1 Department of Obstetrics and Gynecology, General Teaching Hospital, Charles University, Apolinarska 18, Prague 2, 120 00, 2 Department of Preventive Cardiology, 3 Department of Statistics and 4 Laboratory for Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague 4, 140 21, Czech Republic
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: coronary artery disease/late risks/NIDDM/PCOS
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Previous studies have demonstrated an atherogenic lipid profile (Talbott et al., 1995, 1998
; Robinson et al., 1996
; Rajkhowa et al., 1997
) and enhanced plasminogen activator inhibitor type 1 (PAI-I) production (Sampson et al., 1996
; Atiomo et al., 1998
) in PCOS patients. Peripheral insulin resistance, dyslipidaemia, and increased PAI-I activity are important risk factors for cardiovascular disease in these patients.
In addition to these theoretical considerations, there are only few data confirming an increased risk for certain diseases in PCOS women at a later age. To date, two studies (Dahlgren et al., 1992, 1994
) have focused on the risk of arterial hypertension and NIDDM in women in perimenopausal age with a history of PCOS. In a retrospective cohort study, a higher prevalence of NIDDM and hypertension was demonstrated in a group of 33 patients previously treated for PCOS, when compared to 132 age-matched controls. In the more recent study, a higher prevalence of hypertension and diabetes mellitus was shown in a group of 28 PCOS women, aged 4362 years, matched by age and BMI (body mass index) to 56 controls. Recently, clinical evidence of an increased risk for atherosclerosis in women with PCOS was obtained (Guzick et al., 1996
). Sixteen women >40 years of age, with a history of treatment of PCOS, exhibited significantly greater intima/media thickness and a higher prevalence of plaque measured by carotid artery ultrasonography compared to 16 age-matched controls.
The aim of our study was to evaluate the prevalence of NIDDM, arterial hypertension and coronary artery disease (CAD), and the risk factors for these diseases in a group of women aged 4559 years who had been treated for markedly expressed clinical symptoms of PCOS.
This paper was not supported by a commercial company in any way.
![]() |
Material and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Biochemical assays.
Blood glucose was measured using hexokinase method (Glucose HK-UV test; Olympus Diagnostica GmbH, System Reagents, Listmechan, Co. Clare, Ireland), serum cholesterol and triglycerides were analysed using CHOD-PAP and GPO-PAPbased kits respectively (Oxochrom cholesterol 2500; Oxochrom Triacylgycerol T 500 respectively; Oxychrome, Lachema a.s., Czech Republic), high density lipoprotein (HDL)-cholesterol was determined by an immunoinhibition method (HDL-C Direct, Wako Chemicals GmbH, Neuss, Germany).
Controls
A control group of 752 women was selected; the women were aged 4559 years and were selected from 3209 women representing a random population sample (1% of permanent residents of nine districts of the Czech Republic) aged 2564 years to be screened for cardiovascular risk factors. The overall response rate was 64.4%.
Biochemical assays.
Laboratory tests were performed in a WHO Regional Lipid Reference Laboratory (Institute for Clinical and Experimental Medicine, Prague, Czech Republic). Glucose was analysed enzymatically (Lachema, Brno, Czech Republic). Serum cholesterol and triglyceride concentrations were measured by a fully automated (Cobas Mira S autoanalyzer; Hoffman-La Roche, Basel, Switzerland) enzymatic method (reagents from Boehringer Mannheim, Germany and Hoffmann-LaRoche). HDL-cholesterol was determined by the same method after precipitation of serum lipoproteins with sodium phosphotungstate and magnesium chloride (kits from Boehringer Mannheim, Germany). Low density lipoprotein (LDL)-cholesterol was calculated using the Friedewald formula (LDL-cholesterol = total cholesterol HDL cholesterol triglyceride/ 2.19 mmol/l; Friedewald et al., 1972).
Clinical investigations
All women had their family history taken with regard to hypertension, NIDDM and CAD in their parents. Each patient had her height and weight taken and her BMI was calculated; waist and hip circumferences were measured in the standing position at the levels of the umbilicus and spina iliaca anterior superior and the waisthip ratio (WHR) was calculated. Venous blood samples were drawn from an antecubital vein after an overnight fast and glucose, total cholesterol, HDL-cholesterol and triglyceride concentrations were estimated. Blood pressure readings were taken twice in the sitting position after 10 min rest and the average of both determinations was calculated. Arterial hypertension was defined as a blood pressure 140/90 mm Hg at clinical examination or by current use of antihypertensive medication. CAD was defined as follows: chest pain evaluated as definite or possible angina, a history of definite or possible myocardial infarction, a history of transluminal percutaneous coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG). NIDDM was defined as a fasting glucose concentration
7.0 mmol/l at clinical examination or current medical treatment of NIDDM. All cases and controls were seen by a specialist in cardiology or internal medicine.
Statistical methods
Statistical analysis was performed using the 2 test with Yates' correction and Student's two-sample t-test. Gaussian distribution of data was identified in all variables except triglycerides and fasting glucose. Therefore these variables were logarithmically transformed. A two-way analysis of variance together with Bonferroni's method of multiple comparison was used to evaluate differences between pre- and post-menopausal subgroups. The study was approved by the Local Ethics Committees.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
While only 35.7% of women in the PCOS group were post-menopausal, the corresponding value for the control group was 60.2% (i.e. 433/719, excluding 33 women for whom records not available; see below). There were no significant differences between post-menopausal PCOS women and controls in the mean age of menopause (48.7 ± 4.16 versus 47.8 ± 4.61 respectively) and the mean number of postmenopausal years (5.2 ± 2.53 versus 5.5 ± 3.95 respectively).
Because of the different proportions of post-menopausal women in the two groups, each group was subdivided into pre- and post-menopausal subgroups. A reliable history of menopause was not available in 33 controls; therefore they were excluded from further analysis. Again, no differences were found in anthropometric parameters, mean blood pressure, lipids and fasting glucose between the four tested subgroups (Table IV).
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The higher prevalence of central obesity, manifesting itself as a greater waist circumference or a higher WHR, in PCOS women of fertile age has been repeatedly reported in the literature (Lapidus et al., 1984; Talbott et al., 1995
). The volume of visceral fat is an important risk factor for the development of cardiovascular disease. Although age range was the only criterion for selecting the control group, our controls did not differ from PCOS women in mean BMI, waist circumference and WHR. Our results indicate that, in older age, there is a trend for the difference between PCOS women and the general population in these anthropometric parameters to minimize.
Only 35.7% of women with a history of PCOS, compared to 58.2% in the control group, were post-menopausal (P < 0.05). This is in agreement with the previous studies (Dahlgren et al., 1992, 1994
). We can speculate that the number of ovulations during life or an impaired process of apoptosis could play a role in determining the age of the menopause.
It was previously reported that women with PCOS have higher very low density lipoprotein (VLDL; Robinson et al., 1996) and lower HDL concentrations (Wild et al., 1985). This was later confirmed to be independent of weight (Wild et al., 1988). Recently, a large study of 206 women with PCOS confirmed higher total cholesterol, LDL-cholesterol and triglycerides, and lower HDL-cholesterol concentrations after adjustment for BMI (Holte et al., 1994).
Compared to controls, there was no difference in the mean values of any of the lipid parameters. The proportion of women with elevated lipid concentrations likewise did not differ between the two groups. We thus confirmed the data reported by a previous elegant study (Talbott et al., 1995), which found that PCOS women <40 years of age had substantially higher LDL and total cholesterol concentrations after adjustment for BMI and insulin concentrations, and which observed only minor differences between PCOS women and controls in the >40 years group. Although there were some methodological differences in biochemical assays in our study, both laboratories were standardized with the Center for Disease Control (Atlanta, GA, USA).
One of the parameters possibly determining serum lipid concentrations, blood pressure and body fat distribution is decreasing oestrogen production in menopause. Because of the unequal proportion of postmenopausal women, each group was subdivided to reflect the history of menopause. Again, there were no differences found between the tested subgroups in the above parameters.
An increased prevalence of impaired glucose tolerance and NIDDM in women with PCOS has been demonstrated in many studies (Dunaif et al., 1987; Harris et al., 1987
; Dahlgren et al., 1992
, 1994
; Holte et al., 1994). However, the relative contribution of insulin resistance and ß-cell dysfunction to the pathogenesis of NIDDM has been controversial; it has been postulated (Ehrmann, 1997
) that only women with PCOS who have an additional defect, such as hypersecretion of insulin, tend to develop NIDDM.
Some studies showed data confirming an increased risk for hypertension and CAD in PCOS women. An increased risk for arterial hypertension in women with a history of PCOS at older age has been repeatedly demonstrated (Dahlgren et al., 1992, 1994
). Higher daytime systolic arterial mean blood pressure, which persisted after adjustment for BMI, insulin sensitivity and body fat distribution, in women with PCOS of fertile age has also been documented (Holte et al., 1996
). A New Zealand study demonstrated a high prevalence of sonographically verified polycystic ovaries in women with documented coronary artery disease (CAD) (White et al., 1994
). A higher incidence of hirsutism in women with CAD compared to women without this finding was demonstrated using coronary arteriography (Wild et al., 1990
).
Cardiovascular disease patterns show an EastWest gradient with the highest mortality rates in Eastern Europe, including the former Czechoslovakia (Sans et al., 1997). In agreement with this expectation, the prevalence of NIDDM, arterial hypertension, and CAD was high in our control group. When comparing our controls (752 women) to the control group in the study of Dahlgren et al. (120 women), our study showed a markedly higher prevalence of NIDDM (8 versus 2.3%) as well as that of hypertension (39 versus 11%). Despite this high incidence of NIDDM in the Czech population, the prevalence of NIDDM (but not hypertension) was significantly higher in the group of PCOS women. The incidence of NIDDM and CAD in our women with a history of PCOS was four times that of a control group representing the Czech female population. The difference was not statistically significant regarding the incidence of hypertension. One in two women with PCOS was diagnosed to have hypertension, one in three met the criteria of NIDDM and one in five was being treated for CAD. At the same time, there was no difference between the two groups in the family histories of the diseases studied and smoking habits.
In conclusion, the group of women with PCOS did not differ from the large control group in their basic anthropometric criteria (BMI, WHR, waist circumference), family history, or proportions of smokers. The identical lipid profiles between these groups were most probably the consequence of a deteriorating status in a population of older age. Despite the identical risk for the development of the diseases studied, the prevalence of NIDDM and CAD was significantly higher in PCOS women. Our results confirm that women with markedly expressed clinical symptoms of PCOS make up a subgroup in the general population, at high risk for the development of NIDDM and CAD.
![]() |
Acknowledgments |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Conway, G.S. and Jacobs, H.S. (1993) Clinical implications of hyperinsulinaemia in women. Clin. Endocrinol., 39, 623632.[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]
Dahlgren, E., Janson, P.O., Johansson, S. et al. (1994) Hemostatic and metabolic variables in women with polycystic ovary syndrome. Fertil. Steril., 61, 455460.[ISI][Medline]
Dunaif, A. and Finegood, D.T. (1996) Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 81, 942947.[Abstract]
Dunaif, A., Graf, M., Mandeli, J. et al. (1987) Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J. Clin. Endocrinol. Metab., 65, 499507.[Abstract]
Ehrmann, D.A. (1997) Relation of functional ovarian hyperandrogenism to non-insulin dependent diabetes mellitus. Baillière's Clin. Obstet. Gynecol., 11, 335346.[ISI][Medline]
Ehrman, D.A., Sturis, J., Byrne, M.M. et al. (1995) Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin dependent diabetes mellitus. J. Clin. Invest., 96, 520527.[ISI][Medline]
Friedewald, W.T., Levy, R.I. and Frederickson, D.S. (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of preparative ultracentrifuge. Clin. Chem., 18, 499502.
Guzick, D.S., Talbott, E.O., Sutton-Tyrrell, K. et al. (1996) Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study. Am. J. Obstet. Gynecol., 174, 12241232.[ISI][Medline]
Harris, M.I., Hadden, W.C. and Knowler, W.C. (1987) Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in a US population aged 2074 yr. Diabetes, 36, 523534.[Abstract]
Holte, J., Bergh, T., Berne, Ch. et al. (1994a) Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables. Clin. Endocrinol., 41, 463471.[ISI][Medline]
Holte, J., Bergh, T., Berne, C. et al. (1994b) Enhanced early insulin response in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. J. Clin. Endocrinol. Metab., 78, 10521058.[Abstract]
Holte, J., Gennnarelli, G., Berne, C. et al. (1996) Elevated ambulatory day-time blood pressure in women with polycystic ovary syndrome: a sign of a pre-hypertensive state? Hum. Reprod., 11, 2328.[Abstract]
Lapidus, L., Bengtsson, C., Larsson, B. et al. (1984) Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. Br. Med. J., 289, 12571261.[ISI][Medline]
Rajkhowa, Z., Neary, R.H., Kumptala, P. et al. (1997) Altered composition of high density lipoproteins in women with the polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 82, 33893394.
Robinson, S., Henderson, A.D., Gelding, S.V. et al. (1996) Dyslipidemia is associated with insulin resistance in women with polycystic ovaries. Clin. Endocrinol., 44, 277284.[ISI][Medline]
Sampson, M., Kong, Ch., Patel, A. et al. (1996) Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome. Clin. Endocrinol., 45, 623629.[ISI][Medline]
Sans, S., Kesteloot, H. and Kromhout, D. (1997) The burden of cardiovascular diseases mortality in Europe. Eur. Heart J., 18, 12311248.[ISI]
Talbott, E., Guzick, D., Clerici, A. et al. (1995) Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler. Thromb. Vasc. Biol., 15, 821826.
Talbott, E., Clerici, A., Berga, S.L. et al. (1998) Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a case-control study. J. Clin. Epidemiol., 51, 415422.[ISI][Medline]
White, H.D., Birdsall, M.A. and Farquhar, C.M. (1994) Association of polycystic ovaries with coronary artery disease (Abstract 686). Circulation, 90, 686.[Abstract]
Wild, R.A. and Bartholomew, M.J. (1988) The influence of body weight on lipoprotein lipids in patients with polycystic ovary syndrome. Am. J. Obstet. Gynecol., 159, 423427.[ISI][Medline]
Wild, R.A., Painter, P.C., Coulson, P.B. et al. (1985) Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 61, 946951.[Abstract]
Wild, R.A., Grubb, B., Hartz, A. et al. (1990) Clinical signs of androgen excess as risk factors for coronary artery disease. Fertil. Steril., 54, 255259.[ISI][Medline]
Yen, S.S.C. (1986) Chronic anovulation caused by peripheral endocrine disorders. In Yen, S.S.C. and Jaffe, R. (eds), Reproductive Endocrinology. Physiology, Pathophysiology and Clinical Management, 2nd edition. Saunders, Philadelphia, pp. 441499.
Submitted on September 27, 1999; accepted on December 20, 1999.