Effect of low-dose combined oral contraceptive on aerobic capacity

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Marcos Felipe Silva de Sá c. , Ester da Silva a,b. aUniversidade Federal de São Carlos, 13565905 São Carlos-SP, Brazil. bUniversidade Metodista de ...
Contraception 81 (2010) 309 – 315

Original research article

Effect of low-dose combined oral contraceptive on aerobic capacity and anaerobic threshold level in active and sedentary young women☆ Ana Cristina S. Rebeloa,b,⁎, Roberta S. Zuttinb , Rozangela Verlengiab , Marcelo de C. Cesarb , Marcos Felipe Silva de Sác , Ester da Silvaa,b a Universidade Federal de São Carlos, 13565905 São Carlos-SP, Brazil Universidade Metodista de Piracicaba, Faculdade de Ciências da Saúde, 13400911 Piracicaba-SP, Brazil c Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Ginecologia e Obstetrícia, 14048900 Riberão Preto-SP, Brazil Received 6 October 2009; revised 3 November 2009; accepted 9 November 2009 b

Abstract Background: The purpose of this study was to evaluate the effect of long-term use of oral contraceptives (OC) containing 0.20 mg of ethinylestradiol (EE) combined with 0.15 mg of gestodene (GEST) on the peak aerobic capacity and at the anaerobic threshold (AT) level in active and sedentary young women. Study Design: Eighty-eight women (23±2.1 years old) were divided into four groups — active-OC (G1), active-NOC (G2), sedentary-OC (G3) and sedentary-NOC (G4) — and were submitted to a continuous ergospirometric incremental test on a cycloergometer with 20 to 25 W min−1 increments. Data were analyzed by two-way ANOVA with Tukey post hoc test. Level of significance was set at 5%. Results: The OC use effect for the variables relative and absolute oxygen uptake V̇O2 mL kg−1 min−1; V̇O2, L min−1, respectively), carbon dioxide output (V̇CO2, L min−1), ventilation (VE, L min−1), heart rate (HR, bpm), respiratory exchange ratio (RER) and power output (W) data, as well as the interaction between OC use and exercise effect on the peak of test and at the AT level did not differ significantly between the active groups (G1 and G2) and the sedentary groups (G3 and G4). As to the exercise effect, for all variables studied, it was noted that the active groups presented higher values for the variables V̇O2, V̇CO2, VE and power output (pb.05) than the sedentary groups. The RER and HR were similar (pN.05) at the peak and at the AT level between G1 vs. G3 and G2 vs. G4. Conclusions: Long-term use of OC containing EE 0.20 mg plus GEST 0.15 mg does not affect aerobic capacity at the peak and at the AT level of exercise tests. © 2010 Elsevier Inc. All rights reserved. Keywords: Oral contraceptive; Ethinylestradiol; Gestodene; Aerobic capacity

1. Introduction Oral contraceptives (OCs) are used by many women for a variety of purposes, including contraception, cycle regulation, control of dysmenorrhea and medical treatment in women with long-standing amenorrhea [1]. OCs are generally well tolerated, but some women experience side ☆ This research was supported by CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Process no. 370448/2007-3) and FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo, Process no. 2006/56788-1). ⁎ Corresponding author. Universidade Metodista de Piracicaba, Faculdade de Ciências da Saúde, Rodovia do Açúcar, km 156; 13400911 Piracicaba-SP, Brazil. Fax: +55 19 3124 1515x1558. E-mail address: [email protected] (A.C.S. Rebelo).

0010-7824/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2009.11.005

effects, such as headaches, nausea, breast tenderness, weight gain [2] and unfavorable modifications of homeostasis metabolism [3,4]. Some studies have investigated both the long-term and short-term effects of OC use on physical performance, but the results are conflicting. Some studies suggest that long-term use of monophasic OCs containing ethinylestradiol (EE) 30 mcg plus 0.4 mg of norethindrone (NORE) [5], EE plus 0.075–0.15 mg of gestodene (GEST) or desogestrel [6], and triphasic OC with 35 mcg EE plus 0.5–1.0 mg of NORE [7,8] negatively affects aerobic capacity or peak oxygen uptake (V̇O2 peak). These results have not been observed by other studies with 30–50 mcg EE plus 0.3–0.5 mg norgestel or 0.1 mg NORE [9], and 20–35 mcg EE plus 0.075 mg of GEST, 1 mg cyproterone acetate and 3 mg drospirenone [10] all showed

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no adverse effects on V̇O2 peak. However, for the short-term use of OC, a prospective study, in which women were measured during 1 month of OC use containing 35 mcg EE plus 1 mg NORE, showed no adverse effects on V̇O2 peak [11], and OC containing 20–35 mcg EE plus 0.15 mg levonorgestrel or 0.5 mg NORE [12,13] presented neither exercise performance nor energy metabolism change during pill cycle. The ventilatory and metabolic variables obtained at the anaerobic threshold (AT) have great importance, since this parameter has been extensively used for the evaluation of aerobic capacity at submaximal levels of physical exercise and for the prescription of individual physical training [14–16]. Few studies have focused on exercise responses to OC use at the AT. Redman et al. [17] showed that longterm use of an OC containing 35 mcg EE and 0.5–1 mg of NORE does not affect the physiological responses at the AT. These data agree with a Santos et al. [10] study which examined women users of different doses of progestin. The majority of the literature has investigated women using EE plus levonorgestrel and EE plus NORE combination on performance [11–13]. The purpose of the present study was to examine the effects of a combined OC containing 0.20 mg of EE plus 0.15 mg of GEST on peak aerobic capacity and at the AT level in active and sedentary young women.

2. Materials and methods 2.1. Subjects In this cross-sectional study, we investigated 88 healthy young women (23±2.1 years old) who were university students. Ethical approval was obtained from the institution's ethics committee (protocol number 43/06), and all participants gave written informed consent. 2.2. Clinical assessment All subjects underwent a clinical examination, and assessment was performed between the 7th and 10th day after menstruation, when body mass index (BMI, kg m−2) was calculated. Fasting venous blood samples were collected for biochemical evaluation after 12 h of overnight fast. Serum glucose was measured by the glucose oxidase method. Levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, urea and creatinine were determined by enzymatic colorimetric assays (BioSystems, Barcelona, Spain). Low-density lipoprotein (LDL) levels were calculated using Friedewald's formula. An evaluation form was completed on daily habits, previous family history of existing pathologies, use of OCs and the level of physical activities. A standard 12-lead electrocardiogram (ECG) was conducted at rest and maximum exercise test. Heart rate (HR) and blood pressure (BP) were evaluated after 5 min of rest in the supine and

sitting positions during two visits to the laboratory. All subjects were in good health and biochemical parameters were within normal ranges. The OC users were classified as Category 1 by WHO criteria, i.e., the method can be used in any circumstance [18]. 2.3. Experimental design The OC groups were composed of women who used 21 active pills containing EE 0.20 mg plus GST 0.15 mg and seven inactive/sugar pills for at least 18 months. The nonOC (NOC) groups were composed of subjects with regular menstrual cycles who had been off OC in the previous 10 months. Subjects were divided into four groups according to their physical status and to the use or nonuse of OC: activeOC (G1), active-NOC (G2), sedentary-OC (G3) and sedentary-NOC (G4). The active subjects had been engaging in regular physical activities (running and spinning, four to five times per week) and sedentary subjects had not engaged in any regular exercise in the previous 12 months. 2.4. Testing protocol All subjects taking part in the present study were also subjected to a maximum ramp exercise test. Experiments were always carried out in the afternoon to avoid response differences caused by circadian changes. Room temperature was kept at 22°C, and relative air humidity was between 40% and 60%. Subjects were acquainted with the experimental protocol and instructed to abstain from stimulants (coffee, tea, soft drinks) and alcoholic beverages, from extenuating physical activity during the 24 h preceding the exam and to ingest a light meal at least 2 h before the measurement. The subjects had a continuous dynamic exercise test on a cycle ergometer (Quinton Corival 400, Seattle, WA, USA) with 20 to 25 W min−1 increments up to physical exhaustion, which corresponded to the time when they were unable to keep up the speed of 60 rpm, or the appearance of a limiting symptom or respiratory fatigue. Power output increases were determined for each subject, according to the formula proposed by Wasserman et al. [15]: power output increase (W)=[(height−age)×14]−[150+(6×body mass)]/100. During the test, ECG and HR were recorded beat-to-beat on a one-channel heart monitor (MINISCOPE II Instramed, Porto Alegre, RS, Brazil) and processed with an analog-todigital converter (Lab PC+, National Instruments, Co., Austin, TX, USA), which acted as an interface between the heart monitor and a microcomputer. The ECG signal was recorded in real time after analog-to-digital conversion at a sampling rate of 500 Hz [19]. Ventilatory and metabolic measurements were obtained on a breath-by-breath basis using a specific metabolic analyzer (CPXD, Medical Graphics, St. Paul, MN, USA). Aerobic capacity was then evaluated using power output (W), relative and absolute V̇O2 (mL kg−1 min−1 and

A.C.S. Rebelo et al. / Contraception 81 (2010) 309–315 Table 1 Characteristics of the subjects: baseline clinical features of NOC (sedentary and active) and OC (sedentary and active) groups

Age (years) Weight (kg) Height (cm) BMI (kg m−2) HR supine (bpm) HR sitting (bpm) SBP (mmHg) DBP (mmHg) Length of menstrual cycle (days) Period under OCs (months) Exercise (min per session) Exercise (years)

Active-OC (G1) (n=2Q)

Active-NOC (G2) (n=23)

SedentaryOC (G3) (n=23)

SedentaryNOC (G4) (n=22)

23.1±2.9 59.6±6.3 165±8.0 22.0±1.8 66.4±11.5⁎

205±3.8 58.8±8.3 166±8.1 21.5±1.7 60.0±7.3†

24.4±4.2 58.1±5.7 162±4.5 21.6±2.3 69.0±9.7

24.6±4.0 58.9.2±6.1 162±6.5 22.2±1.5 75.0±12.5

69.7±16.0

64.0±4.7

77.2±12.3

75.2±7.6

105.9±7.0 70.9±8.3 28

28.8±7.2

110.0±7.9 68.8±2.5 29



110.2±8.8 74.5±3.2 28

29.9±6.9

109.3±8.7 70.2±7.7 29



135±25.1

141±21.3





5.6±5.0

6.4±4.0





Values are means±SD; BMI=body mass index, HR=heart rate, SBP=systolic blood pressure, DBP=diastolic blood pressure, OC=oral contraceptive. Two-way ANOVA with Tukey post hoc test. ⁎ pb.05=Comparison of active-OC and sedentary-OC groups. † pb.05=Comparison of active-NOC and sedentary-NOC groups.

L min−1 , respectively), carbon dioxide output V̇CO2 (L min−1), ventilation (VE, L min−1), HR (bpm) and respiratory exchange ratio (RER) data obtained at the peak of the exercise test and at the AT level. Three properly trained observers evaluated the AT using the graphic visual method for the estimation of the disproportionate increase in ventilatory and metabolic variables, during the incremental dynamic exercise. The criterion adopted was the parallelism loss between carbon output (V̇CO2) and V̇O2 [16,20]. 2.5. Statistical methods The statistical power test was analyzed and sample size estimated using GraphPad StatMate 2.0 for Windows software, based on mean value and standard deviation of V̇O2 peak data obtained in previous studies. For an alpha error of 0.05 and test power of 80%, the indication was eight subjects in each group. All data were tested for distribution normality and variance homogeneity. Characteristics of the subjects and cardiorespiratory variables were expressed in mean and standard deviation. Baseline differences between the four groups were evaluated. The two-way ANOVA with Tukey post hoc test was used to determine significant differences between groups (level of significance was set at .05). All analyses were performed using the statistical software package SPSS 16.0 for Windows.

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3. Results 3.1. Subjects A total of 112 subjects were recruited for the evaluation, and 22 subjects were excluded during the assessments due to presenting effort-reactive hypertension, respiratory distress and changes in ECG with effort. Of the remaining subjects, 88 completed all steps of the study (Fig. 3). Baseline characteristics including anthropometric variables, HR, BP (systolic and diastolic pressures), length of menstrual cycle length and time of exercise were comparable between the active (G1 and G2) and sedentary (G3 and G4) groups (Table 1). No significant differences in mean age, weight, height, BMI, BP (systolic and diastolic pressures), length of menstrual cycle, duration of OC use and duration of exercise between groups were observed. However, in the active groups (G1 and G2), the HR supine data was lower than in the sedentary groups (G3 and G4) (pb.05). The biochemical characteristics of the groups are presented in Table 2. Total cholesterol, triglycerides and LDL levels were higher in the sedentary groups (G3 and G4) than in the active groups (G1 and G2) (pb.05). There were no significant differences in fasting glucose (mg dL−1), urea (mg dL−1) and creatinine level (mg dL−1) between groups. 3.2. Aerobic function capacity Table 3 summarizes the mean values and standard deviations for the HR, power output and ventilatory responses. The OC had no effect on V̇O2, V̇CO2, VE, HR, RER and power output data. Also, the association between Table 2 Characteristics of biochemical data of the NOC (sedentary and active) and OC (sedentary and active) groups Parameter

Fasting glucose (mg dL−1) Urea (mg dL−1) Creatinine (mg dL−1) Total cholesterol (mg dL−1) LDL-C (mg dL−1) HDL-C (mg dL−1) Triglycerides (mg dL−1)

Active-OC (G1) (n=2Q)

Active-NOC (G2) (n=23)

SedentaryOC (G3) (n=23)

SedentaryNOC (G4) (n=22)

70.1±10.7

68.6±8.9

69.1±3.7

72.6±6.9

21.2±5.5

24.8±2.4

22.2±5.0

23.1±4.4

0.7±03

0.8±0.5

0.7±0.1

0.6±0.3

148.4±31.2

146.1±26.8

174.7±24.7

165±29.1

75.0±22.6⁎

72.6±31.8†

105.1±24.4

107.7±14.0

58.1±6.6

53.4±11.4

48.6±10.9

45.6±5.6

60.8±20.2⁎

55.3±27.1†

102.3±31

90.3±26.0

Data presented as mean±SD. HDL=High-density lipoprotein; LDL=lowdensity lipoprotein. Two-way ANOVA with Tukey post hoc test. ⁎ pb.05=Comparison of active-OC and sedentary-OC groups. † pb.05=Comparison of active-NOC and sedentary-NOC groups.

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Table 3 Mean and standard deviations of dependent variables for cardiorespiratory and ventilatory responses to peak and at the AT of NOC (sedentary and active) and OC (sedentary and active) groups during the performance test (peak and AT) Variables

Peak

AT

−1

−1

V̇O2 (mL kg min ) V̇O2 (L min−1) Power output (W) V̇CO2 (L min−1) VE (L min−1) RER HR (bpm) V̇O2 (mL kg−1 min−1) V̇O2 (L min−1) Power output (W) V̇CO2 (L min−1) VE (L min−1) RER HR (bpm)

Active-OC (G1) (n=20)

Active-NOC (G2) (n=23)

Sedentary-OC (G3) (n=23)

Sedentary-NOC (G4) (n=22)

p values C

E

I

32.0±1.3 1.9±0.3 180.9±26.2 2.1±0.2 67.4±13.5 1.1±0.1 182.8±16.0 20.4±5.0 1.20±0.2 117.7±29.2 1.15±0.25 31.5±8.3 0.95±0.3 137.8±19.6

33.0±1.6 1.9±0.2 179.4±29.6 2.3±0.4 64.0±13.5 1.2±0.8 178.8±10 20.6±3.10 1.21±0.28 111.5±21.2 1.14±0.27 30.0±6.8 0.94±0.3 137.3±13.2

23.1±2.88 1.3±0.1 124.1±18.9 1.6±0.2 47.76±11.1 1.2±0.1 176.2±11 14.3±3.4 0.85±0.21 78.3±18.7 0.81±0.20 22.5±5.3 0.94±0.3 132.3±13.5

23.4±2.4 1.4±0.2 138.0±30.5 1.8±0.3 51.4±11.9 1.0±2.7 172.9±16.9 13.6±2.1 0.84±0.21 85.2±22.3 0.80±0.21 21.6±4.4 0.95±0.1 135.6±9.7

.12 .13 .08 .44 .87 .33 .46 .71 .98 .87 .87 .16 .93 .56

b.001 b.001 b.001 b.001 b.001 .41 .10 b.001 b.001 b.001 b.001 b.001 .69 .12

.28 .85 .07 .89 .18 .41 .63 .55 .88 .19 .96 .45 .08 .48

NOC=Nonusers of oral contraceptives; OC=users of oral contraceptives; AT=anaerobic threshold; V̇O2=oxygen uptake; V̇CO2=carbon dioxide output; HR=heart rate; RER (respiratory exchange ratio)=ratio of V̇CO2 to V̇O2; VE=ventilation; two-way ANOVA with Tukey post hoc test; C=effect of oral contraceptives; E=effect of exercise; I=interaction between C and E.

OC use and exercise did not affect significantly (pN.05) the peak of exercise test and the AT between the active groups (G1 and G2), as well as in the sedentary groups (G3 and G4). Regarding the exercise effect for all variables studied, it was observed that the active groups presented higher values for V̇O2, V̇CO2, VE and power output (pb.05) than the sedentary groups (G1 vs. G3 and G2 vs. G4) at the peak of exercise test. Nevertheless, the variables RER and HR at the AT level did not show significant difference (pN.05) on the peak of exercise test and at the AT level, between the active and sedentary groups (G1 vs. G3 and G2 vs. G4). The OC does not affect the aerobic capacity at the V̇O2 peak and V̇O2 AT (pN.05) in the active intragroup comparison (G1 vs. G2) (Fig. 1) and in the sedentary intragroup comparison (G3 vs. G4) (Fig. 2).

Fig. 1. Oxygen uptake at the peak exercise and at the AT during the physical exercise dynamic test of the ramp type by the groups studied: active-OC (G1) and active-NOC (G2); two-way ANOVA with Tukey post hoc test.

4. Discussion In this cross-sectional study, we investigated the effect of a combined monophasic OC with EE and GEST on aerobic capacity. The GEST is a third-generation progestin with weaker androgenic properties than the majority of progestins [17,21–23]. In this study, the data showed that the long-term use of EE 0.20 mg plus GEST 0.15 mg does not reduce aerobic capacity (V̇O2 peak) or cause any alteration in the cardiorespiratory variables and aerobic capacity at the peak and the AT level of exercise in both groups, active (G1 and G2) and sedentary (G3 and G4) women. The long-term use of the OC did not decrease stroke volume, oxygen-carrying capacity (hemoglobin levels), muscle blood flow or oxygen

Fig. 2. Oxygen uptake at the peak of exercise and at the AT during the physical exercise dynamic test of the ramp type by the groups studied: sedentary-OC (G3) and sedentary-NOC (G4); two-way ANOVA with Tukey post hoc test.

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Fig. 3. Participant flow through study.

extraction, or changes in the pattern of substrate utilization in active and sedentary young women. During exercise, the cardiorespiratory system, based on the cardiogenic command, makes adjustments to oxygen transport to peripheral tissues and removes the carbon dioxide produced during cellular metabolism [15]. The use of the OC does not seem to affect the interactions between the cardiorespiratory and metabolic systems, observed from the VE, V̇O2 and V̇CO2 variables on the peak and at the AT of exercise. This finding is partially compatible with that of Santos et al. [10], since performance and ventilatory response (V̇O2, V̇CO2, RER, VE) at the peak and at the AT level of exercise did not differ between the group of users and nonusers of OC containing varying types of progestin. Our results for the active group are in agreement with the Redman et al. [17] study, which did not observe either any influence of monophasic OC use and any influence on the HR, V̇O2, V̇CO2, RER and VE response at the AT level. According to Rechichi et al. [24], the variation between different contraceptives agents is due to the opposing actions of estrogen and progestin on metabolism. Rechichi

et al. [24] also stated that the effects of progestin are thought to be centrally modulated and include an increased chemosensitivity to hypoxia and hypercapnia and cause an increase in respiratory drive [3,25–29]. Action of steroid contraceptives on metabolism is known to be dose dependent. Thus, it is possible that no differences were noted in the present study because of the low dose of the OC used, which was not sufficient to induce any alteration on the analyzed parameters. Aerobic capacity (V̇O2 peak) has been shown to decrease by 5% to 15% following 2 to 4 months of OC use in both untrained and trained subjects, possibly through cellular changes including decrease in muscle mitochondrial citrate [8]. Additionally, this negative outcome could be attributed to reduction of circulating catecholamine levels, reduction of glucose production and elevation of nitric oxide, with a consequent increase in vasodilatation [7]. A slight reduction in carbohydrate metabolism during submaximal aerobic exercise with OC use occurs primarily due to decreased dependence on glycogen and altered secretion rates of glucoregulatory hormones [9,17]. The results of the present

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study, however, are incompatible with the above-cited findings, since performance and ventilatory response at the AT and at the peak of exercise did not differ between the OC and NOC groups. Moreover, the present study observed no change in cardiorespiratory responses in long-term OC use. The influence of OC use on exercise was evidenced by the early studies of Notelovitz et al. [5] and Giacomoni and Falgairette [6], which suggest that OCs negatively affect aerobic capacity and performance. Notelovitz et al. [5] described a 7% deterioration in exercise performance in women using an OC containing 0.4 mg of NORE, while Giacomoni and Falgairette [6] studied subjects using GEST or desogestrel and found a 5.8% decrease in V̇O2 peak. Supporting the influence of OC use on performance, a longitudinal study by Casazza et al. [4] reported a decrease in V̇O2 peak in moderately trained women after 4 months of triphasic OCs, with different doses than those in the present study (combination monophasic OC). Reduction of circulating plasma catecholamine could explain the lower V̇O2 peak observed with high ovarian hormone concentrations, because catecholamines are directly involved in glycogen mobilization during strenuous exercise. Although they evaluated short-term OC use, our data are consistent with a randomized study of Bryner et al. [11] of 10 young users of OCs (combined with NORE) and with the Bushman et al. [30] study of 17 users of monophasic (n=2) and multiphasic (n=15) OC use. Neither found any changes in V̇O2 peak after 21 days of OC use. But the results were discordant with the Daggett et al. [31] study which described an 11% deterioration in performance with 2 months of OC use containing 0–25 mg levonorgestrel. The suggestion that the use of OCs will diminish performance has led many trainers and athletes to avoid their use, thus depriving the women of many benefits that the OC has to offer. However, the results of the present study do not support the view that low-dose OC (GEST) use has an effect upon V̇O2 peak and AT. The large variation in the level of conditioning and the resulting large standard deviation in the measured variables may be the reason for the lack of significance. Our findings suggest that a low-dose thirdgeneration OC does not adversely affect performance during a maximal test. The results of this study demonstrated that the long-term use of the OC containing EE 0.20 mg plus GEST 0.15 mg did not affect aerobic capacity at the peak and at the AT level. However, more detailed studies with large sampling numbers and longitudinal studies are needed so that conclusive results can be obtained concerning the effects of OCs on ventilatory and metabolic variables during peak aerobic and AT performance.

Acknowledgments The authors thank M.I.L. Montebelo for statistical support.

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