Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, The University of Adelaide, The Queen Elizabeth Hospital, Woodville Road, Woodville, South Australia 5011, Australia
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: glucose tolerance/non-insulin-dependent diabetes mellitus/normoglycaemia/polycystic ovarian syndrome
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Cross-sectional studies of PCOS have indicated a relatively high frequency of impaired glucose tolerance (IGT) and NIDDM (Ehrmann et al.1999; Legro et al.1999
). Ehrmann et al. recently documented that insulin secretory dysfunction in women with PCOS contributed significantly to the observed glucose intolerance with up to 40% of women demonstrating either IGT or NIDDM (Ehrmann et al.1999
). Further, the onset of NIDDM in PCOS women occurs at an earlier age than in the general population, particularly when occurring in combination with obesity. Treatment for ovarian dysfunction has also been associated with NIDDM (Dunaif, 1995
). Dahlgren et al. found a high prevalence of NIDDM in women who had a wedge resection of the ovary performed some years previously (Dahlgren et al.1992
). In terms of final end points, Pierpoint et al. showed an increase in NIDDM on death certificates of women who had PCOS (Pierpoint et al.1998
).
Despite these cross-sectional observations, the longitudinal study of change in glucose tolerance in women with PCOS is rare. For example, Ehrmann et al. followed 25 PCOS women over 25.7 months (range 660) and showed that of the 11 women with normal glucose tolerance, five (45%) remained normal and 6 (55%) converted to NIDDM or to IGT (Ehrmann et al.1999). It was also observed that those who became glucose intolerant tended to be more obese than those who did not change.
In summary, although the association of impaired glucose metabolism, resulting in IGT, and NIDDM, to obesity in PCOS women is well documented in cross-sectional studies, prospective long-term studies of glucose metabolism in large groups of subjects with PCOS are lacking. Information on the incidence of IGT and NIDDM would assist clinicians in the assessment and management of risk in women with PCOS, particularly where the condition exists in conjunction with obesity.
The aim of the present study was to establish the frequency of change of IGT and NIDDM over an average period of 6.2 years within a group of women with PCOS.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Subjects with PCOS ceased taking all hormone therapy for a month prior to measurements in the original study and were either in the follicular phase of their cycle or anovular, defined as an absence of LH surge. Women with a history of diabetes mellitus were excluded. Family history data of diabetes mellitus was not obtained at the initial interview.
Procedures at baseline
All subjects underwent an oral glucose tolerance test (GTT) using a standard 75 g glucose dose and lipid and other metabolic measurement studies were performed on the fasting specimen as described previously (Norman et al.1995a, b
). NIDDM and IGT were defined according to the World Health Organization criteria (Alberti and Zimmet, 1998
), viz. IGT being a glucose value at 2 h after 75 g glucose ingestion of between 7.8 and 11.0 mmol/l and NIDDM as
11.1 mmol/l.
Follow-up study
All women from the original study with normal glucose tolerance or IGT in the initial study were contacted in 1997 (n = 148). Sixty-seven of the women with PCOS (54.9% of initial group) agreed to be re-examined and returned for a second glucose tolerance test using the same protocol, assays, and laboratory as the initial study. These methods have been described previously (Norman et al.1995b). Interassay variation within years during the period of follow up has always been <7%. The length of follow-up from the initial examination was normally distributed with an average follow up of 6.2 years (SD 1.2 years, range 4.08.6 years).
Hormone and lipid measurements
These have been fully described previously (Norman et al.1995b). In brief, glucose was measured by a glucose oxidase method. Cholesterol was measured by a cholesterol esterase-cholesterol oxidase method while triglyceride was measured by an enzymatic glycerokinase method. The apolipoproteins (A1 and B) were assayed nephelometrically. Testosterone and androstenedione were both measured using radioimmunoassay techniques while insulin was measured with an immunoradiometric assay.
Statistical analysis
Chi-square (2) or Fisher's exact test was used to test the difference in proportions of IGT or NIDDM between examinations. Student's t-tests were used to assess the change in body mass index (BMI), weight and waist measurements over the follow-up period.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Table II shows the frequency of change in glycaemic status of women from a baseline. Of women who were normoglycaemic at baseline, 9% had developed IGT (n = 5) and 8% developed NIDDM (n = 4), at an annualized incidence rate of 2.2%. Of those with IGT at baseline, 54% converted to NIDDM at follow-up. This represents an annualized incidence rate of 8.7%. Some 15% of those with IGT at baseline obtained a normal GT measurement at follow-up, and 31% remained in the same category as baseline.
|
|
Table IV shows the relative risks of change from normoglycaemic to IGT or NIDDM by BMI category. Obese PCOS women (BMI > 30 kg/m2) had a tenfold increase in their risk of developing IGT or NIDDM compared with women with BMI < 25 kg/m2 (P < 0.01). For women with BMI of 2530 kg/m2, the 7-fold relative risk was still very substantial (P < 0.01).
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It would be valuable to compare the rates obtained in this study with population estimates for women in a comparable age group, but as yet there are no reliable published population estimates of prevalence or incidence of IGT or NIDDM for the Australian population, although estimates for women aged 3544 years from a representative national survey are likely to yield prevalence estimates of 6% for IGT and 2% for clinical diabetes (P.Zimmet, personal communication). A further indication of the relative magnitude of the IGT and NIDDM reported here can be made by comparing our results with those of a large screening survey of patients aged >40 years and identified at elevated risk of NIDDM by general practitioners in Western Australia on the basis of a questionnaire (Welborn et al., 1997). Patients with elevated risk were given an oral glucose tolerance test. Among the 50 859 high risk patients completing the study, 2.0% were newly diagnosed with diabetes, 3.4% had IGT, and 10.8% had previously diagnosed diabetes. These estimates emphasize the high rates of IGT (13.4%) and NIDDM (16.4%) observed in the present study, particularly as the present study precluded from follow-up, patients with NIDDM at baseline, and the observed changes in the present study were achieved over a relatively short period of 6.2 years.
This study also confirmed that obesity is a strong predictor of deteriorating glucose metabolism. Obese PCOS women had a 10-fold increase in their risk of suffering from IGT or NIDDM compared with normal weight (BMI <25 kg/m2) PCOS women. Even those moderately obese PCOS women (BMI 2530 kg/m2) still had an approximately 7-fold increase.
The capacity to generalize the results of the present study was limited by the number of women studied, and the use of a sample drawn from a patient population. Nevertheless, the rate of change in glucose tolerance observed here is important for presenting a clear image of the population of patients presenting routinely and repeatedly for care in an infertility clinic. Despite non-significant differences in baseline characteristics between participants and non-participants, it is possible that the rates of change observed in this study are elevated to some extent by participation bias, as those women with an emergent disorder of glucose metabolism may have been more willing to participate in the follow-up study.
It is concluded that women with PCOS presenting for infertility care have a high frequency of hyperinsulinaemia and NIDDM, which is associated with a high concomitant incidence of deterioration in glycaemic control over 6 years. Routine assessment of glucose tolerance should occur in women with PCOS, particularly those with a high BMI.
![]() |
Acknowledgements |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Alberti, K.G. and Zimmet, P.Z. (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet. Med., 15, 539553.[ISI][Medline]
Dahlgren, E., Johansson, S., Lindstedt, G. et al. (1992) Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil. Steril., 57, 505513.[ISI][Medline]
Dunaif, A. (1994) Polycystic ovary syndrome. Curr. Ther. Endocrinol. Metab., 5, 222229.[Medline]
Dunaif, A. (1995) Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am. J. Med., 98, 33s39s.
Ehrmann, E., Cavaghan, M.K., Barnes, R.B. et al. (1999) Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care, 22, 141146.[Abstract]
Franks, S. (1995) Polycystic ovary syndrome [published erratum appears in N. Engl. J. Med., 1995 Nov 23, 333, 1435] N. Engl. J. Med., 333, 853861.
Holte, J., Gennarelli, G., Wide, L. et al. (1998) High prevalence of polycystic ovaries and associated clinical, endocrine, and metabolic features in women with previous gestational diabetes mellitus. J. Clin. Endocrinol. Metab., 83, 11431150.
Legro, R.S., Kunselman, A.R., Dodson, W.C. and Dunaif, A. (1999) 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. J. Clin. Endocrinol. Metab., 84, 165169.
Lesser, K.B. and Garcia, F.A. (1997) Association between polycystic ovary syndrome and glucose intolerance during pregnancy. J. Matern. Fetal Med., 6, 303307.[Medline]
Norman, R.J. and Clark, A.M. (1998) Obesity and reproductive disorders. Reprod. Fertil. Dev., 10, 5563.[ISI][Medline]
Norman, R.J., Hague, W.M., Masters, S.C. and Wang, X.J. (1995a) Subjects with polycystic ovaries without hyperandrogenaemia exhibit similar disturbances in insulin and lipid profiles as those with polycystic ovary syndrome. Hum. Reprod., 10, 22582261.[Abstract]
Norman, R.J., Masters, S.C., Hague, W. et al. (1995b) Metabolic approaches to the subclassification of polycystic ovary syndrome. Fertil. Steril., 63, 329335.[ISI][Medline]
Paradisi, G., Fulghesu, A.M., Ferrazzani, S. et al. (1998) Endocrino-metabolic features in women with polycystic ovary syndrome during pregnancy. Hum. Reprod., 13, 542546.[Abstract]
Pierpoint, T., McKeigue, P.M., Isaacs, A.J. et al. (1998) Mortality of women with polycystic ovary syndrome at long-term follow-up. J. Clin. Epidemiol., 51, 581586.[ISI][Medline]
Welborn. T.A., Reid, C.M. and Marriott, G. (1997) Australian Diabetes Screening Study: impaired glucose tolerance and non- insulin-dependent diabetes mellitus. Metabolism, 46, 3539.[ISI][Medline]
Submitted on March 2, 2001; accepted on May 8, 2001.