MECHANISMS IN ENDOCRINOLOGY: Metabolic syndrome through the female life cycle

in European Journal of Endocrinology
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  • 1 Department of Endocrinology and Diabetes, Department of Clinical Medicine and Surgery, Department of Sports Science and Wellness, Fertility Techniques SSD, Unit of Reproductive Endocrinology, Hellenic Red Cross Hospital, Athanasaki 1, 11526 Athens, Greece

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The normal function of the female reproductive system is closely linked to energy homeostasis with the ultimate scope of fertility and human race perpetuation through the centuries. During a woman's lifetime there are normal events such as puberty, pregnancy and menopause which are related to alterations in energy homeostasis and gonadal steroids levels followed by increase of body fat and insulin resistance, important components of metabolic syndrome (MetS). Pathological conditions such as premature adrenarche, polycystic ovary syndrome and gestational diabetes also present with shifts in gonadal steroid levels and reduced insulin sensitivity. The aim of this review is to discuss these conditions, both normal and pathological, analyzing the changes or abnormalities in ovarian function that coexist with metabolic abnormalities which resemble MetS in relationship with environmental, genetic and epigenetic factors.

Abstract

The normal function of the female reproductive system is closely linked to energy homeostasis with the ultimate scope of fertility and human race perpetuation through the centuries. During a woman's lifetime there are normal events such as puberty, pregnancy and menopause which are related to alterations in energy homeostasis and gonadal steroids levels followed by increase of body fat and insulin resistance, important components of metabolic syndrome (MetS). Pathological conditions such as premature adrenarche, polycystic ovary syndrome and gestational diabetes also present with shifts in gonadal steroid levels and reduced insulin sensitivity. The aim of this review is to discuss these conditions, both normal and pathological, analyzing the changes or abnormalities in ovarian function that coexist with metabolic abnormalities which resemble MetS in relationship with environmental, genetic and epigenetic factors.

Introduction

Metabolic syndrome (MetS) or insulin resistance syndrome or syndrome X was first described by G Reaven in 1988 (1). It refers to a clustering of cardiovascular disease risk factors whose underlying pathophysiology are thought to be related to insulin resistance and central obesity like glucose intolerance, dyslipidemia, hypertension, prothrombotic and proinflammatory factors (2). Since the first definition of MetS by the World Health Organisation (WHO) in 1998 at least four other definitions have been proposed with different diagnostic parameters and threshold values. The definition of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) in 2001 is more often used in epidemiological studies. Nowadays, many scientists doubt the existence of MetS and the usefulness of the term, nevertheless the importance of the cardiovascular disease risk factors that it comprises cannot be doubted (3).

Adipose tissue functions as an endocrine gland with multiple actions in other organ-tissue targets including the brain (4). The synthesis and secretion of a great variety of proteins like leptin and adiponectin, cytokines like tumor necrosis factor-alpha (TNF-α) and interlukin-6 (IL-6) and metabolic substrates like free fatty acids allow adipose tissue to play an important role in energy balance and glucose homeostasis (5). Furthermore, adipose tissue participates actively in the regulation of coagulation/fibrinolysis and, through enzymatic conversion of sex steroids and corticosteroids can modify the function of the cardiovascular, immune and reproductive systems (6). Adipose tissue dysfunction leads apart from visceral obesity to ectopic accumulation of lipids in other tissues such as the skeletal muscles, liver, pancreas and heart, and contributes to insulin resistance and metabolic disease (7).

During a woman's lifetime, there are physiological events such as puberty, pregnancy and menopause, which are closely related to alterations in energy homeostasis and gonadal steroids levels followed by an increase of insulin resistance and body fat, important components of MetS (8). In addition, pathological conditions may exist such as premature adrenarche, polycystic ovary syndrome (PCOS) and gestational diabetes, which also present with alterations in gonadal steroid levels and increased insulin resistance (9).

The aim of this article is to discuss both physiological and pathological events during a woman's lifetime analyzing the changes or abnormalities in ovarian function that co-exist with metabolic abnormalities that resemble MetS.

Ovarian function and energy homeostasis

The relationship between reproductive function with energy homeostasis and fat stores is now well-established. Adipose tissue seems to be the connecting link between these two systems through a complicated network of endocrine, autocrine, intracrine and paracrine interactions (4, 10). The discoveries of leptin 20 years ago and of adiponectin and resistin more recently have contributed in understanding the interactions of energy metabolism in hypothalamus–pituitary and peripheral organs, such as gonads, skeletal muscles and adipose tissue (11). The onset of menarche and reproductive function prerequisites the existence of a critical adipose mass, which, through leptin, sends a message to hypothalamus that the woman's energy stores are sufficient to support a pregnancy. The age of menarche has been found to be correlated to risk factors for metabolic disease and this association worsened when obesity was present (12). On the other hand, obesity leads to menstrual abnormalities, chronic anovulation, subfertility and in the case of pregnancy to higher frequency of abortions, gestational diabetes and pre-eclampsia (13).

Ovarian steroids influence both fat disposal and tissue sensitivity to insulin action. Estrogens promote peripheral fat distribution and improve insulin sensitivity, whereas testosterone promotes central fat distribution and reduces insulin sensitivity (14). The role of adrenal androgens, DHEA and DHEAS remains to be elucidated. Recent data converge to an anti-atherogenic action of those hormones through an improvement both in insulin resistance and lipids metabolism (15). Moreover, sex hormone-binding globulin (SHBG) alters the biologic effects of sex hormones (testosterone and estrogen) on peripheral tissues (i.e. liver, muscle, and fat). Higher levels of SHBG are associated with lower BMI, increased insulin sensitivity, lower likelihood of hypertension and more favourable lipid-profile and C-reactive protein (CRP) levels. Low SHBG levels are considered a biomarker of the MetS and may predict the development of type 2 diabetes and cardiovascular disease especially in women (16, 17, 18).

MetS and puberty

Puberty is a normal process through which an immature girl transforms to a mature and capable to reproduce woman. This transition period is characterized by rapid increase of length growth, appearance of secondary sex characteristics and alterations in psychology and behavior. Still, it is accompanied by alterations in body composition with increase in lean and especially fat mass. This is known as the ‘critical weight hypothesis’, which means that a minimum weight or body fat percentage is necessary for pubertal development and menstrual function. Furthermore, conditions of severe metabolic stress and energy unbalance are commonly linked to alterations in puberty onset (19, 20). Puberty can be described as an insulin-resistant condition. A 30% decrease in tissue insulin sensitivity is recorded during progression from Tanner stage 1 to Tanner stage 3, which is accompanied by high fasting glucose and insulin levels, and a decrease in glucose disposition index. This abnormality is fully restored by completion of puberty (19). The mechanism responsible for insulin resistance during puberty has not yet been clarified. In a cohort of 3530 Chinese children aged 6–18 years, leptin levels emerged as a stronger predictor of insulin resistance than traditional anthropometric characteristics (19). Recent data show that increased insulin resistance during puberty is related to parallel increase in growth hormone, insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3) and leptin levels and decrease in IGFBP-1 and SHBG levels whereas it seems to be independent of alterations in body fat and serum levels of androgens and estrogens (19, 20). In vitro studies have indicated that insulin has trophic actions on ovarian theca-stromal cells by elevating luteinizing hormone (LH)-induced androgen production. It is noted that high doses of insulin can stimulate theca cell androgen production even in the absence of LH (21). Additional studies showed a positive correlation between fasting insulin and free testosterone in groups of pubertal girls (22, 23). Another study provided evidence that levels of insulin can also predict the levels of free testosterone (24).

Premature adrenarche is defined as the appearance of pubic hair before the age of 8 in girls due to premature increase in adrenal androgen secretion (DHEA and DHEAS) of unknown etiology. It has been shown that girls with premature adrenarche have higher levels of insulin and insulin resistance compared to normal girls with similar BMI and androgen levels, just before the beginning of puberty. Specifically, a cross-sectional study, which evaluated the association of MetS and premature adrenarche in 63 prepubertal girls with premature adrenarche and 80 healthy age-matched control girls demonstrated that childhood MetS was more common in those with premature adrenarche than control children by both the WHO and modified ATP definition criteria. Additionally, girls with premature adrenarche had higher BMI and insulin and DHEAS levels (25). Moreover, a higher prevalence of functional ovarian hyperadrogenemia, dyslipidemia, and obesity has been observed in these girls after puberty (26). The previous abnormalities are more frequent in low-birth weight girls (< –1.5 s.d.), a finding consistent with the theory of ‘fetal programming’ of reproductive function (27). Body weight reduction or metformin administration, either prepubertally or postpubertally in girls with premature adrenarche, resulted in a significant improvement in insulin sensitivity, lipid profile, adipokine levels and a decrease of androgen levels as well (28). Thus, premature adrenarche could be the precursor of MetS in adult life, particularly in low-birth weight girls.

MetS and PCOS

PCOS is the most common endocrinopathy of women of reproductive age. Hyperandrogenism, insulin resistance, and chronic anovulation are the cardinal features of PCOS (29). The pathogenesis of PCOS is still unclear, though there is strong evidence that genetic factors are part of the syndrome's etiology, since high prevalence of the syndrome is recorded in members of the same family (30). Insulin resistance, high androgen levels (31) and dyslipidemia (32) have been found even in ‘normal’ members of patients’ families. Research in determining the syndrome's background is focused to the two most prominent poles of its pathogenesis: steroidogenetic alterations and insulin resistance (33). Metabolic abnormalities met in PCOS are obesity, dyslipidemia, insulin resistance, hyperinsulinemia and glucose intolerance.

Obesity is reported in 25–70% of women with PCOS. This broad disparity is due to the different criteria used for the diagnosis of the syndrome and differences in geographical and environmental factors in relevant studies (34). Patients with PCOS usually show central obesity independently of BMI (35) and this characteristic affects the various phenotypes of the syndrome (36). It has been shown that PCOS women with central obesity have more often defects in insulin secretion and action, glucose intolerance, abnormalities in lipid metabolism, higher diastolic pressure and higher androgen levels compared to women of the same age and BMI (37). Obesity contributes to insulin resistance, which is an intrinsic feature of the syndrome and an aggravating factor of dyslipidemia (38). As insulin resistance is tightly related to adiponectin levels, women with PCOS have lower serum adiponectin levels than women without PCOS (39). With advanced age, the distribution of PCOS phenotypes seems to change with decline of hyperandrogenemia and worsening of insulin resistance (40). Moreover, age along with obesity appear to be better predictors of MetS in these women than the presence of the syndrome per se (41).

Dyslipidemia is probably the most frequent metabolic disorder in PCOS detected in 70% of patients according to the guidelines of NCEP and is due to its inherent characteristics (42). The most frequent abnormalities are low HDL-cholesterol, high LDL-cholesterol, low triglyceride and VLDL-cholesterol levels (43). A higher frequency of hypertension can be expected in women with PCOS, due to obesity and insulin resistance. However, hypertension is not a typical finding of the syndrome, at least during reproductive age (44).

Insulin resistance has been shown very early in a significant number of patients, independently of body weight (45), but tightly dependent on total fat mass and central fat mass (46). It is considered an important component of the syndrome and is thought to play a crucial role in PCOS pathogenesis. The assessment of insulin resistance in the various phenotypes of PCOS has shown that it is more pronounced in women with the severe phenotype and less in others with the ovulatory phenotype without any differences from control women (47). Insulin resistance is due to a defect in the intracellular transmission of insulin sign in muscles and adipose tissue, which appears to be related to excessive serine phosphorylation of the insulin receptor, in 50% of the patients. Insulin resistance in PCOS patients seems to be selective, as it only concerns metabolic and not mitogenic actions of insulin (48). There is a 35–40% reduction of insulin-depended glucose uptake by the tissues similar to type 2 diabetes, which is independent of obesity, fat distribution and lean body mass (45). The noted insulin resistance leads to compensative hyperinsulinemia with negative effects in various tissues. Hyperinsulinemia contributes to hyperandrogenemia that characterizes PCOS by increasing androgen secretion, due to direct stimulation of theca cells and by increasing androgen bioavailability due to decrease of SHBG secretion by the liver (49). Moreover, hyperinsulinemia is associated with endothelium dysfunction and alterations in lipid metabolism (50). In addition to insulin resistance there is a defect in early-phase insulin secretion in some patients (51), which along with positive family history of type 2 diabetes constitute predisposing factors for glucose intolerance and type 2 diabetes (52).

Recent data show that MetS in PCOS women may be present from puberty (53) and increases significantly by the third decade of life (54, 55). The increased prevalence of MetS in PCOS women has been reported in many ethnicities and different races (56). In the largest cohort study of Caucasian women with PCOS, the prevalence of MetS varied depending on PCOS criteria and MetS definition, but it was constantly and independently high when these women fulfilled the NIH criteria (57). Obesity and hyperandrogenemia seem to be aggravating factors (53, 56) while healthy lifestyle and Mediterranean diet acts beneficially (58).

Glucose intolerance or type 2 diabetes is reported in 20–40% of obese PCOS women by the fourth decade of their life, compared to 10% in the general population (59). Moreover, 15% of PCOS postmenopausal women present with type 2 diabetes, compared to 2.3% of normal women (60). It is noteworthy that glucose intolerance can be manifested even during puberty (59). In a recent meta-analysis PCOS was associated with a 2.5-fold higher risk for impaired glucose tolerance (IGT), a 4.5-fold for DM2 and 2.2-fold for MetS compared to BMI-matched control women (61).

Women with PCOS are a unique biological model to examine the combined effects of androgen excess, insulin resistance and dyslipidemia on the cardiovascular system. Metabolic abnormalities in PCOS may appear early in adolescence. Consequently these young patients are in high risk for early development of cardiovascular disease (62). There is controversy between the results of the studies assessing the potential association between PCOS and cardiovascular comorbidities. Particularly, the study by Wild et al. (63) showed that women with PCOS did not differ from age-matched controls in coronary artery mortality and morbidity despite having significantly higher prevalence of both diabetes and family history of cardiovascular disease (63). On the other hand, PCOS patients have been estimated to have seven times greater risk of myocardial infarction (64). Similarly a fourfold risk in cardiac events among women with PCOS was reported in a cohort from the Czech Republic (65). Studies in a small numbers of patients showed high serum markers of early atherogenesis in women with PCOS like CRP, IL-18 and homocysteine (66) and endothelium dysfunction (67, 68, 69). The cardiometabolic risk has been reported to be worse in women with PCOS with hyperandrogenism compared to women without hyperandrogenism (70). Accordingly, higher androgen levels were reported in women with PCOS and MetS compared to women without PCOS and MetS (71). The assessment of preclinical or asymptomatic vascular disease with non-invasive procedures showed increased predisposition for atherosclerosis in young and middle-aged women with PCOS while a greater carotid intima-media thickness has been recorded (72, 73) compared to healthy women.

Two studies in younger (25–34 years old) (74) and older (35–62 years old) (75) women with PCOS demonstrated an elevated accumulation of coronary artery calcium measured by electron beam tomography independently of age and BMI. Data from small cross-sectional studies support an increased predisposition for atherosclerosis in premenopausal women with PCOS, but this has not been confirmed in retrospective studies (64, 76). Moreover, there are no clear answers if this premature atherosclerosis translates into increased cardiovascular morbidity or mortality after menopause (77, 78).

MetS and pregnancy

Pregnancy is a normal but stressful condition, characterized by various hormonal, biochemical and anatomical changes, as a gradual adjustment of the mother's body for a normal development of the fetus (79). These changes comprise increased insulin resistance, immunologic tolerance with a dominant Th2 response, thrombophilia and hyperdynamic circulation. Pregnancy is very important for the possible development of MetS both for the mother and the fetus. Regarding the mother, the adaptive changes can lead to the onset of gestational diabetes and/or pre-eclampsia, in a genetically predisposed person. Regarding the fetus, the nutritional, hormonal and metabolic environment afforded by the mother may program differentiating target tissues of the offspring towards the development of MetS and/or PCOS phenotype, which shares many components of MetS, in adult life.

Mother

The most important metabolic change that is noted in pregnancy is the gradual decrease in insulin sensitivity after the middle term of pregnancy that reaches the levels of type 2 diabetes (45–70%) in the third trimester. Insulin resistance increases in parallel to the growth of the embryo-placental unit and decreases immediately postpartum. These changes seem to be the result of mother's body weight increase and insulin-desensitization action due to increased circulating galactogen and progesterone levels, secreted by the placenta, prolactin and cortisol levels. As the pancreas responds to insulin resistance with a parallel increase of insulin production, there is a two- to threefold increase in fasting and postprandial insulin levels in normal pregnant women, which is attributed both to pancreas β-cells hyperplasia and increased sensitivity to secretive stimulations (79). BMI before pregnancy and antenatal fasting plasma glucose has been found to be the most predictive factors of MetS after delivery (80).

Gestational diabetes mellitus (GDM) appears as a result of the pancreas secretive failure to respond to the metabolic stress of pregnancy. In the majority of women, this occurs in the second half of pregnancy as mild glucose intolerance and is actually the evolution of MetS, which usually preexists (81). In a Greek cohort maternal MetS according to NHLBI/AHA criteria was found to predispose to gestational diabetes (relative risk=3.17) (82). The prevalence of GDM has been increased in developed countries during the last 20 years from 2.9% to 8.8% and even more in susceptible immigrant populations, partly as a result of the increased prevalence of obesity. Kim et al. 2002 estimated that 50–60% of the women which developed GDM are more prone to develop type 2 diabetes after 10 years (83). A prospective population-based study, which estimated the prevalence and the risk for diabetes and hypertension 20 years after delivery, the Northern Finland Birth Cohort, confirmed that women who were both overweight and developed GDM had significantly higher risk for diabetes and hypertension. Overweight women with normal oral glucose tolerance test prior to pregnancy showed increased risk for subsequent diabetes and hypertension (84). Two other prospective studies in Caucasian women showed that the prevalence of MetS in women with a history of GDM treated by diet alone was threefold higher compared to controls after 10 years of follow-up. In this group of women, the prevalence was even higher (5.6- to sevenfold) if they were overweight (85, 86).

Preeclampsia is a multi-systemic abnormality of unknown etiology affecting 3–5% of pregnancies. This disorder warrants high morbidity for the mother and serious implications for the embryo (perinatal death, premature labour, endometrial growth delay). It is characterized by inappropriate vascular response to placentogenesis, which is related to endothelium dysfunction and increased peripheral vascular resistance, coagulation system activation and platelet agglutination. It is clinically manifested by hypertension and proteinuria with or without other multi-systemic anomalies. The embryo usually presents with delay in endometrial growth, decrease in amniotic fluid and oxygen insufficiency (87). Moreover, several epidemiological studies revealed that preeclampsia is associated with an increased cardiovascular risk and a predisposition for chronic renal disease (88).

Obesity, insulin resistance and preexisting diabetes are risk factors for the development of preeclampsia (89, 90). Many epidemiological studies showed higher prevalence of insulin resistance in women with preeclampsia compared to controls, both prior and during pregnancy (91). Many researchers share the opinion that insulin sensitivity reduction, as expressed by the decrease in SHBG or adiponectin levels, predisposes to preeclampsia. Specifically, it was shown that women with decreased levels of SHBG during the first trimester of pregnancy presented an increased risk for preeclampsia (92). In accordance, decreased levels of serum high-molecular weight adiponectin were correlated with mild preeclampsia (93).

Fetus

Evidence suggests that the environment afforded by the mother may permanently program differentiating target tissues of the offspring toward the development of MetS and/or PCOS phenotype in adult life (94). In general, we could say that the association of birth weight and MetS seems to be U-shaped, with a higher prevalence of MetS occurring in subjects with both low and high birth weights.

At first, epidemiological observations provided a link between intrauterine undernutrition and increased risk for later obesity. Individuals who were in utero during the Dutch famine at the end of World War II had low birth weight and impaired glucose tolerance at the age of 50 years. This association was stronger regarding the last trimester of pregnancy (95, 96). After this very interesting study, other epidemiological studies followed showing that low birth weight is associated with increased BMI, higher prevalence of impaired glucose tolerance and/or high risk of coronary heart disease (97, 98).

A number of clinical studies have shown that association between low birth weight and MetS in adult life (99, 100, 101), with some supporting that higher prevalence of diabetes occurs in subjects with both low and high birth weights (99). The second association can be largely explained by the presence of maternal diabetes during pregnancy. High birth-weight children from mothers with GDM or MetS during pregnancy are at high risk for the development of obesity and MetS, during early childhood. A 15-year follow-up Chinese study confirmed that adolescent offspring of mothers with GDM, independently of birth weight, showed a 17-fold increase in MetS and a tenfold increase in overweight at adolescence (102). Obese mothers tend to have obese children (103) but clinical interventions targeting maternal weight loss can have a positive effect on reducing risk of obesity in offspring (104).

Of great interest, other studies have shown that the highest risk for development of MetS and diabetes occur in adults who are born small and become overweight in early childhood. This is also associated with early pubertal development in girls followed by functional hyperandrogenism in adolescence and the development of PCOS in adult life (105, 106). This phenomenon can be explained by the very early development of insulin resistance that affects body composition and leads to PCOS through an hyperinsulinemic pathway (105, 106). However, a direct link between birth weight and PCOS has not yet been documented (107).

Experimental animal studies investigating the link between early programming and adult metabolic disease have mainly concentrated on the effects of prenatal nutritional environment and especially on the effects of calorie or protein restriction and showed that the effects of intrauterine deprivation are either due to inadequate maternal diet or poor placental function. Both functions are thought to be mediated by glucocorticoids. Furthermore, it has been proposed that overexposure of the fetus to excess glucocorticoids may be implicated in the association between fetal growth restriction and the programming of adult metabolic disease (108, 109).

Intrauterine deprivation may program adipocyte metabolism and fat mass to give rise to later obesity or may affect the pancreatic islet neogenesis impairing the capacity of β-cell regeneration (108). Besides prenatal undernutrition models, metabolic intrauterine environment may also be modified in case of prenatal overnutrition and this has been shown by experimental models as well, which gave evidence that increased dietary fat intake during pregnancy and lactation predisposes the offspring to developing an MetS-like phenotype in adult life (110). A number of animal studies, most of them using the prenatally androgenized female rhesus monkey, have also shown that experimentally induced androgen excess during fetal life may lead not only to reproductive but also metabolic abnormalities in later life that resemble those found in women with PCOS (111).

The mechanisms of fetal programming are not well understood. At first, the altered tissue differentiation may be the result of the phenomenon of developmental plasticity which represents homeostatic adaptations due to alterations in fetal nutrition (17). For example, the fetus can decrease basal metabolic rate and nutrient delivery to tissues by reducing the capillary network (112). It can also reduce the size of the most metabolically active tissues such as nephrons or alter the balance between energy-consuming and energy-storing tissues (113). Furthermore, tissues under the influence of androgen excess which may act as potent gene transcription factors may be directed toward a more masculine phenotype in fact toward to MetS and/or PCOS adult phenotype (114). Of great interest, androgens are potent inhibitors of adipogenic differentiation of pre-adipocytes into adipocytes. Thus, when androgens are in excess the capacity of subcutaneous adipose tissue expansion in a metabolically safe way is diminished. This may lead to a more visceral fat distribution phenotype in adult life (115).

The role of epigenetics cannot be overlooked. The term refers to heritable changes, which affect gene function without modifying the DNA sequence. Epigenetic marks are tissue specific and include DNA methylation and histone modifications. Methylation is usually obtained through the addition of a methyl group (CH3—) to a cytosine positioned next to a guanine nucleotide. Methylation in a promoter region results in the repression (silencing) of gene expression. Potential epigenetic mechanisms have been suggested for MetS and refer mostly to: the FTO locus, which is a DNA-demethylase enzyme (116), the MC4R gene which has reduced methylation following long-term exposure to a high fat diet (117), the PPARγ protein, which interacts with histone acetyltransferases during adipogenesis and on the effect of diet on methylation of POMC (118) and Leptin (119). Interestingly, epigenetic changes can be inherited, explaining at least in part the familial clustering of MetS.

MetS and menopause

Menopause is a normal biological phenomenon due to the final exhaustion of ovarian pool of follicles and is defined clinically by the absence of menstrual bleeding for at least 12 months. It is accompanied by hormonal alterations and signals a high-risk period for the manifestation of metabolic abnormalities and cardiovascular disease.

During menopause, a significant fall in estrogen levels is observed (80%), though ovarian androgen production is reduced only by 30% due to the maintenance of a small steroidogenic ability, which comes from epithelial and mesenchymatic cells of the stroma and mainly concerns the production of androgens (120). This ‘relative’ adequacy of androgens seems to be independent of menopause and is related to the normal procedure of ageing. Adipose tissue contributes to partial restoration of this alteration of steroid hormones through aromatization of weak adrenal androgens (DHEA and DHEAS), into more active androgens or/and estrogens (121).

The incidence of cardiovascular disease, which is the leading single cause of death among women, increases substantially after menopause. The prevalence of cardiovascular disease differs significantly between men and premenopausal women of similar age possibly due to the action of estrogens as no difference has been observed between men and postmenopausal women at the age of seventy (122). Estrogens exert a cardio-protective role in several ways: direct actions on vascular wall (increased vascular dilation, inhibition of the response to vessels injury), improvement in lipid profile and insulin sensitivity and enhanced peripheral deposition of fat. The role of androgens in cardiovascular disease pathogenesis in women has not yet been clarified and results from epidemiologic studies are contrasting. Whether or not menopause has a causative contribution to the deteriorating metabolic profile that is independent of chronological aging is still being debated (121). Pro-atherogenic changes in lipid and apolipoprotein profiles seem to be specifically related to ovarian aging; unfavorable changes in other cardiovascular risk factors may be influenced more by chronologic aging (122). The onset of MetS after menopause is mostly due to estrogen deficiency that encourages an unfavourable change of body composition, mainly increase in central obesity (123).

Changes recorded after menopause that are stably related to MetS are: i) redistribution of body fat, ii) decrease in tissues’ insulin sensitivity and glucose intolerance that are directly related to the degree of central obesity, iii) alterations in lipid profile with a decrease in HDL2-cholesterol and increase in triglycerides, LDL-cholesterol and Lp(a), iv) increase in plasminogen activator inhibitor-1 (PAI-1) and activator of tissue plasminogen (t-PA) and v) increase in pro-inflammatory markers, like IL-6 and CRP 9 (120, 121, 122, 123, 124). Very recent studies showed an association between MetS and serum leptin levels in postmenopausal women (125) and a possible inverse association of higher serum 25(OH)D concentrations with adiposity, triglycerides, triglyceride:HDL ratio and MetS (126). Also, low levels of SHBG are independently related to the degree of central obesity, insulin resistance and pro-inflammatory states in older women and are considered a biomarker of the MetS in menopause (18, 19).

Conclusions

Women with premature adrenarche, PCOS, GDM in combination with obesity, low or high birth-weight and positive family history for type 2 diabetes and cardiovascular disease should be evaluated for metabolic abnormalities. Menopause, although a normal event in a woman's life, is associated with weight gain, increased central fat mass, abnormal lipid metabolism, insulin resistance and susceptibility to MetS (Fig. 1).

Figure 1
Figure 1

Normal and pathological events related to metabolic syndrome through the female life cycle. A full colour version of this figure is available at http://dx.doi.org/10.1530/EJE-15-0275.

Citation: European Journal of Endocrinology 173, 5; 10.1530/EJE-15-0275

The increasing prevalence of obesity, MetS and comorbidities necessitate prompt identification and early management of subjects at high risk. Recognition and treatment of MetS from childhood should be the main target for clinicians. Modification in lifestyle, such as balanced diet and frequent physical activity, are interventions of great importance in order to improve the metabolic abnormalities and achieve a decrease of subsequent cardiovascular risk. In the case of women, all these gain double importance, not only for themselves but also for their, continuing the perpetual cycle of life.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

A Vryonidou contributed in the conception, design, drafting and revision of the paper critically for important intellectual content. S A Paschou contributed in the conception, design and drafting the paper. G Muscogiuri, F Orio and D G Goulis contributed in revising the paper critically for important intellectual content.

References

  • 1

    Reaven GM. Role of insulin resistance in human disease. Diabetes 1998 37 15951607. (doi:10.2337/diab.37.12.1595).

  • 2

    Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Diabetologia 2005 48 16841699. (doi:10.1007/s00125-005-1876-2).

    • Search Google Scholar
    • Export Citation
  • 3

    Cameron AJ, Zimmet P, Shaw J, Alberti KG. The metabolic syndrome: in need of global mission statement. Diabetic Medicine 2009 26 306309. (doi:10.1111/j.1464-5491.2009.02681.x).

    • Search Google Scholar
    • Export Citation
  • 4

    Ahima RS. Central actions of adipocyte hormones. Trends in Endocrinology and Metabolism 2005 16 307313. (doi:10.1016/j.tem.2005.07.010).

  • 5

    Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Molecular and Cellular Endocrinology 2010 316 129139. (doi:10.1016/j.mce.2009.08.018).

    • Search Google Scholar
    • Export Citation
  • 6

    Ahima RS. Adipose tissue as an endocrine organ. Obesity 14 Suppl 5 2006 242S249S. (doi:10.1038/oby.2006.317).

  • 7

    Blüher M. Adipose tissue dysfunction contributes to obesityrelated metabolic diseases. Best Practice & Research. Clinical Endocrinology & Metabolism 2013 27 163177. (doi:10.1016/j.beem.2013.02.005).

    • Search Google Scholar
    • Export Citation
  • 8

    Catalano P. Obesity and pregnancy – the propagation of a viscous cycle? Journal of Clinical Endocrinology and Metabolism 2003 88 35053506. (doi:10.1210/jc.2003-031046).

    • Search Google Scholar
    • Export Citation
  • 9

    Gluckman P, Hanson M. The developmental origins of the metabolic syndrome. Trends in Endocrinology and Metabolism 2004 15 183187. (doi:10.1016/j.tem.2004.03.002).

    • Search Google Scholar
    • Export Citation
  • 10

    Mitchell M, Armstrong D, Robker R, Norman R. Adipokines: implications for female fertility and obesity. Reproduction 2005 130 583597. (doi:10.1530/rep.1.00521).

    • Search Google Scholar
    • Export Citation
  • 11

    Chou SH, Mantzoros C. Role of leptin in human reproduction. Journal of Endocrinology 2014 223 T49T62. (doi:10.1530/JOE-14-0245).

  • 12

    Tzeng CR, Chang YC, Chang YC, Wang CW, Chen CH, Hsu MI. Cluster analysis of cardiovascular and metabolic risk factors in women of reproductive age. Fertility and Sterility 2014 101 404410. (doi:10.1016/j.fertnstert.2014.01.023).

    • Search Google Scholar
    • Export Citation
  • 13

    Pasquali R, Patton L, Gambineri A. Obesity and infertility. Current Opinion in Endocrinology, Diabetes, and Obesity 2007 14 482487. (doi:10.1097/MED.0b013e3282f1d6cb).

    • Search Google Scholar
    • Export Citation
  • 14

    Bruns C, Kemnitz J. Sex hormones, insulin sensitivity and diabetes mellitus. ILAR Journal 2004 45 160169. (doi:10.1093/ilar.45.2.160).

  • 15

    Dhatariya K, Bigelow M, Nair S. Effect of dehydroepiandrosterone replacement on insulin sensitivity and lipids in hypoadrenal women. Diabetes 2005 54 765769. (doi:10.2337/diabetes.54.3.765).

    • Search Google Scholar
    • Export Citation
  • 16

    Haffner SM. Sex hormone-binding protein, hyperinsulinemia, insulin resistance and noninsulin diabetes mellitus. Hormone Research 1999 45 233237. (doi:10.1159/000184794).

    • Search Google Scholar
    • Export Citation
  • 17

    Xita N, Tsatsoulis A. Genetic variants of sex hormone-binding globulin and their biological consequences. Molecular and Cellular Endocrinology 2010 316 6065. (doi:10.1016/j.mce.2009.08.025).

    • Search Google Scholar
    • Export Citation
  • 18

    Maggio M, Ceda GP, Lauretani F, Bandinelli S, Corsi AM, Giallauria F, Guralnik JM, Zuliani G, Cattabiani C, Parrino S et al.. SHBG, sex hormones, and inflammatory markers in older women. Journal of Clinical Endocrinology and Metabolism 2011 96 10531059. (doi:10.1210/jc.2010-1902).

    • Search Google Scholar
    • Export Citation
  • 19

    Goran M, Gower B. Longitudinal study on pubertal insulin resistance. Diabetes 2001 50 24442450. (doi:10.2337/diabetes.50.11.2444).

  • 20

    Roa J, Garcia-Galiano D, Castellano JM, Gaytan F, Pinilla L, Tena-Sempere M. Metabolic control of puberty onset: new players, new mechanisms. Molecular and Cellular Endocrinology 2010 324 8794. (doi:10.1016/j.mce.2009.12.018).

    • Search Google Scholar
    • Export Citation
  • 21

    Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocrine Reviews 1999 20 535582. (doi:10.1210/edrv.20.4.0374).

    • Search Google Scholar
    • Export Citation
  • 22

    McCartney CR, Prendergast KA, Chhabra S, Eagleson CA, Yoo R, Chang RJ, Foster CM, Marshall JC. The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism. Journal of Clinical Endocrinology and Metabolism 2006 91 17141722. (doi:10.1210/jc.2005-1852).

    • Search Google Scholar
    • Export Citation
  • 23

    McCartney CR, Blank SK, Prendergast KA, Chhabra S, Eagleson CA, Helm KD, Yoo R, Chang RJ, Foster CM, Caprio S et al.. Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls. Journal of Clinical Endocrinology and Metabolism 2007 92 430436. (doi:10.1210/jc.2006-2002).

    • Search Google Scholar
    • Export Citation
  • 24

    Knudsen KL, Blank SK, Burt Solorzano C, Patrie JT, Chang RJ, Caprio S, Marshall JC, McCartney CR. Hyperandrogenemia in obese peripubertal girls: correlates and potential etiological determinants. Obesity 2010 18 21182124. (doi:10.1038/oby.2010.58).

    • Search Google Scholar
    • Export Citation
  • 25

    Utriainen P, Jääskeläinen J, Romppanen J, Voutilainen R. Childhood metabolic syndrome and its components in premature adrenarche. Journal of Clinical Endocrinology and Metabolism 2007 92 42824285. (doi:10.1210/jc.2006-2412).

    • Search Google Scholar
    • Export Citation
  • 26

    Ibanez L, Dimartino-Nardi J, Poteu N, Saenger P. Premature adrenarche – normal variant or forerunner of adult disease? Endocrine Reviews 2000 21 671696.

    • Search Google Scholar
    • Export Citation
  • 27

    Davies M, Norman R. Programming and reproductive functioning. Trends in Endocrinology and Metabolism 2002 13 386392. (doi:10.1016/S1043-2760(02)00691-4).

    • Search Google Scholar
    • Export Citation
  • 28

    Ibanez L, Valls C, Markos M-V, Ong K, Dunger D, De Zegher F. Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and postpubertal discontinuation of metformin treatment. Journal of Clinical Endocrinology and Metabolism 2004 89 43314337. (doi:10.1210/jc.2004-0463).

    • Search Google Scholar
    • Export Citation
  • 29

    Diamanti-Kandarakis E, Kouli C, Bergiele A, Filandra F, Tsianateli T, Spina G, Zapanti E, Bartzis M. A survey of the polycystic ovary syndrome in the Greek Island of Lesbos: hormonal and metabolic profile. Journal of Clinical Endocrinology and Metabolism 1999 84 40064011. (doi:10.1210/jcem.84.11.6148).

    • Search Google Scholar
    • Export Citation
  • 30

    Kosova G, Urbanek M. Genetics of the polycystic ovary syndrome. Molecular and Cellular Endocrinology 2013 373 2938. (doi:10.1016/j.mce.2012.10.009).

    • Search Google Scholar
    • Export Citation
  • 31

    Legro R, Bentley-Lewis R, Driscoll D, Wang S, Dunaif A. Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. Journal of Clinical Endocrinology and Metabolism 2002 87 21282133. (doi:10.1210/jcem.87.5.8513).

    • Search Google Scholar
    • Export Citation
  • 32

    Sam S, Legro R, Bentley-Lewis R, Dunaif A. Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2005 90 47974802. (doi:10.1210/jc.2004-2217).

    • Search Google Scholar
    • Export Citation
  • 33

    Ehrmann DA. Polycystic ovary syndrome. New England Journal of Medicine 2005 352 12231236. (doi:10.1056/NEJMra041536).

  • 34

    Franks S. Polycystic ovary syndrome. New England Journal of Medicine 1995 333 853861. (doi:10.1056/NEJM199509283331307).

  • 35

    Talbott E, Guzick D, Clerici A, Berga S, Detre K, Weimer K, Kuller L. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology 1995 15 821826. (doi:10.1161/01.ATV.15.7.821).

    • Search Google Scholar
    • Export Citation
  • 36

    Moran C, Arriaga M, Rodriguez G, Moran S. Obesity differentially affects phenotypes of polycystic ovary syndrome. International Journal of Endocrinology 2012 2012 317241. (doi:10.1155/2012/317241).

    • Search Google Scholar
    • Export Citation
  • 37

    Pasquali R, Casimirri F, Venturoli S, Antonio M, Morselli L, Reho S, Pezzoli A, Paradisi R. Body fat distribution has weight independent effects on clinical, hormonal, and metabolic features in women with PCOS. Metabolism 1994 43 706713. (doi:10.1016/0026-0495(94)90118-X).

    • Search Google Scholar
    • Export Citation
  • 38

    Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obesity Reviews 2013 14 95109. (doi:10.1111/j.1467-789X.2012.01053.x).

    • Search Google Scholar
    • Export Citation
  • 39

    Toulis KA, Goulis DG, Farmakiotis D, Georgopoulos N, Katsikis I, Tarlatzis BC, Papadimas I, Panidis D. Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Human Reproduction Update 2009 15 297307. (doi:10.1093/humupd/dmp006).

    • Search Google Scholar
    • Export Citation
  • 40

    Panidis D, Tziomalos K, Macut D, Delkos D, Betsas G, Misichronis G, Katsikis I. Cross-sectional analysis of the effects of age on the hormonal, metabolic, and ultrasonographic features and the prevalence of the different phenotypes of polycystic ovary syndrome. Fertility and Sterility 2012 97 494500. (doi:10.1016/j.fertnstert.2011.11.041).

    • Search Google Scholar
    • Export Citation
  • 41

    Panidis D, Tziomalos K, Macut D, Kandaraki EA, Tsourdi EA, Papadakis E, Katsikis I. Age- and body mass index-related differences in the prevalence of metabolic syndrome in women with polycystic ovary syndrome. Gynecological Endocrinology 2013 29 926930. (doi:10.3109/09513590.2013.819079).

    • Search Google Scholar
    • Export Citation
  • 42

    Legro R, Kunselman A, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. American Journal of Medicine 2001 111 607613. (doi:10.1016/S0002-9343(01)00948-2).

    • Search Google Scholar
    • Export Citation
  • 43

    Diamanti-Kandarakis E, Papavassiliou AG, Kandarakis SA, Chrousos GP. Pathophysiology and types of dyslipidemia in PCOS. Trends in Endocrinology and Metabolism 2007 18 280285. (doi:10.1016/j.tem.2007.07.004).

    • Search Google Scholar
    • Export Citation
  • 44

    Zimmerman S, Phillis RA, Dunaif A, Finegood D, Krakoff L. PCOS: lack of hypertension despite profound insulin resistance. Journal of Clinical Endocrinology and Metabolism 1992 75 508513.

    • Search Google Scholar
    • Export Citation
  • 45

    Dunaif A, Futterweit W, Segal KR, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in the polycystic ovary syndrome. Diabetes 1989 38 11651174. (doi:10.2337/diab.38.9.1165).

    • Search Google Scholar
    • Export Citation
  • 46

    Tosi F, Di Sarra D, Kaufman JM, Bonin C, Moretta R, Bonora E, Zanolin E, Moghetti P. Total body fat and central fat mass independently predict insulin resistance but not hyperandrogenemia in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2015 100 661669. (doi:10.1210/jc.2014-2786).

    • Search Google Scholar
    • Export Citation
  • 47

    Panidis D, Tziomalos K, Misichronis G, Papadakis E, Betsas G, Katsikis I, Macut D. Insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study. Human Reproduction 2012 27 541549. (doi:10.1093/humrep/der418).

    • Search Google Scholar
    • Export Citation
  • 48

    Dunaif A, Wu X, Lee A, Diamanti-Kandarakis E. Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). American Journal of Physiology. Endocrinology and Metabolism 2001 281 E392E399.

    • Search Google Scholar
    • Export Citation
  • 49

    Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocrine Reviews 2012 33 9811030. (doi:10.1210/er.2011-1034).

    • Search Google Scholar
    • Export Citation
  • 50

    Ovalle F, Azziz R. Insulin resistance, polycystic ovary syndrome and type 2 diabetes mellitus. Fertility and Sterility 2002 77 10951105. (doi:10.1016/S0015-0282(02)03111-4).

    • Search Google Scholar
    • Export Citation
  • 51

    Dunaif A, Finegood DT. β-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 1996 81 942947.

    • Search Google Scholar
    • Export Citation
  • 52

    Colilla S, Cox N, Ehrmann D. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives. Journal of Clinical Endocrinology and Metabolism 2001 86 20272031.

    • Search Google Scholar
    • Export Citation
  • 53

    Coviello A, Legro R, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. Journal of Clinical Endocrinology and Metabolism 2006 91 492497. (doi:10.1210/jc.2005-1666).

    • Search Google Scholar
    • Export Citation
  • 54

    Glueck C, Papanna R, Wang P, Goldenberg N, Sieve-Smith L. Prevalence of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome. Metabolism 2003 52 908915. (doi:10.1016/S0026-0495(03)00104-5).

    • Search Google Scholar
    • Export Citation
  • 55

    Apridonidze T, Essah P, Iuormo M, Nestler J. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2005 90 19291935. (doi:10.1210/jc.2004-1045).

    • Search Google Scholar
    • Export Citation
  • 56

    Ehrmann D, Liljenquist D, Kasza K, Azziz R, Legro R, Ghazzi M. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2006 91 4853. (doi:10.1210/jc.2005-1329).

    • Search Google Scholar
    • Export Citation
  • 57

    Panidis D, Macut D, Tziomalos K, Papadakis E, Mikhailidis K, Kandaraki EA, Tsourdi EA, Tantanasis T, Mavromatidis G, Katsikis I. Prevalence of metabolic syndrome in women with polycystic ovary syndrome. Clinical Endocrinology 2013 78 586592. (doi:10.1111/cen.12008).

    • Search Google Scholar
    • Export Citation
  • 58

    Carmina E, Napoli N, Longo R, Rini G, Lobo R. Metabolic syndrome in polycystic ovary syndrome (PCOS): lower prevalence in southern Italy than USA and the influence of criteria for the diagnosis of PCOS. European Journal of Endocrinology 2006 154 141145. (doi:10.1530/eje.1.02058).

    • Search Google Scholar
    • Export Citation
  • 59

    Legro R, Kunselman A, Dodoson W, 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. Journal of Clinical Endocrinology and Metabolism 1999 84 165169.

    • Search Google Scholar
    • Export Citation
  • 60

    Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999 22 141146. (doi:10.2337/diacare.22.1.141).

    • Search Google Scholar
    • Export Citation
  • 61

    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. Human Reproduction Update 2010 16 347363. (doi:10.1093/humupd/dmq001).

    • Search Google Scholar
    • Export Citation
  • 62

    Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocrine Reviews 2003 24 302312. (doi:10.1210/er.2003-0004).

    • Search Google Scholar
    • Export Citation
  • 63

    Wild S, Pierpoint T, McKeigue PM, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long term follow-up: a retrospective cohort study. Clinical Endocrinology 2000 52 595600. (doi:10.1046/j.1365-2265.2000.01000.x).

    • Search Google Scholar
    • Export Citation
  • 64

    Dahlgren E, Janson PO, Johansson S, Lapidus L, Odén A. Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstetricia et Gynecologica Scandinavica 1992 71 599604. (doi:10.3109/00016349209006227).

    • Search Google Scholar
    • Export Citation
  • 65

    Cibula D, Cífková R, Fanta M, Poledne R, Zivny J, Skibová J. Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome. Human Reproduction 2000 15 785789. (doi:10.1093/humrep/15.4.785).

    • Search Google Scholar
    • Export Citation
  • 66

    Guzick DS. Cardiovascular risk in PCOS. Journal of Clinical Endocrinology and Metabolism 2004 89 36943695. (doi:10.1210/jc.2004-1136).

  • 67

    Paradisi G, Steinberg HO, Hempfling A, Cronin J, Hook G, Shepard M, Baron A. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation 2001 103 14101415. (doi:10.1161/01.CIR.103.10.1410).

    • Search Google Scholar
    • Export Citation
  • 68

    Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I. Elevated endothelin-1 levels in women with the polycystic ovary syndrome and the beneficial effect of metformin therapy. Journal of Clinical Endocrinology and Metabolism 2001 86 46664673. (doi:10.1210/jcem.86.10.7904).

    • Search Google Scholar
    • Export Citation
  • 69

    Orio F, Palomba S, Cascella T, De Simone B, Di Biase S, Russo T, Labella D, Zullo F, Lombardi G, Colao A. Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2004 89 45884593. (doi:10.1210/jc.2003-031867).

    • Search Google Scholar
    • Export Citation
  • 70

    Daan NM, Louwers YV, Koster MP, Eijkemans MJ, de Rijke YB, Lentjes EW, Fauser BC, Laven JS. Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk? Fertility and Sterility 2014 102 14441451. (doi:10.1016/j.fertnstert.2014.08.001).

    • Search Google Scholar
    • Export Citation
  • 71

    Tziomalos K, Katsikis I, Papadakis E, Kandaraki EA, Macut D, Panidis D. Comparison of markers of insulin resistance and circulating androgens between women with polycystic ovary syndrome and women with metabolic syndrome. Human Reproduction 2013 28 785793. (doi:10.1093/humrep/des456).

    • Search Google Scholar
    • Export Citation
  • 72

    Talbott E, Guzick D, Sutton-Tyrrell K, McHugh-Pemu K, Zborowski J, Remsberg K, Kuller L. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arteriosclerosis, Thrombosis, and Vascular Biology 2000 20 24142421. (doi:10.1161/01.ATV.20.11.2414).

    • Search Google Scholar
    • Export Citation
  • 73

    Vryonidou A, Papatheodorou A, Tavridou A, Terzi T, Loi V, Vatalas I-A, Batakis N, Phenekos C, Dionyssiou-Asteriou A. Association of hyperandrogenemic and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2005 90 27402746. (doi:10.1210/jc.2004-2363).

    • Search Google Scholar
    • Export Citation
  • 74

    Christian R, Dumesic D, Behrenbeck T, Oberg A, Sheedy P, Fitzpatrick L. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2003 88 25622568. (doi:10.1210/jc.2003-030334).

    • Search Google Scholar
    • Export Citation
  • 75

    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. Journal of Clinical Endocrinology and Metabolism 2004 89 54545461. (doi:10.1210/jc.2003-032237).

    • Search Google Scholar
    • Export Citation
  • 76

    Pierpoint T, McKeigue P, Isaacs A, Wild S. Mortality of women with polycystic ovary syndrome at long-term follow-up. Journal of Clinical Epidemiology 1998 7 581586. (doi:10.1016/S0895-4356(98)00035-3).

    • Search Google Scholar
    • Export Citation
  • 77

    Talbott EO, Zborowski J, Rager J, Stragand JR. Is there an independent effect of polycystic ovary syndrome (PCOS) and menopause on the prevalence of subclinical atherosclerosis in middle aged women? Vascular Health Risk Management 2008 4 453462.

    • Search Google Scholar
    • Export Citation
  • 78

    Sathyapalan T, Atkin SL. Recent advances in cardiovascular aspects of polycystic ovary syndrome. European Journal of Endocrinology 2012 166 575583. (doi:10.1530/EJE-11-0755).

    • Search Google Scholar
    • Export Citation
  • 79

    Buchanan T, Xiang A. Gestational diabetes mellitus. Journal of Clinical Investigation 2005 115 485491. (doi:10.1172/JCI200524531).

  • 80

    Barquiel B, Herranz L, Hillman N, Burgos , Pallardo LF. Prepregnancy body mass index and prenatal fasting glucose are effective predictors of early postpartum metabolic syndrome in spanish mothers with gestational diabetes. Metabolic Syndrome and Related Disorders 2014 12 457463. (doi:10.1089/met.2013.0153).

    • Search Google Scholar
    • Export Citation
  • 81

    Buchanan T. Pancreatic β-cells defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 2001 86 989993. (doi:10.1210/jcem.86.3.7339).

    • Search Google Scholar
    • Export Citation
  • 82

    Chatzi L, Plana E, Pappas A, Alegkakis D, Karakosta P, Daraki V, Vassilaki M, Tsatsanis C, Kafatos A, Koutis A et al.. The metabolic syndrome in early pregnancy and risk of gestational diabetes mellitus. Diabetes & Metabolism 2009 35 490494. (doi:10.1016/j.diabet.2009.07.003).

    • Search Google Scholar
    • Export Citation
  • 83

    Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2009 25 18621868. (doi:10.2337/diacare.25.10.1862).

    • Search Google Scholar
    • Export Citation
  • 84

    Pirkola J, Pouta A, Bloigu A, Miettola S, Hartikainen AL, Järvelin MR, Vääräsmäki M. Prepregnancy overweight and gestational diabetes as determinants of subsequent diabetes and hypertension after 20-year follow-up. Journal of Clinical Endocrinology and Metabolism 2010 95 772778. (doi:10.1210/jc.2009-1075).

    • Search Google Scholar
    • Export Citation
  • 85

    Lauenborg J, Mathiesen E, Hansen T, GlŰmer C, Jørgensen T, Borch-Johnsen K, Hornnes P, Pedersen O, Damm P. The prevalence of metabolic syndrome in a Danish population of women with previous gestational diabetes mellitus is threefold higher than in the general population. Journal of Clinical Endocrinology and Metabolism 2005 90 40044010. (doi:10.1210/jc.2004-1713).

    • Search Google Scholar
    • Export Citation
  • 86

    Verma A, Boney C, Tucker R, Vohr B. Insulin resistance syndrome in women with prior history of gestational diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 2002 87 32273235. (doi:10.1210/jcem.87.7.8684).

    • Search Google Scholar
    • Export Citation
  • 87

    Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005 365 785799. (doi:10.1016/S0140-6736(05)71003-5).

  • 88

    Chen CW, Jaffe IZ, Karumanchi SA. Pre-eclampsia and cardiovascular disease. Cardiovascular Research 2014 101 579586. (doi:10.1093/cvr/cvu018).

  • 89

    Esplin M, Fausett M, Fraser A. Paternal and maternal components of the predisposition to preeclampsia. New England Journal of Medicine 2001 344 867872. (doi:10.1056/NEJM200103223441201).

    • Search Google Scholar
    • Export Citation
  • 90

    Duckitt K, Harrington D. Risk factors for pre-eclamsia at antenatal booking: systematic review of controlled studies. BMJ 2005 330 565571. (doi:10.1136/bmj.38380.674340.E0).

    • Search Google Scholar
    • Export Citation
  • 91

    Solomon C, Seely E. Hypertension in pregnancy: a manifestation of the insulin resistance syndrome? Hypertension 2001 37 232239. (doi:10.1161/01.HYP.37.2.232).

    • Search Google Scholar
    • Export Citation
  • 92

    Wolf M, Sandler L, Muñoz K, Hsu K, Ecker JL, Thadhani R. First trimester insulin resistance and subsequent preeclampsia: a prospective study. Journal of Clinical Endocrinology and Metabolism 2002 87 15631568. (doi:10.1210/jcem.87.4.8405).

    • Search Google Scholar
    • Export Citation
  • 93

    Mazaki-Tovi S, Romero R, Vaisbuch E, Erez O, Mittal P, Chaiworapongsa T, Kim SK, Pacora P, Yeo L, Gotsch F et al.. Maternal serum adiponectin multimers in gestational diabetes. Journal of Perinatal Medicine 2009 37 637650. (doi:10.1515/JPM.2009.101).

    • Search Google Scholar
    • Export Citation
  • 94

    Xita N, Tsatsoulis A. Fetal origins of the metabolic syndrome. Annals of the New York Academy of Sciences 2010 1205 148155. (doi:10.1111/j.1749-6632.2010.05658.x).

    • Search Google Scholar
    • Export Citation
  • 95

    Ravelli GP, Stein ZA, &Susser MW. Obesity in young men after famine exposure in utero and early infancy. New England Journal of Medicine 1976 295 349353. (doi:10.1056/NEJM197608122950701).

    • Search Google Scholar
    • Export Citation
  • 96

    Ravelli AC, Van Der Meulen JH, Osmond C, Barker DJ, Bleker OP. Obesity at the age of 50 y in men and women exposed to famine prenatally. American Journal of Clinical Nutrition 1999 70 811816.

    • Search Google Scholar
    • Export Citation
  • 97

    Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991 303 10191022. (doi:10.1136/bmj.303.6809.1019).

    • Search Google Scholar
    • Export Citation
  • 98

    Osmond C, Barker DJ, Winter PD, Fall CH, Simmonds SJ. Early growth and death from cardiovascular disease in women. BMJ 1993 307 15191524. (doi:10.1136/bmj.307.6918.1519).

    • Search Google Scholar
    • Export Citation
  • 99

    McCance DR, Pettitt DJ, Hanson RL, Jacobsson LT, Knowler WC, Bennett PH. Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ 1994 308 942945. (doi:10.1136/bmj.308.6934.942).

    • Search Google Scholar
    • Export Citation
  • 100

    Loos RJ, Beunen G, Fagard R, Derom C, Vlietinck R. Birth weight and body composition in young women: a prospective twin study. American Journal of Clinical Nutrition 2002 75 676682.

    • Search Google Scholar
    • Export Citation
  • 101

    Gale CR, Martyn CN, Kellingray S, Eastell R, Cooper C. Intrauterine programming of adult body composition. Journal of Clinical Endocrinology and Metabolism 2001 86 267272.

    • Search Google Scholar
    • Export Citation
  • 102

    Tam WH, Ma RC, Yang X, Li AM, Ko GT, Kong AP, Lao TT, Chan MH, Lam CW, Chan JC. Glucose intolerance and cardiometabolic risk in adolescents exposed to maternal gestational diabetes: a 15-year follow-up study. Diabetes Care 2010 33 13821384. (doi:10.2337/dc09-2343).

    • Search Google Scholar
    • Export Citation
  • 103

    Dabelea D, Mayer-Davis EJ, Lamichhane AP. Association of intrauterine exposure to maternal diabetes and obesity with type 2 diabetes in youth: the SEARCH case–control study. Diabetes Care 2008 31 14221426. (doi:10.2337/dc07-2417).

    • Search Google Scholar
    • Export Citation
  • 104

    Smith J, Cianflone K, Biron S. Effects of maternal surgical weight loss in mothers on intergenerational transmission of obesity. Journal of Clinical Endocrinology and Metabolism 2009 94 42754283. (doi:10.1210/jc.2009-0709).

    • Search Google Scholar
    • Export Citation
  • 105

    Ibáñez L, Potau N, Francois I, de Zegher F. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. Journal of Clinical Endocrinology and Metabolism 1998 83 35583562.

    • Search Google Scholar
    • Export Citation
  • 106

    Ong K. Catch-up growth in small for gestational age babies: good or bad? Current Opinion in Endocrinology, Diabetes, and Obesity 2007 14 3034. (doi:10.1097/MED.0b013e328013da6c).

    • Search Google Scholar
    • Export Citation
  • 107

    Paschou SA, Ioannidis D, Vassilatou E, Mizamtsidi M, Panagou M, Lilis D, Tzavara I, Vryonidou A. Birth weight and polycystic ovary syndrome in adult life: is there a causal link? PLoS ONE 2015 10 e0122050. (doi:10.1371/journal.pone.0122050).

    • Search Google Scholar
    • Export Citation
  • 108

    Stocker CJ, Arch JR, Cawthorne MA. Fetal origins of insulin resistance and obesity. Proceedings of the Nutrition Society 2005 64 143151. (doi:10.1079/PNS2005417).

    • Search Google Scholar
    • Export Citation
  • 109

    Lesage J, Del-Favero F, Leonhardt M, Louvart H, Maccari S, Vieau D, Darnaudery M. Prenatal stress induces intrauterine growth restriction and programmes glucose intolerance and feeding behaviour disturbances in the aged rat. Journal of Endocrinology 2004 181 291296. (doi:10.1677/joe.0.1810291).

    • Search Google Scholar
    • Export Citation
  • 110

    Buckley AJ, Keserü B, Briody J, Thompson M, Ozanne SE, Thompson CH. Altered body composition and metabolism in the male offspring of high fat-fed rats. Metabolism 2005 54 500507. (doi:10.1016/j.metabol.2004.11.003).

    • Search Google Scholar
    • Export Citation
  • 111

    Forsdike RA, Hardy K, Bull L, Stark J, Webber LJ, Stubbs S, Robinson JE, Franks S. Disordered follicle development in ovaries of prenatally androgenized ewes. Journal of Endocrinology 2007 192 421428. (doi:10.1677/joe.1.07097).

    • Search Google Scholar
    • Export Citation
  • 112

    Barker DJ, Eriksson JG, Forsén T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. International Journal of Epidemiology 2002 31 12351239. (doi:10.1093/ije/31.6.1235).

    • Search Google Scholar
    • Export Citation
  • 113

    Wintour EM, Moritz KM, Johnson K, Ricardo S, Samuel CS, Dodic M. Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoids treatment. Journal of Physiology 2003 549 929935. (doi:10.1113/jphysiol.2003.042408).

    • Search Google Scholar
    • Export Citation
  • 114

    Robinson J. Prenatal programming at the female reproductive neuroendocrine system by androgens. Reproduction 2006 132 539547. (doi:10.1530/rep.1.00064).

    • Search Google Scholar
    • Export Citation
  • 115

    de Zegher F, Lopez-Bermejo A, Ibanez L. Adipose tissue expandability and the early origins of PCOS. Trends in Endocrinology and Metabolism 2009 20 418423. (doi:10.1016/j.tem.2009.06.003).

    • Search Google Scholar
    • Export Citation
  • 116

    Gerken T, Girard CA, Tung YC. The obesity-associated FTO gene encodes a 2-oxoglutaratedependent nucleic acid demethylase. Science 2007 318 14691472. (doi:10.1126/science.1151710).

    • Search Google Scholar
    • Export Citation
  • 117

    Widiker S, Karst S, Wagener A, Brockmann GA. High-fat diet leads to a decreased methylation of the Mc4r gene in the obese BFMI and the lean B6 mouse lines. Journal of Applied Genetics 2010 51 193197. (doi:10.1007/BF03195727).

    • Search Google Scholar
    • Export Citation
  • 118

    Plagemann A, Harder T, Brunn M. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. Journal of Physiology 2009 587 49634976. (doi:10.1113/jphysiol.2009.176156).

    • Search Google Scholar
    • Export Citation
  • 119

    Milagro FI, Campion J, Garcia-Diaz DF, Goyenechea E, Paternain L, Martinez JA. High fat diet-induced obesity modifies the methylation pattern of leptin promoter in rats. Journal of Physiology and Biochemistry 2009 65 19. (doi:10.1007/BF03165964).

    • Search Google Scholar
    • Export Citation
  • 120

    Mesch VR, Siseles NO, Maidana PN, Boero LE, Sayegh F, Prada M, Royer M, Schreier L, Benencia HJ, Berg GA. Androgens in relationship to cardiovascular risk factors in the menopausal transition. Climacteric 2008 11 509517. (doi:10.1080/13697130802416640).

    • Search Google Scholar
    • Export Citation
  • 121

    Polotsky HN, Polotsky AJ. Metabolic implications of menopause. Seminars in Reproductive Medicine 2010 28 426434. (doi:10.1055/s-0030-1262902).

    • Search Google Scholar
    • Export Citation
  • 122

    Chae CU, Derby CA. The menopausal transition and cardiovascular risk. Obstetrics and Gynecology Clinics of North America 2011 38 477488. (doi:10.1016/j.ogc.2011.05.005).

    • Search Google Scholar
    • Export Citation
  • 123

    Lizcano F, Guzmán G. Estrogen deficiency and the origin of obesity during menopause. BioMed Research International 2014 2014 757461. (doi:10.1155/2014/757461).

    • Search Google Scholar
    • Export Citation
  • 124

    Janssen I, Powell LH, Crawford S, Lasley B, Sutton-Tyrrell K. Menopause and the metabolic syndrome: The Study of Women's Health Across the Nation. Archives of Internal Medicine 2008 168 15681575. (doi:10.1001/archinte.168.14.1568).

    • Search Google Scholar
    • Export Citation
  • 125

    Lee SW, Jo HH, Kim MR, You YO, Kim JH. Association between metabolic syndrome and serum leptin levels in postmenopausal women. Journal of Obstetrics and Gynaecology 2012 32 7377. (doi:10.3109/01443615.2011.618893).

    • Search Google Scholar
    • Export Citation
  • 126

    Chacko SA, Song Y, Manson JE, Van Horn L, Eaton C, Martin LW, McTiernan A, Curb JD, Wylie-Rosett J, Phillips LS et al.. Serum 25-hydroxyvitamin D concentrations in relation to cardiometabolic risk factors and metabolic syndrome in postmenopausal women. American Journal of Clinical Nutrition 2011 94 209217. (doi:10.3945/ajcn.110.010272).

    • Search Google Scholar
    • Export Citation

 

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  • 1

    Reaven GM. Role of insulin resistance in human disease. Diabetes 1998 37 15951607. (doi:10.2337/diab.37.12.1595).

  • 2

    Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Diabetologia 2005 48 16841699. (doi:10.1007/s00125-005-1876-2).

    • Search Google Scholar
    • Export Citation
  • 3

    Cameron AJ, Zimmet P, Shaw J, Alberti KG. The metabolic syndrome: in need of global mission statement. Diabetic Medicine 2009 26 306309. (doi:10.1111/j.1464-5491.2009.02681.x).

    • Search Google Scholar
    • Export Citation
  • 4

    Ahima RS. Central actions of adipocyte hormones. Trends in Endocrinology and Metabolism 2005 16 307313. (doi:10.1016/j.tem.2005.07.010).

  • 5

    Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Molecular and Cellular Endocrinology 2010 316 129139. (doi:10.1016/j.mce.2009.08.018).

    • Search Google Scholar
    • Export Citation
  • 6

    Ahima RS. Adipose tissue as an endocrine organ. Obesity 14 Suppl 5 2006 242S249S. (doi:10.1038/oby.2006.317).

  • 7

    Blüher M. Adipose tissue dysfunction contributes to obesityrelated metabolic diseases. Best Practice & Research. Clinical Endocrinology & Metabolism 2013 27 163177. (doi:10.1016/j.beem.2013.02.005).

    • Search Google Scholar
    • Export Citation
  • 8

    Catalano P. Obesity and pregnancy – the propagation of a viscous cycle? Journal of Clinical Endocrinology and Metabolism 2003 88 35053506. (doi:10.1210/jc.2003-031046).

    • Search Google Scholar
    • Export Citation
  • 9

    Gluckman P, Hanson M. The developmental origins of the metabolic syndrome. Trends in Endocrinology and Metabolism 2004 15 183187. (doi:10.1016/j.tem.2004.03.002).

    • Search Google Scholar
    • Export Citation
  • 10

    Mitchell M, Armstrong D, Robker R, Norman R. Adipokines: implications for female fertility and obesity. Reproduction 2005 130 583597. (doi:10.1530/rep.1.00521).

    • Search Google Scholar
    • Export Citation
  • 11

    Chou SH, Mantzoros C. Role of leptin in human reproduction. Journal of Endocrinology 2014 223 T49T62. (doi:10.1530/JOE-14-0245).

  • 12

    Tzeng CR, Chang YC, Chang YC, Wang CW, Chen CH, Hsu MI. Cluster analysis of cardiovascular and metabolic risk factors in women of reproductive age. Fertility and Sterility 2014 101 404410. (doi:10.1016/j.fertnstert.2014.01.023).

    • Search Google Scholar
    • Export Citation
  • 13

    Pasquali R, Patton L, Gambineri A. Obesity and infertility. Current Opinion in Endocrinology, Diabetes, and Obesity 2007 14 482487. (doi:10.1097/MED.0b013e3282f1d6cb).

    • Search Google Scholar
    • Export Citation
  • 14

    Bruns C, Kemnitz J. Sex hormones, insulin sensitivity and diabetes mellitus. ILAR Journal 2004 45 160169. (doi:10.1093/ilar.45.2.160).

  • 15

    Dhatariya K, Bigelow M, Nair S. Effect of dehydroepiandrosterone replacement on insulin sensitivity and lipids in hypoadrenal women. Diabetes 2005 54 765769. (doi:10.2337/diabetes.54.3.765).

    • Search Google Scholar
    • Export Citation
  • 16

    Haffner SM. Sex hormone-binding protein, hyperinsulinemia, insulin resistance and noninsulin diabetes mellitus. Hormone Research 1999 45 233237. (doi:10.1159/000184794).

    • Search Google Scholar
    • Export Citation
  • 17

    Xita N, Tsatsoulis A. Genetic variants of sex hormone-binding globulin and their biological consequences. Molecular and Cellular Endocrinology 2010 316 6065. (doi:10.1016/j.mce.2009.08.025).

    • Search Google Scholar
    • Export Citation
  • 18

    Maggio M, Ceda GP, Lauretani F, Bandinelli S, Corsi AM, Giallauria F, Guralnik JM, Zuliani G, Cattabiani C, Parrino S et al.. SHBG, sex hormones, and inflammatory markers in older women. Journal of Clinical Endocrinology and Metabolism 2011 96 10531059. (doi:10.1210/jc.2010-1902).

    • Search Google Scholar
    • Export Citation
  • 19

    Goran M, Gower B. Longitudinal study on pubertal insulin resistance. Diabetes 2001 50 24442450. (doi:10.2337/diabetes.50.11.2444).

  • 20

    Roa J, Garcia-Galiano D, Castellano JM, Gaytan F, Pinilla L, Tena-Sempere M. Metabolic control of puberty onset: new players, new mechanisms. Molecular and Cellular Endocrinology 2010 324 8794. (doi:10.1016/j.mce.2009.12.018).

    • Search Google Scholar
    • Export Citation
  • 21

    Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocrine Reviews 1999 20 535582. (doi:10.1210/edrv.20.4.0374).

    • Search Google Scholar
    • Export Citation
  • 22

    McCartney CR, Prendergast KA, Chhabra S, Eagleson CA, Yoo R, Chang RJ, Foster CM, Marshall JC. The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism. Journal of Clinical Endocrinology and Metabolism 2006 91 17141722. (doi:10.1210/jc.2005-1852).

    • Search Google Scholar
    • Export Citation
  • 23

    McCartney CR, Blank SK, Prendergast KA, Chhabra S, Eagleson CA, Helm KD, Yoo R, Chang RJ, Foster CM, Caprio S et al.. Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls. Journal of Clinical Endocrinology and Metabolism 2007 92 430436. (doi:10.1210/jc.2006-2002).

    • Search Google Scholar
    • Export Citation
  • 24

    Knudsen KL, Blank SK, Burt Solorzano C, Patrie JT, Chang RJ, Caprio S, Marshall JC, McCartney CR. Hyperandrogenemia in obese peripubertal girls: correlates and potential etiological determinants. Obesity 2010 18 21182124. (doi:10.1038/oby.2010.58).

    • Search Google Scholar
    • Export Citation
  • 25

    Utriainen P, Jääskeläinen J, Romppanen J, Voutilainen R. Childhood metabolic syndrome and its components in premature adrenarche. Journal of Clinical Endocrinology and Metabolism 2007 92 42824285. (doi:10.1210/jc.2006-2412).

    • Search Google Scholar
    • Export Citation
  • 26

    Ibanez L, Dimartino-Nardi J, Poteu N, Saenger P. Premature adrenarche – normal variant or forerunner of adult disease? Endocrine Reviews 2000 21 671696.

    • Search Google Scholar
    • Export Citation
  • 27

    Davies M, Norman R. Programming and reproductive functioning. Trends in Endocrinology and Metabolism 2002 13 386392. (doi:10.1016/S1043-2760(02)00691-4).

    • Search Google Scholar
    • Export Citation
  • 28

    Ibanez L, Valls C, Markos M-V, Ong K, Dunger D, De Zegher F. Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and postpubertal discontinuation of metformin treatment. Journal of Clinical Endocrinology and Metabolism 2004 89 43314337. (doi:10.1210/jc.2004-0463).

    • Search Google Scholar
    • Export Citation
  • 29

    Diamanti-Kandarakis E, Kouli C, Bergiele A, Filandra F, Tsianateli T, Spina G, Zapanti E, Bartzis M. A survey of the polycystic ovary syndrome in the Greek Island of Lesbos: hormonal and metabolic profile. Journal of Clinical Endocrinology and Metabolism 1999 84 40064011. (doi:10.1210/jcem.84.11.6148).

    • Search Google Scholar
    • Export Citation
  • 30

    Kosova G, Urbanek M. Genetics of the polycystic ovary syndrome. Molecular and Cellular Endocrinology 2013 373 2938. (doi:10.1016/j.mce.2012.10.009).

    • Search Google Scholar
    • Export Citation
  • 31

    Legro R, Bentley-Lewis R, Driscoll D, Wang S, Dunaif A. Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. Journal of Clinical Endocrinology and Metabolism 2002 87 21282133. (doi:10.1210/jcem.87.5.8513).

    • Search Google Scholar
    • Export Citation
  • 32

    Sam S, Legro R, Bentley-Lewis R, Dunaif A. Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2005 90 47974802. (doi:10.1210/jc.2004-2217).

    • Search Google Scholar
    • Export Citation
  • 33

    Ehrmann DA. Polycystic ovary syndrome. New England Journal of Medicine 2005 352 12231236. (doi:10.1056/NEJMra041536).

  • 34

    Franks S. Polycystic ovary syndrome. New England Journal of Medicine 1995 333 853861. (doi:10.1056/NEJM199509283331307).

  • 35

    Talbott E, Guzick D, Clerici A, Berga S, Detre K, Weimer K, Kuller L. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology 1995 15 821826. (doi:10.1161/01.ATV.15.7.821).

    • Search Google Scholar
    • Export Citation
  • 36

    Moran C, Arriaga M, Rodriguez G, Moran S. Obesity differentially affects phenotypes of polycystic ovary syndrome. International Journal of Endocrinology 2012 2012 317241. (doi:10.1155/2012/317241).

    • Search Google Scholar
    • Export Citation
  • 37

    Pasquali R, Casimirri F, Venturoli S, Antonio M, Morselli L, Reho S, Pezzoli A, Paradisi R. Body fat distribution has weight independent effects on clinical, hormonal, and metabolic features in women with PCOS. Metabolism 1994 43 706713. (doi:10.1016/0026-0495(94)90118-X).

    • Search Google Scholar
    • Export Citation
  • 38

    Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obesity Reviews 2013 14 95109. (doi:10.1111/j.1467-789X.2012.01053.x).

    • Search Google Scholar
    • Export Citation
  • 39

    Toulis KA, Goulis DG, Farmakiotis D, Georgopoulos N, Katsikis I, Tarlatzis BC, Papadimas I, Panidis D. Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Human Reproduction Update 2009 15 297307. (doi:10.1093/humupd/dmp006).

    • Search Google Scholar
    • Export Citation
  • 40

    Panidis D, Tziomalos K, Macut D, Delkos D, Betsas G, Misichronis G, Katsikis I. Cross-sectional analysis of the effects of age on the hormonal, metabolic, and ultrasonographic features and the prevalence of the different phenotypes of polycystic ovary syndrome. Fertility and Sterility 2012 97 494500. (doi:10.1016/j.fertnstert.2011.11.041).

    • Search Google Scholar
    • Export Citation
  • 41

    Panidis D, Tziomalos K, Macut D, Kandaraki EA, Tsourdi EA, Papadakis E, Katsikis I. Age- and body mass index-related differences in the prevalence of metabolic syndrome in women with polycystic ovary syndrome. Gynecological Endocrinology 2013 29 926930. (doi:10.3109/09513590.2013.819079).

    • Search Google Scholar
    • Export Citation
  • 42

    Legro R, Kunselman A, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. American Journal of Medicine 2001 111 607613. (doi:10.1016/S0002-9343(01)00948-2).

    • Search Google Scholar
    • Export Citation
  • 43

    Diamanti-Kandarakis E, Papavassiliou AG, Kandarakis SA, Chrousos GP. Pathophysiology and types of dyslipidemia in PCOS. Trends in Endocrinology and Metabolism 2007 18 280285. (doi:10.1016/j.tem.2007.07.004).

    • Search Google Scholar
    • Export Citation
  • 44

    Zimmerman S, Phillis RA, Dunaif A, Finegood D, Krakoff L. PCOS: lack of hypertension despite profound insulin resistance. Journal of Clinical Endocrinology and Metabolism 1992 75 508513.

    • Search Google Scholar
    • Export Citation
  • 45

    Dunaif A, Futterweit W, Segal KR, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in the polycystic ovary syndrome. Diabetes 1989 38 11651174. (doi:10.2337/diab.38.9.1165).

    • Search Google Scholar
    • Export Citation
  • 46

    Tosi F, Di Sarra D, Kaufman JM, Bonin C, Moretta R, Bonora E, Zanolin E, Moghetti P. Total body fat and central fat mass independently predict insulin resistance but not hyperandrogenemia in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2015 100 661669. (doi:10.1210/jc.2014-2786).

    • Search Google Scholar
    • Export Citation
  • 47

    Panidis D, Tziomalos K, Misichronis G, Papadakis E, Betsas G, Katsikis I, Macut D. Insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study. Human Reproduction 2012 27 541549. (doi:10.1093/humrep/der418).

    • Search Google Scholar
    • Export Citation
  • 48

    Dunaif A, Wu X, Lee A, Diamanti-Kandarakis E. Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). American Journal of Physiology. Endocrinology and Metabolism 2001 281 E392E399.

    • Search Google Scholar
    • Export Citation
  • 49

    Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocrine Reviews 2012 33 9811030. (doi:10.1210/er.2011-1034).

    • Search Google Scholar
    • Export Citation
  • 50

    Ovalle F, Azziz R. Insulin resistance, polycystic ovary syndrome and type 2 diabetes mellitus. Fertility and Sterility 2002 77 10951105. (doi:10.1016/S0015-0282(02)03111-4).

    • Search Google Scholar
    • Export Citation
  • 51

    Dunaif A, Finegood DT. β-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 1996 81 942947.

    • Search Google Scholar
    • Export Citation
  • 52

    Colilla S, Cox N, Ehrmann D. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives. Journal of Clinical Endocrinology and Metabolism 2001 86 20272031.

    • Search Google Scholar
    • Export Citation
  • 53

    Coviello A, Legro R, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. Journal of Clinical Endocrinology and Metabolism 2006 91 492497. (doi:10.1210/jc.2005-1666).

    • Search Google Scholar
    • Export Citation
  • 54

    Glueck C, Papanna R, Wang P, Goldenberg N, Sieve-Smith L. Prevalence of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome. Metabolism 2003 52 908915. (doi:10.1016/S0026-0495(03)00104-5).

    • Search Google Scholar
    • Export Citation
  • 55

    Apridonidze T, Essah P, Iuormo M, Nestler J. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2005 90 19291935. (doi:10.1210/jc.2004-1045).

    • Search Google Scholar
    • Export Citation
  • 56

    Ehrmann D, Liljenquist D, Kasza K, Azziz R, Legro R, Ghazzi M. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2006 91 4853. (doi:10.1210/jc.2005-1329).

    • Search Google Scholar
    • Export Citation
  • 57

    Panidis D, Macut D, Tziomalos K, Papadakis E, Mikhailidis K, Kandaraki EA, Tsourdi EA, Tantanasis T, Mavromatidis G, Katsikis I. Prevalence of metabolic syndrome in women with polycystic ovary syndrome. Clinical Endocrinology 2013 78 586592. (doi:10.1111/cen.12008).

    • Search Google Scholar
    • Export Citation
  • 58

    Carmina E, Napoli N, Longo R, Rini G, Lobo R. Metabolic syndrome in polycystic ovary syndrome (PCOS): lower prevalence in southern Italy than USA and the influence of criteria for the diagnosis of PCOS. European Journal of Endocrinology 2006 154 141145. (doi:10.1530/eje.1.02058).

    • Search Google Scholar
    • Export Citation
  • 59

    Legro R, Kunselman A, Dodoson W, 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. Journal of Clinical Endocrinology and Metabolism 1999 84 165169.

    • Search Google Scholar
    • Export Citation
  • 60

    Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999 22 141146. (doi:10.2337/diacare.22.1.141).

    • Search Google Scholar
    • Export Citation
  • 61

    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. Human Reproduction Update 2010 16 347363. (doi:10.1093/humupd/dmq001).

    • Search Google Scholar
    • Export Citation
  • 62

    Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocrine Reviews 2003 24 302312. (doi:10.1210/er.2003-0004).

    • Search Google Scholar
    • Export Citation
  • 63

    Wild S, Pierpoint T, McKeigue PM, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long term follow-up: a retrospective cohort study. Clinical Endocrinology 2000 52 595600. (doi:10.1046/j.1365-2265.2000.01000.x).

    • Search Google Scholar
    • Export Citation
  • 64

    Dahlgren E, Janson PO, Johansson S, Lapidus L, Odén A. Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstetricia et Gynecologica Scandinavica 1992 71 599604. (doi:10.3109/00016349209006227).

    • Search Google Scholar
    • Export Citation
  • 65

    Cibula D, Cífková R, Fanta M, Poledne R, Zivny J, Skibová J. Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome. Human Reproduction 2000 15 785789. (doi:10.1093/humrep/15.4.785).

    • Search Google Scholar
    • Export Citation
  • 66

    Guzick DS. Cardiovascular risk in PCOS. Journal of Clinical Endocrinology and Metabolism 2004 89 36943695. (doi:10.1210/jc.2004-1136).

  • 67

    Paradisi G, Steinberg HO, Hempfling A, Cronin J, Hook G, Shepard M, Baron A. Polycystic ovary syndrome is associated with endothelial dysfunction. Circulation 2001 103 14101415. (doi:10.1161/01.CIR.103.10.1410).

    • Search Google Scholar
    • Export Citation
  • 68

    Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I. Elevated endothelin-1 levels in women with the polycystic ovary syndrome and the beneficial effect of metformin therapy. Journal of Clinical Endocrinology and Metabolism 2001 86 46664673. (doi:10.1210/jcem.86.10.7904).

    • Search Google Scholar
    • Export Citation
  • 69

    Orio F, Palomba S, Cascella T, De Simone B, Di Biase S, Russo T, Labella D, Zullo F, Lombardi G, Colao A. Early impairment of endothelial structure and function in young normal-weight women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2004 89 45884593. (doi:10.1210/jc.2003-031867).

    • Search Google Scholar
    • Export Citation
  • 70

    Daan NM, Louwers YV, Koster MP, Eijkemans MJ, de Rijke YB, Lentjes EW, Fauser BC, Laven JS. Cardiovascular and metabolic profiles amongst different polycystic ovary syndrome phenotypes: who is really at risk? Fertility and Sterility 2014 102 14441451. (doi:10.1016/j.fertnstert.2014.08.001).

    • Search Google Scholar
    • Export Citation
  • 71

    Tziomalos K, Katsikis I, Papadakis E, Kandaraki EA, Macut D, Panidis D. Comparison of markers of insulin resistance and circulating androgens between women with polycystic ovary syndrome and women with metabolic syndrome. Human Reproduction 2013 28 785793. (doi:10.1093/humrep/des456).

    • Search Google Scholar
    • Export Citation
  • 72

    Talbott E, Guzick D, Sutton-Tyrrell K, McHugh-Pemu K, Zborowski J, Remsberg K, Kuller L. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arteriosclerosis, Thrombosis, and Vascular Biology 2000 20 24142421. (doi:10.1161/01.ATV.20.11.2414).

    • Search Google Scholar
    • Export Citation
  • 73

    Vryonidou A, Papatheodorou A, Tavridou A, Terzi T, Loi V, Vatalas I-A, Batakis N, Phenekos C, Dionyssiou-Asteriou A. Association of hyperandrogenemic and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2005 90 27402746. (doi:10.1210/jc.2004-2363).

    • Search Google Scholar
    • Export Citation
  • 74

    Christian R, Dumesic D, Behrenbeck T, Oberg A, Sheedy P, Fitzpatrick L. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2003 88 25622568. (doi:10.1210/jc.2003-030334).

    • Search Google Scholar
    • Export Citation
  • 75

    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. Journal of Clinical Endocrinology and Metabolism 2004 89 54545461. (doi:10.1210/jc.2003-032237).

    • Search Google Scholar
    • Export Citation
  • 76

    Pierpoint T, McKeigue P, Isaacs A, Wild S. Mortality of women with polycystic ovary syndrome at long-term follow-up. Journal of Clinical Epidemiology 1998 7 581586. (doi:10.1016/S0895-4356(98)00035-3).

    • Search Google Scholar
    • Export Citation
  • 77

    Talbott EO, Zborowski J, Rager J, Stragand JR. Is there an independent effect of polycystic ovary syndrome (PCOS) and menopause on the prevalence of subclinical atherosclerosis in middle aged women? Vascular Health Risk Management 2008 4 453462.

    • Search Google Scholar
    • Export Citation
  • 78

    Sathyapalan T, Atkin SL. Recent advances in cardiovascular aspects of polycystic ovary syndrome. European Journal of Endocrinology 2012 166 575583. (doi:10.1530/EJE-11-0755).

    • Search Google Scholar
    • Export Citation
  • 79

    Buchanan T, Xiang A. Gestational diabetes mellitus. Journal of Clinical Investigation 2005 115 485491. (doi:10.1172/JCI200524531).

  • 80

    Barquiel B, Herranz L, Hillman N, Burgos , Pallardo LF. Prepregnancy body mass index and prenatal fasting glucose are effective predictors of early postpartum metabolic syndrome in spanish mothers with gestational diabetes. Metabolic Syndrome and Related Disorders 2014 12 457463. (doi:10.1089/met.2013.0153).

    • Search Google Scholar
    • Export Citation
  • 81

    Buchanan T. Pancreatic β-cells defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 2001 86 989993. (doi:10.1210/jcem.86.3.7339).

    • Search Google Scholar
    • Export Citation
  • 82

    Chatzi L, Plana E, Pappas A, Alegkakis D, Karakosta P, Daraki V, Vassilaki M, Tsatsanis C, Kafatos A, Koutis A et al.. The metabolic syndrome in early pregnancy and risk of gestational diabetes mellitus