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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
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
2
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
3
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
4
PCOS and when preventive actions against metabolic and cardiovascular diseases should be 72
implemented. 73
74
5
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
6
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
7
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
8
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
9
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
10
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
11
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
12
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
13
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
14
(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
15
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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
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)
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.
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)
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.
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)
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)