome. Chem. Interactions 2016, 259, 8–16. [Google Scholar] [CrossRef]
  87. Liu, X.; Zhang, Y.; Zheng, S.-Y.; Lin, R.; Xie, Y.-J.; Chen, H.; Zheng, Y.-X.; Liu, E.; Chen, L.; Yan, J.-H.; et al. Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome. Clin. Endocrinol. 2017, 87, 767–774. [Google Scholar] [CrossRef]
  88. Elkind-Hirsch, K.; Marrioneaux, O.; Bhushan, M.; Vernor, D. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2008, 93, 2670–2678. [Google Scholar] [CrossRef]
  89. Elkind-Hirsch, K.E.; Paterson, M.S.; Seidemann, E.L.; Gutowski, H.C. Short-term therapy with combination dipeptidyl peptidase-4 inhibitor saxagliptin/metformin extended release (XR) is superior to saxagliptin or metformin XR monotherapy in prediabetic women with polycystic ovary syndrome: A single-blind, randomized, pilot study. Fertil. Steril. 2017, 107, 253–260.e1. [Google Scholar]
  90. Seyam, E.; Al Gelany, S.; Abd Al Ghaney, A.; Mohamed, M.A.A.; Youseff, A.M.; Ibrahim, E.M.; Khalifa, E.M.; Hefzy, E. Evaluation of prolonged use of statins on the clinical and biochemical abnormalities and ovulation dysfunction in single young women with polycystic ovary syndrome. Gynecol. Endocrinol. 2018, 34, 589–596. [Google Scholar] [CrossRef]
  91. Malik, M.; Tasnim, N.; Mahmud, G. Effect of Metformin Alone Compared with Metformin Plus Simvastatin on Polycystic Ovarian Syndrome in Pakistani Women. J. Coll. Physicians Surg. Pak. 2018, 28, 184–187. [Google Scholar] [CrossRef]
  92. Maki, K.C.; Diwadkar-Navsariwala, V.; Kramer, M.W. Statin use and risk for type 2 diabetes: What clinicians should know. Postgrad. Med. 2018, 130, 166–172. [Google Scholar] [CrossRef]
  93. MacKenzie, I.; Boyd, P.; Ferguson, J. Chorion villus sampling and randomisation. Lancet 1986, 327, 969–970. [Google Scholar] [CrossRef]
  94. Yang, K.; Zeng, L.; Bao, T.; Ge, J. Effectiveness of Omega-3 fatty acid for polycystic ovary syndrome: A systematic review and meta-analysis. Reprod. Boil. Endocrinol. 2018, 16, 27. [Google Scholar] [CrossRef]
  95. Sadeghi, A.; Djafarian, K.; Mohammadi, H.; Shab-Bidar, S. Effect of omega-3 fatty acids supplementation on insulin resistance in women with polycystic ovary syndrome: Meta-analysis of randomized controlled trials. Diabetes Metab. Syndr. 2017, 11, 157–162. [Google Scholar] [CrossRef]
  96. Unfer, V.; Porcaro, G. Updates on the myo-inositol plus D-chiro-inositol combined therapy in polycystic ovary syndrome. Expert Rev. Clin. Pharmacol. 2014, 7, 623–631. [Google Scholar] [CrossRef]
  97. Unfer, V.; Facchinetti, F.; Orrù, B.; Giordani, B.; Nestler, J. Myo-inositol effects in women with PCOS: A meta-analysis of randomized controlled trials. Endocr. Connect. 2017, 6, 647–658. [Google Scholar] [CrossRef]
  98. Pkhaladze, L.; Barbakadze, L.; Kvashilava, N. Myo-Inositol in the Treatment of Teenagers Affected by PCOS. Int. J. Endocrinol. 2016, 2016, 1–6. [Google Scholar] [CrossRef] [Green Version]
  99. Deswal, R.; Nanda, S.; Dang, A.S. Unveiling the association between Vitamin D receptor and poly cystic ovary syndrome – A systematic review and meta-analysis. Int. J. Vitam. Nutr. Res. 2017, 87, 207–218. [Google Scholar] [CrossRef]
  100. Shi, X.-Y.; Huang, A.-P.; Xie, D.-W.; Yu, X.-L. Association of vitamin D receptor gene variants with polycystic ovary syndrome: A meta-analysis. BMC Med Genet. 2019, 20, 32. [Google Scholar] [CrossRef]
  101. Jamilian, M.; Foroozanfard, F.; Rahmani, E.; Talebi, M.; Bahmani, F.; Asemi, Z. Effect of two different doses of vitamin D supplementation on metabolic profiles of insulin-resistant patients with polycystic ovary syndrome. Nutr. 2017, 9, 1280. [Google Scholar] [CrossRef]
  102. Jamilian, M.; Samimi, M.; Mirhosseini, N.; Ebrahimi, F.A.; Aghadavod, E.; Talaee, R.; Jafarnejad, S.; Dizaji, S.H.; Asemi, Z. The influences of vitamin D and omega-3 co-supplementation on clinical, metabolic and genetic parameters in women with polycystic ovary syndrome. J. Affect. Disord. 2018, 238, 32–38. [Google Scholar] [CrossRef]
  103. Seyyed Abootorabi, M.; Ayremlou, P.; Behroozi-Lak, T.; Nourisaeidlou, S. The effect of vitamin D supplementation on insulin resistance, visceral fat and adiponectin in vitamin D deficient women with polycystic ovary syndrome: A randomized placebo-controlled trial. Gynecol. Endocrinol. 2018, 34, 489–494. [Google Scholar] [CrossRef]
  104. Javed, Z.; Papageorgiou, M.; Deshmukh, H.; Kilpatrick, E.S.; Mann, V.; Corless, L.; Abouda, G.; Rigby, A.S.; Atkin, S.L.; Sathyapalan, T. A Randomized, Controlled Trial of Vitamin D Supplementation on Cardiovascular Risk Factors, Hormones, and Liver Markers in Women with Polycystic Ovary Syndrome. Nutrients 2019, 11, 188. [Google Scholar] [CrossRef]
  105. 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. Horm. Metab. Res. 2019, 51, 279–287. [Google Scholar] [CrossRef]
  106. Jamilian, M.; Mansury, S.; Bahmani, F.; Heidar, Z.; Amirani, E.; Asemi, Z. The effects of probiotic and selenium co-supplementation on parameters of mental health, hormonal profiles, and biomarkers of inflammation and oxidative stress in women with polycystic ovary syndrome. J. Ovarian Res. 2018, 11, 80. [Google Scholar] [CrossRef]
  107. Mohammad Hosseinzadeh, F.; Hosseinzadeh-Attar, M.J.; Yekaninejad, M.S.; Rashidi, B. Effects of selenium supplementation on glucose homeostasis and free androgen index in women with polycystic ovary syndrome: A randomized, double blinded, placebo controlled clinical trial. J. Trace Elem. Med. Biol. 2016, 34, 56–61. [Google Scholar] [CrossRef]
  108. 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. Biol. Trace Elem. Res. 2018, 184, 300–307. [Google Scholar] [CrossRef]
  109. Jamilian, M.; Asemi, Z. The effects of soy isoflavones on metabolic status of patients with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2016, 101, 3386–3394. [Google Scholar] [CrossRef]

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Shah, R. Emerging Topics in Cardiometabolic and Psychologic Sequelae, Pathogenesis, and Treatment of Polycystic Ovarian Syndrome: A Review. Children 2019, 6, 89. https://doi.org/10.3390/children6080089

AMA Style

Shah R. Emerging Topics in Cardiometabolic and Psychologic Sequelae, Pathogenesis, and Treatment of Polycystic Ovarian Syndrome: A Review. Children. 2019; 6(8):89. https://doi.org/10.3390/children6080089

Chicago/Turabian Style

Shah, Rachana. 2019. "Emerging Topics in Cardiometabolic and Psychologic Sequelae, Pathogenesis, and Treatment of Polycystic Ovarian Syndrome: A Review" Children 6, no. 8: 89. https://doi.org/10.3390/children6080089

APA Style

Shah, R. (2019). Emerging Topics in Cardiometabolic and Psychologic Sequelae, Pathogenesis, and Treatment of Polycystic Ovarian Syndrome: A Review. Children, 6(8), 89. https://doi.org/10.3390/children6080089

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