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1 Weight Gain and Dyslipidemia in Early Adulthood Associate with Polycystic Ovary Syndrome: 1 Prospective Cohort Study 2 3 Ollila M.-M. 1 , Piltonen T. 1 , Puukka K. 2 , Ruokonen A. 2 , Järvelin M.-R. 3,4,5,6 , Tapanainen J.S. 1,7 , Franks 4 S. 8 , and Morin-Papunen L. 1 5 6 1 Department of Obstetrics and Gynecology, University Hospital of Oulu, University of Oulu, 7 Medical Research Center Oulu and PEDEGO Research Unit (Research Unit for Pediatrics, 8 Dermatology, Clinical Genetics, Obstetrics and Gynecology) Oulu, Finland 9 2 NordLab Oulu, Department of Clinical Chemistry, University Hospital of Oulu, University of Oulu 10 and Medical Research Center Oulu, Oulu, Finland 11 3 Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School 12 of Public Health, Imperial College London, UK 13 4 Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland, 14 5 Biocenter Oulu, University of Oulu, Oulu, Finland 15 6 Unit of Primary Care, University Hospital of Oulu, Oulu, Finland, 16 7 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 17 Helsinki, Finland 18 8 Institute of Reproductive and Developmental Biology, Imperial College London, UK. 19 20 Abbreviated title: Weight gain through life and PCOS 21 Key terms: Polycystic ovary syndrome, body mass index (BMI), weight gain, hyperandrogenism, free 22 androgen index (FAI). 23 Word count: 3574 24 Number of figures and tables: 6 25 26 27

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Page 1: Weight Gain and Dyslipidemia in Early Adulthood Associate ... · 1 1 Weight Gain and Dyslipidemia in Early Adulthood Associate with Polycystic Ovary Syndrome: 2 Prospective Cohort

 

Weight Gain and Dyslipidemia in Early Adulthood Associate with Polycystic Ovary Syndrome: 1 

Prospective Cohort Study 2 

Ollila M.-M.1, Piltonen T.1, Puukka K.2, Ruokonen A.2, Järvelin M.-R.3,4,5,6, Tapanainen J.S.1,7, Franks 4 

S.8, and Morin-Papunen L.1 5 

1Department of Obstetrics and Gynecology, University Hospital of Oulu, University of Oulu, 7 

Medical Research Center Oulu and PEDEGO Research Unit (Research Unit for Pediatrics, 8 

Dermatology, Clinical Genetics, Obstetrics and Gynecology) Oulu, Finland 9 

2NordLab Oulu, Department of Clinical Chemistry, University Hospital of Oulu, University of Oulu 10 

and Medical Research Center Oulu, Oulu, Finland 11 

3Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School 12 

of Public Health, Imperial College London, UK 13 

4Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland, 14 

5Biocenter Oulu, University of Oulu, Oulu, Finland 15 

6Unit of Primary Care, University Hospital of Oulu, Oulu, Finland, 16 

7Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 17 

Helsinki, Finland 18 

8Institute of Reproductive and Developmental Biology, Imperial College London, UK. 19 

20 

Abbreviated title: Weight gain through life and PCOS 21 

Key terms: Polycystic ovary syndrome, body mass index (BMI), weight gain, hyperandrogenism, free 22 

androgen index (FAI). 23 

Word count: 3574 24 

Number of figures and tables: 6 25 

26 

27 

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28 

Corresponding author and person to whom reprint requests should be addressed: 29 

Laure Morin-Papunen, MD., Ph.D., Adjunct Professor 30 

Department of Obstetrics and Gynecology 31 

Oulu University Hospital 32 

PL 23 90029 OYS, Finland 33 

Phone: +35883154109 34 

Fax: +35883154130 35 

E-mail: [email protected] 36 

37 

Grants and funding: The Finnish Medical Society Duodecim, the North Ostrobothnia Regional 38 

Fund, the Academy of Finland (Project grants 104781, 120315, 129269, 1114194, 24300796), the 39 

Sigrid Juselius Foundation, Biocenter Oulu, Oulu University Hospital and University of Oulu 40 

(75617), Medical Research Center Oulu, National Institute for Health Research (UK), Medical 41 

Research Council (UK). 42 

43 

Disclosure statement: The authors have nothing to disclose. 44 

45 

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Abstract 46 

Context: Obesity affects the majority of women with polycystic ovary syndrome (PCOS), but 47 

previous studies are inconsistent about the prevalence of obesity and the importance of weight gain in 48 

the development of the syndrome. 49 

Objective: To explore the association between weight, weight gain, hyperandrogenism and PCOS 50 

from adolescence to late adulthood. 51 

Design: A prospective Northern Finland Birth Cohort 1966 study including 5889 females born in 52 

1966 and followed at the ages of 14, 31 and 46 years. 53 

Setting: General community. 54 

Participants: Women presenting both oligo/amenorrhea (OA) and hirsutism (H) at age 31 (N=125) or 55 

with formally diagnosed PCOS by age 46 (N=181) were compared with women without PCOS 56 

symptoms or diagnosis (n=1577). 57 

Interventions: None. 58 

Main Outcome Measures: Body-mass-index (BMI), weight change through life, waist 59 

circumference, Free Androgen Index (FAI), lipids, glucose, insulin, high-sensitivity C-reactive protein 60 

(hs-CRP), homeostatic model assessment for insulin resistance (HOMA-IR) and PCOS. 61 

Results: Women with OA+H at age 31 or diagnosis of PCOS by age 46 had the highest BMI at all 62 

ages compared with the controls. Increase of BMI between ages 14 and 31, but not between 31 and 63 

46, was greater in women with isolated OA (P=.006), OA+H (P=.001) and diagnosis of PCOS 64 

(P=.001) compared with controls. In the multivariate analysis, PCOS was significantly associated 65 

with BMI at all ages (BMI at age 31: OR=1.05 [95%CI: 1.00-1.10], FAI (OR=1.08 [95%CI: 1.03-66 

1.14]), serum levels of insulin (OR=1.05 [95%CI: 1.00-1.09]) and triglycerides (OR=1.48 [95%CI: 67 

1.08-2.03]). 68 

Conclusions: Symptoms or diagnosis of PCOS are associated with dyslipidemia, hyperandrogenemia 69 

and significantly increased weight gain especially in early adulthood. This observation is important as 70 

it may identify a sensitive time period when weight gain plays a crucial role in the emergence of 71 

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PCOS and when preventive actions against metabolic and cardiovascular diseases should be 72 

implemented. 73 

74 

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Introduction 75 

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premenopausal 76 

women, affecting 6-18% of reproductive aged women, depending on the source population and the 77 

diagnostic criteria (1,2). According to the Rotterdam criteria, PCOS is defined by the presence of at 78 

least two of the following three features: menstrual irregularities (oligo- or anovulation), 79 

hyperandrogenism (clinical and/or biochemical) or polycystic ovaries (PCO), after excluding other 80 

etiologies (3). PCOS is known to have multiple unfavorable effects on women’s health probably as a 81 

consequence of both hyperandrogenism (4) and insulin resistance (3,5,6). In some reported series, 82 

more than 50 percent of PCOS women are obese, and abdominal obesity and increased visceral fat 83 

distribution are common among these women (7). However, the prevalence of obesity in reported 84 

series is widely variable, probably reflecting the nature of presenting symptoms and therefore the 85 

specialist clinic to which women with PCOS may be referred. Adipose tissue, particularly visceral 86 

adipose, is an active metabolic and endocrine organ (8) and obesity significantly exacerbates all 87 

metabolic and reproductive disturbances of the syndrome (9). Excess adiposity is associated with 88 

insulin resistance and compensatory hyperinsulinemia, and leads to decreased sex-hormone binding 89 

globulin (SHBG) synthesis in the liver and excessive androgen production in the ovaries, which all 90 

contribute to an hyperandrogenic state (7). Visceral obesity increases the risk of impaired glucose 91 

tolerance and type 2 diabetes mellitus (T2DM), metabolic syndrome and cardiovascular morbidity, 92 

and that is particularly the case in women with PCOS (10-12). Previous studies have demonstrated 93 

that women with PCOS have a worse metabolic profile, including elevated triglyceride levels that are 94 

already apparent at a young age and are independent of obesity (12,13) 95 

Although it is well known that obesity exacerbates PCOS symptoms and increases the 96 

risks for T2DM and cardiovascular diseases (6), the results of previous studies have been inconsistent 97 

regarding the association between weight, weight gain and prevalence of PCOS during reproductive 98 

life. Some data suggest that the adverse outcomes are mainly related to obesity (14), whereas others 99 

claim that the syndrome per se is the most important factor (15,16). However, many studies have been 100 

underpowered and most of them are cross-sectional, using hospital-based populations and focusing 101 

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only on obese subjects and/or women seeking for infertility treatment, and thus possibly not 102 

representing the general population. If obesity is a trigger or contributing factor for the development 103 

of PCOS in patients pre-disposed to the condition, it would be expected that the dramatic worldwide 104 

increase of obesity not only in adulthood, but also in childhood and adolescence, (17,18) would result 105 

in an increasing prevalence of PCOS with its significant health and economic burdens. 106 

Our previous study from the Northern Finland Birth cohort 1966 (NFBC66) reported 107 

the association between body mass index (BMI) from birth to early adulthood and self-reported PCOS 108 

symptoms at age 31 (19). That study showed the importance of obesity in adolescence and in early 109 

adulthood, and crucial role of weight gain in early adulthood, in predicting PCOS symptoms at age 110 

31. The present study had two main aims. First, by using the same study population as in the above 111 

mentioned study, to extend the follow-up time of the weight change in women with self-reported 112 

symptoms in early adulthood (31 years) or diagnosis of PCOS until late adulthood (46 years) and to 113 

compare it with the changes in weight over the same time period in healthy women. The second aim 114 

was to identify the most significant clinical, metabolic and hormonal indices in early adulthood (at 115 

age 31) that are associated with the diagnosis of PCOS by age 46. 116 

Materials and Methods 117 

Study subjects 118 

This study is based on a unique, large, longitudinal, prospective, population-based NFBC66, 119 

comprising all expected births in 1966 in the two northernmost provinces of Finland. The study was 120 

approved by the Ethics Committee of the Northern Ostrobothnia Hospital District. All participants 121 

provided an informed consent. 122 

In 1966, 5889 females were born alive. Enrollment in this database begun at the 24th 123 

gestational week and, so far, data collection points have been established at ages 14, 31 and 46 124 

(Figure 1). At age 14, the adolescent females (n=5455, response rate 95%) answered a postal 125 

questionnaire, with the help of their parents, including questions about weight and height. No other 126 

clinical data were collected at that age. 127 

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At age 31, a postal questionnaire was sent to 5608 women and 4523 (81%) of them 128 

answered. The questionnaire included questions about weight and height and two questions on 129 

excessive body hair and oligoamenorrhea: 1) is your menstrual cycle longer than 35 days more than 130 

twice a year and 2) do you have excessive body hair? Pregnant women, women using hormonal 131 

contraception (n=1459) and women not permitting use of their data (n=41), were excluded from the 132 

analyses. Isolated oligoamenorrhea (isOA) was reported by 11.2% (n=330) of the women who 133 

returned the questionnaire, 10.9% (n=321) reported isolated hirsutism (isH) and 4.2% (n=125) 134 

reported both of these symptoms (OA+ H) (Figure 1). The validity of this questionnaire to distinguish 135 

PCOS cases has already been shown in our previous studies from the same cohort as the women with 136 

both OA+H present the typical metabolic and hormonal profile of PCOS (20,21). 137 

In addition to this questionnaire, 4074 women living in Northern Finland or in the 138 

Helsinki metropolitan area were invited to a clinical examination. In total, 3127 (76%) women 139 

participated in a clinical examination including anthropometric measurements and blood samples for 140 

hormonal and metabolic parameters. Body mass index (BMI) was calculated as the ratio of weight 141 

(kg) and height squared (m2). Waist circumference was measured at the level midway between the 142 

lowest rib margin and the iliac crest. 143 

At age 46, a questionnaire covering several health aspects and an invitation to clinical 144 

examination was sent. 5123 women received the questionnaire and 3706 (72%) of them answered. 145 

The questionnaire included a question “Have you ever been diagnosed as having polycystic ovaries 146 

(PCO) and/or polycystic ovary syndrome (PCOS) during your life?” and 181 “yes” (considered as 147 

women with diagnosis of PCOS). The control group included all other women without any PCOS 148 

symptoms at age 31 and without diagnosis of PCOS at age 46 (n=1577). 149 

Furthermore, 3280 women (64.0%) participated in the clinical examinations (anthropometric 150 

measurements and blood samples). 151 

The flowcharts of the study are presented in Figures 1 and 2. 152 

Laboratory methods 153 

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At age 31, plasma glucose, and serum concentrations of total cholesterol, high-density lipoprotein 154 

cholesterol (HDL-cholesterol), low-density lipoprotein cholesterol (LDL-cholesterol), triglycerides, 155 

fasting insulin, high sensitivity C-reactive protein (hsCRP) and sex hormone binding globulin 156 

(SHBG) were all assayed as previously described (20). Serum samples for testosterone (T) were 157 

assayed using Agilent triple quadrupole 6410 LC/MS equipment with an electrospray ionization 158 

source operating in positive-ion mode (Agilent Technologies, Wilmington, DE, USA). Multiple 159 

reaction monitoring was used to quantify testosterone by using d3-testosterone, with the following 160 

transitions: m/z 289.2 to 97 and 289.2 to 109 for T and 292.2 to 97 and 292.2 to 109 for d3-161 

testosterone. The intra-assay CVs of the method were 5.3%, 1.6% and 1.2% for Tat 0.6, 6.6 and 27.7 162 

nmol/l, respectively. The interassay CVs were 5.3%, 4.2% and 1.0% for the respective concentrations. 163 

The free androgen index (FAI) was calculated by using the equation 100×T (nmol/l)/SHBG (nmol/l). 164 

To quantify the degree of insulin sensitivity, homeostasis model assessment (HOMA-IR) values were 165 

calculated using the validated calculator available at http://www.dtu.ox.ac.uk. 166 

BMI values at ages 31 and 46 from clinical examination and postal questionnaire were 167 

combined to create a variable where clinically measured BMI was used if available and self-reported 168 

BMI was used in other cases. The data were also analyzed using only self-reported or only clinically 169 

measured BMI values, and the results were comparable. Women were categorized into BMI groups 170 

by WHO criteria for normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2) and obese (BMI 171 

> 30.0 kg/m2) (22). 172 

Statistical methods 173 

Differences in continuous anthropometric parameters were analyzed by non-parametric Mann-174 

Whitney U-test due to the skewed distribution of variables and the differences in categorical 175 

parameters (prevalence of overweight and obesity) by Pearson’s Chi-squared test. Binary logistic 176 

regression modelling was used to determine the parameters associated with diagnosis of PCOS. We 177 

included into the multivariate binary logistic regression modelling the parameters significantly 178 

associated (P<.15) with the diagnosis of PCOS (23). FAI was used in the models as it is generally 179 

considered as the best indicator for biochemical hyperandrogenism in PCOS women (3). HOMA-IR 180 

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was selected for the multivariate modelling in order to estimate insulin resistance, providing 181 

information from both glucose and insulin levels, and the serum levels of LDL and triglycerides were 182 

included to the models as they are the most typical lipid disorders observed in women with PCOS and 183 

linked to cardiovascular risks (6). The maximum number of variables was limited to 5 in each model. 184 

Results were reported as odds ratios (ORs) with 95% confidence intervals (95% CIs). 185 

Drop out analyses were performed to study any differences between women who only 186 

participated in the 31year study (both questionnaire and clinical examination) and the follow-up 187 

women participating in both the 31 and 46 year studies (at 31 years: both postal questionnaire and 188 

clinical examination; at 46 years: a postal questionnaire or a clinical examination or both). 189 

Statistical analyses were performed using IBM SPSS Statistics 22.0 (SPSS, Inc., 1989, 190 

2013, IBM Corp.). P-value < .05 was considered statistically significant. 191 

Results 192 

BMI and BMI change from adolescence (14 years) to late adulthood (46 years) in women with 193 

symptoms or diagnosis of PCOS 194 

Women with self-reported OA+H at age 31 as well as women with diagnosis of PCOS 195 

by age 46 had significantly greater BMI values and greater prevalence of obesity compared with the 196 

control women at all three time-points (14, 31 and 46 years) (Table 1 and Figures 3 and 4a). These 197 

women exhibited also significantly greater abdominal obesity, measured by waist circumference, both 198 

at age 31 and 46 compared with the control women (P < .001 for both comparisons) (Table 1). 199 

Women presenting with isOA or isH at age 31 had significantly greater BMI at ages 200 

14, 31 and 46 as well as greater abdominal obesity. These women also presented more often with 201 

overweight and obesity than the control women (Table 1, Figures 3 and 4a). 202 

The weight change between ages 14 and 31 was significantly greater in women with 203 

self-reported OA+H, isOA and in women with diagnosis of PCOS by age 46 compared with the 204 

change in the control women between ages 14 and 31, but this was not the case between ages 31 and 205 

46 (Table 1, Figure 4a). Of note, women presenting with both OA+H at age 31 and the women with 206 

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both symptoms at age 31 and diagnosis of PCOS at age 46 exhibited the greatest prevalence of obesity 207 

and the most important weight gain from adolescence to late adulthood (Figures 3, 4a and 4b). 208 

Women with both isOA at age 31 and diagnosis of PCOS by age 46 had significantly 209 

greater BMI at age 14 (P = .009), 31 (P < .001) and 46 (P = .002) when compared with the women 210 

with isOA at age 31 but without diagnosis of PCOS by age 46 (Figure 4b). Women with both isH at 211 

age 31 and diagnosis of PCOS by age 46 did not significantly differ as regards of BMIs or change of 212 

BMI when compared with women with isH at age 31 and without diagnosis of PCOS by age 46. 213 

The subgroup of women without any symptoms at age 31 but with diagnosis of PCOS 214 

by age 46 (n=33) had similar BMI as the control group at ages 14 (19.15±1.9 vs. 19.08±2.4 kg/m2) 215 

and 31 (24.22±4.0 vs. 23.61±4.2 kg/m2), but their BMI was significantly greater at age 46 (28.24±5.4 216 

vs. 26.34±5.3 kg/m2, P = .028). 217 

Risk factors for reporting diagnosis of PCOS by age 46 218 

Univariate and multivariate binary logistic regression analyses were used to reveal the association of 219 

different parameters at age 31 with diagnosis of PCOS by age 46 (Table 2). 220 

Univariate analysis 221 

As expected, both isOA (OR=9.32 [95%CI: 5.75-15.12]) and isH (OR= 7.80 [95%CI: 4.69-12.97]) 222 

were the most significant indices that were associated with diagnosis of PCOS by age 46. 223 

Furthermore, BMI at all three time points, as well as waist circumference at ages 31 and 46, were also 224 

significantly associated with the diagnosis of PCOS. Of these, BMI at age 31 was the strongest 225 

predictor (highest R2-value .028). Importantly, the change in BMI between 14 and 31 years (R2-value 226 

= .013), but not between 31 and 46 years, was a significant risk factor for PCOS. Additionally, at age 227 

31 serum concentrations of T, SHBG, FAI, fasting insulin, LDL, CRP, total cholesterol, triglycerides 228 

and HOMA-IR were significantly associated with diagnosis of PCOS by age 46 (Table 2). 229 

Multivariate analysis 230 

Multivariate models were used to identify the most significant variables associated with the diagnosis 231 

of PCOS by age 46. In the models I-III, the most significant index at age 31 associated with the 232 

diagnosis of PCOS by age 46 was FAI (Table 2, Model I- III). Serum levels of FAI, T, SHBG, insulin 233 

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and triglycerides at age 31 were significantly associated with diagnosis of PCOS independently of 234 

obesity (Table 2, Models IV-VIII). After the addition of isOA or isH to the models, all other indices 235 

lost their significance (Models I-III). BMI at age 31 remained a significant factor for PCOS together 236 

with isOA (Appendix 1, models V and VII) and SHBG remained significant together with isH 237 

(Appendix 2, model VII). 238 

Drop Out analysis 239 

Of the women who had participated in the 31year data collection, 536 did not participate in the 46 240 

year data collection and 2568 participated in both data collections. There were no significant 241 

differences between dropout (n=18) and follow-up (n=63) groups of women with self-reported OA+ 242 

H at age 31. 243 

Discussion 244 

The NFBC66 data set provides a unique opportunity to investigate the relationships between weight 245 

and change in weight from adolescence until late adulthood, PCOS symptoms, and diagnosis of 246 

PCOS. In the present analysis, weight, weight gain, serum levels of triglycerides as well as 247 

hyperandrogenemia in early adulthood emerged as significant risk factors associated with PCOS later 248 

in life. The women with isOA, both OA+H, and those with the diagnosis of PCOS, experienced 249 

significantly greater weight gain in early adulthood and through life, indicating the importance of an 250 

active screening for these symptoms as well as of the role of weight management already at 251 

adolescence. 252 

In the present study, women with OA+H as well as those with both OA+H at age 31 253 

and diagnosis of PCOS by age 46 exhibited the greatest weight gain and also the highest prevalence of 254 

obesity throughout life, suggesting that the presence of both symptoms already in early adulthood is 255 

associated with the most severe form of the syndrome. Previous studies addressing the relationship 256 

between BMI and PCOS have been inconclusive. A study from Greece reported that BMI was similar 257 

in PCOS and referent groups (15), which may be due to the fact that the prevalence of obesity in 258 

women with PCOS shows great variation between different cultures (9), probably as a result of 259 

different lifestyle and dietary habits. In this study, obesity was present in 34% of the women with the 260 

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diagnosis of PCOS, which is greater than in Italy (14%) (24), but lower than in USA (74%) (16). 261 

Selection bias, such as the use of hospital based populations (24) or smaller sample size (15) may also 262 

explain these discrepancies. 263 

The present data analysis was able to strengthen our previous findings (19) and to 264 

extend the observations by follow-up until late adulthood, showing that weight gain in early 265 

adulthood, but not later, is significantly associated with symptoms or diagnosis of PCOS. Our results 266 

are consistent with a recent longitudinal study (25), showing that obesity and greater weight gain 267 

between ages of 20 and 30 were associated with PCOS status at age 27-30. This observation is 268 

important as it may identify a sensitive time period for the development of PCOS. All these findings 269 

also emphasize the importance of weight management in early life to avoid the onset of PCOS or 270 

attenuate its severity. The slower weight gain in late adulthood in our population may be due to 271 

improvements of diet and exercise because of a better recognition and uptake of healthy lifestyle 272 

recommendations (26), but it also might reflect a predisposition of women with PCOS for an early 273 

development of overweight/obesity. The presence not only of both symptoms, but also of isOA or 274 

isH, were the most significant factors associated with PCOS diagnosis in the multivariate analyses and 275 

with weight as well as weight gain in early adulthood. This lends emphasis to the importance of 276 

screening for these symptoms early in life. 277 

In line with previous studies (7,19,27), we found that abdominal obesity was also 278 

strongly associated with the syndrome and increased in a similar manner to BMI from early to late 279 

adulthood. One of the few studies prospectively investigating the changes of abdominal obesity in 280 

PCOS women showed that women with PCOS experienced a progressive increase in waist-hip ratio 281 

even in the absence of weight gain between ages of 20-25 and 40-45 years (28). The development of 282 

abdominal obesity may be more strongly linked to PCOS as it has been shown to contribute to 283 

hyperinsulinemia and reduce insulin sensitivity (29). In keeping with this observation, in the present 284 

study, serum insulin levels at age 31 were significantly associated with diagnosis of PCOS by age 46, 285 

independently of BMI. Of note, a recent study has suggested that the differences in insulin resistance 286 

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between PCOS and healthy women may also arise from functional differences in visceral adipose 287 

tissue between the two groups (30). 288 

Hyperandrogenemia in early adulthood was an important risk factor for diagnosis of 289 

PCOS in later life. Although the evidence is still weak, the development of PCOS has been proposed 290 

to be a consequence of an exposure to androgen excess in the intrauterine environment possibly 291 

leading to an altered programming of the fetus’s ovarian androgen production and hypothalamic-292 

pituitary function. The phenotype is further modified by mainly dietary and secondary genetic factors 293 

explaining the heterogeneous nature of the syndrome (31). Moreover, it has been proposed that lean 294 

women with PCOS have the most severe defect in the ovarian steroidogenesis and thus they do not 295 

need any exogenous factors to provoke development of PCOS, whereas women with mild defect need 296 

the contribution of obesity, abdominal obesity or insulin resistance to develop the full-blown 297 

syndrome (4,32). The present results support this hypothesis as the most significant factors associated 298 

with diagnosis of PCOS were obesity and hyperandrogenemia in early life. In line with this, previous 299 

studies have suggested that PCOS manifested itself after a significant weight gain (7) and that obesity 300 

was strongly associated with hyperandrogenemia already in adolescence (33,34), with a higher risk of 301 

PCOS and infertility problems in later life (35). 302 

Dyslipidemia at age 31 (elevated serum levels of LDL and triglycerides) was 303 

significantly associated with the diagnosis of PCOS and the association with serum levels of 304 

triglycerides remained significant independently of BMI. Elevated triglycerides, a well-established 305 

risk factor for the development of atherosclerosis and cardiovascular morbidity in later age, especially 306 

in women (36), has been shown to be manifest in young women with PCOS independently of obesity 307 

(13). The present observation fits also well with recent epidemiologic data indicating that PCOS has 308 

profound medical implications for the health of women by increasing the prevalence of ischemic heart 309 

and cerebrovascular diseases (37,38). 310 

The main strength of the present study is that it is a prospective population based 311 

cohort study, with the longest follow-up compared with previously published longitudinal cohort 312 

studies which have investigated the association of weight and weight gain with PCOS diagnosis 313 

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(16,25,28). Moreover, the present study consists of a research population with high participation and 314 

response rates. Dropout rates were similarly low, and there was no difference between the 315 

symptomatic dropout and follow-up subjects in metabolic and hormonal indices. Furthermore, 316 

anthropometric parameters were not merely self-reported. Limitations include self-reported symptoms 317 

and diagnosis of PCOS. Hirsutism is subjective and may be over-reported. However, we have 318 

previously shown that self-reported isolated hirsutism does correlate with increased androgen 319 

secretion in this population (20,21). The questionnaire at age 46 did not distinguish between 320 

polycystic ovaries (PCO) on ultrasound and PCOS. However, it is expected that women with only 321 

PCO morphology would exhibit milder hormonal and metabolic disorders and thus the differences 322 

between the groups would be even greater after excluding women with PCO only. 323 

Conclusions 324 

The results of this prospective population-based cohort study indicate that BMI, and especially weight 325 

gain in early adulthood, plays a crucial role for the emergence of PCOS and that women with PCOS 326 

present with an unfavorable lipid profile already in early adulthood. We were also able to show that 327 

isOA or isH, screened by a simple questionnaire at the time of early adulthood, are good predictors for 328 

the diagnosis of PCOS in later adulthood and can be used to identify the women at risk. Given the 329 

worldwide progression of the obesity epidemic, (17,18) our results suggest that an increasing 330 

prevalence of symptomatic PCOS can be expected in the future and emphasize the role of weight 331 

management during adolescence and early adulthood. Possible prevention or postponement of 332 

symptoms of PCOS would have major beneficial effects on individual’s health and quality of life and 333 

decrease significantly the health and economic burden of the syndrome. 334 

Acknowledgements 335 

We thank T. Nordström for her help with the statistical analyses and the late Professor Paula 336 

Rantakallio (The founder of NFBCs).337 

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445 

446 

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Figure legends 447 

448 

Figure 1. Flow chart of the study 449 

450 

Figure 2. Description of women with diagnosis of PCOS by age 46 according to the 31-year status. 451 

452 

Figure 3. Prevalence of overweight and obesity in the women with PCOS and PCOS related 453 

symptoms. The difference in the prevalence of overweight and obesity between different groups were 454 

analyzed by Chii squared test.* P < .05, ** P < .01 and *** P < .001 compared with the prevalence in 455 

controls in the same age group. 456 

457 

Figure 4a and 4b. BMI at the different time points according to the presence of PCOS and PCOS 458 

related symptoms. BMI values are reported as mean ± SE at each time point and the differences 459 

between groups were analyzed using Mann-Whitney U-test. Figure 4a: * P < .05, ** P < .01 and *** 460 

P < .001 for the comparison with controls in the same age group. Figure 4b: Women with both isOA 461 

at age 31 and diagnosis of PCOS by age 46 had significantly greater BMI at age 14 (P = .009), 31 (P 462 

< .001) and 46 (P = .002) when compared with the women with isOA at age 31 but without diagnosis 463 

of PCOS by age 46. is: isolated OA: Oligoamenorrhea, H: Hirsutism. 464 

465 

466 

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Table 1. Anthropometric profile at different time-points according to the symptoms of PCOS at age 31 and the diagnosis of PCOS by age 46.

At age 31 At age 46

Referentsa Only OA Only H Both Symptoms PCOS

BMI 14 yr (kg/m2) 19.08±2.37 (N=1338)

19.55±2.65b

(N=260) 19.66±2.78c

(N=279) 20.34±3.22d

(N=102) 19.78±2.48c

(N=147)

BMI 31 yr (kg/m2) 23.61±4.18 (N=1564)

24.79±5.26d

(N=328) 24.28±4.63b

(N=320) 27.25±6.86d (N=121)

25.86±5.73d

(N=169)

BMI 46 yr (kg/m2) 26.34±5.29 (N=1569)

27.33±5.69c

(N=256) 27.31±5.98b

(N=250) 29.13±5.99d

(N=90) 28.49±6.51d

(N=180)

Waist 31 yr (cm) 78.29±11.35 (N=1118)

80.96±14.15b

(N=221) 79.12±11.75

(N=219) 88.03±17.75d

(N=81) 83.63±15.22d

(N=135)

Waist 46 yr (cm) 86.58±13.03 (N=1325)

88.93±13.74b

(N=210) 88.99±14.11b (N=219)

93.27±15.20d

(N=75) 91.16±14.98d (N=154)

Overweight 31 yr (N and %)

328 (21.0%) 85 (25.9 %)c 64 (20.0%) 34 (28.1%)c 39 (23.1%)

Obese 31 yr (N and %) 104 (6.7%) 41 (12.5 %)d 37 (11.6%)c

31 (25.6%)d 35 (20.7%)d

Overweight 46 yr (N and %) 500 (31.9%)

81 (31.9 %) 95 (38.0%)b 22 (24.4%) 61 (34.1%)b

Obese 46 yr (N and %) 332 (21.2%) 68 (26.8 %)b 57 (22.8%)

39 (43.3%)d 61 (34.1%)d

Weight gain between 14 and 31 years

14.60±9.21 (N=1343)

16.87±11.91c

(N=269) 14.65±9.48 (N=283)

19.09±12.92c (N=101)

18.04±11.92c (N=144)

Weight gain between 31 and 46 years 7.26±8.55 (N=1562)

7.24±9.58 (N=255)

7.68±8.54 (N=249)

5.15±11.40 (N=88)

7.29±9.98 (N=169)

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The numbers in separate analyses vary due to non-response to some items. OA: Oligoamenorrhea, H: Hirsutism.

a Women without any PCOS symptom (hirsutism or oligoamenorrhea) at age 31 and without diagnosis of PCOS by age 46.

The continuous data are reported as mean ± SD and the comparison of differences between groups were performed using Mann-Whitney U-test. Categorical

data were analyzed by Chi-squared test. b P<0.05, c P<0.01 and d P<0.001 compared with control women.

 

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Table 2. Univariate and multivariate binary logistic regression analysis for the parameters at age 31 associated with diagnosis of PCOS by age 46.

Variables Univariate OR (95 % CI)

Multivariate: Model I OR (95 % CI)

Multivariate: Model II OR (95 % CI)

Multivariate Model III OR (95 % CI)

Multivariate Model IV OR (95 % CI)

Multivariate Model V OR (95 % CI)

Multivariate Model VI OR (95 % CI)

Multivariate Model VII OR (95 % CI)

Multivariate Model VIII OR (95 % CI)

BMI 14yr 1.12 (1.05-1.19) 1.08 (0.99-1.17)

BMI 31yr 1.09 (1.06-1.13) 1.05 (1.00-1.10) 1.07 (1.03-1.11) 1.07 (1.03-1.11) 1.06 (1.01-1.10) 1.10 (1.07-1.14) 1.07 (1.03-1.11)

BMI 46yr 1.06 (1.04-1.09)

Waist 31yr 1.03 (1.02-1.05) 1.02 (0.99-1.04)

Waist 46yr 1.02 (1.01-1.04)

Change of BMI 14-31yr

1.09 (1.04-1.14)

Testosterone 31yr

1.55 (1.24–1.93) 1.44 (1.15-1.81)

SHBG 31yr 1.01 (1.00–1.01) 1.01 (1.00-1.01)

FAI 31yr 1.12 (1.07–1.17) 1.07 (1.00-1.13) 1.08 (1.02-1.14) 1.13 (1.06-1.19) 1.08 (1.03-1.14)

LDL 31yr 1.31 (1.06-1.61) 1.30 (0.98-1.73) 1.24 (0.95-1.61) 1.21 (0.92-1.60)

HDL 31yr 0.63 (0.38-1.03)

hsCRP 31yr 1.05 (1.01-1.10)

Total Choles-terol 31yr

1.30 (1.08-1.57)

Triglycerides 31yr

1.89 (1.43-2.52) 1.28 (0.82-2.00) 1.18 (0.77-1.82) 0.81 (0.48-1.36) 1.48(1.08-2.03)

Insulin 31yr

1.09 (1.05-1.13) 1.05 (1.00-1.09)

Glucose 31yr 0.99 (0.68-1.43)

HOMA-IR 31yr

1.89 (1.39-2.56) 1.07 (0.61-1.89) 0.92 (0.53-1.60) 0.99 (0.55-1.77)

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Parameters with a P-value <.15 (23) in the univariate binary logistic regression model and which were not significantly correlated were used in the

multivariate binary logistic regression models. All the parameters included in the models were assessed at age 31, unless stated elsewise.

Model I: BMI 14yr, FAI, LDL, triglycerides and HOMA-IR

Model II: BMI, FAI, LDL, triglycerides and HOMA-IR

Model III: Waist, FAI, LDL, triglycerides and HOMA-IR

Model IV: BMI and triglycerides

Model V: BMI and insulin

Model VI: BMI and FAI

Model VII: BMI and SHBG

Model VIII: BMI and T

BMI=Body-Mass-Index, T=Testosterone, FAI=Free Androgen Index, LDL=Low density lipoprotein, HOMA-IR= Homeostasis model assessment-insulin

resistance, SHBG=Sex hormone binding globulin, HDL=High density lipoprotein and hsCRP=High sensitive C-reactive protein.

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Supplemental table 1. Univariate and multivariate binary logistic regression analysis for the parameters at age 31 associated with diagnosis of PCOS by age 46

Variables Univariate OR (95 % CI)

Multivariate: Model I OR (95 % CI)

Multivariate: Model II OR (95 % CI)

Multivariate Model III OR (95 % CI)

Multivariate Model IV OR (95 % CI)

Multivariate Model V OR (95 % CI)

Multivariate Model VI OR (95 % CI)

Multivariate Model VII OR (95 % CI)

Multivariate Model VIII OR (95 % CI)

isOA 31yr 9.32 (5.75-15.12)

12.13(5.82-25.28)

14.12(7.45-26.76)

15.49(8.04-29.83)

10.94(6.38-18.78)

11.51(6.67-19.86)

13.34(7.18-24.79)

11.64(6.76-20.06)

13.61(7.34-25.23)

BMI 14yr 1.12 (1.05-1.19) 1.02 (0.89-1.17)

BMI 31yr 1.09 (1.06-1.13) 1.05 (0.98-1.14) 1.05 (0.99-1.11) 1.07 (1.00-1.13) 1.04 (0.98-1.10) 1.06 (1.01-1.12) 1.05 (0.99-1.11)

BMI 46yr 1.06 (1.04-1.09)

Waist 31yr 1.03 (1.02-1.05) 1.02 (0.99-1.06)

Waist 46yr 1.02 (1.01-1.04)

Change of BMI 14-31yr

1.09 (1.04-1.14)

Testosterone 31yr

1.55 (1.24–1.93) 1.04 (0.73-1.47)

SHBG 31yr 1.01 (1.00–1.01) 1.00 (0.99-1.01)

FAI 31yr 1.12 (1.07–1.17) 1.04 (0.94-1.14) 1.03 (0.94-1.13) 1.04 (0.95-1.14) 1.03 (0.95-1.12)

LDL 31yr 1.31 (1.06-1.61) 1.50 (0.99-2.26) 1.30 (0.90-1.87) 1.34 (0.93-1.95)

HDL 31yr 0.63 (0.38-1.03)

hsCRP 31yr 1.05 (1.01-1.10)

Total Choles-terol 31yr

1.30 (1.08-1.57)

Triglycerides 31yr

1.89 (1.43-2.52) 1.15 (0.55-2.43) 1.21 (0.60-2.41) 0.99 (0.46-2.12) 1.30(0.78-2.17)

Insulin 31yr

1.09 (1.05-1.13) 0.99 (0.92-1.09)

Glucose 31yr 0.99 (0.68-1.43)

HOMA-IR 31yr

1.89 (1.39-2.56) 0.94 (0.41-2.14) 0.67 (0.28-1.62) 0.62 (0.25-1.52)

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Supplemental table 2. Univariate and multivariate binary logistic regression analysis for the parameters at age 31 associated with diagnosis of PCOS by age 46

Variables Univariate OR (95 % CI)

Multivariate: Model I OR (95 % CI)

Multivariate: Model II OR (95 % CI)

Multivariate Model III OR (95 % CI)

Multivariate Model IV OR (95 % CI)

Multivariate Model V OR (95 % CI)

Multivariate Model VI OR (95 % CI)

Multivariate Model VII OR (95 % CI)

Multivariate Model VIII OR (95 % CI)

isH 31yr 7.80 (4.69-12.97)

12.88(6.22-26.69)

13.09(6.74-25.41)

12.75(6.44-25.22)

10.09(5.79-17.58

10.47(5.98-18.33)

11.94(6.28-22.70)

10.53(5.98-18.57)

11.61(6.14-21.94)

BMI 14yr 1.12 (1.05-1.19) 1.02 (0.88-1.17)

BMI 31yr 1.09 (1.06-1.13) 1.00 (0.91-1.09) 1.02 (0.95-1.09) 1.02 (0.96-1.09) 1.02 (0.94-1.10) 1.05 (0.99-1.11) 1.01 (0.94-1.09)

BMI 46yr 1.06 (1.04-1.09)

Waist 31yr 1.03 (1.02-1.05) 1.01 (0.97-1.05)

Waist 46yr 1.02 (1.01-1.04)

Change of BMI 14-31yr

1.09 (1.04-1.14)

Testosterone 31yr

1.55 (1.24–1.93) 1.08 (0.73-1.60)

SHBG 31yr 1.01 (1.00–1.01) 1.01 (1.00-1.01)

FAI 31yr 1.12 (1.07–1.17) 0.99 (0.90-1.09) 0.98 (0.89-1.08) 0.99 (0.90-1.09) 0.99 (0.90-1.09)

LDL 31yr 1.31 (1.06-1.61) 1.21 (0.79-1.86) 1.29 (0.86-1.92) 1.22 (0.81-1.85)

HDL 31yr 0.63 (0.38-1.03)

hsCRP 31yr 1.05 (1.01-1.10)

Total Choles-terol 31yr

1.30 (1.08-1.57)

Triglycerides 31yr

1.89 (1.43-2.52) 1.31 (0.57-3.02) 1.44 (0.68-3.07) 1.21 (0.52-2.81) 1.49 (0.88-2.52)

Insulin 31yr

1.09 (1.05-1.13) 1.04 (0.97-1.12)

Glucose 31yr 0.99 (0.68-1.43)

HOMA-IR 31yr

1.89 (1.39-2.56) 1.19 (0.48-2.95) 1.18 (0.47-2.98) 1.15 (0.45-2.99)

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