doi:10.1111/j.1447-0756.2007.00690.

J. Obstet. Gynaecol. Res. 2007

Abnormal glucose tolerance in polycystic ovary syndrome

Sudhindra M. Bhattacharya
Sri Aurobinda Seva Kendra and Vivekananda Institute of Medical Sciences, Kolkata, India

Abstract
Aim: To investigate the incidence of abnormal glucose tolerance (AGT) in women with polycystic ovary syndrome (PCOS), and the reliability of fasting plasma glucose level (FPG) as a screening test for this metabolic abnormality. Methods: Two hundred and three women (62 adolescents and 141 adults) diagnosed with PCOS underwent estimation of FPG and 2-h plasma glucose after ingestion of 75 g of glucose on an empty stomach. In each case, body mass index (BMI) was calculated from height and weight measurements. Results: AGT was found in 16.3% of cases (33/203). AGT was found in 9.7% of adolescent cases (6/62) and 19.1% of adults (27/141) (P = 0.03). Women with abnormal glucose tolerance had higher BMI than those with normal glucose tolerance in the two subgroups (not statistically signicant). Difference in BMI between adults and adolescents with normal glucose tolerance was statistically signicant, but not in cases with AGT. Conclusion: AGT was found in 16.3% of women with PCOS (19.1% of adults and 9.7% of adolescents). BMI alone is not a signicant contributory factor causing deterioration of glucose tolerance as a woman with PCOS matures. Other clinical parameters of obesity such as upper body obesity need to be studied. All women with PCOS should undergo periodic screening for abnormal glucose tolerance. Fasting plasma glucose is a poor screening test to detect abnormal glucose tolerance. Key words: abnormal glucose tolerance, adolescent, adult, polycystic ovary syndrome.

Introduction
Polycystic ovary syndrome (PCOS) is one of the most common endocrinological problems in women that every gynecologist has to care for. The manifestations of androgen excess and/or the menstrual disorder typically found in these women bring them to the gynecologist, even in adolescence. It is already reported that women with PCOS carry an increased risk of subsequently developing diabetes mellitus (DM). So any intervention to prevent deterioration of glucose tolerance (GT) in these women is justied to prevent the long-term complications of insulin resistance/glucose intolerance.

A state of impaired glucose tolerance (IGT) precedes the onset of DM and usually remains asymptomatic. In some women, DM may remain asymptomatic in early stages. So it is important for a clinician to identify these at risk cases at an opportune time. There are many studies on abnormal glucose tolerance (AGT) in adult PCOS women but few studies have been reported in adolescents. With this view the present study was undertaken to assess: (i) the incidence of AGT in women with PCOS (in adolescence and adults separately) before they reach the fourth decade of life; and (ii) whether fasting plasma glucose (FPG) can be used as a screening test in these women to detect this metabolic abnormality.

Received: February 15 2007. Accepted: August 3 2007. Reprint request to: Prof. Sudhindra M. Bhattacharya, Flat-4, Mohona, 5, New Raipur, Kolkata 700084, India. Email: sudhin@vsnl.net

2007 The Author Journal compilation 2007 Japan Society of Obstetrics and Gynecology

S. M. Bhattacharya

Patients and Methods

Two hundred and three women (62 adolescents with minimum gynecologic age of 3 years, and 141 adults) presenting to the authors clinic at Sri Aurobinda Seva Kendra (SASK), Kolkata, India between June 2003 to May 2006 with the complaint of oligomenorrhoea (six or fewer menses per year) with clinical evidence of hyperandrogenism (hirsutism/acne) underwent detailed hormonal evaluations for the diagnosis of PCOS (as per the criteria laid down by the Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group).1 Secondary causes of hyperandrogenism-like 21-hydroxylase deciency, Cushing syndrome, hypothyroidism, hyperprolactinemia and androgensecreting tumors were excluded by appropriate clinical and/or laboratory tests. Body mass index (BMI) was calculated in each case from height and weight measurements taken during clinical examination. Height was recorded to the nearest 0.5 cm and weight was taken on a platform type (bathroom scale) machine, the accuracy of which was checked each time before weighing. The weight was recorded in kilograms with minimal garments on the subject. Ultrasonography of the lower abdomen was done in each case to note the status of the ovaries. After the diagnosis of PCOS was made, each woman underwent an FPG estimation and plasma glucose estimation 2 h after taking 75 g glucose (oral glucose tolerance test). The Ethics Committee of SASK approved the study and all women agreed to the investigation protocol. For adolescent girls, one of the parents gave consent for the study.

(5.7%) had AGT. In women aged 2529 years, 39 (27.7%) had NGT while 13 (9.2%) had AGT. In women aged 3034 years, 10 (7.1%) had NGT while 4 (2.8%) had AGT. In women aged 3539 years, 1 (0.7%) had NGT while 2 (1.4%) had AGT. The hormonal pattern of the adult women was as follows: among women with NGT, 99 (70.2%) had normal testosterone levels (<2.7 nmol/L) and 15 (10.6%), while in women with AGT, 19 (13.5%) had normal testosterone levels and 8 (5.7%) had high testosterone levels. The exclusion criteria were: (i) women older than 40 years with irregular periods; (ii) girls with gynecologic age less than 3 years; (iii) cases with hyperprolactinemia/hypothyroidism; (iv) secondary causes of androgen excess; and (v) women on medications known to affect carbohydrate metabolism, such as corticosteroids, in the preceding month or oral contraceptive pill use in the preceding 3 months. GT was evaluated using both the criteria of the World Health Organization (WHO)2 and the revised criteria for the diagnosis and classication of diabetes by American Diabetes Association (ADA).3 Determination of glucose tolerance was made as follows: Normal fasting glucose: <110 mg/dL (6.1 mmol/L). Impaired fasting glucose (IFG): FPG 110 mg/dL (6.1 mmol/L) but <126 mg/dL (7.0 mmol/L). NGT: 2-h post-oral glucose load (2-h PG) <140 mg/dL (7.8 mmol/L). AGT includes IGT and DM. IGT: 2-h PG 140 mg/dL (7.8 mmol/L) but <200 mg/dL (11.1 mmol/L). DM: 2-h PG 200 mg/dL (11.1 mmol/L).

Clinical characteristics of the studied women The adolescents ranged in age from 14 to 19 years, with a minimum gynecologic age of 3 years. In patients aged 1416 years, 22 cases (39.3%) had normal glucose tolerance (NGT) and ve cases (83.3%) had AGT. In patients aged 1719 years, 34 cases (60.7%) had NGT and one case (16.6%) had AGT. The hormonal pattern of the adolescent girls was as follows: in girls with NGT, 49 cases (87.5%) had normal testosterone levels (<2.7 nmol/L) and seven cases (12.5%) had elevated testosterone levels. In girls with AGT, three cases (50%) had normal testosterone levels and three cases (50%) had elevated testosterone levels. Among adults, the age range was 2039 years. In women aged 2024 years, 64 (45.4%) had NGT while 8

Results
Table 1 shows the clinical characteristics of the women (62 adolescents and 141 adults). Those with AGT had higher BMI compared to those with NGT (the whole group and the adolescent and adult subgroups). Table 2 shows the incidences of AGT in the whole group of 203 women and that in the two subgroups. AGT was found in 16.3% of women (whole group; IGT in 13.3% and DM in 3% of cases.). In adolescents, the incidence of AGT was 9.7% and in the adult group it was 19.1%. This difference in the incidence of AGT between adolescents and adults, as shown in Table 2, was analyzed statistically by Z statistic (the null hypothesis, that the observed difference is by chance only, was rejected) and found to be highly signicant.

2007 The Author Journal compilation 2007 Japan Society of Obstetrics and Gynecology

Glucose intolerance in women with PCOS

Table 1 Clinical characteristics of the studied women. Data are number (%) or means (SD) Parameter No. cases (%) Age (years) (SD) BMI (kg/m2) (SD) Whole group NGT 170 (83.7) 22.1 (4.8) 26.5 (4.7) Adolescent group AGT 33 (16.3) 24.9 (5.8) 28.4 (4.3) NGT 56 (9.7) 16.9 (1.7) 25.6 (4.5) AGT Adult group NGT 114 (19.1) 24.6 (3.5) 27.0 (4.8) AGT 27 (19.1) 26.8 (4.5) 28.5 (4.5)

6 (9.7) 16.3 (1.5) 27.8 (3.5)

AGT, abnormal glucose tolerance (impaired glucose tolerance and diabetes mellitus); BMI, body mass index; NGT, normal glucose tolerance; SD, standard deviation.

Table 2 Incidences of AGT in the different group/ subgroups Group (n) Whole group (203) No. NGT cases 170 No. AGT cases 33 IGT 27 DM 6 6 27 % 16.3 13.3 3 9.7 19.1

Table 4 FPG and 2-h PG in the two subgroups Adolescents (n) FPG <110 mg/dL (6.1 mmol/L) 110 mg/dL (6.1 mmol/L) IFG as screening To detect AGT Sensitivity Specicity Positive predictive value Negative predictive value NGT, AGT 55, 4 1, 2 Adults (n) NGT, AGT 112, 23 2, 4

Adolescent subgroup (62) Adult subgroup (141)

56 114

Z-value of proportion difference in the incidences of AGT between adults and adolescents was 1.88 and the tabled value at 5% level of signicance (one sided) was 1.64 (P = 0.03). There was a highly signicant difference between the two subgroups. AGT, abnormal glucose tolerance (impaired glucose tolerance and diabetes mellitus); IGT, impaired glucose tolerance; NGT, normal glucose tolerance.

33% 98% 67% 93%

15% 98% 67% 83%

Table 3 Differences of the BMI among different categories of the two groups BMI (kg/m2) Adolescents with NGT Adolescents with AGT Adults with NGT Adults with AGT Adolescents with NGT Adults with NGT Adolescents with AGT Adults with AGT Number 56 6 114 27 56 114 6 27 Mean (SD) 25.6 (4.5) 27.8 (3.5) 27.0 (4.8) 28.5 (4.5) 25.6 (4.5) 27.0 (4.8) 27.8 (3.5) 28.5 (4.5) P 0.07 0.06 0.03 0.4

AGT, abnormal glucose tolerance (impaired glucose tolerance and diabetes mellitus); FPG, fasting plasma glucose; IFG, impaired fasting glucose; NGT, with normal glucose tolerance; PG, plasma glucose.

Table 4 shows the patterns of FPG in relation to 2-h PG. It also shows the sensitivity, specicity, positive predictive value and negative predictive value of FPG as a screening test to detect AGT (as detected by 2-h glucose load).

Discussion
Prevention of DM, or at least delaying its onset, has attracted the attention of clinicians throughout the world. It is important to identify the at risk population and then to institute appropriate preventive interventions. The gynecologist has the opportunity to detect these at risk women with PCOS even in the adolescence period at an asymptomatic stage. This study was done among Bengali (Indian)women for which little published data is available. The present study shows that the overall incidence of AGT in women with PCOS is 16.3%. It includes IGT (13.3%) and DM (3%). All these women were asymptomatic of this metabolic abnormality and were yet to reach the fourth decade of life. Ehrmann et al., in a study of 122 women, found AGT in 45% cases (35% had

P < 0.05 was considered signicant. AGT, abnormal glucose tolerance (impaired glucose tolerance and diabetes mellitus); BMI, body mass index; NGT, normal glucose tolerance.

Table 3 shows the results of the statistical analysis (Z statistic under the null hypothesis that the differences in the parameters as shown in each category are insignicant). In Table 3 comparisons were done between the BMI of those with NGT and those with AGT in adolescents and adults separately. Although the women with AGT in both the subgroups had a higher BMI than those with NGT, statistical analysis did not show any signicant differences. BMI difference between adolescents and adults with NGT was signicant but not between adolescents and adults with AGT.

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S. M. Bhattacharya

IGT and 10% had DM).4 Legro et al. reported an incidence of IGT of 31.1% and of diabetes of 7.5% in women with PCOS.5 The present study shows that the adults have almost twice the incidence of AGT compared to that in adolescents. (19.1% vs 9.7%). This increased incidence in adults is also highly statistically signicant. (Table 2). This shows that many adolescents with PCOS can have deterioration of glucose tolerance as they mature to adulthood even before they reach the fourth decade of life. So PCOS adolescent girls, if found to have NGT, must be screened again in adulthood, if necessary by repeat screening. However, the BMI difference between adults and adolescents with NGT is statistically signicant. This may be due to the fact that BMI may not always correspond to the same body fat distributions in the two subgroups. It may also be due to the fact that all the studied women had BMI more than the normal value of healthy urban Indians (<23 kg/m2) established by Snehalatha et al.6 Thus in women with PCOS, BMI may not be the only contributory factor causing deterioration of glucose tolerance as the woman matures. Further studies are needed to see whether controlling upper body adiposity by lifestyle changes, proper dietary advices etc. can help to prevent this deterioration of glucose tolerance as these girls mature. In fact Snehalatha et al.6 and Ramachandran et al.7 in studies on Indian women found that upper body adiposity was a major factor in increasing the incidences of DM, in addition to increased change in life style patterns etc. They found higher upper body adiposity in Indians despite having lean BMI. Weiss et al.8 showed that 25% of adolescents with IGT develop overt or silent type 2 DM where as 45% converted to NGT. In this study, those who developed type 2 DM were more obese at baseline and continued to gain weight during follow up, whereas those who converted to NGT maintained their bodyweight without further weight gain. FPG is a cheap and quick test and is easily available even in resource-poor set up. Criteria for FPG indicating IGT (IFG) or the diagnosis of DM have already been established.3 Applying these criteria to the study population, it is found that it has poor sensitivity and high specicity both in adolescents and adults. The diagnostic yield expressed by the positive predictive value (67% in both the subgroups) is much lower compared to the power of the test in excluding AGT, expressed by the negative predictive value (93% in adolescents and 83% in adults). Thus the positive predictive value is

insufcient to support the use of FPG alone to screen these women for this metabolic abnormality. Therefore one can easily miss AGT (detected by WHO criteria) if relying entirely on FPG (as per ADA criteria). Larsson et al.9 and De Vegt et al.10 had also reported that when FPG is measured, IGT remains undetected in many subjects.

Conclusion
A study of 203 women with PCOS showed that the overall incidence of AGT was 16.3% (IGT in 13.3% and DM in 3% cases), based on the 2-h PG values as per the WHO criteria. In adults with PCOS the incidence is almost twice of that in adolescent girls (19.1% vs 9.7%) that is highly statistically signicant. FPG level cannot be used as a dependable screening test alone to detect this metabolic abnormality. It remains to be seen in further studies the effects of proper dietary habits, lifestyle pattern etc. on adolescents in reducing the signicant deterioration in glucose tolerance as they mature to adulthood and preventing the long-term problems, such as cardiovascular problems, as the adolescence period is the crucial habit-forming phase of ones life that will accompany them into the adult life. This study stresses the importance of widespread screening of women with PCOS for the status of glucose tolerance by OGTT if required by repeated tests.

Acknowledgment
The author is extremely grateful to Mr S. M. Bhattacharjee M.Sc (Math.) for carrying out the statistical analysis and inferences.

References
1. Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 9: 4147. 2. World Health Organization. Diabetes Mellitus. Report of a WHO Study Group. Geneva: The Organization, 1985 Technical Report Ser. no. 727. 3. Expert committee on the Diagnosis and Classication of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classication of Diabetes Mellitus. Diabetes Care 1997; 20: 11831197. 4. Ehrmann DA, Barnes RB, Roseneld RL, Cavaghan MK, Imperial J. Prevalence of Impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999; 22: 141146.

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Glucose intolerance in women with PCOS

5. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for Type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective controlled study in 254 affected women. J Clin Endocrinol Metab 1999; 84: 165169. 6. Snehalatha C, Viswanathan V, Ramachandran A. Cutoff values for normal anthropometric variables in Asian Indian Adults. Diabetes Care 2003; 26: 13801384. 7. Ramachandran A, Snehalatha C, Dharmaraj D, Viswanathan M. Prevalence of glucose intolerance in Asian Indians. Urban rural differences and signicance of upper body adiposity. Diabetes Care 1992; 15: 13481355.

8. Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of changes in glucose tolerance status in obese youth. Diabetes Care 2005; 28: 902909. 9. Larsson M, Bergluna G, Lindgarde F, Ahren B. Comparison of ADA and WHO criteria for diagnosis of diabetes and glucose tolerance. Diabetologia 1998; 41: 11241125. 10. De Vegt F, Dekker JM, Stehouwer CD, Nijpels G, Bouter LM, Heine RJ. The 1997 American Diabetes Association criteria versus the 1985 World Health Organization criteria for the diagnosis of abnormal glucose tolerance: poor agreement in the Hoorn study. Diabetes Care 1998; 21: 16861690.

2007 The Author Journal compilation 2007 Japan Society of Obstetrics and Gynecology