Disponible en ligne sur
ScienceDirect www.sciencedirect.com Annales d’Endocrinologie 75 (2014) 194–199
Review
Long term complications of polycystic ovary syndrome (PCOS) Complications à long terme du syndrome des ovaires polykystiques (SOPK) Maëliss Peigné a,∗,b , Didier Dewailly a,b a
Department of Endocrine Gynaecology and Reproductive Medicine, hôpital Jeanne-de-Flandre, CHRU, avenue Eugène-Avinée, 59037, Lille cedex, France b Université Lille 2, Lille, France
Abstract Polycystic ovary syndrome (PCOS) is a frequent endocrine disease affecting 10 to 15% of women. Menstrual disorders, hyperandrogenism and ultrasonographic aspect of ovaries are typical of the disease and are established diagnostic criteria. But PCOS has also long term complications frequently forgotten and underestimated. During pregnancy, gestational diabetes and gestational hypertensive disorders can occur. At an older age, metabolic disease such as glucose intolerance, type 2 diabetes or dyslipidaemia are frequently described. Women with PCOS have increased classical cardiovascular risks and increased subclinical cardio-vascular disease without proven increase of cardiovascular morbidity and mortality. Finally, endometrial cancer seems to be more frequent in women with PCOS. Therefore, PCOS have numerous long-term health risks and a life-long follow-up is necessary for these women “at-risk” to detect and prevent complications as soon as possible. © 2014 Published by Elsevier Masson SAS. Keywords: PCOS; Complications; Health; Cancer; Cardio-vascular disease
Résumé Le syndrome des ovaires polykystiques (SOPK) est une pathologie fréquente touchant près de 10 à 15 % de la population féminine. La dysovulation, l’hyperandrogénie et les signes échographiques qui le caractérisent sont bien connus mais cette pathologie comprend également des complications à moyen et long terme, moins connues et donc moins bien prises en charge. Pendant la grossesse, ces patientes sont plus à risque de diabète gestationnel et de complications obstétricales. À plus long terme, les complications sont à type de troubles métaboliques comme l’insulinorésistance, le diabète de type 2 et la dyslipidémie. Les femmes atteintes d’un SOPK ont une augmentation des facteurs et des marqueurs de risque cardio-vasculaire sans qu’une augmentation de la morbidité et de la mortalité cardio-vasculaire de ces patientes soit actuellement démontrée. Enfin, une augmentation du risque du cancer de l’endomètre est décrite. Toutes ces complications impliquent la mise en place d’une politique de prévention et de dépistage systématique à mettre en place dès le diagnostic de SOPK posé. © 2014 Publié par Elsevier Masson SAS. Mots clés : SOPK ; Complications ; Santé ; Cancer ; Pathologie cardio-vasculaire
Polycystic ovary syndrome (PCOS) is recognized as the most common endocrine disorder in women but it is also a life-long disease. During the early reproductive years, the main symptoms are menstrual disorders, hyperandrogenism and/or infertility (Fig. 1). But women and physicians must be aware of life-long complications of this syndrome. Indeed, progressively, reproductive dysfunction will be replaced by metabolic disorders in
about 50% patients. At an older age, pregnancy complications, obesity, glucose intolerance, type 2 diabetes, cardiovascular disease and gynaecologic cancers can occur (Fig. 1). A life-long follow-up is necessary for these women “at-risk” and preventive measures must be taken as soon as possible.
1. Medium term complications: pregnancy complications ∗
Corresponding author. E-mail addresses: [email protected] (M. Peigné), [email protected] (D. Dewailly). http://dx.doi.org/10.1016/j.ando.2014.07.111 0003-4266/© 2014 Published by Elsevier Masson SAS.
Women with PCOS have a higher risk of pregnancy complications such as gestational diabetes (OR = 2.94) [1,2]
M. Peigné, D. Dewailly / Annales d’Endocrinologie 75 (2014) 194–199
195
Fig. 1. Life-long symptoms and complications of PCOS.
and associated foetal macrosomia. A screening of gestational diabetes should be proposed to every woman with PCOS performing the usual tests: fasting glucose measurement during the first trimester of pregnancy and, if this first test is normal, Oral Glucose Tolerance Test (OGTT) (75 g, 0-, 1-hour and 2-hour values) between 24 and 28 weeks of gestation (WG). Gestational hypertensive disorders are also more frequent (preeclampsia OR = 3.67, gravid hypertension OR = 3.47) [1]. Even without official guidelines, a closer monitoring of blood pressure and measurement of uterine blood flow during second trimester of pregnancy should be considered (Table 1) [3]. Finally, the risks of preterm delivery (OR = 1.75) and perinatal mortality
(OR = 3.07) are higher in women with PCOS [1]. Obesity, altered glucose metabolism and disturbances in uterine blood flow have been incriminated [4] and might be confounding factors [3]. Since no benefit was found with the use of metformin before conception or during pregnancy, its routine use is not recommended [4] but lifestyle management, especially during pregnancy, is essential. 2. Overweight, obesity and their consequences The prevalence of overweight (Body Mass Index [BMI] 25 to 30 kg/m2 ) or obesity (BMI > 30 kg/m2 ) in PCOS women is quite
Table 1 Major long-term complications of PCOS and method of screening. Major complications
Screening
Pregnancy complications Gestational diabetes Hypertensive disorders Glucose intolerance
(No official guidelines) Fasting glucose measurement during the first trimester of pregnancy and OGTT during the second trimester Monitoring blood pressure and, maybe, measurement of uterine blood flow during second trimester of pregnancy Amsterdam ESHRE consensus [3] Oral Glucose Tolerance Test (75 g, 0- and 2-hour values) in PCOS women with BMI>30 kg/m2 and/or Waist circumference over 88 cm and/or Acanthosis nigricans and/or Familial history of type 2 diabetes and/or Personal history of gestational diabetes and/or Both menstrual disorders and hyperandrogenia present Amsterdam ESHRE consensus [3] At any age, in women with PCOS, screening of Waist circumference Blood pressure Lipide profile Physical activity Nutrition Smoking Amsterdam ESHRE consensus [3] Checking the endometrium by ultrasound or endometrial biopsy in women with a long amenorrhea period To prevent endometrial hyperplasia, a minimum of 4 induced withdrawals bleeding per year is needed
Cardiovascular risk
Endometrial cancer
196
M. Peigné, D. Dewailly / Annales d’Endocrinologie 75 (2014) 194–199
variable from one country to another one. For example, in the UK 90% of PCOS women have a BMI > 25 kg/m2 whereas they are only 20% in China. The highest prevalence of obesity in women with PCOS is reported in USA (61%) and Australia (76%) [4]. Compared with weight-matched controls, women with PCOS are more likely to have abdominal obesity which is associated with metabolic diseases. Indeed, abdominal fat is directly correlated with insulin resistance. As the waist circumference is directly correlated to abdominal fat, it is a precious and easily measurable marker of metabolic disease. In Europe a waist circumference over 80 cm defines abdominal adiposity. In addition, as explained further, women with PCOS, even the lean ones, are more insulino-resistant and obesity magnifies this disease [5,6]. Abdominal obesity can be part of the so-called “metabolic syndrome”. It is defined by the association of three of the following: abdominal obesity, low HDL-cholesterol, high triglyceride level, high blood pressure, glucose intolerance. These additional cardiovascular risks must be screened, as explained further in the “cardiovascular risk” chapter. The prevalence of metabolic syndrome in PCOS patients seems to be higher than in control patients in several studies [7–12] but a bias exists. In fact, in these studies, women with PCOS were more obese than controls. In a recent study by Panidis et al. [13] the prevalence of metabolic syndrome is not different between women with PCOS and BMImatched controls. Therefore, PCOS does not seem to increase the risk of metabolic syndrome independently from abdominal obesity. As in control women, obesity in PCOS patients can be complicated by arterial hypertension, obstructive sleep apnea, dyslipidaemia, mood disorders, etc., which must be screened as explained further in the “cardiovascular risk” chapter, but these complications seem more severe and more frequent when associated to PCOS [14], presumably because insulin resistance is more prominent in PCOS. Regarding mood disorders, a specific link may exist with PCOS [14], for example more depression and more anxiety. The high prevalence of psychological pathologies does not seem to be exclusively linked to obesity, infertility and/or hirsutism and should imply a psychological assessment in the initial evaluation and in the follow-up [14].
glucose intolerant and type 2 diabetic is respectively 2.5 and 4.1 fold higher in women with PCOS than in BMI- matched controls. Thus, even with a normal weight, women with PCOS are exposed to the risk of glucose intolerance and type 2 diabetes and the risk is magnified by obesity. Insulin resistance is mostly prevalent and severe in women with the PCOS phenotype involving hyperandrogenism and anovulation. The Amsterdam ESHRE consensus [4] recommends a systematic screening of glucose intolerance in PCOS women with BMI > 30 kg/m2 and/or waist circumference over 88 cm and/or acanthosis nigricans and/or familial history of type 2 diabetes and/or personal history of gestational diabetes (Table 1). The screening must be performed by Oral Glucose Tolerance Test (OGTT) (75 g, 0and 2-hour values). They also recommended OGTT when both menstrual disorders and hyperandrogenia are present because some studies proved a direct correlation between the number of PCOS symptoms and the occurrence of glucose intolerance or type 2 diabetes [4]. If the patient can not or do not want to perform OGTT, HbA1C measurement can be considered [21]. The PCOS has recently been identified by the American Diabetes Association as a specific risk factor for type 2 diabetes. However, only cross sectional observational, retrospective and short term prospective studies were available [6] until a recent long term prospective Italian study by Gambineri et al. [22]. This study demonstrated that the risk of type 2 diabetes is elevated in middle-age women with PCOS (incidence rate of 1.05 per 100 person-years, 2,6 times higher than that of the general population). This risk increases with BMI, high fasting glucose and low sex hormone-binding globulin (SHBG) circulating levels. This study reinforces the need for routine screening for diabetes in PCOS patients over time [22]. The first-line treatment of glucose intolerance is the lifestyle management, especially with physical activity [21]. Counselling by non-medical professional groups seems to be efficient and may be recommended [23]. Metformin treatment can be indicated in case of proved glucose intolerance and when the lifestyle management is ineffective [4,24]. 4. Cardiovascular diseases 4.1. Cardiovascular pathology
3. Insulin resistance, glucose intolerance and type 2 diabetes Insulin resistance (IR) is a prominent feature of PCOS. Pathophysiology of IR remains controversial and could be due to a defect in signal transduction of insulin [15–18]. Except for clinical features such as acanthosis nigricans and abdominal adiposity, IR diagnosis is not easy. IR Index, such as Homeostasis Model Assessment (HOMA) or quantitative insulin sensitivity check (QUICKI), have been developed but in clinical practice the ratio fasting glycaemia (mg/dL)/insulinaemia (U/mL) is the easiest criteria to evaluate IR [19]. Progressively, IR can lead to glucose intolerance, which occurs in 40% of women with PCOS after the age of 40 [20] and, in six years, half of these women become diabetic. Indeed, in the meta-analysis of Moran et al. [6], the risk of becoming
Numerous observational studies focused on cardiovascular disease in women with PCOS. Their conclusions are still contradictory. For example, in Rizzo et al. review [25], five studies concluded that PCOS women are at risk for cardiovascular diseases, which was not proved in three other studies. Definition of PCOS, cardiovascular endpoints and median age of patients were different in each study. Series were sometimes very small, some included patients too young to have time to develop cardiovascular disease and after menopause it is difficult to retrospectively diagnose PCOS. The meta-analysis of Groot et al. [26] based on five cohort studies, again with different definitions of PCOS, showed a higher risk of coronary heart disease or cerebrovascular disease in PCOS women compared to controls (effect size = 2, IC95 = 1.47–2.76). Recently, a large retrospective study by Mani et al. [27], conducted in more than 2000
M. Peigné, D. Dewailly / Annales d’Endocrinologie 75 (2014) 194–199
women with PCOS over 11 years, has reported an increased agespecific prevalence for both myocardial infraction and angina in women with PCOS. However, in this population with 80% of the subjects under 45 years old, the overall rates of myocardial infraction and angina did not differ from the reference population. Finally, a very large dataset in UK (21,000 women with PCOS) reported no evidence of an increase in cardiovascular disease, but once again the population was young and the diagnosis of PCOS was questionable [28]. In contrast with cardiovascular heart disease, cerebrovascular disease is unanimously proved to be more frequent in women with PCOS (OR = 2.8), even when patients are compared to BMI-matched controls (OR = 3.4) [29]. In conclusion, a higher cardiovascular morbidity or mortality of women with PCOS is not obviously demonstrated. Nevertheless, in post-menopausal women, a personal history of clinical hyperandrogenism or menstrual disorders expose to an increased cardiovascular disease risk [30,31]. Large scale prospective studies are needed to clearly prove an increased prevalence of cardiovascular events in PCOS women compared to age- and BMI-matched controls.
197
seem to have an increased risk of sleep disorders compared to healthy BMI-matched women [14]. The presence of obstructive sleep apnea must be screened by questionnaires and patient should be referred to a center of sleep disorders for further evaluation [14]. Jovanovic and al. [41] proved that the more the PCOS phenotype is complete the more the cardiovascular risk markers are present. The recommended cardio-vascular risk assessment by Amsterdam ESHRE consensus includes assessment of blood pressure, glucose and lipid profiles, waist circumference, physical activity, nutrition and smoking at any age [4] (Table 1). If the lipid profile and the OGTT are normal, they must be rechecked every two years [42]. In conclusion, classical cardiovascular risk markers are more prevalent in women with PCOS, even if they are not obese, and these risks are magnified by obesity. The long-term metabolic disease of women with PCOS affects the subclinical vascular pathology markers and, even if a higher cardiovascular morbidity or mortality is not definitively proved, caution is warranted. Indeed, a life-long metabolic dysfunction can exaggerate the risk for cardio-vascular disease, especially after menopause.
4.2. Subclinical vascular disease Even if a higher cardiovascular pathology in PCOS women is still controversial, the subclinical vascular disease is proved to be higher in PCOS women compared with age- and BMI-matched controls. Three markers are commonly used in clinical research to evaluate sub-clinical atherosclerosis: the carotid intima-media thickening, the arterial stiffness and the coronary artery calcification. They are all increased in women with PCOS compared to controls, independently from age and BMI [32–36]. 4.3. Classical cardiovascular risk factors As expected, since the subclinical cardiovascular disease is higher in PCOS women, the classical cardiovascular risks are more frequent. Indeed, arterial hypertension, dyslipidaemia and especially low HDL-cholesterol (High Density Lipoprotein-cholesterol), insulin resistance or type 2 diabetes and obesity, especially abdominal obesity, are more frequent in PCOS women [4,37,38]. Dyslipidaemia is very frequent among women with PCOS. Almost 70% of women with PCOS suffer from dyslipidaemia, most often represented by hypertriglyceridemia and low HDL-cholesterol and sometimes by high LDL-cholesterol (low density lipoprotein cholesterol) [14]. The abdominal obesity, detected by the waist circumference over 88 cm (and over 80 cm in Europe population), and the decrease of HDL-cholesterol under 0.5 g/L are the first risk factors to appear; they must be screened as soon as possible. The metabolic syndrome, as defined above, is not required for cardiovascular risk disease since even with one criteria the cardiovascular risk is increased [39]. In some studies, the risk of obstructive sleep apnea is five times higher in PCOS women compared to controls regardless the BMI [40]. But, normal weight women with PCOS do not
5. Gynaecological malignancies 5.1. Endometrial cancer A meta-analysis in 2009 [43], proved that the risk to develop an endometrial cancer was higher in women with PCOS (OR = 2.7, IC95 = 1.00–7.29), which was confirmed in a recent systematic review with a 3 fold higher risk in women with PCOS compared to controls [44]. Another previous study concluded that the risk of endometrial cancer was 5.3 times higher in PCOS women and 6.1 times increased in obese PCOS women [29]. Nevertheless, most endometrial cancers are well differentiated and have good prognosis. Chronic anovulation and therefore the prolonged exposure to unopposed oestrogen can lead to endometrial hyperplasia and to endometrial cancer. But other factors could interact in cancer process, such as progesterone dependant gene dysregulation, hyperandrogenism, hyperinsulinism and/or LH hypersecretion [45]. Moreover, when adjusted with BMI, endometrial cancer risk in women with PCOS is half-reduced, demonstrating that obesity is a very important confounding factor [45]. The recent Amsterdam ESHRE consensus recommends checking the endometrium by ultrasound or endometrial biopsy in women with a long amenorrhea period. To prevent endometrial hyperplasia, a minimum of four induced withdrawals bleeding per year is needed [4] (Table 1). 5.2. Breast cancer Data about breast cancer in PCOS women are limited. The meta-analysis of Chittenden et al. [43], based on three old studies with a few PCOS patients, showed no difference between women with and without PCOS for breast cancer risk.
198
M. Peigné, D. Dewailly / Annales d’Endocrinologie 75 (2014) 194–199
Nowadays, there is no particular recommendation for the follow-up of women with PCOS about breast cancer. 5.3. Ovarian cancer Limited data exists. Indeed, only one study tried to evaluate the association between PCOS and ovarian cancer. Even if it is usually said that the less is the ovulation number the less is the risk for ovarian cancer, this study showed that PCOS women have 2.5-fold more risk to develop ovarian cancer than non PCOS women [46]. However, the number of PCOS women in this study was very small. In the opposite, another study showed a lower mortality by ovarian cancer in PCOS patients than in non PCOS women [47]. Thus, these limited data do not allow concluding that women with PCOS are at increased risk for ovarian cancer. However, it must be reminded that women with PCOS have other recognized risk factors such as nulliparity, infertility and its treatment, anovulation and obesity. There is no current particular recommendation for screening ovarian cancer in PCOS women. 6. Conclusions PCOS is a life-long disease and has long term complications frequently forgotten and underestimated. Obesity and altered glucose metabolism are the most common complications described in women with PCOS. Metabolic dysfunction leads to pregnancy complications and to metabolic disease with increased classical cardiovascular risks and increased subclinical cardio-vascular disease without proven increase of cardiovascular morbidity and mortality with aging. More data are needed to definitively prove a higher cardiovascular morbidity or mortality. Indeed, longitudinal studies are very scarce and without standardisation of diagnostic criteria of PCOS. Endometrial cancer seems to be more frequent in women with PCOS. Therefore, PCOS has numerous long-term health risks and a lifelong follow-up is necessary. Indeed, for prevention of long-term complications of PCOS, information and education are crucial because all complications, metabolic disorders and endometrial cancer, can be prevented by an early care. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Boomsma CM, Eijkemans MJC, Hughes EG, Visser GHA, Fauser BCJM, Macklon NS. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update 2006;12:673–83. [2] Veltman-Verhulst SM, Haeften van TW, Eijkemans MJC, Valk de HW, Fauser BCJM, Goverde AJ. Sex hormone-binding globulin concentrations before conception as a predictor for gestational diabetes in women with polycystic ovary syndrome. Hum Reprod 2010;25:3123–8. [3] Bruyneel A, Catteau-Jonard S, Decanter C, Clouqueur E, Tomaszewski C, Subtil D, et al. [Polycystic ovary syndrome: what are the obstetrical risks?]. Gynecol Obstet Fertil 2014;42:104–11.
[4] Fauser BCJM, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 2012;97, 28–38.e25. [5] Carmina E, Bucchieri S, Esposito A, Puente AD, Mansueto P, Orio F, et al. Abdominal fat quantity and distribution in women with polycystic ovary syndrome and extent of its relation to insulin resistance. JCEM 2007;92:2500–5. [6] Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2010;16:347–63. [7] Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:1929–35. [8] Carmina E, Napoli N, Longo RA, Rini GB, Lobo RA. Metabolic syndrome in polycystic ovary syndrome (PCOS): lower prevalence in southern Italy than in the USA and the influence of criteria for the diagnosis of PCOS. Eur J Endocrinol 2006;154:141–5. [9] Hahn S, Tan S, Sack S, Kimmig R, Quadbeck B, Mann K, et al. Prevalence of the metabolic syndrome in German women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 2007;115:130–5. [10] Cussons AJ, Watts GF, Burke V, Shaw JE, Zimmet PZ, Stuckey BGA. Cardiometabolic risk in polycystic ovary syndrome: a comparison of different approaches to defining the metabolic syndrome. Hum Reprod 2008;23:2352–8. [11] Gambineri A, Repaci A, Patton L, Grassi I, Pocognoli P, Cognigni GE, et al. Prominent role of low HDL-cholesterol in explaining the high prevalence of the metabolic syndrome in polycystic ovary syndrome. Nutr Metab Cardiovasc Dis 2009;19:797–804. [12] Hosseinpanah F, Barzin M, Tehrani FR, Azizi F. The lack of association between polycystic ovary syndrome and metabolic syndrome: Iranian PCOS prevalence study. Clin Endocrinol (Oxf) 2011;75: 692–7. [13] Panidis D, Macut D, Tziomalos K, Papadakis E, Mikhailidis K, Kandaraki EA, et al. Prevalence of metabolic syndrome in women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2013;78:586–92. [14] Conway GS, Dewailly D, Diamanti-Kandarakis E, Escobar Morreale H, Franks S, Gambineri A, et al. The polycystic ovary syndrome: an endocrinological perspective from the European Society of Endocrinology. Eur J Endocrinol 2014 [Jul 21. pii: EJE-14-0252]. [15] Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995;96:801–10. [16] Zhang LH, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci USA 1995;92:10619–23. [17] Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 2012;33:981–1030. [18] Dunaif A, Wu X, Lee A, Diamanti-Kandarakis E. Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Am J Physiol Endocrinol Metab 2001;281:E392–9. [19] Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocr Rev 2003;24:302–12. [20] Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective controlled study in 254 affected women. JCEM 1999;84:165–9. [21] Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. Diagnosis and treatment of polycystic ovary syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2013;98:4565–92. [22] Gambineri A, Patton L, Altieri P, Pagotto U, Pizzi C, Manzoli L, et al. Polycystic ovary syndrome is a risk factor for type 2 diabetes results from a long-term prospective study. Diabetes 2012;61:2369–74.
M. Peigné, D. Dewailly / Annales d’Endocrinologie 75 (2014) 194–199 [23] Jebb SA, Ahern AL, Olson AD, Aston LM, Holzapfel C, Stoll J, et al. Primary care referral to a commercial provider for weight loss treatment versus standard care: a randomised controlled trial. Lancet 2011;378:1485–92. [24] Franks S. When should an insulin sensitizing agent be used in the treatment of polycystic ovary syndrome? Clin Endocrinol (Oxf) 2011;74:148–51. [25] Rizzo M, Berneis K, Spinas G, Rini GB, Carmina E. Long-term consequences of polycystic ovary syndrome on cardiovascular risk. Fertil Steril 2009;91:1563–7. [26] Groot de PCM, Dekkers OM, Romijn JA, Dieben SWM, Helmerhorst FM. PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Hum Reprod Update 2011;17:495–500. [27] Mani H, Levy MJ, Davies MJ, Morris DH, Gray LJ, Bankart J, et al. Diabetes and cardiovascular events in women with polycystic ovary syndrome: a 20-year retrospective cohort study. Clin Endocrinol (Oxf) 2013;78:926–34. [28] Morgan CL, Jenkins-Jones S, Currie CJ, Rees DA. Evaluation of adverse outcome in young women with polycystic ovary syndrome versus matched, reference controls: a retrospective, observational study. J Clin Endocrinol Metab 2012;97:3251–60. [29] Wild S, Pierpoint T, Jacobs H, McKeigue P. Long-term consequences of polycystic ovary syndrome: results of a 31 year follow-up study. Hum Fertil (Camb) 2000;3:101–5. [30] Shaw LJ, Bairey Merz CN, Azziz R, Stanczyk FZ, Sopko G, Braunstein GD, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health—National Heart, Lung, and Blood Institute sponsored women’s ischemia syndrome evaluation. J Clin Endocrinol Metab 2008;93:1276–84. [31] Krentz AJ, von Mühlen D, Barrett-Connor E. Searching for polycystic ovary syndrome in postmenopausal women: evidence for a dose-effects association with prevalent cardiovascular disease. Menopause 2007;14:284–92. [32] Talbott EO, Guzick DS, Sutton-Tyrrell K, McHugh-Pemu KP, Zborowski JV, Remsberg KE, et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged Women. Arterioscler Thromb Vasc Biol 2000;20:2414–21. [33] Talbott EO, Zborowski JV, Rager JR, Boudreaux MY, Edmundowicz DA, Guzick DS. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. JCEM 2004;89:5454–61.
199
[34] Soares GM, Vieira CS, Martins WP, Franceschini SA, Dos Reis RM, Silva de Sá MF, et al. Increased arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS) without comorbidities: one more characteristic inherent to the syndrome? Clin Endocrinol 2009;71:406–11. [35] Luque-Ramírez M, Mendieta-Azcona C, Álvarez-Blasco F, EscobarMorreale HF. Androgen excess is associated with the increased carotid intima-media thickness observed in young women with polycystic ovary syndrome. Hum Reprod 2007;22:3197–203. [36] Christian RC, Dumesic DA, Behrenbeck T, Oberg AL, Sheedy PF, Fitzpatrick LA. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. JCEM 2003;88:2562–8. [37] Tamimi W, Siddiqui IA, Tamim H, AlEisa N, Adham M. Effect of body mass index on clinical manifestations in patients with polycystic ovary syndrome. Int J Gynecol Obstet 2009;107:54–7. [38] Wild RA, Rizzo M, Clifton S, Carmina E. Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. Fertil Steril 2011;95, 1073–1079.e11. [39] Reaven GM. The metabolic syndrome: requiescat in pace. Clin Chem 2005;51:931–8. [40] Nitsche K, Ehrmann DA. Obstructive sleep apnea and metabolic dysfunction in polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab 2010;24:717–30. [41] Jovanovic VP, Carmina E, Lobo RA. Not all women diagnosed with PCOS share the same cardiovascular risk profiles. Fertil Steril 2010;94:826–32. [42] ESHRE Capri Workshop Group. Health and fertility in World Health Organization group 2 anovulatory women. Hum Reprod Update 2012;18:586–99. [43] Chittenden BG, Fullerton G, Maheshwari A, Bhattacharya S. Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Reprod Biomed Online 2009;19:398–405. [44] Haoula Z, Salman M, Atiomo W. Evaluating the association between endometrial cancer and polycystic ovary syndrome. Hum Reprod 2012;27:1327–31. [45] Dumesic DA, Lobo RA. Cancer risk and PCOS. Steroids 2013;78:782–5. [46] Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C. Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstet Gynecol 1996;88:554–9. [47] Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS. Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol 1998;51:581–6.
ScienceDirect www.sciencedirect.com Annales d’Endocrinologie 75 (2014) 194–199
Review
Long term complications of polycystic ovary syndrome (PCOS) Complications à long terme du syndrome des ovaires polykystiques (SOPK) Maëliss Peigné a,∗,b , Didier Dewailly a,b a
Department of Endocrine Gynaecology and Reproductive Medicine, hôpital Jeanne-de-Flandre, CHRU, avenue Eugène-Avinée, 59037, Lille cedex, France b Université Lille 2, Lille, France
Abstract Polycystic ovary syndrome (PCOS) is a frequent endocrine disease affecting 10 to 15% of women. Menstrual disorders, hyperandrogenism and ultrasonographic aspect of ovaries are typical of the disease and are established diagnostic criteria. But PCOS has also long term complications frequently forgotten and underestimated. During pregnancy, gestational diabetes and gestational hypertensive disorders can occur. At an older age, metabolic disease such as glucose intolerance, type 2 diabetes or dyslipidaemia are frequently described. Women with PCOS have increased classical cardiovascular risks and increased subclinical cardio-vascular disease without proven increase of cardiovascular morbidity and mortality. Finally, endometrial cancer seems to be more frequent in women with PCOS. Therefore, PCOS have numerous long-term health risks and a life-long follow-up is necessary for these women “at-risk” to detect and prevent complications as soon as possible. © 2014 Published by Elsevier Masson SAS. Keywords: PCOS; Complications; Health; Cancer; Cardio-vascular disease
Résumé Le syndrome des ovaires polykystiques (SOPK) est une pathologie fréquente touchant près de 10 à 15 % de la population féminine. La dysovulation, l’hyperandrogénie et les signes échographiques qui le caractérisent sont bien connus mais cette pathologie comprend également des complications à moyen et long terme, moins connues et donc moins bien prises en charge. Pendant la grossesse, ces patientes sont plus à risque de diabète gestationnel et de complications obstétricales. À plus long terme, les complications sont à type de troubles métaboliques comme l’insulinorésistance, le diabète de type 2 et la dyslipidémie. Les femmes atteintes d’un SOPK ont une augmentation des facteurs et des marqueurs de risque cardio-vasculaire sans qu’une augmentation de la morbidité et de la mortalité cardio-vasculaire de ces patientes soit actuellement démontrée. Enfin, une augmentation du risque du cancer de l’endomètre est décrite. Toutes ces complications impliquent la mise en place d’une politique de prévention et de dépistage systématique à mettre en place dès le diagnostic de SOPK posé. © 2014 Publié par Elsevier Masson SAS. Mots clés : SOPK ; Complications ; Santé ; Cancer ; Pathologie cardio-vasculaire
Polycystic ovary syndrome (PCOS) is recognized as the most common endocrine disorder in women but it is also a life-long disease. During the early reproductive years, the main symptoms are menstrual disorders, hyperandrogenism and/or infertility (Fig. 1). But women and physicians must be aware of life-long complications of this syndrome. Indeed, progressively, reproductive dysfunction will be replaced by metabolic disorders in
about 50% patients. At an older age, pregnancy complications, obesity, glucose intolerance, type 2 diabetes, cardiovascular disease and gynaecologic cancers can occur (Fig. 1). A life-long follow-up is necessary for these women “at-risk” and preventive measures must be taken as soon as possible.
1. Medium term complications: pregnancy complications ∗
Corresponding author. E-mail addresses: [email protected] (M. Peigné), [email protected] (D. Dewailly). http://dx.doi.org/10.1016/j.ando.2014.07.111 0003-4266/© 2014 Published by Elsevier Masson SAS.
Women with PCOS have a higher risk of pregnancy complications such as gestational diabetes (OR = 2.94) [1,2]
M. Peigné, D. Dewailly / Annales d’Endocrinologie 75 (2014) 194–199
195
Fig. 1. Life-long symptoms and complications of PCOS.
and associated foetal macrosomia. A screening of gestational diabetes should be proposed to every woman with PCOS performing the usual tests: fasting glucose measurement during the first trimester of pregnancy and, if this first test is normal, Oral Glucose Tolerance Test (OGTT) (75 g, 0-, 1-hour and 2-hour values) between 24 and 28 weeks of gestation (WG). Gestational hypertensive disorders are also more frequent (preeclampsia OR = 3.67, gravid hypertension OR = 3.47) [1]. Even without official guidelines, a closer monitoring of blood pressure and measurement of uterine blood flow during second trimester of pregnancy should be considered (Table 1) [3]. Finally, the risks of preterm delivery (OR = 1.75) and perinatal mortality
(OR = 3.07) are higher in women with PCOS [1]. Obesity, altered glucose metabolism and disturbances in uterine blood flow have been incriminated [4] and might be confounding factors [3]. Since no benefit was found with the use of metformin before conception or during pregnancy, its routine use is not recommended [4] but lifestyle management, especially during pregnancy, is essential. 2. Overweight, obesity and their consequences The prevalence of overweight (Body Mass Index [BMI] 25 to 30 kg/m2 ) or obesity (BMI > 30 kg/m2 ) in PCOS women is quite
Table 1 Major long-term complications of PCOS and method of screening. Major complications
Screening
Pregnancy complications Gestational diabetes Hypertensive disorders Glucose intolerance
(No official guidelines) Fasting glucose measurement during the first trimester of pregnancy and OGTT during the second trimester Monitoring blood pressure and, maybe, measurement of uterine blood flow during second trimester of pregnancy Amsterdam ESHRE consensus [3] Oral Glucose Tolerance Test (75 g, 0- and 2-hour values) in PCOS women with BMI>30 kg/m2 and/or Waist circumference over 88 cm and/or Acanthosis nigricans and/or Familial history of type 2 diabetes and/or Personal history of gestational diabetes and/or Both menstrual disorders and hyperandrogenia present Amsterdam ESHRE consensus [3] At any age, in women with PCOS, screening of Waist circumference Blood pressure Lipide profile Physical activity Nutrition Smoking Amsterdam ESHRE consensus [3] Checking the endometrium by ultrasound or endometrial biopsy in women with a long amenorrhea period To prevent endometrial hyperplasia, a minimum of 4 induced withdrawals bleeding per year is needed
Cardiovascular risk
Endometrial cancer
196
M. Peigné, D. Dewailly / Annales d’Endocrinologie 75 (2014) 194–199
variable from one country to another one. For example, in the UK 90% of PCOS women have a BMI > 25 kg/m2 whereas they are only 20% in China. The highest prevalence of obesity in women with PCOS is reported in USA (61%) and Australia (76%) [4]. Compared with weight-matched controls, women with PCOS are more likely to have abdominal obesity which is associated with metabolic diseases. Indeed, abdominal fat is directly correlated with insulin resistance. As the waist circumference is directly correlated to abdominal fat, it is a precious and easily measurable marker of metabolic disease. In Europe a waist circumference over 80 cm defines abdominal adiposity. In addition, as explained further, women with PCOS, even the lean ones, are more insulino-resistant and obesity magnifies this disease [5,6]. Abdominal obesity can be part of the so-called “metabolic syndrome”. It is defined by the association of three of the following: abdominal obesity, low HDL-cholesterol, high triglyceride level, high blood pressure, glucose intolerance. These additional cardiovascular risks must be screened, as explained further in the “cardiovascular risk” chapter. The prevalence of metabolic syndrome in PCOS patients seems to be higher than in control patients in several studies [7–12] but a bias exists. In fact, in these studies, women with PCOS were more obese than controls. In a recent study by Panidis et al. [13] the prevalence of metabolic syndrome is not different between women with PCOS and BMImatched controls. Therefore, PCOS does not seem to increase the risk of metabolic syndrome independently from abdominal obesity. As in control women, obesity in PCOS patients can be complicated by arterial hypertension, obstructive sleep apnea, dyslipidaemia, mood disorders, etc., which must be screened as explained further in the “cardiovascular risk” chapter, but these complications seem more severe and more frequent when associated to PCOS [14], presumably because insulin resistance is more prominent in PCOS. Regarding mood disorders, a specific link may exist with PCOS [14], for example more depression and more anxiety. The high prevalence of psychological pathologies does not seem to be exclusively linked to obesity, infertility and/or hirsutism and should imply a psychological assessment in the initial evaluation and in the follow-up [14].
glucose intolerant and type 2 diabetic is respectively 2.5 and 4.1 fold higher in women with PCOS than in BMI- matched controls. Thus, even with a normal weight, women with PCOS are exposed to the risk of glucose intolerance and type 2 diabetes and the risk is magnified by obesity. Insulin resistance is mostly prevalent and severe in women with the PCOS phenotype involving hyperandrogenism and anovulation. The Amsterdam ESHRE consensus [4] recommends a systematic screening of glucose intolerance in PCOS women with BMI > 30 kg/m2 and/or waist circumference over 88 cm and/or acanthosis nigricans and/or familial history of type 2 diabetes and/or personal history of gestational diabetes (Table 1). The screening must be performed by Oral Glucose Tolerance Test (OGTT) (75 g, 0and 2-hour values). They also recommended OGTT when both menstrual disorders and hyperandrogenia are present because some studies proved a direct correlation between the number of PCOS symptoms and the occurrence of glucose intolerance or type 2 diabetes [4]. If the patient can not or do not want to perform OGTT, HbA1C measurement can be considered [21]. The PCOS has recently been identified by the American Diabetes Association as a specific risk factor for type 2 diabetes. However, only cross sectional observational, retrospective and short term prospective studies were available [6] until a recent long term prospective Italian study by Gambineri et al. [22]. This study demonstrated that the risk of type 2 diabetes is elevated in middle-age women with PCOS (incidence rate of 1.05 per 100 person-years, 2,6 times higher than that of the general population). This risk increases with BMI, high fasting glucose and low sex hormone-binding globulin (SHBG) circulating levels. This study reinforces the need for routine screening for diabetes in PCOS patients over time [22]. The first-line treatment of glucose intolerance is the lifestyle management, especially with physical activity [21]. Counselling by non-medical professional groups seems to be efficient and may be recommended [23]. Metformin treatment can be indicated in case of proved glucose intolerance and when the lifestyle management is ineffective [4,24]. 4. Cardiovascular diseases 4.1. Cardiovascular pathology
3. Insulin resistance, glucose intolerance and type 2 diabetes Insulin resistance (IR) is a prominent feature of PCOS. Pathophysiology of IR remains controversial and could be due to a defect in signal transduction of insulin [15–18]. Except for clinical features such as acanthosis nigricans and abdominal adiposity, IR diagnosis is not easy. IR Index, such as Homeostasis Model Assessment (HOMA) or quantitative insulin sensitivity check (QUICKI), have been developed but in clinical practice the ratio fasting glycaemia (mg/dL)/insulinaemia (U/mL) is the easiest criteria to evaluate IR [19]. Progressively, IR can lead to glucose intolerance, which occurs in 40% of women with PCOS after the age of 40 [20] and, in six years, half of these women become diabetic. Indeed, in the meta-analysis of Moran et al. [6], the risk of becoming
Numerous observational studies focused on cardiovascular disease in women with PCOS. Their conclusions are still contradictory. For example, in Rizzo et al. review [25], five studies concluded that PCOS women are at risk for cardiovascular diseases, which was not proved in three other studies. Definition of PCOS, cardiovascular endpoints and median age of patients were different in each study. Series were sometimes very small, some included patients too young to have time to develop cardiovascular disease and after menopause it is difficult to retrospectively diagnose PCOS. The meta-analysis of Groot et al. [26] based on five cohort studies, again with different definitions of PCOS, showed a higher risk of coronary heart disease or cerebrovascular disease in PCOS women compared to controls (effect size = 2, IC95 = 1.47–2.76). Recently, a large retrospective study by Mani et al. [27], conducted in more than 2000
M. Peigné, D. Dewailly / Annales d’Endocrinologie 75 (2014) 194–199
women with PCOS over 11 years, has reported an increased agespecific prevalence for both myocardial infraction and angina in women with PCOS. However, in this population with 80% of the subjects under 45 years old, the overall rates of myocardial infraction and angina did not differ from the reference population. Finally, a very large dataset in UK (21,000 women with PCOS) reported no evidence of an increase in cardiovascular disease, but once again the population was young and the diagnosis of PCOS was questionable [28]. In contrast with cardiovascular heart disease, cerebrovascular disease is unanimously proved to be more frequent in women with PCOS (OR = 2.8), even when patients are compared to BMI-matched controls (OR = 3.4) [29]. In conclusion, a higher cardiovascular morbidity or mortality of women with PCOS is not obviously demonstrated. Nevertheless, in post-menopausal women, a personal history of clinical hyperandrogenism or menstrual disorders expose to an increased cardiovascular disease risk [30,31]. Large scale prospective studies are needed to clearly prove an increased prevalence of cardiovascular events in PCOS women compared to age- and BMI-matched controls.
197
seem to have an increased risk of sleep disorders compared to healthy BMI-matched women [14]. The presence of obstructive sleep apnea must be screened by questionnaires and patient should be referred to a center of sleep disorders for further evaluation [14]. Jovanovic and al. [41] proved that the more the PCOS phenotype is complete the more the cardiovascular risk markers are present. The recommended cardio-vascular risk assessment by Amsterdam ESHRE consensus includes assessment of blood pressure, glucose and lipid profiles, waist circumference, physical activity, nutrition and smoking at any age [4] (Table 1). If the lipid profile and the OGTT are normal, they must be rechecked every two years [42]. In conclusion, classical cardiovascular risk markers are more prevalent in women with PCOS, even if they are not obese, and these risks are magnified by obesity. The long-term metabolic disease of women with PCOS affects the subclinical vascular pathology markers and, even if a higher cardiovascular morbidity or mortality is not definitively proved, caution is warranted. Indeed, a life-long metabolic dysfunction can exaggerate the risk for cardio-vascular disease, especially after menopause.
4.2. Subclinical vascular disease Even if a higher cardiovascular pathology in PCOS women is still controversial, the subclinical vascular disease is proved to be higher in PCOS women compared with age- and BMI-matched controls. Three markers are commonly used in clinical research to evaluate sub-clinical atherosclerosis: the carotid intima-media thickening, the arterial stiffness and the coronary artery calcification. They are all increased in women with PCOS compared to controls, independently from age and BMI [32–36]. 4.3. Classical cardiovascular risk factors As expected, since the subclinical cardiovascular disease is higher in PCOS women, the classical cardiovascular risks are more frequent. Indeed, arterial hypertension, dyslipidaemia and especially low HDL-cholesterol (High Density Lipoprotein-cholesterol), insulin resistance or type 2 diabetes and obesity, especially abdominal obesity, are more frequent in PCOS women [4,37,38]. Dyslipidaemia is very frequent among women with PCOS. Almost 70% of women with PCOS suffer from dyslipidaemia, most often represented by hypertriglyceridemia and low HDL-cholesterol and sometimes by high LDL-cholesterol (low density lipoprotein cholesterol) [14]. The abdominal obesity, detected by the waist circumference over 88 cm (and over 80 cm in Europe population), and the decrease of HDL-cholesterol under 0.5 g/L are the first risk factors to appear; they must be screened as soon as possible. The metabolic syndrome, as defined above, is not required for cardiovascular risk disease since even with one criteria the cardiovascular risk is increased [39]. In some studies, the risk of obstructive sleep apnea is five times higher in PCOS women compared to controls regardless the BMI [40]. But, normal weight women with PCOS do not
5. Gynaecological malignancies 5.1. Endometrial cancer A meta-analysis in 2009 [43], proved that the risk to develop an endometrial cancer was higher in women with PCOS (OR = 2.7, IC95 = 1.00–7.29), which was confirmed in a recent systematic review with a 3 fold higher risk in women with PCOS compared to controls [44]. Another previous study concluded that the risk of endometrial cancer was 5.3 times higher in PCOS women and 6.1 times increased in obese PCOS women [29]. Nevertheless, most endometrial cancers are well differentiated and have good prognosis. Chronic anovulation and therefore the prolonged exposure to unopposed oestrogen can lead to endometrial hyperplasia and to endometrial cancer. But other factors could interact in cancer process, such as progesterone dependant gene dysregulation, hyperandrogenism, hyperinsulinism and/or LH hypersecretion [45]. Moreover, when adjusted with BMI, endometrial cancer risk in women with PCOS is half-reduced, demonstrating that obesity is a very important confounding factor [45]. The recent Amsterdam ESHRE consensus recommends checking the endometrium by ultrasound or endometrial biopsy in women with a long amenorrhea period. To prevent endometrial hyperplasia, a minimum of four induced withdrawals bleeding per year is needed [4] (Table 1). 5.2. Breast cancer Data about breast cancer in PCOS women are limited. The meta-analysis of Chittenden et al. [43], based on three old studies with a few PCOS patients, showed no difference between women with and without PCOS for breast cancer risk.
198
M. Peigné, D. Dewailly / Annales d’Endocrinologie 75 (2014) 194–199
Nowadays, there is no particular recommendation for the follow-up of women with PCOS about breast cancer. 5.3. Ovarian cancer Limited data exists. Indeed, only one study tried to evaluate the association between PCOS and ovarian cancer. Even if it is usually said that the less is the ovulation number the less is the risk for ovarian cancer, this study showed that PCOS women have 2.5-fold more risk to develop ovarian cancer than non PCOS women [46]. However, the number of PCOS women in this study was very small. In the opposite, another study showed a lower mortality by ovarian cancer in PCOS patients than in non PCOS women [47]. Thus, these limited data do not allow concluding that women with PCOS are at increased risk for ovarian cancer. However, it must be reminded that women with PCOS have other recognized risk factors such as nulliparity, infertility and its treatment, anovulation and obesity. There is no current particular recommendation for screening ovarian cancer in PCOS women. 6. Conclusions PCOS is a life-long disease and has long term complications frequently forgotten and underestimated. Obesity and altered glucose metabolism are the most common complications described in women with PCOS. Metabolic dysfunction leads to pregnancy complications and to metabolic disease with increased classical cardiovascular risks and increased subclinical cardio-vascular disease without proven increase of cardiovascular morbidity and mortality with aging. More data are needed to definitively prove a higher cardiovascular morbidity or mortality. Indeed, longitudinal studies are very scarce and without standardisation of diagnostic criteria of PCOS. Endometrial cancer seems to be more frequent in women with PCOS. Therefore, PCOS has numerous long-term health risks and a lifelong follow-up is necessary. Indeed, for prevention of long-term complications of PCOS, information and education are crucial because all complications, metabolic disorders and endometrial cancer, can be prevented by an early care. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Boomsma CM, Eijkemans MJC, Hughes EG, Visser GHA, Fauser BCJM, Macklon NS. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update 2006;12:673–83. [2] Veltman-Verhulst SM, Haeften van TW, Eijkemans MJC, Valk de HW, Fauser BCJM, Goverde AJ. Sex hormone-binding globulin concentrations before conception as a predictor for gestational diabetes in women with polycystic ovary syndrome. Hum Reprod 2010;25:3123–8. [3] Bruyneel A, Catteau-Jonard S, Decanter C, Clouqueur E, Tomaszewski C, Subtil D, et al. [Polycystic ovary syndrome: what are the obstetrical risks?]. Gynecol Obstet Fertil 2014;42:104–11.
[4] Fauser BCJM, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 2012;97, 28–38.e25. [5] Carmina E, Bucchieri S, Esposito A, Puente AD, Mansueto P, Orio F, et al. Abdominal fat quantity and distribution in women with polycystic ovary syndrome and extent of its relation to insulin resistance. JCEM 2007;92:2500–5. [6] Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2010;16:347–63. [7] Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:1929–35. [8] Carmina E, Napoli N, Longo RA, Rini GB, Lobo RA. Metabolic syndrome in polycystic ovary syndrome (PCOS): lower prevalence in southern Italy than in the USA and the influence of criteria for the diagnosis of PCOS. Eur J Endocrinol 2006;154:141–5. [9] Hahn S, Tan S, Sack S, Kimmig R, Quadbeck B, Mann K, et al. Prevalence of the metabolic syndrome in German women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 2007;115:130–5. [10] Cussons AJ, Watts GF, Burke V, Shaw JE, Zimmet PZ, Stuckey BGA. Cardiometabolic risk in polycystic ovary syndrome: a comparison of different approaches to defining the metabolic syndrome. Hum Reprod 2008;23:2352–8. [11] Gambineri A, Repaci A, Patton L, Grassi I, Pocognoli P, Cognigni GE, et al. Prominent role of low HDL-cholesterol in explaining the high prevalence of the metabolic syndrome in polycystic ovary syndrome. Nutr Metab Cardiovasc Dis 2009;19:797–804. [12] Hosseinpanah F, Barzin M, Tehrani FR, Azizi F. The lack of association between polycystic ovary syndrome and metabolic syndrome: Iranian PCOS prevalence study. Clin Endocrinol (Oxf) 2011;75: 692–7. [13] Panidis D, Macut D, Tziomalos K, Papadakis E, Mikhailidis K, Kandaraki EA, et al. Prevalence of metabolic syndrome in women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2013;78:586–92. [14] Conway GS, Dewailly D, Diamanti-Kandarakis E, Escobar Morreale H, Franks S, Gambineri A, et al. The polycystic ovary syndrome: an endocrinological perspective from the European Society of Endocrinology. Eur J Endocrinol 2014 [Jul 21. pii: EJE-14-0252]. [15] Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995;96:801–10. [16] Zhang LH, Rodriguez H, Ohno S, Miller WL. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci USA 1995;92:10619–23. [17] Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 2012;33:981–1030. [18] Dunaif A, Wu X, Lee A, Diamanti-Kandarakis E. Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Am J Physiol Endocrinol Metab 2001;281:E392–9. [19] Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocr Rev 2003;24:302–12. [20] Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective controlled study in 254 affected women. JCEM 1999;84:165–9. [21] Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. Diagnosis and treatment of polycystic ovary syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2013;98:4565–92. [22] Gambineri A, Patton L, Altieri P, Pagotto U, Pizzi C, Manzoli L, et al. Polycystic ovary syndrome is a risk factor for type 2 diabetes results from a long-term prospective study. Diabetes 2012;61:2369–74.
M. Peigné, D. Dewailly / Annales d’Endocrinologie 75 (2014) 194–199 [23] Jebb SA, Ahern AL, Olson AD, Aston LM, Holzapfel C, Stoll J, et al. Primary care referral to a commercial provider for weight loss treatment versus standard care: a randomised controlled trial. Lancet 2011;378:1485–92. [24] Franks S. When should an insulin sensitizing agent be used in the treatment of polycystic ovary syndrome? Clin Endocrinol (Oxf) 2011;74:148–51. [25] Rizzo M, Berneis K, Spinas G, Rini GB, Carmina E. Long-term consequences of polycystic ovary syndrome on cardiovascular risk. Fertil Steril 2009;91:1563–7. [26] Groot de PCM, Dekkers OM, Romijn JA, Dieben SWM, Helmerhorst FM. PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Hum Reprod Update 2011;17:495–500. [27] Mani H, Levy MJ, Davies MJ, Morris DH, Gray LJ, Bankart J, et al. Diabetes and cardiovascular events in women with polycystic ovary syndrome: a 20-year retrospective cohort study. Clin Endocrinol (Oxf) 2013;78:926–34. [28] Morgan CL, Jenkins-Jones S, Currie CJ, Rees DA. Evaluation of adverse outcome in young women with polycystic ovary syndrome versus matched, reference controls: a retrospective, observational study. J Clin Endocrinol Metab 2012;97:3251–60. [29] Wild S, Pierpoint T, Jacobs H, McKeigue P. Long-term consequences of polycystic ovary syndrome: results of a 31 year follow-up study. Hum Fertil (Camb) 2000;3:101–5. [30] Shaw LJ, Bairey Merz CN, Azziz R, Stanczyk FZ, Sopko G, Braunstein GD, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health—National Heart, Lung, and Blood Institute sponsored women’s ischemia syndrome evaluation. J Clin Endocrinol Metab 2008;93:1276–84. [31] Krentz AJ, von Mühlen D, Barrett-Connor E. Searching for polycystic ovary syndrome in postmenopausal women: evidence for a dose-effects association with prevalent cardiovascular disease. Menopause 2007;14:284–92. [32] Talbott EO, Guzick DS, Sutton-Tyrrell K, McHugh-Pemu KP, Zborowski JV, Remsberg KE, et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged Women. Arterioscler Thromb Vasc Biol 2000;20:2414–21. [33] Talbott EO, Zborowski JV, Rager JR, Boudreaux MY, Edmundowicz DA, Guzick DS. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. JCEM 2004;89:5454–61.
199
[34] Soares GM, Vieira CS, Martins WP, Franceschini SA, Dos Reis RM, Silva de Sá MF, et al. Increased arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS) without comorbidities: one more characteristic inherent to the syndrome? Clin Endocrinol 2009;71:406–11. [35] Luque-Ramírez M, Mendieta-Azcona C, Álvarez-Blasco F, EscobarMorreale HF. Androgen excess is associated with the increased carotid intima-media thickness observed in young women with polycystic ovary syndrome. Hum Reprod 2007;22:3197–203. [36] Christian RC, Dumesic DA, Behrenbeck T, Oberg AL, Sheedy PF, Fitzpatrick LA. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. JCEM 2003;88:2562–8. [37] Tamimi W, Siddiqui IA, Tamim H, AlEisa N, Adham M. Effect of body mass index on clinical manifestations in patients with polycystic ovary syndrome. Int J Gynecol Obstet 2009;107:54–7. [38] Wild RA, Rizzo M, Clifton S, Carmina E. Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. Fertil Steril 2011;95, 1073–1079.e11. [39] Reaven GM. The metabolic syndrome: requiescat in pace. Clin Chem 2005;51:931–8. [40] Nitsche K, Ehrmann DA. Obstructive sleep apnea and metabolic dysfunction in polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab 2010;24:717–30. [41] Jovanovic VP, Carmina E, Lobo RA. Not all women diagnosed with PCOS share the same cardiovascular risk profiles. Fertil Steril 2010;94:826–32. [42] ESHRE Capri Workshop Group. Health and fertility in World Health Organization group 2 anovulatory women. Hum Reprod Update 2012;18:586–99. [43] Chittenden BG, Fullerton G, Maheshwari A, Bhattacharya S. Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Reprod Biomed Online 2009;19:398–405. [44] Haoula Z, Salman M, Atiomo W. Evaluating the association between endometrial cancer and polycystic ovary syndrome. Hum Reprod 2012;27:1327–31. [45] Dumesic DA, Lobo RA. Cancer risk and PCOS. Steroids 2013;78:782–5. [46] Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C. Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstet Gynecol 1996;88:554–9. [47] Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS. Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol 1998;51:581–6.
