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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 8 2967-2971
Copyright © 2006 by The Endocrine Society

Cardiopulmonary Impairment in Young Women with Polycystic Ovary Syndrome

Francesco Orio, Jr., Francesco Giallauria, Stefano Palomba, Teresa Cascella, Francesco Manguso, Laura Vuolo, Tiziana Russo, Achille Tolino, Gaetano Lombardi, Annamaria Colao and Carlo Vigorito

Departments of Molecular and Clinical Endocrinology and Oncology (F.O., T.C., L.V., G.L., A.C.), Obstetrics and Gynecology (A.T.), and Clinical Medicine (F.G., C.V.), Cardiovascular and Immunological Sciences, Cardiac Rehabilitation Unit, University "Federico II" Naples, 80131 Naples, Italy; Department of Obstetrics and Gynecology (S.P., T.R.), University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy; and Gastroenterology Unit (F.M.), "Cardarelli" Hospital, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Francesco Orio, M.D., Ph.D., Department of Molecular, Clinical Endocrinology, and Oncology, University "Federico II" of Naples, Via S. Pansini 5, 80131 Naples, Italy. E-mail: francescoorio{at}virgilio.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Insulin resistance is a feature of polycystic ovary syndrome (PCOS), and it is related to mitochondrial function, particularly with maximal oxygen consumption (VO2max). At the moment, no evaluation of cardiopulmonary functional capacity in young patients with PCOS has been performed.

Objective: Our objective was to assess cardiopulmonary functional capacity in young PCOS overweight patients.

Design and Setting: We conducted a prospective baseline-controlled clinical study at University "Federico II" of Naples, School of Medicine (Naples, Italy).

Patients: Forty-five PCOS patients were matched with 45 healthy women for age (mean ± SD, 21.3 ± 2.0 vs. 21.6 ± 1.9 yr, respectively) and body mass index (29.4 ± 3.6 vs. 29.0 ± 3.4 kg/m2, respectively).

Mean Outcome Measures: We assessed hormonal and metabolic pattern and functional capacity by cardiopulmonary exercise testing to evaluate maximal oxygen consumption (VO2max), oxygen consumption at anaerobic threshold (VO2AT), and the maximal workload at peak exercise.

Results: VO2max (17.0 ± 3.7 vs. 26.8 ± 3.5 ml/kg·min), oxygen consumption at anaerobic threshold (13.9 ± 3.0 vs. 21.2 ± 3.8 ml/kg·min), and maximal workload at peak exercise (101.3 ± 25.2 vs. 135 ± 22.6 W) were significantly (P < 0.001) reduced in PCOS subjects compared with healthy women. The multiple linear regression analysis showed that only homeostasis model assessment appears to have a strong negative linear relation with VO2max in PCOS. No relation was found in controls.

Conclusions: Our data demonstrate a reduced cardiopulmonary functional capacity in young PCOS patients.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is a common endocrine-metabolic disorder that occurs in about 7% of reproductive-age women (1). Chronic anovulation, hyperandrogenism, and insulin resistance (IR) are the main characteristics of this multifaceted syndrome (2). Even if IR is not a key factor to diagnose PCOS (3), there is a consensus that, apart from body weight, subjects affected by this syndrome are more insulin resistant than healthy women (2).

Insulin is a major regulator of muscle proteins and can stimulate the synthesis of mitochondrial proteins (4), and an impaired mitochondrial function can promote IR in men (5).

IR is associated with a range of cardiovascular risk factors including dyslipidemia, hypertension, glucose intolerance, and diabetes (6).

The effect of PCOS on cardiovascular mortality is currently unclear. Mounting evidence (7, 8, 9, 10) indicates several cardiovascular risk factors to be clearly present and higher in PCOS compared with healthy women. It is well known that reduced functional capacity is associated with an increased risk in terms of cardiovascular mortality (11), both in healthy subjects and coronary heart disease patients.

The maximal oxygen consumption (VO2max), probably the best predictor of functional capacity (12), is positively correlated to insulin sensitivity (13, 14) and is considered a strong determinant of insulin sensitivity index in both men and women (15). Testosterone levels seem also to correlate positively with VO2max (5), although little is known about how testosterone (T) might influence insulin action.

To date, there are no data available regarding the cardiopulmonary assessment in PCOS. This study aims at evaluating functional capacity in PCOS compared with healthy young women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The institutional review board of University "Federico II" of Naples approved the present study. The purpose of the protocol was explained to each subject, and written consent was obtained from each before beginning the study.

Subjects

Forty-five young overweight nonsmoker women with PCOS were selected from the wide patient population of the Department of Molecular and Clinical Endocrinology and Oncology in Naples, Italy. All the PCOS patients achieved the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine criteria for the PCOS diagnosis (2). Polycystic ovaries (PCO) were identified by transvaginal ultrasonography (TV-USG) examination (16) and hirsutism by Ferriman-Gallwey score more than 8 (17). Exclusion criteria included pregnancy, glucose intolerance as screened by a 3-h oral glucose tolerance test (OGTT) and diabetes, hypothyroidism, hyperprolactinemia, Cushing’s syndrome, nonclassical congenital adrenal hyperplasia, and use of oral contraceptives, glucocorticoids, antiandrogens, ovulation induction agents, antidiabetic or antiobesity drugs, or other hormonal drugs within the previous 6 months. Subjects with neoplastic, hepatic, respiratory, and any cardiovascular disorder or other concurrent medical illness (i.e. respiratory and heart failure and renal disease) were also excluded from the study.

Another 45 healthy age- and body mass index (BMI)-matched women were studied and considered as controls. Each control was defined as age and BMI matched with a PCOS case when the differences between the case and control were less than 2 yr and 1 kg/m2 for age and BMI, respectively. The healthy state of the controls was determined by medical history, physical and pelvic examination, and complete blood chemistry. Their normal ovulatory state was confirmed by TV-USG and plasma progesterone (P) assay. Both procedures were performed during the luteal phase of the menstrual cycle (7 d before the expected menses). The presence of fluid in the cul-de-sac at TV-USG and a plasma P assay greater than 31.8 nmol/liter (>10 ng/ml, metric units) were considered criteria for ovulation having occurred (18).

All subjects (PCOS and healthy women) had normal physical activity, and none drank alcoholic beverages.

Protocol

At study entry, all subjects underwent blood sampling for a hormonal assessment, lipid profile, and fasting glucose and insulin levels. All blood samples were obtained in the morning between 0800 and 0900 h after an overnight fasting during the early follicular phase (d 2–4) of a spontaneous or P-induced menstrual cycle. Blood samples were collected into tubes containing EDTA after a 30-min resting period in the supine position. All blood samples were immediately centrifuged at 4 C for 20 min at 1600 x g and stored at –20 C until assayed.

During the same visit, all subjects underwent TV-USG; anthropometric measurements, including height, weight, BMI (ratio between the weight and the square of the height), and waist to hip ratio (WHR, ratio between the smallest circumference at the torso and the widest circumference at the hip); evaluation of resting heart rate and diastolic blood pressure (DBP) and systolic blood pressure (SBP); and assessments of daily physical activity in their job and home using a well-validated semiquantitative questionnaire (7, 8). Finally, all subjects underwent cardiopulmonary exercise testing to assess functional capacity.

Throughout the study, no changes in lifestyle were implemented, and subjects were instructed to follow their usual diet.

Biochemical assays

Plasma LH, FSH, prolactin, estradiol, P, 17{alpha}-hydroxyprogesterone (17-OHP), T, androstenedione (A), and dehydroepiandrosterone sulfate (DHEA-S) levels were measured by specific RIAs as previously described (7, 8). The levels of SHBG were measured using an immunoradiometric assay (4, 7), and the free androgen index (FAI) was calculated [T (nmol/liter)/SHBG (nmol/liter) x 100].

Blood insulin and glucose levels were measured by a solid-phase chemiluminescent enzyme immunoassay and the glucose oxidase method, respectively (7, 8). The estimate of IR by homeostasis model assessment (HOMA) score [fasting serum insulin (µU/ml) x fasting plasma glucose (mmol/liter)/22.5] (19) and glucose to insulin ratio (GIR) (20) were calculated in all the subjects. Glucose and insulin concentrations were measured also 30 min after insertion of the iv catheter to detect the fasting levels (time 0) before OGTT. Successively, each subject received a 75-g glucose load orally. Additional blood samples (10 ml each) were obtained at 30-min intervals for the following 3 h during the infusion period (times 30, 60, 90, 120, 150, and 180 min), and glucose and insulin concentrations were determined. In the PCOS and control groups, the glucose and insulin response to OGTT was analyzed by calculating the area under curve (AUC). The AUCs for glucose (AUCGLU) and insulin (AUCINS) were determined according to the mathematical method described by Tai (20) for the metabolic curves. The AUCGLU/AUCINS ratio was also calculated in each subject (21).

The lipid profile consisted of serum total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglycerides (TG) levels as previously described (7, 8). C-reactive protein (CRP) was measured as recently shown (22).

Cardiopulmonary exercise test

All patients underwent an incremental cardiopulmonary exercise test on a bicycle ergometer. Before each test, oxygen and carbon dioxide analyzers and a flow mass sensor were calibrated by use of available precision gas mixtures and a 3-liter syringe, respectively. To stabilize gas measurements, patients were asked to remain still on the ergometer for at least 3 min before starting exercise. After a 1-min warm-up period at 0 W workload, a ramp protocol of 15 W/min was started and continued until exhaustion. The pedaling was kept constant at 55–65 revolutions per minute. A 12-lead electrocardiogram was monitored continuously during the test, and cuff blood pressure was manually recorded every 2 min.

Respiratory gas exchange measurements were obtained breath by breath with the use of a computerized metabolic cart (Vmax 29C; Sensormedics, Yorba Linda, CA). VO2max was recorded as the mean value of VO2 during the last 20 sec of the test, evidenced by a failure for VO2 to increase further despite an increase in work rate, and was expressed in milliliters per kilogram per minute. At the end of the cardiopulmonary exercise test, patients were asked to identify the primary reason for stopping.

Medical treatment administered the day of exercise testing was recorded. Maximal oxygen consumption (VO2max) and oxygen consumption at anaerobic threshold (VO2AT) were measured and compared with maximal predicted VO2 by use of a sex-, age-, height-, and weight-adjusted and protocol-specific formula outlined by Wassermann et al. (23). The ventilatory anaerobic threshold (AT) was detected by two experienced reviewers (C.V. and F.G.) by use of the V-slope method (24). The ventilation (VE) vs. carbon dioxide production (VCO2) relationship was measured by plotting VE against VCO2 obtained every 10 sec of exercise (VE/VCO2slope); both VE and VCO2 were measured in liters per minute. The VE/VCO2slope was calculated as a linear regression function, excluding the nonlinear part of the relationship after the onset of acidotic drive to ventilation.

Statistical analysis

The comparison among controls and patients in biochemical, hormonal, and ventilatory function data was performed by the Student’s t test for unpaired data.

Multiple linear regression analysis was performed to evaluate the relative importance of VO2max as a dependent variable against predictor variables age, BMI, HOMA, FAI, lipid profile, SBP, and DBP. In assessing the suitability of the data for a linear regression model, the collinearity diagnostics were evaluated. Data are presented as mean and SD, and P < 0.05 was considered statistically significant. All analyses were run using SPSS 14.0 (SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In the present work, only data obtained from the initial cardiopulmonary exercise test will be shown, whereas the other subanalyses will be shown elsewhere.

Patients’ characteristics and hormonal profile are presented in Table 1Go. The groups were adequately and closely matched for age and BMI. The Ferriman-Gallwey scores were significantly higher (P < 0.05) in PCOS than in the control group. A significant (P < 0.05) difference was observed in LH, P, 17-OHP, T, A, DHEA-S, and SHBG. The FAI was also significantly (P < 0.05) higher in PCOS than in the control group (Table 1Go).


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  		TABLE 1. Clinical and hormonal profile in PCOS and controls

 
All PCOS patients (100%) showed PCO and anovulation. Forty patients (88.8%) had clinical hyperandrogenism, and 28 (62.2%) showed biochemical hyperandrogenism.

In Table 2Go is shown the metabolic and cardiovascular risk profile in the PCOS and control group. No difference was detected in fasting glucose and AUCGLU, whereas fasting insulin levels, HOMA index, and AUCINS were significantly (P < 0.05) higher in PCOS than control women (Table 2Go). GIR and AUCGLU/AUCINS ratio were also significantly (P < 0.05) lower in PCOS than controls. No significant difference in serum TC, LDL-C, HDL-C, and TG levels was detected between PCOS and control group. CRP concentrations were significantly (P < 0.05) increased in PCOS in comparison with healthy women.


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  		TABLE 2. Metabolic and cardiovascular risk profile in PCOS and controls

 
VO2max (17.2 ± 3.7 vs. 26.8 ± 3.5 ml/kg·min), percent VO2max (44.8 ± 7.5 vs. 63.5 ± 5.2 ml/kg·min), VO2AT (13.9 ± 3.0 vs. 21.2 ± 3.8 ml/kg·min), percent VO2AT (47.6 ± 13.1 vs. 68.2 ± 11.4 ml/kg·min), and maximal workload at peak exercise (101.3 ± 25.2 vs. 135 ± 22.6 W) were significantly (P < 0.001) reduced in PCOS compared with healthy women. No significant difference was observed in heart rate, SBP, and DBP between PCOS and control women (Table 3Go).


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  		TABLE 3. Cardiopulmonary and cardiovascular parameters in PCOS and controls

 
The multiple linear regression analysis showed a significant (P < 0.001) relationship between HOMA, GIR, and AUCINS with VO2max in PCOS subjects. In PCOS patients, no other parameter showed a relationship to VO2max. No relationship in any parameter was found in the controls (Table 4Go).


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  		TABLE 4. Multiple linear regression analysis showing HOMA GIR and AUCINS as predictors of VO2max in PCOS

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first study to assess cardiopulmonary functional capacity and VO2max in PCOS.

The maximal capacity of an individual to perform aerobic work is defined by VO2max, which is the product of cardiac output and arterial-venous oxygen difference at exhaustion. VO2max is affected by age, sex, conditioning status, and the presence of diseases or medications that influence its components. Generally, at any age, VO2max in women is 10–20% lower than in men, in part because of a lower hemoglobin concentration, a smaller proportion of muscle mass, and a lower stroke volume in women (12). It has been demonstrated that increased VO2max is associated with a decreased cardiovascular mortality, even in subjects with cardiovascular disease (11, 25, 26).

Our findings show that PCOS patients had impaired maximal and submaximal cardiopulmonary responses to exercise compared with age- and BMI-matched healthy women. This probably may result from several mechanisms and factors and may involve IR and myocardial and skeletal muscle energy metabolism.

We can also hypothesize that IR is the main pathophysiological mechanism for the reduced functional capacity probably related to the impairment of mitochondrial function; on the other hand, a reduced functional capacity may contribute to maintaining IR long term. This may be because of a decrease in availability of muscle metabolic substrates.

The molecular mechanisms implicated in IR are related to the increased expression and/or activity of key enzymes and signaling proteins regulating skeletal muscle glucose and fat metabolism, and they probably are involved in the inflammatory pathway (27). One of these proteins is the glucose transporter isoform 4 (GLUT-4), strongly associated with improved insulin action in glucose uptake (28). Furthermore, the expression and/or activity of proteins involved in insulin signal transduction in skeletal muscle may play a fundamental role.

It is well known that insulin stimulates the synthesis of mitochondrial proteins (29). In this view, an impaired functional capacity of mitochondria in skeletal muscle is observed in type 2 diabetes (30). Moreover, the impairment of the myocardial and skeletal muscle energy metabolism observed in type 2 diabetic patients is related to changes in circulating metabolic substrates (31).

These alterations may overlap in the IR phenotype that could be viewed as a chronic and low-grade inflammatory state (32). On the other hand, an elevated maximal oxygen uptake decreases HOMA and reduces the inflammatory marker CRP, suggesting a mechanism of action of the exercise habit in the primary prevention of coronary heart disease (33).

An intriguing hypothesis involving the role of IR and thus of reactive hyperinsulinemia as a mediator of impaired cardiopulmonary functional capacity in PCOS women regards the role of respiratory muscles. In fact, ventilatory function is partially determined by respiratory muscle strength, and a low level of skeletal muscle strength predicted higher levels of fasting insulin (34). Therefore, a reduced respiratory muscle strength associated with IR may be at least in part responsible for the reduced VO2max.

Impaired lung function has attracted growing interest as a potentially novel risk factor for glucose intolerance (35), IR (36), and type 2 diabetes (37, 38). Possible mechanisms for the hypothesized link include direct effects of hypoxemia on glucose and insulin regulation (39) and lung-related inflammatory mediators and their effects on insulin signaling (40, 41).

Previous reports suggest that subjects with reduced insulin sensitivity usually show higher WHR, higher blood pressure, lower VO2max, lower glucose tolerance, and fasting dyslipidemia and dysfibrinolysis (42, 43).

In the present study, multivariate analysis indicated that in PCOS patients, VO2max is inversely related only to indexes of IR, i.e. HOMA, GIR, and AUCINS, and that this change is not related to any metabolic, lipid, or other hormonal variables considered. Thus, IR could be hypothesized as the leading cause of a cardiopulmonary impairment in young PCOS women, whereas hyperandrogenism could be excluded as a putative or associated cause.

In conclusion, young PCOS women are characterized by a subclinical cardiopulmonary impairment with a reduced cardiopulmonary functional capacity that could increase the risk for cardiovascular disease, even at an early age. Additional studies are needed to clarify whether intense changes in lifestyle, in particular the role of an exercise training program on the muscle mass, metabolic substrate availability, and strength, could improve the cardiopulmonary functional capacity and insulin sensitivity in PCOS women, reducing the cardiovascular risk profile in this population.


   Acknowledgments
 
We are sincerely grateful to Mr. Christian Siatka, "Ecole de l’ADN", Nimes, France, for his great help in the analysis and the elaboration of the data.


   Footnotes
 
This work was supported by COFIN 2004 prot. 2004062889.

First Published Online June 6, 2006

Abbreviations: A, Androstenedione; AUC, area under the curve; AUCGLU, AUC for glucose; AUCINS, AUC for insulin; BMI, body mass index; CRP, C-reactive protein; DBP, diastolic blood pressure; DHEA-S, dehydroepiandrosterone sulfate; FAI, free androgen index; GIR, glucose to insulin ratio; HDL-C, high-density lipoprotein-cholesterol; HOMA, homeostasis model assessment; IR, insulin resistance; LDL-C, low-density lipoprotein-cholesterol; OGTT, oral glucose tolerance test; 17-OHP, 17{alpha}-hydroxyprogesterone; P, progesterone; PCO, polycystic ovary; PCOS, PCO syndrome; SBP, systolic blood pressure; T, testosterone; TC, total cholesterol; TG, triglyceride; TV-USG, transvaginal ultrasonography; VCO2, carbon dioxide production; VE, ventilation; VO2AT, oxygen consumption at anaerobic threshold; VO2max, maximal oxygen consumption; WHR, waist to hip ratio.

Received January 31, 2006.

Accepted May 26, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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