1 Department of Clinical Chemistry and 2 Department of Obstetrics and Gynecology, University of Oulu and Oulu University Hospital, 90014 Oulu, 3 Department of Public Health Science and General Practice, University of Oulu, 90014 Oulu, 4 Family Federation of Finland, 90220, Oulu, Finland, 5 Department of Epidemiology and Public Health, Imperial College London, London W2 1PG, UK, 6 Oulu Regional Institute of Occupational Health, 90220 Oulu, Finland, 7 Institute of Reproductive and Developmental Biology, Imperial College London, London W12 0NN and 8 Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LJ, UK and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
9 To whom correspondence should be addressed at: Department of Clinical Chemistry, University of Oulu, PL 5000, 90014 University of Oulu, Finland. e-mail: saara.taponen{at}mail.suomi.net
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Abstract |
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Key words: cohort/hirsutism/oligomenorrhoea/polycystic ovaries/ultrasound
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Introduction |
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The diagnostic criteria for PCOS have long been an issue of debate. However, a much-needed consensus was recently reached at a congress of the ESHRE and American Society for Reproductive Medicine (ASRM) in Rotterdam on May 13, 2003, on the diagnostic criteria and long-term health risks related to PCOS. The newly revised criteria for the diagnosis of PCOS are: (two out of three) (i) oligo- and/or anovulation, (ii) clinical and/or biochemical signs of hyperandrogenism and (iii) PCO. Other aetiologies such as congenital adrenal hyperplasia, androgen-secreting tumours and Cushings syndrome have to be excluded (Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group, 2004).
We studied data from a birth cohort of almost 6000 women in Northern Finland (Rantakallio, 1988) to investigate the relationships between self-reported hirsutism and oligomenorrhoea, ovarian morphology and biochemical findings. A previous study of these data indicated that self-reported symptoms can be used to distinguish women with biochemical features typical of PCOS (Taponen et al., 2003
). In this study, we aimed to confirm the validity of self-reported symptoms in screening for PCOS in the general population. We hypothesized that women with self-reported symptoms suggesting PCOS have a higher rate of PCO than controls and that symptomatic women with PCO have less favourable levels of biochemical markers than symptomatic women with normal ovaries or controls.
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Materials and methods |
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Blood samples and laboratory methods
Blood samples were drawn in the morning (08:0011:00) after an overnight fast. The samples could not be timed to the womans menstrual cycle for practical reasons. Blood glucose samples were stored at 4°C and analysed the same day. Serum insulin samples were stored at 20°C and were analysed within 7 days of sampling. Testosterone, sex hormone-binding globulin (SHBG), insulin-like growth factor-binding protein-1 (IGFBP-1) and LH samples were stored at 80°C until analysed. Free androgen index (FAI) was calculated according to the equation testosteronex100/SHBG.
Concentrations of SHBG and LH were analysed by fluoroimmunoassay (Wallac Ltd, Finland), testosterone by automated chemiluminescence system (Ciba-Corning ACS-180; USA), insulin by radioimmunoassay (Pharmacia Diagnostics, Sweden), IGFBP-1 by immunoenzymometric assay (Medix Biochemica, Finland) and blood glucose by a glucose dehydrogenase method (Granutest 250; Diagnostica Merck, Germany). The intra- and inter-assay coefficients of variation were 1.3 and 5.1% for SHBG, 4.9 and 6.5% for LH, 4.0 and 5.6% for testosterone, 5.3 and 7.6% for insulin, 3.4 and 7.4 for IGFBP-1 and 1.5 and 2.3% for blood glucose.
Transvaginal ultrasound
Transvaginal ultrasonography of the ovaries was carried out to measure ovarian volumes and the number of follicles (Toshiba SSA-270A; Toshiba Co., Tokyo) using a 6 MHz curvilinear transvaginal probe, PVF-651VT, with a scanning angle of 120°. Ultrasound examinations were performed by two investigators (S.A. and R.K.) on period day 35, or if amenorrhoea was present, at any time. Polycystic ovaries were defined as 10 follicles 28 mm in diameter in one plane of either ovary in association with increased and/or hyperechogenic ovarian stroma, evaluated visually (Adams et al., 1986
). Volume determinations were carried out using the formula for the volume of an ellipsoid: 0.523xlengthxwidthxthickness.
Statistical analysis
Results are expressed as percentages for categorical variables and means and 95% confidence intervals or medians and interquartile ranges (where distribution persisted skewed after log-transformation) for continuous variables. Overall significance of differences between the three groups (cases with PCO, cases with normal ovaries, controls) by one-way ANOVA or KruskalWallis test was analysed first. Because of our hypothesis and the many significant differences found, this was followed by paired tests between cases with PCO and controls, cases with normal ovaries and controls, and cases with PCO and cases with normal ovaries. Students two-tailed t-test was used to test the statistical significance of differences between groups of normally distributed variables. Log-transformation was used where needed to normalize the distribution. The MannWhitney U-test was used for variables with distributions that were skewed even after log-transformations. Statistical analysis of frequency differences between groups was evaluated by using Pearsons 2-test for independence. P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 11.5 for Windows (Statistical Package for Social Science, Inc., USA). Positive and negative predictive values of symptoms of oligomenorrhoea and hirsutism were calculated. In this study, positive predictive value is the probability that an individual actually has PCO given that she has symptoms of PCOS (oligomenorrhoea and hirsutism). Negative predictive value is the probability that an individual truly has normal ovaries given that she has no symptoms of PCOS.
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Results |
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Discussion |
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To our knowledge, this is the first general population-based study on self-reported symptoms of PCOS and associated ultrasound findings and biochemical changes. The greatest strength of this study is the large and stable general female cohort followed longitudinally since the fetal period (Rantakallio, 1988). No notable differences were found in clinical or biochemical parameters between attendees and non-attendees of ultrasonographic examination. Therefore there seems to be no substantial outcome-related selection bias and the subjects who attended the gynaecological ultrasound examination represent well the entire casecontrol population in that sense.
The prevalence of PCOS is estimated to be 412% (Dunaif and Thomas, 2001). Among unselected women, the prevalence of PCOS defined histopathologically is 1.43.5% (Goldzieher, 1981
), defined by biochemical parameters 2.57.5% (Futterweit and Mechanick, 1988
; Polson et al., 1988
), by the presence of oligomenorrhoea and biochemical hyperandrogenism 7% (Diamanti-Kandarakis et al., 1999
) and by oligo-ovulation and clinical hyperandrogenism 4% (Knochenhauer et al., 1998
).
In our study, the prevalence of PCO among women who reported symptoms of oligomenorrhoea and/or hirsutism (37%) was lower than reported previously in hospital-based studies among women with these symptoms (70%) (Adams et al., 1986
; Hull, 1987
; Franks, 1989
; ODriscoll et al., 1994
). However, this difference is not surprising given that our subjects were defined on the basis of self-reported symptoms unlike in other studies with symptomatic clinic-based patients. In one study of a volunteer population of young women aged 1825 years, the prevalence of PCO was as high as 33% (Michelmore et al., 1999
). Previous studies have reported that 92% of women with idiopathic hirsutism and 87% of women with oligomenorrhoea have PCO (Adams et al., 1986
) and that, of women attending a joint skin/endocrine clinic with hirsutism and/or androgenic alopecia, 81% of those with erratic cycles and 52% of those with normal cycles had PCO (ODriscoll et al., 1994
).
Our present general population-based study confirmed that, of women who report both hirsutism and oligomenorrhoea, 70% have PCO. We have shown in our previous study that women with both symptoms have the most severe changes in hormonal profile (Taponen et al., 2003). We found that, of those who reported only oligomenorrhoea, 48% had PCO and of those who reported only hirsutism, 18% had PCO. Supporting these results, the group with oligomenorrhoea alone seemed to represent all cases (hirsutism and/or oligomenorrhoea) with respect to hormonal profile and those with hirsutism alone were closer to the control group by hormonal findings (Taponen et al., 2003
). The positive predictive value of oligomenorrhoea and hirsutism was 70.4% and the negative predictive value 81.8%, further supporting the finding that these symptoms of PCOS are indicative of the morphology of the ovaries. The percentage of PCO in the group with hirsutism only was indistinguishable from that of the controls, which is partly explained by the symptom of hirsutism being truly subjective. This study showed that the prevalence of PCO in asymptomatic women is 18%, which confirms the results of previous clinic-based patient studies (Polson et al., 1988
; Koivunen et al., 1999
). Our results provide even more support to previous studies when one considers the fact that we excluded probably the most severe cases because of their use of oral contraceptives.
In our study population, cases with PCO had significantly higher BMI, WHR rate of infertility, ovarian volume, mean follicle number, FAI, insulin and glucose, lower SHBG and IGFBP-1 and a tendency to higher testosterone and lower glucose/insulin than controls. Compared with cases with normal ovaries, cases with PCO had higher BMI, ovarian volume, mean follicle number, testosterone, FAI and insulin and a tendency to lower SHBG and glucose/insulin. These results agree with our hypothesis that those with both symptoms and PCO have more marked biochemical changes than controls or cases with normal ovaries. Cases with normal ovaries but with symptoms of oligomenorrhoea and/or hirsutism did not differ from the controls except in infertility rate, which was significantly higher in cases with normal ovaries. Cases with normal ovaries probably include those whose symptoms are mild, especially concerning hirsutism, and whose symptoms would not be classified as hirsutism if a clinical scale were applied. BMI was higher in cases with PCO than in cases with normal ovaries. Thus, cases with PCO form a high risk group for the development of type 2 diabetes, and these women should also receive lifestyle counselling from their physicians aimed at optimizing body weight. In our study, features of metabolic syndrome were studied in young adults, while clinical manifestations would usually appear later. Thus ongoing surveillance of this group of women will be important as they reach middle age.
In conclusion, women with symptoms of oligomenorrhoea and/or hirsutism have more PCO than asymptomatic women and, of those with both symptoms, 70% have PCO. Women with symptoms and PCO have clinical and biochemical characteristics that are distinguishable from controls and women with symptoms and normal ovaries. Hence, ultrasound examination of the ovaries in women with oligomenorrhoea and hirsutism seems to be a valuable tool in detecting those with the most severe biochemical findings and hence the greatest risk of adverse future health outcomes.
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Acknowledgements |
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References |
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Submitted on November 14, 2004; accepted on February 18, 2004.