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Exercise Decreases Plasma Total Homocysteine in Overweight Young Women with Polycystic Ovary Syndrome

The Sir Quinton Hazel Molecular Medicine Research Centre (H.S.R., K.C.L., C.O., E.W.H.), University of Warwick, Coventry CV4 7AL, United Kingdom; Department of Diabetes and Metabolic Disorders (J.D., L.C.), The Medical University of Lodz, PL 90-131 Lodz, Poland; Department of Human Sciences (K.B.-W.), Loughborough University, Leicestershire LE11 3TU, United Kingdom; Department of Community Health and Epidemiology (C.O.), Queen’s University, Kingston, Ontario, Canada K7L 3N6; and Department of Medicine, Royal Free & University College Medical School (G.M.P.), London NW3 2PF, United Kingdom

Address all correspondence and requests for reprints to: Dr. Harpal S. Randeva, The Sir Quinton Hazel Molecular Medicine Research Centre, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom. E-mail: hrandeva{at}bio.warwick.ac.uk.

Abstract

Women with polycystic ovary syndrome (PCOS) have a clustering of cardiovascular risk factors, such as obesity, lipid abnormalities, impaired glucose tolerance, insulin resistance, and hypertension. Exercise is reported to lower the incidence of cardiac events. The effect of exercise on plasma homocysteine concentrations, an independent cardiovascular risk factor, has not been previously reported in women with PCOS.

We examined the effects of exercise on plasma total homocysteine concentrations in young overweight or obese PCOS women [age (mean ± SD), 30.6 ± 6.6 yr; body mass index, 35.49 ± 7.57 kg/m²]. Twenty-one women consented to a 6-month exercise program; 12 women (exercisers) adhered to the program, whereas 9 (nonexercisers) did not. In both groups of women, the following parameters were recorded at baseline and 6 months: body mass index, waist-to-hip ratio, and aerobic capacity (maximal oxygen consumption); blood samples were taken after an overnight fast for plasma total homocysteine, insulin, and other biochemical parameters.

A significant decrease in plasma total homocysteine concentrations (P < 0.001) and waist-to-hip ratio (P = 0.041) and a significant increase in maximal oxygen consumption (P = 0.019) were recorded at 6 months, compared with baseline in the exercise group. This decrease in homocysteine was not explained by changes in anthropometric or biochemical parameters. In contrast, no significant changes in any of the variables were observed in the nonexercise group.

Our study has provided the first evidence that regular exercise significantly lowers plasma homocysteine in young overweight or obese women with PCOS, a group at increased risk of premature atherosclerosis. The precise mechanism by which exercise is associated with a reduction in homocysteine remains to be elucidated.

ELEVATED PLASMA LEVELS of homocysteine, denoted hyperhomocysteinemia, have adverse effects on the cardiovascular system, including enhanced oxidation of low-density lipoprotein, proliferation of smooth muscle cells, increased platelet adhesiveness, and endothelial cytotoxicity (1). The clinical manifestations of hyperhomocysteinemia are the increased risk of atherosclerotic coronary, cerebral, and peripheral vascular disease, and also deep vein thrombosis and thromboembolism (2, 3). A clear association between plasma homocysteine concentrations and mortality has been demonstrated in patients with angiographic coronary artery disease (4), and a 5-µM increase in homocysteine concentrations has been shown to increase risk of cardiovascular disease (CVD) by some 80% in women and 60% in men (5). On the other hand, lowering plasma homocysteine improves endothelial function in individuals with coronary artery disease (1) and decreases the incidence of major cardiac events (6). Plasma homocysteine levels have been shown to correlate positively with blood pressure (7), and an association between hyperhomocysteinemia and insulin resistance has been suggested (8, 9, 10).

Polycystic ovary syndrome (PCOS), the commonest endocrinopathy in women of reproductive age, is a multifaceted metabolic disease linked with insulin resistance (11). It is characterized by hyperandrogenism, anovulation, and hyperinsulinemia (11). Over 30% of lean and 75% of obese women with PCOS are hyperinsulinemic. Insulin resistance, together with dyslipidemia, impaired glucose tolerance, type 2 diabetes mellitus, and elevated systolic blood pressure, which are more prevalent in obese young women with PCOS than in weight-matched controls (12, 13, 14), suggests that women with PCOS are at an increased risk of CVD (11, 15). A long-term follow-up of women with a history of ovarian wedge resection for PCOS demonstrated a significantly higher incidence of type 2 diabetes mellitus, hypertension, and myocardial infarction compared with age-matched controls (16), although some studies are not consistent with this (17, 18). More recently, however, raised plasma homocysteine levels, an independent cardiovascular risk factor, have been noted in women with PCOS (19).

Treatment of PCOS is symptomatic, but lifestyle measures, such as diet and exercise, could play an important role. Although the exact mechanism is not known, exercise has many benefits for health and CVD risk factors, and reduces cardiovascular morbidity and mortality (20, 21). In women, walking has been associated with substantial reduction in the incidence of type 2 diabetes mellitus (22) and has also been shown to decrease significantly the risk of coronary heart disease (23). Although acute exercise does not affect homocysteine levels (24), a 4-wk exercise program was associated with a reduction in homocysteine levels in healthy men (25). Given these observations, the objective of our study was to investigate the effect of a 6-month sustained exercise program on total plasma homocysteine concentrations in young overweight or obese women with PCOS.

Subjects and Methods

Subjects

All overweight and obese women with PCOS attending our Reproductive Endocrine Clinic between April and December 1998 had been offered to participate in an exercise program as sole therapy for their condition. The diagnosis of PCOS was based on typical clinical (menstrual irregularity and/or hirsutism), biochemical [hyperandrogenemia, defined as a free androgen index (FAI) of >6, or raised androstenedione], and ovarian ultrasound features (26). Exclusion criteria included age over 40 yr; body mass index (BMI) less than 25 kg/m²; known CVD, thyroid disease, current smoking, diabetes mellitus, hypertension (blood pressure, >140/90 mm Hg), renal impairment (serum creatinine, >150 µmol/liter); and any medications, e.g. estrogenic, antiandrogenic, or antihypertensive medication. Exclusion criteria also included any other endocrinopathy, and related disorders were ruled out by measuring basal serum 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and prolactin levels.

Thirty-five women expressed their interest and were screened for the purpose of this study. Of these, 21 women consented to participate in the 6-month exercise program and agreed to return the required monthly exercise questionnaires. They were asked to stop all medications and to have had no regular participation in exercise for at least 3 months before starting the exercise program. In addition, subjects were instructed to make no conscious change to their dietary composition and nutrient intake during the study period. Dietary intakes were assessed at baseline and 6 months using weighed inventories, and subsequently validated through a review of dietary questionnaires (7-d food diaries) at the beginning and at the end of the study. Of the 21 women mentioned, 12 (exercisers) adhered to the exercise program, whereas 9 (nonexercisers) failed to take up or complete the exercise program. Individual subjects were therefore identified retrospectively, nonexercisers being those who failed to take up or complete the exercise program.

This was therefore an open, longitudinal study, each subject acting as their own control, and the nonexercisers were used as the control group in the subanalysis. The study was approved by University College Hospital London Ethics Committee, and subjects gave full informed written consent.

Cardiorespiratory fitness

Exercise tests were performed at baseline and after 6 months to detect any physiological adaptation that might provide objective evidence of adherence to the exercise prescription. Because laboratory safety guidelines prohibit maximal testing in patients at increased risk of CVD or metabolic disorder, maximal oxygen consumption (VO₂max) was predicted using submaximal treadmill walking tests. Such tests have been found to provide a valid estimate of VO₂max in young women (27). An initial visit (at baseline only) included a treadmill familiarization session and a preliminary test, in which subjects walked at a constant speed with treadmill grade being increased every 4 min until heart rate reached 70–85% of age-predicted maximum. Oxygen consumption and carbon dioxide production were measured using an automated system (Jaeger, Höchberg, Germany), and heart rate was continuously monitored by an electrocardiogram. The relationship between treadmill grade and oxygen consumption was used to prescribe an individualized test, performed at baseline and repeated after 6 months. In this individualized test, subjects walked at a constant speed, with grade being increased every 4 min to elicit approximately 50, 60, 70, and 80% of each individual’s initial VO₂max. Oxygen consumption and heart rate were recorded for the final minute of each stage, as described previously. VO₂max was predicted from the relationship between heart rate and oxygen consumption (28).

Exercise program

After baseline testing, subjects were instructed to take up regular exercise, comprising sustained brisk walking at a self-selected brisk pace described as "faster than normal walking but a pace that could be sustained for at least 20 min." Subjects were instructed to complete at least three walks per week, each walk of 20- to 60-min duration. Volume of walking was prescribed by means of fortnightly targets, which increased from 120 min in the first fortnight to 420 min per fortnight (equivalent to 30 min/d) in fortnight 6 and thereafter. Target exercise frequency increased likewise from three to five walks per week over the first 6 wk. Subjects recorded the duration of walking completed each day on training diary sheets, which were returned monthly. All walking was in addition to any normal habitual activity. After 6 months, all women had their aerobic capacity measured as described above.

Biochemical analyses

All women were asked about their last menstrual period. Those with oligomenorrhea had blood tests in the early follicular phase, whereas amenorrheic women were tested with no special timing. Both at baseline and 6 months, venous blood samples were taken at 0900 h after an overnight fast. Serum and plasma were immediately aliquoted on ice and stored at -70 C. Insulin measurements were performed in duplicate using an Enzyme Immunoassay (DAKO Diagnostic Ltd., Cambridgeshire, UK), with intra- and interassay variations of 6.5% and 7.9%, respectively. Testosterone levels were measured using a RIA (EURO/Diagnostic Products, Ltd., Gwynedd, UK) with intra- and interassay variations of 7% and 8.1%, respectively, and SHBG concentrations were assessed by a commercial RIA (Orion Diagnostica, Espoo, Finland). The FAI was calculated from the total testosterone and SHBG levels. Assays for serum creatinine, cholesterol, and triglyceride were performed in our hospital’s laboratory using an automated analyzer (Abbott Architect, Abbott Laboratories, Abbott Park, IL) and free T₄ (FT₄) using the Roche Modular P system (Roche Diagnostic Systems, Somerville, NJ). Vitamin B₁₂ and folate levels were measured by microparticle immunoenzymatic assay with the use of the IMx automated system equipment and reagents purchased from Abbott Laboratories. Intra- and interassay variation for vitamin B₁₂ were 4.2% and 7.4%, and for folate, 3.8% and 5.1%, respectively. Reference range for vitamin B₁₂ is 223-1132 pg/ml, and for folate, 3.1–12.4 ng/ml.

Total plasma homocysteine was measured by HPLC with Hewlett-Packard 1100 Series system consisting of a quaternary pump, autosampler, thermostated column compartment, vacuum degasser, and diode-array detector (Hewlett-Packard Co., Waldbronn, Germany). Details of HPLC measurements have been described elsewhere (29). Briefly, separation was performed with an analytical reversed-phase column C₁₈ LiChroCART, 125 x 4 mm internal diameter, packed with 5-µm particles of LiChrosfer RP-18. The autosampler injected 20-µl aliquots of final analytical solutions. Separations were isocratic using mobile phase consisting of 0.04 M trichloroacetic buffer adjusted to pH 2.5 with lithium hydroxide and methanol in the ratio of 9:1 (vol/vol) pumped at 0.5 ml/min at 40 C. The absorbances were measured at 312 nm. Identification of peaks was based on comparison of retention times and diode-array spectra, with the corresponding set of data obtained by analyzing authentic compounds. For instrument control, data acquisition, and data analysis, a HP ChemStation for LC 3D system, including single instrument HP ChemStation software and Vectra color computer, was used. The reproducibility for total homocysteine was 5.6% and 2.8% for level of 6.4 µmol/liter (endogenous homocysteine) and 46.4 µmol/liter (endogenous spiked with 40 µmol/liter), respectively. Recovery and imprecision at the level of 2.5 µmol/liter–the lowest concentration on the standard curve–were 96.0% and 2.7%, respectively.

Statistical analysis

For each covariate recorded, descriptive statistics (N, mean, SD) were calculated by group at each time point. Nonindependence of observations within individuals was accounted for in statistical assessments of: 1) the two groups at baseline, 2) the two time points for each group (evaluated independently of the other), and 3) differences over time in the exercise group (group 2) contrasted with differences in the nonexercise group (i.e. where those who failed to adhere to the exercise program were treated as controls), by means of generalized linear hierarchical analysis (allowing for between- and within-patient variation). Multiple variable models with homocysteine as outcome were also assessed. In all analyses, statistical significance was considered to be achieved for P values less than 0.05.

Results

Patient characteristics at baseline are presented in Table 1. Women who did not exercise are presented as group 1 (G1; n = 9), and those who exercised as group 2 (G2; n = 12). None of the measured variables differed significantly between the two groups at baseline. Mean plasma total homocysteine concentrations were similar in both groups. Predicted VO₂max was slightly higher in the exercise than the nonexercise group, but the difference was nonsignificant. Blood pressure, thyroid function (FT₄), and serum creatinine concentrations were normal, as expected given the exclusion criteria.

View larger version (25K): [in this window] [in a new window]   Figure 1. Baseline and 6-month homocysteine levels observed in nonexercise (A; group 1) and exercise (B; group 2) groups. x, Individual subjects; •, overall mean values; vertical lines, 95% error bars.

In both groups of women, blood levels of vitamin B₁₂, folate, FT₄, insulin, and creatinine, factors known to influence homocysteine levels, were not significantly different between baseline and observation at 6 months. In multiple variable models, only age in years was statistically significantly associated with homocysteine levels (P = 0.003).

Discussion

The most important finding of our study is that 6 months of brisk walking results in a significant reduction in total plasma homocysteine concentrations in overweight or obese young women with PCOS, a patient group at increased risk of CVD. In the present study, although there was no significant change in BMI, there was a significant reduction in WHR in the exercise group. In addition, women who adhered to the exercise program had a significant increase in aerobic capacity (VO₂max), which remained significant when contrasted to the nonexercise group at 6 months, inferring that compliance was sufficient to provoke physiological adaptation. This increase was modest, but of similar magnitude to that observed in conjunction with significant improvements in lipoprotein levels after a program of walking in premenopausal women (30). The findings of our study are thus consistent with observations that the intensity of exercise needed to produce health benefits is considerably less than that needed to produce physical benefits (23, 30, 31).

In our study, the type of exercise selected was regular brisk walking, a cheap and socially acceptable form of activity that can be conducted frequently without requiring special equipment or facilities. Brisk walking carries a low risk of injury and has known health benefits (32). Recently, in a large cohort study of female health professionals, exercise–both vigorous activities and walking–was associated with lower coronary heart disease rates compared with no regular walking (23). In addition, we considered the exercise program more appropriate for our study population, given that they are a group with high CVD risk. The program was progressive to further minimize risk of injury or discomfort, with target volume increasing to 30 min/d, a volume associated with a substantial reduction in the risk of coronary heart disease in women (33). Brisk walking thus appears to be an achievable form of exercise for overweight women with PCOS. Furthermore, given that brisk walking lowers coronary heart disease rates (23, 33), the fall in homocysteine levels with exercise, in our study, is of interest.

Boushey et al. (5) have estimated that 10% of the risk of coronary artery disease in the general population is attributable to homocysteine. They reported that an increase of 5 µmol/liter in plasma homocysteine concentration raises the risk of CVD by 60% in men and 80% in women. It should be noted that pre-exercise total plasma homocysteine concentrations in our subjects were very similar to the levels observed in the recent Framingham Offspring Study (34), which included over 2000 nondiabetic subjects with insulin resistance syndrome. Thus, a mean reduction in total plasma homocysteine concentrations of 2.7 µmol/liter documented in our study could be relevant in reducing cardiovascular risk in women with PCOS, recently shown to have raised homocysteine levels compared with age-matched controls (19).

Some studies have suggested a link between insulin concentrations and plasma homocysteine concentrations (35, 36); however, others have not observed this association (37, 38, 39, 40), despite various methods used to measure insulin sensitivity, such as fasting insulin and intravenous glucose tolerance test (37), HOMA model (39), or when assessed by the steady-state plasma glucose concentration during the insulin suppression test (38, 40). Fasting insulin levels have been used as a screening test for insulin resistance (41, 42), and persistent elevation of plasma insulin has been associated with increased cardiovascular risk in children and young adults (43). In the present study, we did not show any association between fasting insulin and plasma homocysteine concentrations, either before or after exercise; nor did we observe a significant change in fasting insulin levels with exercise.

Apart from inherited enzyme defects, homocysteine concentrations in plasma are a sensitive indicator of cobalamin (vitamin B₁₂) and folate deficiencies (44, 45), in addition to renal function and thyroid status. It is unlikely that these parameters contributed to the observed fall in homocysteine after exercise, given that there were no significant changes in these parameters in either group of women. The precise mechanism by which exercise is associated with a reduction in homocysteine remains to be elucidated. It is, however, of interest that elevated plasma homocysteine levels have been associated with a lack of exercise (46).

Homocysteine has been reported to promote atherosclerosis by inducing endothelial dysfunction (47) through limited bioavailability of nitric oxide and altered blood vessel elasticity; whereas, regular physical exercise improves endothelial function, by increasing vasculature shear stress and by increased production of nitric oxide (48). Lowering plasma homocysteine has been shown to slow the progression of subclinical atherosclerosis (49) and also improve endothelial function in men with coronary artery disease (50). It may therefore seem reasonable to speculate that the fall in homocysteine with regular exercise, as seen in our study, may be one of many mediating factors leading to the beneficial effects of exercise on endothelial function; these observations may be particularly relevant in overweight subjects who have reported endothelial dysfunction (51). Further studies are required to establish a possible cause-effect relationship.

Besides endothelial dysfunction, hyperhomocysteinemia leads to enhanced activation of the coagulation system and increased platelet adhesiveness (1), whereas, a fall in homocysteine levels leads to an improvement in these parameters. It is known that regular exercise, even in overweight individuals, leads to both an improvement in the fibrinolytic system (52) and decreased platelet adhesiveness (53), although the precise mechanism is not clear. However, the significant decrease in plasma homocysteine after a regular exercise program, as documented in our study, may partly explain these observations.

The limitations of our study are related to its observational nature and to the fact that the fall of homocysteine after exercise occurred within the reference range (54). However, a significant increase in 6-yr cumulative all-cause mortality has been documented in subjects with total homocysteine levels above 8.2 µmol/liter (55), a value in the reference range. There was, however, no difference in mortality figures between the group in the middle (6.2–8.1 µmol/liter) and lower (<6.2 µmol/liter) tertiles of total homocysteine concentrations. Extrapolating the above data to our study, it seems reasonable to assume that an average pre-exercise homocysteine level of approximately10 µmol/liter, as in our patients, may contribute to increased cardiovascular risk, and a reduction to a mean value of 7.36 µmol/liter, as with exercise, may confer cardiovascular benefit. Interestingly, in a more recent study, lowering plasma homocysteine levels from 11.1 ± 4.3 to 7.2 ± 2.4 µmol/liter significantly reduced the rate of coronary restenosis after angioplasty and decreased the incidence of major adverse cardiac events (6). Thus, lowering homocysteine levels within the normal range may be beneficial in a way similar to lowering cholesterol in subjects without overt hyperlipidemia, in whom a reduction in acute coronary events has been shown (56). It is worth noting that the above mentioned studies (6, 55) were in older subjects; therefore, it seems likely that our findings may be even more important in women with PCOS, who have raised homocysteine levels (19) and are at an increased risk of developing early-onset atherosclerosis (57).

In conclusion, the mechanisms through which exercise may reduce CVD risk and decrease overall mortality rate remain to be fully elucidated. The findings of our observational study may have potential important clinical implications in view of the clear association of plasma homocysteine with atherosclerotic manifestations, which seems to be particularly relevant to women with PCOS (57). There is an urgent need for larger prospective, randomized studies not only to confirm our finding, but also to establish whether exercise-induced fall in homocysteine concentrations may be translated into clinically significant reduction in CVD and mortality.

Acknowledgments

Footnotes

Abbreviations: BMI, Body mass index; CVD, cardiovascular disease; FAI, free androgen index; PCOS, polycystic ovary syndrome; VO₂max, maximal oxygen consumption; WHR, waist-to-hip ratio.

Received December 27, 2001.

Accepted June 26, 2002.

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