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Exercise Physiology Research Unit (L.M.R.), Discipline of Physiology, and Reproductive Medicine Unit (L.M.R., G.W., R.J.N.), Department of Obstetrics and Gynaecology, University of Adelaide; and Department of Thoracic Medicine (G.C.S.), Royal Adelaide Hospital, Adelaide SA 5000, Australia
Address all correspondence and requests for reprints to: Leanne M. Redman, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808-4124. E-mail: Leanne.Redman{at}PBRC.edu.
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Abstract |
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Objective: The objective of this study was to examine the effect of a synthetic progestin on aspects of exercise status in young women.
Design, Patients, Setting: Twenty-three young, healthy, habitually sedentary women participated in a single-blind, randomized, counterbalanced, cross-over study in a university-based laboratory setting.
Intervention: Two monophasic oral contraceptive pills (OCPs) were administered in which the dose of the synthetic progestin, norethisterone, was 2-fold different but the dose of the synthetic estrogen, ethinyl estradiol, was constant. During each month of OCP aspects of exercise status were assessed during incremental exercise to exhaustion and steady-state submaximal exercise and with a performance test.
Main Outcome Measures: The main outcome measures were peak oxygen uptake (
O2peak), respiratory exchange ratio (RER), time to exhaustion, lactate concentrations, and total work done.
Results: Peak heart rates were approximately 95% of age-predicted values with both OCP preparations, whereas O2peak was approximately 30% above age-predicted values. Peak postincremental exercise plasma lactate concentrations exceeded those reported for males and females, whereas the RER was below expected values throughout both incremental and steady-state exercise. The effects on O2peak and RER were increased with the higher dose progestin OCP, as were exercise time to exhaustion and total work done.
Conclusion: Synthetic progestins in OCP formulations can have a significant effect on the exercise status of young, sedentary women, possibly through an effect on stroke volume and a shift in the principal energy substrate used during exercise from carbohydrate to lipid.
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Introduction |
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The specific mechanism by which female sex steroids alter energy metabolism is not known. In those studies in which synthetic sex steroids have been administered, either the dose of progestin has been kept constant while varying the dose of estrogen (17) or the doses of the two synthetic hormones varied concurrently (8). From these studies, several estrogen-mediated hypotheses have been proposed, including increased glycogenesis and lipolysis and inhibition of gluconeogenesis and glycogenolysis (for review, see Ref. 18). There appear to be no studies that have implemented a similar regimen whereby the dose of estrogen is fixed and the dose of progestin modified, despite attempts to define a potential role of progestins (8, 17). This is surprising, given that, in comparison with 17ß-estradiol, progesterone has greater fluctuations during the menstrual cycle, with mean concentrations some 20-fold different between the two cycle phases.
The present study has been designed to investigate the effects of a synthetic progestin on the exercise status of a single group of sedentary young women in a single blind, randomized, and cross-over design. Two monophasic OCPs were administered whereby the dose of estrogen was constant but the dose of progestin varied 2-fold. In both hormone environments, aspects of exercise status were assessed during incremental exercise to exhaustion and steady-state submaximal exercise and with a performance test.
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Subjects and Methods |
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Twenty-six healthy females aged 18–30 yr, recruited by advertisement, matched the inclusion criteria for this study, namely, taking an OCP for at least 6 months before the study, regular menstruation with OCP use, nonsmoker, not pregnant, not taking any other prescription medication, and a sedentary lifestyle. Subjects met this final inclusion criterion if their occupation did not require physical labor and they did not perform structured physical activity, i.e. exercise, more than once a week (19). Subjects were excluded if they were pregnant; became pregnant; did not comply with normal directions of OCP use; were smokers; or had any history of the following: asthma, diabetes, hypertension, deep vein thrombosis or blood clots, angina, epilepsy, breast, ovary or cervical cancer, or any other endocrine or cardiovascular abnormalities. All subjects completed a questionnaire that assessed general health, gynecological health, and oral contraceptive pill history, and if no other potential contraindications to exercise testing or changing the nature of the current OCP were identified, the subjects were provided with a 1-month supply of two OCP treatments. All subjects were blinded to the nature of the OCP treatments, and the name and contents of each OCP provided could not be identified from the packaging. Before the study commencement, three subjects withdrew due to illness. All data shown are therefore for 23 subjects (age 22.6 ± 3.5 yr; height 1.7 ± 0.1 m; body mass 70.7 ± 7.6 kg; body mass index 24.0 ± 2.9 kg·m2; mean ± SD). The University of Adelaide Human Research Ethics Committee approved the study, and subjects provided written consent after provision of a written and oral explanation of the procedures, protocols, and risks entailed.
Experimental design
Subjects were required to change the nature of their current OCP to a commercially available combined monophasic OCP (Pharmacia, Ellerslie, Auckland, Australia) that contained either 35 µg ethinyl estradiol and 500 µg norethisterone (Brevinor), described in this study as "low P", or 35 µg ethinyl estradiol and 1000 µg norethisterone (Brevinor-1), described in this study as "high P". The order of OCP administration was assigned at random and counterbalanced (using a random number generator, Microsoft Excel for Windows 2000, Redmond, CA) such that 13 subjects began with low P and 10 subjects began with high P. To assess the effectiveness of the OCP and subject compliance to the OCP protocols, all women reported between pill d 10–15 in each OCP cycle in which levels of endogenous 17ß-estradiol and progesterone were measured. In addition, subjects were provided with an OCP diary that required a daily entry for the time of pill ingestion, missed pills, breakthrough bleeding, and menstrual bleeding. With this experimental design, any carryover effect of the subject’s previous OCP was considered unlikely given: 1) 7 d of inert or sugar pill ingestion and menstruation elapsed before administration of the new OCP; 2) the relatively short half-life (13–27 h) of synthetic sex steroids (20); or 3) as with most sex steroids, the new OCP would likely to have reached stable blood concentrations after 5 d of continuous administration (21) at which time the exercise tests were conducted. It is possible however that longer-term metabolic changes induced by the OCP may influence some of the results.
Exercise testing
Subjects were required to attend the laboratory on five separate occasions for an exercise familiarization session and four exercise testing sessions. Exercise tests were completed at the same time of day for each subject to minimize diurnal variation and were separated by at least 10 d to ensure adequate recovery. All exercise tests took place between 0800 and 1600 h. The number of hours from daily pill ingestion to the time of the exercise test was between 2 and 8 h (when the level of the synthetic steroids is expected to have reached steady-state) (21) and was controlled for each subject. Each subject performed an incremental exercise test to exhaustion (incremental exercise test), a steady-state submaximal exercise test, and performance test in each OCP cycle. The incremental exercise tests were completed on pill d 5–7 and the submaximal exercise and performance tests on pill d 15–17, in which d 1 represents the first day of active or hormone pill ingestion.
On the day of testing, each subject reported to the laboratory after a 4-h fast (water only) having abstained from alcohol, caffeine, and strenuous physical activity for the previous 24 h. All subjects were required to complete a 48-h dietary log during the 48-h period before the first exercise test, and all food and drink consumed within this period was self-measured and recorded. The food intake was analyzed for total caloric intake (kilojoules) and relative contributions of carbohydrate, fat, and protein (expressed in grams and as a percentage of total caloric intake) using the SERVE Nutrition Management System for Windows, 1995 (M. H. Williams Pty. Ltd., St. Ives, Australia). Subjects were required to replicate their exact dietary intakes 48 h before each subsequent exercise testing session.
On arrival in the laboratory for each exercise testing session, body mass was measured, chest electrodes applied for electrocardiographic and heart rate (HR) monitoring, and a rubefacient cream (Finalgon, Roche Molecular Biochemicals) was applied to the right earlobe for capillary blood sampling. After 10 min of seated rest, a capillary blood sample was collected the subject was then comfortably seated on a precalibrated cycle ergometer, and a low-resistance respiratory valve and nose clip were fitted to enable gas exchange measurements.
Protocols
Incremental exercise to exhaustion.
All subjects completed an incremental exercise test to exhaustion to determine peak oxygen uptake (O2peak) and the lactate and ventilation thresholds. After a 5-min rest period, exercise began with 2 min of unloaded cycling (0 W) at 50 revolutions·min–1, and thereafter the power output was incremented by 25 W every 2 min until, despite strong vocal exhortation, the subject could not maintain the target pedal cadence.
Steady-state submaximal exercise at 75% O2peak and performance test.
The absolute workload corresponding to 75% O2peak was determined from individual regression analyses of workload against relative exercise intensity (%O2peak) for each OCP. After a 5-min rest period, exercise began at a workload corresponding to a relative exercise intensity of 75% of each subject’s OCP-specific O2peak and continued for 20 min, at which time subjects were instructed to perform a maximal effort until fatigue. This was the performance test, with time to exhaustion, maximal HR, peak power output, and total work done identified as performance indices.
Cardiorespiratory measurements.
During all exercise tests, subjects wore a nose clip and breathed through a low-resistance unidirectional respiratory valve (model R2700; Hans Rudolph, Kansas City, MO) with a precalibrated, high-flow, turbine transducer (P. K. Morgan, London, UK) attached to the inspiratory port. The respiratory valve was held in place by a head support (Hans Rudolph head-support for Rudolph valves, model 2766). Expired air was directed via 1 m of large bore tubing (Clean-Bore, Vacumed, Ventura, CA) to a 2.6-liter mixing chamber (Sportech, Canberra, Australia) from which dried gas was sampled continuously (
700 ml·min–1) and passed through a fast response zirconia oxide O2 analyzer (Rapid Zr, Benchmark, Morgan, UK) and a fast-response nondirectional infrared absorption CO2 analyzer (LB-2, Beckman, Palo Alto, CA) to determine the fractional concentrations of expired gases. Volume calibration was performed before each test using a known volume standard (1 liter) passed through the system 10 times at various flow rates. Calibration was repeated if the error was greater than 2%. The gas analyzers were calibrated before each exercise test with two commercially prepared precision gas mixtures of known O2 and CO2 percentages (BOC Gases, Ryde, Australia) covering the physiological range of measurement. The ventilometer and gas analyzers were interfaced with an IBM-compatible computer that performed all of the necessary calculations using standard algorithms and Labview-based software (metabolic analyzer, ICON Technologies, Victoria Park, Australia) to calculate 30-sec averages of the expired fractions of O2 (FeO2) and CO2 (FeCO2) and minute ventilation (E), oxygen uptake (O2), and carbon dioxide production (CO2) based on the minute volume (I).
The respiratory exchange ratio (RER) was calculated as CO2 divided by O2 and tidal volume (liters) and breathing frequency (fR, breaths·min–1) were also displayed as 30-sec averages. HR (beats·min–1) was recorded continuously as consecutive 5-sec averages. O2peak was designated as the mean O2 of the minute in which the highest 30-sec epoch value was recorded and was expressed in both absolute terms (liters·min–1) and with respect to total body mass (milliliters·kg–1·min–1). Incremental exercise tests were accepted for analysis if subjects achieved within 10% of their sex- and age-predicted O2max (22) or within 11 beats· min–1 of their age-predicted HRmax. The entire metabolic gas analyzer was validated using an automated O2max calibrator (23), and the intraclass correlation coefficient for O2, CO2, and E were 2.0, 2.2, and 1.8%, respectively.
Blood sampling. All blood assays performed during the exercise tests were performed on capillary blood collected from an arterialized earlobe. During the incremental exercise test, 50-µl capillary blood samples were collected in the last 30 sec of each 2-min workload during the test and every min for 10 min post exercise. Throughout the 20 min of steady-state exercise, a 50-µl capillary blood sample was collected in the last 30 sec of each 5-min interval. No samples were taken during the performance test, but on completion capillary blood was collected at 1, 5, and 10 min post exercise.
Blood analyses
Blood concentrations of 17ß-estradiol and progesterone were measured from 5 ml of whole venous blood collected into glass syringes rinsed with sodium heparin (500 IU·ml) and immediately dispensed into a tube containing lithium heparin gel. Blood samples were kept on ice until centrifuged (model TJ-6R refrigerated centrifuge, Beckman) at 4000 x g for 15 min at 4 C, and the plasma was separated and frozen at –20 C for subsequent assay. All samples were thawed and mixed thoroughly in an automixer (Vortex, Chiltern Scientific, Sydney, Australia) and concentrations determined in duplicate in the one assay run using an automated chemiluminescent competitive assay system (ADVIA Centaur System, Bayer Diagnostics, Tarrytown, NJ). The intraassay and interassay coefficients of variation for 17ß-estradiol ranged from 5.0 to 7.4% and 4.5 to 8.1%, respectively, and progesterone ranged from 3.2 to 7.2% and 1.9 to 5.7%, respectively. Lactate and glucose concentrations were analyzed immediately (within 2 min) from 50 µl of whole blood in the ABL System 620 (Radiometer Medical, Copenhagen, Denmark) analyzer.
Data analysis
The changes in O2 (liters·min–1) with increasing exercise intensity (expressed as a percentage of the workload at exhaustion, %WLpeak) and the changes in workload, HR, CO2, and RER with increasing exercise intensity (expressed as %O2peak) were modeled as linear regression equations. For each subject, the values for workload, O2, HR, CO2, and RER, which corresponded, respectively, to consecutive 10% increments in WLpeak or O2peak were predicted from the slope and intercept of each linear regression equation. For each comparison, the coefficient of determination (r2) and the mean squared error (MSE) were calculated to examine the goodness of fit between the observed data and the data predicted by the linear regression model.
The changes in E and plasma lactate concentration with increasing exercise intensity (%O2peak) were modeled for each subject as single exponential functions given by the equation:
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O2peak (x), y is the predicted value for E, or plasma lactate concentration, and a, b, and c are mathematical parameters estimated by minimizing the residual sum of squares between the values for E, and plasma lactate concentration and the curve fit (24). For each comparison, the r2 and the MSE were calculated to examine the goodness of fit between the observed data and the data predicted by the exponential model. Lactate threshold and ventilation threshold determination
This was determined according to the method of Beaver et al. (25) using Excel (Microsoft Excel, version 4.0) macros developed specifically for this purpose. The plasma lactate concentration vs. O2 data and the E vs. O2 data were transformed into logarithms. The log-log relationships were plotted and regression lines fitted through the upper and lower segments of the resultant plots while minimizing the residual sum of squares. The lactate threshold and ventilation thresholds were designated as the O2 corresponding with the point of intersection (expressed as O2 liters·min–1, %O2peak) of the two regression lines that yielded the lowest overall residual sum of squares. For each subject, the r2 and the MSE were calculated to examine the goodness of fit of the observed data to the logarithmic model. The power output and HR corresponding to the O2 at the lactate threshold and the ventilation threshold were also determined from linear regression equations of O2 vs. power output and HR, respectively.
Statistical analysis
Statistical power analysis revealed that a subject cohort of 20 was required to demonstrate a 10% change in cardiorespiratory and metabolic variables between the two OCP preparations. To determine differences between the OCPs and pre- and/or postexercise data, a Student’s paired t test and ANOVA were used where appropriate. To compare the cardiorespiratory and plasma lactate responses during incremental exercise to exhaustion between the OCPs, a two-factor repeated-measures ANOVA, incorporating a Greenhouse-Geisser adjustment for multisample sphericity, was used. The factors tested in the ANOVA were OCP (low P vs. high P), level of exercise intensity (10 time points throughout exercise: rest, 20–100% O2peak or WLpeak) and interaction between OCP and level of exercise intensity for the incremental exercise test and cycle phase and exercise time (5-min intervals during the high-intensity test) for the steady-state submaximal test. When the two-way ANOVA showed a significant interaction effect between OCP and level of exercise intensity, planned comparisons were performed between OCPs using Tukey’s honestly significant difference post hoc analyses incorporating Bonferroni’s correction to allow for multiple comparisons. Unless otherwise stated, data are reported as mean ± SEM, and the level of significance for all statistical tests was set at P 
0.05.
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Results |
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The OCP suppressed 17ß-estradiol and progesterone in each individual, and the concentrations were not different between the two OCP preparations (17ß-estradiol: low P, 21.9 ± 1.0, high P, 31.5 ± 6.2 pg·ml–1; progesterone: low P, 1.3 ± 0.1, high P, 1.2 ± 0.1 nmol·liter–1; SI units: 17ß-estradiol: low P, 80.3 ± 3.8, high P, 115.6 ± 22.8 pmol·liter–1; progesterone: low P, 1.3 ± 0.1, high P, 1.2 ± 0.1 nmol·liter–1).
Preexercise diet
There was no difference in the 48-h self-reported preexercise dietary intakes between low P and high P in terms of total caloric intake (low P, 5682 ± 109, high P, 5712 ± 127 kJ) or relative contributions of carbohydrate (low P, 56 ± 3, high P, 56 ± 2%), fat (low P, 23 ± 1, high P, 22 ± 4%), and protein (low P, 21 ± 4, high P, 22 ± 5%).
Subjects
Physical characteristics. The level of synthetic progestin had no effect on body weight (low P: 70.6 ± 3.5, high P: 70.6 ± 3.4 kg) or body mass index (low P: 24.3 ± 1.0, high P: 24.3 ± 1.0 kg·m2).
Incremental exercise to exhaustion: work parameters
Work. There was a trend (P < 0.07) toward an improvement in peak power output (WLpeak, low P: 202 ± 5.2, high P: 205 ± 4.4 W), time to exhaustion (low P: 17.8 ± 0.4, high P: 18.2 ± 0.4 min), and total work done (low P: 111.7 ± 5.4, high P: 114.7 ± 4.8 kJ) with high P.
Rate of perceived exertion.
The rate of perceived exertion increased from rest and was highest at O2peak. There was no difference in perceived exertion at O2peak (low P: 10.0 ± 0.0, high P: 10 ± 0.0) or with increasing exercise intensity between the two OCP preparations.
Cardiorespiratory variables
Oxygen uptake.
Whereas there was no difference in O2 at rest with the two OCP preparations (Table 1
), there was a trend for a higher value with high P as exercise intensity increased (Fig. 1A), and at O2peak, there was a 4% difference (P < 0.05). Overall the subject group achieved 130 (low P) and 134% (high P) of their age-based predicted absolute O2max values for sedentary females (22).
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CO2 at rest (Table 1
), with increasing exercise intensity during the incremental test and at O2peak, were not different between low P and high P.
Heart rate.
There was no effect of low P and high P on either resting or peak HR (HRpeak) (Table 1) or the HR responses with increasing exercise intensity. Subjects attained 95 ± 1 and 94 ± 1% of their age-predicted HRmax during the low P and high P treatments, respectively.
RER.
There was no difference between the two OCPs at rest or O2peak (Table 1). Despite a consistently lower RER with increasing exercise intensity throughout the incremental test with high P, the repeated-measures ANOVA (RMANOVA) found no significant interaction between RER and the OCPs (Fig. 1B).
Oxygen pulse.
There was no effect of low P and high P on the oxygen pulse at either rest or O2peak (Table 1). However, when the relationships of the two OCP preparations and exercise intensity, expressed as %O2peak, were examined throughout exercise, the RMANOVA and post hoc analysis detected a significant interaction effect, such that at exercise intensities equivalent to 90 and 100% O2peak, the oxygen pulse was increased by 11% with high P, compared with low P (Fig. 1C).
Ventilation.
E at rest and O2peak and the E with increasing exercise intensity were not altered by the level of progestin. Whereas E·O2 was higher at rest with high P administration (P < 0.05), there was no difference in the resting values of E·CO2 between low P and high P (Table 1). Furthermore, E·O2 and E·CO2 either at O2peak or with increasing exercise intensity in the incremental test were not affected by either OCP. Breathing frequency and tidal volume were not different between low P and high P either at rest or O2peak or throughout incremental exercise to exhaustion (Table 1).
Ventilatory threshold.
The ventilatory threshold, when expressed in absolute terms (E: low P, 404.4 ± 43.8, high P, 403.4 ± 43.7 liters·min–1) or relative to O2peak (%O2peak: low P, 35.1 ± 2.1, high P, 35.8 ± 3.2%), was similar between the two OCP treatments. HR and power output at the threshold were also not different between the two OCP preparations.
Metabolic parameters
Lactate.
There was no difference between low P and high P in the resting (low P: 6.3 ± 0.9, high P: 5.4 ± 0.9 mg·dl–1; SI units: low P: 0.7 ± 0.1, high P: 0.6 ± 0.1 mmol·liter–1), end-exercise (low P: 102.7 ± 5.4, high P: 100.9 ± 4.5 mg·dl–1; SI units: low P: 11.4 ± 0.6, high P: 11.2 ± 0.5 mmol·liter–1), or peak postexercise plasma lactate concentrations (low P: 108.1 ± 5.4, high P: 108.1 ± 4.5 mg·dl–1; SI units: low P: 12.0 ± 0.6, high P: 12.0 ± 0.5 mmol·liter–1) or the time to reach peak concentration (low P: 1.4 ± 0.1, high P: 1.7 ± 0.2 min). Furthermore, there was no interaction between plasma lactate concentration and the two OCPs with increasing levels of exercise intensity throughout the incremental test (Fig. 1D).
Lactate threshold (LT).
When expressed in terms of O2 (liters·min–1 or %O2peak), the LT was not different between low P and high P nor were any differences in the HR, plasma lactate concentration, and power output at the LT between the two OCP preparations (Table 2).
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O2peak (carbohydrate, low P: 14.4 ± 0.8, high P, 14.1 ± 0.1; lipid, low P: 2.0 ± 0.6, high P: 2.6 ± 1.0 kcal·min–1), and the RMANOVA revealed no interaction between the type of OCP and substrate utilization with increasing exercise intensity. Steady-state submaximal exercise test
Work load corresponding to 75% O2peak.
There were no differences in the absolute work load corresponding to 75% of each subject’s OCP-specific O2peak applied during the submaximal exercise between the OCPs (workload: low P: 140 ± 3, high P: 141 ± 4 W; O2: low P: 2.2 ± 0.1, high P: 2.2 ± 0.1 liter·min–1; HR: low P: 152 ± 4, high P: 157 ± 2 beats·min–1).
Rate of perceived exertion.
There was no difference in perceived exertion during the submaximal steady-state exercise test at 75% O2peak between the two OCP treatments (low P: 6.8 ± 0.2, high P: 6.2 ± 0.3).
Cardiorespiratory variables
Rest.
O2, CO2, E, HR, RER, oxygen pulse, tidal volume, breathing frequency, and E·CO2 were similar between low and high P, but ventilation and the E·O2 were increased with high P (Table 3).
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O2peak.
Whereas the level of synthetic progestin did not affect O2, CO2, HR, E, E·O2, and E·CO2, the oxygen pulse was increased (P < 0.05) and the RER decreased (P < 0.05) in response throughout steady-state exercise at 75% O2peak in the high P condition (Table 3). Plasma lactate concentration
Rest. Resting plasma lactate concentrations (low P: 7.2 ± 0.9, high P: 7.2 ± 0.9 mg·dl–1; SI units: low P: 0.8 ± 0.1, high P: 0.8 ± 0.1 mmol·liter–1) were not different between the two OCP treatments.
Seventy-five percent O2peak.
During high-intensity steady-state exercise, there was no difference in mean plasma lactate concentrations between low P and high P (low P: 64.0 ± 4.5, high P: 68.5 ± 4.5 mg·dl–1; SI units: low P: 7.1 ± 0.5, high P: 7.6 ± 0.5 mmol·liter–1).
Substrate metabolism
Although there was no difference in carbohydrate (low P: 0.1 ± 0.0, high P: 0.1 ± 0.0 kcal·min–1) or lipid (low P: 1.2 ± 0.1, high P: 1.3 ± 0.1 kcal·min–1) oxidation at rest, there was a significant increase in lipid oxidation with high P, compared with low P, throughout the steady-state exercise test (low P: 6.7 ± 0.2, high P: 7.3 ± 0.2 kcal·min–1, P < 0.05).
Performance test
During the performance test, whereas power output (low P: 175 ± 4, high P: 175 ± 4 W), HR (low P: 190 ± 2, high P: 191 ± 4 beats·min–1), and peak lactate (low P: 91.0 ± 3.6, high P: 88.3 ± 3.6 mg·dl–1; SI units: low P: 10.1 ± 0.4, high P: 9.8 ± 0.4 mmol·liter–1) were not affected by the level of synthetic progestin, exercise time to exhaustion (low P: 33 ± 4, high P: 41 ± 6 sec, P < 0.05) and the total work were increased with high P, and there was a trend toward a higher peak oxygen uptake (low P: 41.0 ± 2.0, high P: 43.5 ± 2.0 liters·min–1, P = 0.06) in this synthetic hormone environment.
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Discussion |
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In terms of aerobic power, the most striking finding was that O2peak with both OCPs was 30% or more above the age-predicted O2max values (liters·min–1) for sedentary females (22). Given that the O2peak values were normally distributed, a differential of this magnitude might suggest that the subject cohort was engaged in regular physical activity, with O2peak values similar to the mean values for sedentary males of a similar age, 47.7 ml · kg–1·min–1 (22). Yet the subject selection process clearly identified these subjects as meeting the inclusion criterion of a sedentary lifestyle (19). Although such a selection process might allow the occasional trained individual to slip into the subject cohort or that the isolated individual might, through genetic endowment, have a O2peak above the age-predicted range, the normal distribution of the present subject cohort makes this unlikely. Therefore, it could be argued that this substantial elevation in O2peak is a consequence of oral contraceptive administration (a history of OCP use for at least 6 months was required for study selection), and furthermore, given that the O2peak value (ml·kg–1·min–1) was higher with the high P than the low P preparation, that this is a progestogenic effect. This finding is contrary to any previous research that examined the effects of female sex steroids, both endogenous and exogenous, on aerobic power.
Some studies, but not all (26, 27) have reported no difference in aerobic capacity per se, during both oral contraceptive administration (28, 29, 30, 31) and the normal menstrual cycle (32, 33, 34, 35), but several have reported an increased time to exhaustion with high levels of progestins (9, 10, 11, 12). How the progestins might have such an effect is uncertain, but given that O2peak is determined by maximal values for cardiac output, oxygen content, and oxygen extraction, the results from the present study provide some clues. In terms of cardiac output, peak HRs during the incremental exercise test were not different from age-predicted values or between the two OCPs, and HRs attained during the steady-state and performance tests were similar with the two OCPs. However, oxygen pulse, regarded by many as an index of stroke volume, was higher with the high P OCP, at both 90 and 100% O2peak during the incremental test and throughout steady-state exercise test at 75% O2peak. This suggests that the increased O2peak values found with both OCPs could be due to an affect of the contained progestin on stroke volume. In support of this contention is the reported finding that synthetic sex steroids increase left ventricular mass, increase end-diastolic volume, and reduce end-systolic volume, with consequent increases in ejection fraction, stroke volume, and cardiac output (36). Furthermore, synthetic progestin administration in rats has been reported to increase blood volume and, through a consequent effect on stroke volume, cardiac output (37).
Whereas an increase in hemoglobin concentration (not measured in the present study) and hence oxygen content could also increase aerobic power with OCP administration, previous research does not support a differential in hemoglobin concentration between women on the OCP and those with normal menstrual cycles (38, 39). Furthermore, this mechanism is unlikely to explain the increase in O2peak when subjects were taking the high P OCP. Although an increase in tissue oxygen extraction with OCP administration could contribute to the improved aerobic power, no previous research could be found documenting such a change. If the increases in aerobic power seen with both OCPs is a progestin-mediated effect using one or more of the mechanisms proposed above, it would be a concern that such an effect occurred after one cycle of exposure. However, all subjects had a previous history of more than 6 months exposure to a progestin-containing monophasic OCP. Nevertheless, the significant 4% differential in O2peak between the low P and high P OCP, which we suggest is a progestin effect, did occur within one cycle.
The other interesting finding in the present study was the shift in energy substrate from carbohydrate to lipid with both OCPs. This was present at rest, during which the RER values suggest exclusive use of lipid as a fuel, and even with the peak workloads achieved during the incremental test, RER did not reach unity. This latter result is surprising and suggests at first sight that the subjects did not expend a maximal effort, given that an RER of 1.1 is an accepted criterion (40). Yet at test termination they met other recognized criteria of a maximal effort, with peak HRs within 5% of age-predicted maximal values and postexercise lactates of 12 mmol·liter–1, and, of course, their O2peak values were 30% or more above age-predicted values for sedentary women. This leads inescapably to the conclusion that lipids dominated as the energy substrate throughout these tests. As with the effect of aerobic power discussed above, this also seems to be a progestogenic effect, given that when subjects were taking the high P OCP, there was a trend for lower RER values throughout the incremental test, a differential that was significant at all time points throughout the steady-state test. The other intriguing result regarding energy metabolism was the acceleration in blood lactate accumulation once the exercise intensity exceeded the LT. This presumably reflects either an increase in production or a reduction clearance or both. Given that the RER values suggest that lipids are the principal energy source with all forms of exercise in the present study, an increase in production seems less likely, although, as the RER value indicates, carbohydrate will be accessed increasingly as workloads increase beyond 50% O2peak. A decrease in plasma clearance of lactate is also a possibility, given that reconversion to pyruvate in skeletal muscle would be hindered by an accumulation of pyruvate secondary to the well-known inhibitory action of lipid oxidation on pyruvate dehydrogenase (41). Furthermore, hepatic clearance of lactate via the Cori cycle might also be reduced by the inhibitory actions of both estrogens and progestins on hepatic gluconeogenesis, for which lactate is an important substrate.
Despite the persuasive nature of the present results, previous studies concerned with exercise status and the OCP have reported no change in substrate utilization between different formulations (42) or between the active and nonactive pill days within one OCP cycle (28, 31). One plausible explanation for the conflicting findings with the current study is a difference between the days on which the exercise testing occurred. Lynch and coworkers (28, 31) reported no change in substrate utilization within a monophasic OCP cycle, yet the two sessions of exercise testing were completed within the 21-d time frame of pill ingestion. Because the blood levels of estrogen and progestin reach steady-state after approximately 5 d of monophasic OCP administration (21), the blood levels of the female sex steroids, and therefore effect on substrate choice, were likely to have been the same on both test days.
Those studies, which have found an effect on substrate choice during exercise in women, have attributed this change to fluctuations in circulating levels of estrogen (7, 8). If there is a role for a progestogenic-induced shift to lipid metabolism, as the results seem to indicate, it requires a plausible mechanism. It is known that high levels of progestin during late gestation, OCP administration, and the luteal phase of normal menstrual cycles induce insulin resistance (43) and glucose intolerance (44). A recent series of experiments in mice further demonstrates the relationship between progesterone and glucose homeostasis. Administration progesterone to wild-type and db/db mice accelerates hyperglycemia and the progression of diabetes, whereas administration of RU486, an antagonist of the progesterone receptor, significantly improves glucose intolerance in these animals. Progesterone receptor knockout mice have improved glucose tolerance owing to an increased insulin secretion (45). Progestins also decrease muscle glucose utilization through effects on GLUT4 (46) and hexokinase (47). Taken together these observations indicate that progestins could push substrate oxidation toward fat by reducing the availability of glucose-6-phosphate for glycolysis and increasing the accessibility of lipid substrates. This shift from carbohydrate to lipid as the preferred energy substrate may, through a consequent glycogen-sparing effect, explain in part the affect of the high P OCP preparation on the performance test. Both total work done and time to exhaustion were increased when compared with the low P OCP cycle. Whereas all the evidence presented from this study suggests that these are progestin-mediated effects, given that the dose of estrogen was constant, an interaction between the two hormones cannot be excluded.
This study provides the first evidence that synthetic progestins in OCP formulations can have a significant effect on maximal aerobic power, possibly through an effect on stroke volume, and, furthermore, promote a shift in the principal energy substrate used during exercise from carbohydrate to lipid. The performance effects of this combination on aerobic power and lipid oxidation are potentially of great significance and have been partially exposed in the increased time to exhaustion and total work done when the OCP with the higher progestin concentration was administered, despite the effects on lactate metabolism. It should be noted that norethisterone, the synthetic progestin administered in this study, binds to the progesterone receptor but also has a low affinity for the androgen receptor (48). Norethisterone therefore can exert both progestogenic and androgenic actions. Whereas the findings presented in this paper suggest a progestin-mediated effect, given that estrogen is also present and that estrogen is required for synthesis of the progestin receptor, an interaction between the two synthetic sex steroids cannot be disregarded. It remains to be seen whether the cardiorespiratory, metabolic, and performance-enhancing effects reported in this study are exclusively effects of the progestins or whether they are the combined effect of estrogen, androgen, and progestin.
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First Published Online April 19, 2005
Abbreviations: fR, Breathing frequency; HR, heart rate; LT, lactate threshold; MSE, mean squared error; OCP, oral contraceptive pill; r2, coefficient of determination; RER, respiratory exchange ratio; RMANOVA, repeated-measures ANOVA; O2peak, peak oxygen uptake; %O2peak, relative exercise intensity; %WLpeak, percentage of the workload at exhaustion.
Received December 8, 2004.
Accepted April 8, 2005.
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