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Cardiometabolic biomarkers in women with polycystic ovary syndrome

2022; Elsevier BV; Volume: 117; Issue: 5 Linguagem: Inglês

10.1016/j.fertnstert.2022.03.008

1556-5653

Kim van der Ham, Yvonne V. Louwers, Joop S.E. Laven,

Reproductive Biology and Fertility

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Apart from the reproductive problems, PCOS is also associated with metabolic disturbances, and therefore, it also affects adolescents and postmenopausal women with PCOS as well as their offspring and other first-degree relatives. Adolescents with PCOS show unfavorable cardiometabolic biomarkers more often than controls, such as overweight/obesity and hyperandrogenism, and studies also suggest an unfavorable lipid profile. During reproductive age, women with PCOS develop additional cardiometabolic biomarkers, such as hypertension, insulin resistance, and metabolic syndrome. Growing evidence also supports the important role of inflammatory cytokines in cardiovascular health in these women. During menopausal transition, some PCOS characteristics ameliorate, whereas other biomarkers increase, such as body mass index, insulin resistance, type 2 diabetes, and hypertension. Offspring of women with PCOS have a lower birth weight and a higher body mass index later in life than controls. In addition, fathers, mothers, and siblings of women with PCOS show unfavorable cardiometabolic biomarkers. Therefore, cardiovascular screening and follow-up of women with PCOS and their offspring and siblings are of utmost importance. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Apart from the reproductive problems, PCOS is also associated with metabolic disturbances, and therefore, it also affects adolescents and postmenopausal women with PCOS as well as their offspring and other first-degree relatives. Adolescents with PCOS show unfavorable cardiometabolic biomarkers more often than controls, such as overweight/obesity and hyperandrogenism, and studies also suggest an unfavorable lipid profile. During reproductive age, women with PCOS develop additional cardiometabolic biomarkers, such as hypertension, insulin resistance, and metabolic syndrome. Growing evidence also supports the important role of inflammatory cytokines in cardiovascular health in these women. During menopausal transition, some PCOS characteristics ameliorate, whereas other biomarkers increase, such as body mass index, insulin resistance, type 2 diabetes, and hypertension. Offspring of women with PCOS have a lower birth weight and a higher body mass index later in life than controls. In addition, fathers, mothers, and siblings of women with PCOS show unfavorable cardiometabolic biomarkers. Therefore, cardiovascular screening and follow-up of women with PCOS and their offspring and siblings are of utmost importance. Essential Points•Adolescents with PCOS have an increased BMI, higher prevalence of hyperandrogenism, and more unfavorable lipid profile than controls.•Women with PCOS show an increase in cardiometabolic biomarkers during their reproductive years, such as obesity, hyperandrogenism, hypertension, insulin resistance, and metabolic syndrome. Moreover, inflammatory cytokines seem to play a negative role in their cardiometabolic profile.•Also in middle-aged and postmenopausal women with PCOS, unfavorable cardiometabolic biomarkers are increased, such as high BMI and the prevalence of hypertension and type 2 diabetes.•Offspring and first-degree relatives of women with PCOS seem to have unfavorable cardiometabolic biomarkers more often than those of controls.•Polycystic ovary syndrome affects women during their whole life span and develops from a more endocrine disease into a more metabolic disease as women become older.DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34678Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, with a prevalence of up to 20% (1Lizneva D. Suturina L. Walker W. Brakta S. Gavrilova-Jordan L. Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome.Fertil Steril. 2016; 106: 6-15Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). The first series of patients with PCOS were described by Stein and Leventhal (2Stein I.F. Leventhal M.L. Amenorrhea associated with bilateral polycystic ovaries.Am J Obstet Gynecol. 1935; 29: 181-191Abstract Full Text PDF Google Scholar) in 1935, and they were all obese and had enlarged polycystic ovaries, hirsutism, and oligomenorrhea or amenorrhea (2Stein I.F. Leventhal M.L. Amenorrhea associated with bilateral polycystic ovaries.Am J Obstet Gynecol. 1935; 29: 181-191Abstract Full Text PDF Google Scholar). Since then, several developments have been made to understand the disorder. To date, 3 diagnostic criteria are used for the diagnosis PCOS, being clinical and/or biochemical hyperandrogenism, oligomenorrhea/amenorrhea anovulation, and polycystic ovaries (3Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop GroupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.Fertil Steril. 2004; 81: 19-25Abstract Full Text Full Text PDF Scopus (4353) Google Scholar). Despite the reproductive issues, it is also known that PCOS is associated with metabolic dysfunction. Moreover, women with PCOS have an increased risk of metabolic abnormalities and type 2 diabetes mellitus (T2DM), infertility, obstetric complications, endometrial cancer, and mood disorders. Although most signs and symptoms are most evident in women of reproductive age, the disorder also affects prepubertal as well as postmenopausal women. There is also an increased prevalence of cardiovascular risk factors, and hence, women with PCOS may also have an increased risk of cardiovascular and cerebrovascular events and venous thromboembolism (4Azziz R. Carmina E. Chen Z. Dunaif A. Laven J.S. Legro R.S. et al.Polycystic ovary syndrome.Nat Rev Dis Primers. 2016; 2: 16057Crossref PubMed Google Scholar). This overview summarizes the current knowledge about these cardiovascular biomarkers in women with PCOS, based on expert opinion and most relevant and recently published literature.Cardiometabolic biomarkers in adolescents with PCOSBody Mass Index and Waist CircumferenceIt is suggested that pubertal obesity is associated with PCOS. The prevalence of PCOS among pubertal patients with overweight or obesity is approximately 22%, which is higher than in adult patients (5Patel S.S. Truong U. King M. Ferland A. Moreau K.L. Dorosz J. et al.Obese adolescents with polycystic ovarian syndrome have elevated cardiovascular disease risk markers.Vasc Med. 2017; 22: 85-95Crossref PubMed Scopus (37) Google Scholar, 6Ybarra M. Franco R.R. Cominato L. Sampaio R.B. Sucena da Rocha S.M. Damiani D. Polycystic ovary syndrome among obese adolescents.Gynecol Endocrinol. 2018; 34: 45-48Crossref PubMed Scopus (9) Google Scholar). When looking at adolescents who were already diagnosed with PCOS, studies have shown that 21%–50% of these adolescents were overweight or obese, and they had a 5 times greater waist circumference than controls (7de Medeiros S.F. de Medeiros M.A.S. Barbosa B.B. Yamamoto M.M.W. Maciel G.A.R. Comparison of metabolic and obesity biomarkers between adolescent and adult women with polycystic ovary syndrome.Arch Gynecol Obstet. 2021; 303: 739-749Crossref Scopus (4) Google Scholar, 8Gambineri A. Fanelli F. Prontera O. Repaci A. Di Dalmazi G. Zanotti L. et al.Prevalence of hyperandrogenic states in late adolescent and young women: epidemiological survey on Italian high-school students.J Clin Endocrinol Metab. 2013; 98: 1641-1650Crossref PubMed Scopus (33) Google Scholar, 9Fazleen 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. 2018; 12: 1083-1090Crossref PubMed Scopus (23) Google Scholar). Given the worrying increase in obesity among adolescents and the association of obesity and PCOS, a rising prevalence of PCOS seems inevitable in these youngsters (10McCartney C.R. Prendergast K.A. Chhabra S. Eagleson C.A. Yoo R. Chang R.J. et al.The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism.J Clin Endocrinol Metab. 2006; 91: 1714-1722Crossref PubMed Scopus (130) Google Scholar, 11Tsikouras P. Spyros L. Manav B. Zervoudis S. Poiana C. Nikolaos T. et al.Features of polycystic ovary syndrome in adolescence.J Med Life. 2015; 8: 291-296PubMed Google Scholar).Insulin Resistance and Impaired Glucose MetabolismThe etiology of PCOS is still not fully elucidated, but recent studies suggest that hyperinsulinemia causes excessive androgen production and that insulin resistance (IR) develops during adolescence (12Blank S.K. Helm K.D. McCartney C.R. Marshall J.C. Polycystic ovary syndrome in adolescence.Ann N Y Acad Sci. 2008; 1135: 76-84Crossref PubMed Scopus (63) Google Scholar). Although the glucose levels in adolescents with PCOS do not seem to differ from controls (9Fazleen 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. 2018; 12: 1083-1090Crossref PubMed Scopus (23) Google Scholar), a small case-control study found that girls with PCOS and obesity were more insulin resistant than obese controls (5Patel S.S. Truong U. King M. Ferland A. Moreau K.L. Dorosz J. et al.Obese adolescents with polycystic ovarian syndrome have elevated cardiovascular disease risk markers.Vasc Med. 2017; 22: 85-95Crossref PubMed Scopus (37) Google Scholar). A recently published study on 493 adolescents with overweight or obesity and PCOS showed a nearly 3 times higher incidence of T2DM than the incidence among adults with PCOS. However, no reliable comparison could be made with obese adolescents without PCOS. Furthermore, 24% had a prediabetes range of hemoglobin A1c at the time of PCOS diagnosis and is related to T2DM development (13Hudnut-Beumler J. Kaar J.L. Taylor A. Kelsey M.M. Nadeau K.J. Zeitler P. et al.Development of type 2 diabetes in adolescent girls with polycystic ovary syndrome and obesity.Pediatr Diabetes. 2021; 22: 699-706Crossref Scopus (2) Google Scholar).DyslipidemiaIt is known that body mass index (BMI) plays a significant negative role in lipid profile. Indeed, a meta-analysis, which included 3 studies, showed that adolescents with PCOS and a high BMI (>25 kg/m2) had higher triglyceride levels and low-density lipoprotein cholesterol (LDL-C) levels and lower high-density lipoprotein cholesterol (HDL-C) levels than normal-weight adolescents with PCOS (14Li L. Feng Q. Ye M. He Y. Yao A. Shi K. Metabolic effect of obesity on polycystic ovary syndrome in adolescents: a meta-analysis.J Obstet Gynaecol. 2017; 37: 1036-1047Crossref PubMed Scopus (25) Google Scholar). However, they also showed, using 5 studies in the meta-analysis, that obese adolescents with PCOS had higher LDL-C levels in serum than obese controls, but HDL-C and triglycerides were not significantly different. It seems that an unfavorable lipid profile is present already at an early age in adolescents with PCOS in addition to the higher BMI.HypertensionContradictory results about blood pressure in adolescents with PCOS are published. The meta-analysis of Fazleen et al. (9Fazleen 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. 2018; 12: 1083-1090Crossref PubMed Scopus (23) Google Scholar) showed significantly higher systolic and diastolic blood pressures in adolescents with PCOS than in the control groups. However, the meta-analysis did not adjust for BMI and showed a 5 times greater waist circumference in adolescents with PCOS, which could result in a higher blood pressure. In a case-control study in which the cases (n = 63) and controls (n = 159) had similar BMIs (<25 kg/m2) and waist circumferences, the systolic and diastolic blood pressures were significantly higher than those in the control group (15Aydin Y. Hassa H. Burkankulu D. Arslantas D. Sayiner D. Ozerdogan N. What is the risk of metabolic syndrome in adolescents with normal BMI who have polycystic ovary syndrome?.J Pediatr Adolesc Gynecol. 2015; 28: 271-274Abstract Full Text Full Text PDF PubMed Google Scholar). However, these values were within normal ranges; the question remains whether this predicts future hypertension or cardiovascular disease (CVD).Inflammatory CytokinesChronic low-grade inflammation is manifested by persistent activity of circulating mononuclear cells and mononuclear cell-derived macrophages in tissue that produce proinflammatory cytokines. Cytokines are signaling proteins and have a specific effect on interactions and communication between cells. Studies suggest that the serum levels of inflammatory cytokines are elevated in women with PCOS and that PCOS is considered a proinflammatory state (16González F. Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction.Steroids. 2012; 77: 300-305Crossref PubMed Scopus (228) Google Scholar, 17Abraham Gnanadass S. Divakar Prabhu Y. Valsala Gopalakrishnan A. Association of metabolic and inflammatory markers with polycystic ovarian syndrome (PCOS): an update.Arch Gynecol Obstet. 2021; 303: 631-643Crossref Scopus (15) Google Scholar). However, not much is known about cytokines in adolescents with PCOS. A case-control study that included 39 women with PCOS with a normal weight and 40 age- and BMI-matched controls, aged approximately 17 years, revealed a significantly lower level of high-molecular-weight (HMW) adiponectin in women with PCOS, which is an anti-inflammatory cytokine, generated by adipose tissue and negatively associated with IR (18Cankaya S. Demir B. Aksakal S.E. Dilbaz B. Demirtas C. Goktolga U. Insulin resistance and its relationship with high molecular weight adiponectin in adolescents with polycystic ovary syndrome and a maternal history of polycystic ovary syndrome.Fertil Steril. 2014; 102: 826-830Abstract Full Text Full Text PDF PubMed Google Scholar). Furthermore, in a study with women with PCOS aged approximately 19 years, adiponectin was reduced compared with that in controls, and the interleukin 6 (IL-6) level was higher in the IR PCOS group. All other cytokines were not different between the PCOS groups and controls (19Fulghesu A.M. Sanna F. Uda S. Magnini R. Portoghese E. Batetta B. IL-6 serum levels and production is related to an altered immune response in polycystic ovary syndrome girls with insulin resistance.Mediators Inflamm. 2011; 2011389317Crossref Scopus (36) Google Scholar).Metabolic SyndromeA group of known risk factors for CVD are clustered in the so-called metabolic syndrome (MetS). These risk factors are abdominal obesity, glucose intolerance and IR, elevated triglyceride level, low HDL-C level, and increased blood pressure. Multiple definitions of MetS in children and adolescents are used in studies, and the International Diabetes Federation (IDF) definition is the latest and is standardized per age group (children and adolescents) (20Zimmet P. Alberti K.G. Kaufman F. Tajima N. Silink M. Arslanian S. et al.The metabolic syndrome in children and adolescents - an IDF consensus report.Pediatr Diabetes. 2007; 8: 299-306Crossref PubMed Scopus (1265) Google Scholar). According to the IDF definition, MetS can be diagnosed in children aged 10–16 years with abdominal obesity (≥90th percentile or adult cutoff if lower) and the presence of ≥2 of the following features: serum triglyceride levels of ≥1.7 mmol/L; serum HDL-C levels of 18 years; when examining only the included studies on women during reproductive age, the risk ratio of T2DM is between 1.77 and 4.35. Insulin resistance increases ovarian androgen production and reduces sex hormone binding globulin serum levels, which results in higher free androgen serum levels. The androgen serum levels and hyperandrogenic PCOS phenotypes are, indeed, associated with elevated insulin levels and homeostasis model assessment for IR indices (33Daan N.M. Jaspers L. Koster M.P. Broekmans F.J. de Rijke Y.B. Franco O.H. et al.Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features.Hum Reprod. 2015; 30: 2376-2386Crossref PubMed Google Scholar, 34Pinola P. Puukka K. Piltonen T.T. Puurunen J. Vanky E. Sundström-Poromaa I. et al.Normo- and hyperandrogenic women with polycystic ovary syndrome exhibit an adverse metabolic profile through life.Fertil Steril. 2017; 107: 788-795.e2Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 35Daan N.M. Louwers Y.V. Koster M.P. Eijkemans M.J. de Rijke Y.B. Lentjes E.W. et al.Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk?.Fertil Steril. 2014; 102: 1444-1451.e3Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). This suggests that hyperandrogenic women with PCOS have an increased risk of T2DM compared with normoandrogenic women with PCOS.DyslipidemiaA meta-analysis, which summarized 30 studies between 1996 and 2008 on women with PCOS using the NIH and Rotterdam criteria, has shown increased total cholesterol, LDL-C, and triglyceride levels and low HDL-C levels in women with PCOS compared with those in controls during their reproductive age (36Wild R.A. Rizzo M. Clifton S. Carmina E. Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis.Fertil Steril. 2011; 95: 1073-1079.e1–11Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar). Women included in these studies were relatively young, and the lipid levels were most often within the normal range. Although BMI may be the main driver for the observed dyslipidemia, PCOS itself also seems to increase the risk of dyslipidemia, and hyperandrogenic PCOS phenotypes seem to increase it even more (35Daan N.M. Louwers Y.V. Koster M.P. Eijkemans M.J. de Rijke Y.B. Lentjes E.W. et al.Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk?.Fertil Steril. 2014; 102: 1444-1451.e3Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 36Wild R.A. Rizzo M. Clifton S. Carmina E. Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis.Fertil Steril. 2011; 95: 1073-1079.e1–11Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 37Valkenburg O. Steegers-Theunissen R.P. Smedts H.P. Dallinga-Thie G.M. Fauser B.C. Westerveld E.H. et al.A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: a case-control study.J Clin Endocrinol Metab. 2008; 93: 470-476Crossref PubMed Scopus (140) Google Scholar).Inflammatory CytokinesIn contrast to the limited studies on inflammatory cytokines in adolescents, much more is known in women of reproductive age. Tumor necrosis factor-alpha (TNF-α) is a cytokine that is involved in IR by blocking tyrosine kinase phosphorylation of the insulin receptor and is especially produced by adipose tissue. Elevated TNF-α levels were found in women with PCOS, and a few studies imply the relationship between TNF-α and hyperandrogenism (23Rojas J. Chávez M. Olivar L. Rojas M. Morillo J. Mejías J. et al.Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth.Int J Reprod Med. 2014; 2014719050Crossref Google Scholar, 38Gao L. Gu Y. Yin X. High serum tumor necrosis factor-alpha levels in women with polycystic ovary syndrome: a meta-analysis.PLoS One. 2016; 11e0164021Crossref Scopus (38) Google Scholar). However, in a meta-analysis, no differences were found in the TNF-α levels in women with PCOS compared with those in controls, but this included studies that were published before 2010 and consisted of small sample sizes (39Escobar-Morreale H.F. Luque-Ramírez M. González F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis.Fertil Steril. 2011; 95: 1048-1058.e1–2Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar).Interleukin 6 can act as a proinflammatory as well as an anti-inflammatory cytokine and is, in addition to TNF-α, an adipokine and may be associated with PCOS. Even though it is produced by adipocytes, studies have shown elevated IL-6 levels in both obese and lean women with PCOS (16González F. Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction.Steroids. 2012; 77: 300-305Crossref PubMed Scopus (228) Google Scholar, 40Tarkun I. Cetinarslan B. Türemen E. Cantürk Z. Biyikli M. Association between circulating tumor necrosis factor-alpha, interleukin-6, and insulin resistance in normal-weight women with polycystic ovary syndrome.Metab Syndr Relat Disord. 2006; 4: 122-128Crossref PubMed Scopus (63) Google Scholar). However, the meta-analysis of Escobar-Morreale et al. (39Escobar-Morreale H.F. Luque-Ramírez M. González F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis.Fertil Steril. 2011; 95: 1048-1058.e1–2Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar) demonstrated no differences in the IL-6 levels between women with PCOS and controls. Studies that are published more recently showed elevated IL-6 levels in women with PCOS but mostly in combination with the obese phenotype or in relation to IR (41Borthakur A. D Prabhu Y. Valsala Gopalakrishnan A. Role of IL-6 signalling in polycystic ovarian syndrome associated inflammation.J Reprod Immunol. 2020; 141103155Crossref Scopus (6) Google Scholar).Leptin is an adipokine that has effect on thermogenesis and feeding behavior and is mediated via the hypothalamic pathways (42Friedman J.M. Halaas J.L. Leptin and the regulation of body weight in mammals.Nature. 1998; 395: 763-770Crossref PubMed Scopus (4408) Google Scholar). Multiple studies have shown that elevated leptin levels are associated with hypertension and atherosclerosis, suggesting leptin as independent risk factor for CVD (43Beltowski J. Leptin and atherosclerosis.Atherosclerosis. 2006; 189: 47-60Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 44Katsiki N. Mikhailidis D.P. Banach M. Leptin, cardiovascular diseases and type 2 diabetes mellitus.Acta Pharmacol Sin. 2018; 39: 1176-1188Crossref PubMed Scopus (0) Google Scholar). The leptin levels in obese women with PCOS seem to be elevated but are clearly associated with BMI (45Delitala A.P. Capobianco G. Delitala G. Cherchi P.L. Dessole S. Polycystic ovary syndrome, adipose tissue and metabolic syndrome.Arch Gynecol Obstet. 2017; 296: 405-419Crossref PubMed Scopus (64) Google Scholar). The independent association between leptin and PCOS has not yet been clarified.The adiponectin level is, in contrast to the leptin level, decreased in humans with obesity, IR, or CVD, and it seems that normal adiponectin levels are necessary to maintain or achieve a noninflammatory state in the arteries (46Matsuzawa Y. Funahashi T. Kihara S. Shimo