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Effects of the menstrual cycle and oral contraceptives on athletic performance Lebrun, Constance Marie Therese 1991

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EFFECTS OF THE MENSTRUAL CYCLE AND ORAL CONTRACEPTIVESON ATHLETIC PERFORMANCEbyCONSTANCE MARIE THERESE LEBRUNB.Sc., University of Manitoba, 1976M.D.C.M., McGill University, 1981A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFMASTER OF PHYSICAL EDUCATIONinTHE FACULTY OF GRADUATE STUDIESDepartment of Sport ScienceSchool of Physical EducationWe accept this thesis as conforming to the required standard:THE UNIVERSITY OF BRITISH COLUMBIADecember, 1991© Constance Marie Lebrun, 1991In presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.(SignatureDepartment of ( The University of British ColumbiaVancouver, CanadaDate^ 9 9 (DE-6 (2/88)11ABSTRACT:There have been few well-controlled studies to date on the influence of different phasesof the menstrual cycle on athletic performance, and information is even more sparse on potentialeffects of oral contraceptive agents (OCAs) on performance. Many of the earlier studies failedto accurately document the phase of the cycle, or used a variety of different oral contraceptiveswith higher dosages of estrogens and progestins than those in current usage. Thus, the purposeof this study was to examine the effects of the endogenous hormonal variations of a normalmenstrual cycle and the administration of a low-dose triphasic oral contraceptive agent (OCA)on selected measures of athletic performance in a group of elite female athletes. Nineteeneumenorrheic women were studied during the midfollicular (day 5.7 ± 0.5; mean + SE) andmidluteal (day 23.3 ± 0.9) phases of a normal menstrual cycle. Cycle phases were confirmed byplasma estradiol and progesterone assays. Following the two menstrual cycle tests, subjects wererandomly assigned in a double blind fashion to either a placebo group (n=7, age=28.3 + 1.6 yr,height=168.6 ± 2.0 cm, weight=60.0 ± 3.5 kg) or an OCA group (n=7, age=27.1 ± 1.6 yr,height=168.5 ± 1.9 cm, weight=60.2 ± 1.7 kg). A third test was carried out during the midcycle(day 14.4 ± 0.54) of the second cycle of the placebo/OCA administration.In the 16 women with hormonal evidence of ovulation, no significant differences wereobserved between the follicular phase and luteal phase tests in weight, percent body fat, sum ofskinfolds, maximum heart rate, maximum minute ventilation, maximum respiratory exchangeratio, anaerobic performance, endurance time to fatigue (at 90% of V0 2..), or isokinetic strengthof knee flexion and extension. There was, however, a small decrease seen from the follicular tothe luteal phases in absolute V02..; from 3.19 ± 0.09 l•min -1 to 3.13 ± 0.08 1.min -1 (p=0.04),iiias well as in relative V02,„,,,; from 53.7 ± 0.9 ml•kg -i •min-1 to 52.8 ± 0.8 ml•kg -i •min-1 (p=0.06).There was a very slight increase in both hemoglobin and hematocrit during the luteal phase.With regards to the effect of the OCA on performance, there was a significant differencein the responses of the two groups while on medication or placebo, in both absolute V0 2..(p=0.05) and in relative V02,„„. (p=0.02). The 7 subjects on OCA had a slight decrease inmaximal oxygen consumption from follicular phase values to the third test (absolute VOA :3.29 ± 0.12 l•mizi l to 3.18 + 0.09 limin4 ; relative VO2,ax: 54.7 + 1.2 ml•kg-l•min-i to 52.0 + 1.0ml•ke•tnin-1); while the 7 women on placebo showed a slight increase over the same time period(absolute V02„.: 3.16 ± 0.15 L•min -1 to 3.18 ± 0.13 l•min 1; relative V02.: 53.0 ± 1.1 ml•kg-innin4 to 53.8 ± 1.7 ml•kg-l •min-1). Weight and percent body fat did not vary significantly ineither group, but the sum of skinfolds changed differentially with a significant increase (p<0.01)in the OCA group as compared to placebo. There were no associated alterations in maximumheart rate, maximum respiratory exchange ratio, maximum minute ventilation, hemoglobinconcentration or hematocrit as a consequence of OCA administration. There were no significantdifferences over all three tests between the two groups in anaerobic performance, endurance timeto fatigue, or isokinetic strength of knee flexion and extension.There were, therefore, no statistically significant changes in selected physiologicalvariables or in the majority of the tests of performance occurring as a function of either the phaseof the menstrual cycle or administration of a low-dose triphasic OCA. However, the smalldecreases in V02. during the luteal phase and while on OCA suggest that the female steroidhormones, estrogen and progesterone, both endogenous and exogenous, may exert a slightdeleterious effect on aerobic capacity with potential implications for elite level performance.ivTABLE OF CONTENTS:ABSTRACT ^  iiTABLE OF CONTENTS ^  ivLIST OF SYMBOLS  viLIST OF TABLES^  viiiLIST OF FIGURES  ixACKNOWLEDGEMENTS ^DEDICATION ^  xiINTRODUCTION  1METHODS AND MATERIALS ^  8SUBJECTS^  8EXPERIMENTAL PROTOCOL  11BODY COMPOSITION^  12BLOOD SAMPLES  12AEROBIC CAPACITY  13ANAEROBIC PERFORMANCE ^  14ENDURANCE PERFORMANCE  14ISOKINETIC STRENGTH  15STATISTICAL ANALYSIS ^  15RESULTS^  17SUBJECTS^  17GROUPS  17EFFECT OF MENSTRUAL CYCLE PHASE^  20BODY COMPOSITION^  20BLOOD TESTS  23EXERCISE PERFORMANCE  23EFFECT OF THE ORAL CONTRACEPTIVE: ^  25BODY COMPOSITION^  25BLOOD TESTS  26EXERCISE PERFORMANCE  26VDISCUSSION ^  33EFFECTS OF MENSTRUAL CYCLE PHASE^  33BODY COMPOSITION^  34BLOOD TESTS  35EXERCISE PERFORMANCE  36EFFECTS OF THE ORAL CONTRACEPTIVE ^  42BODY COMPOSITION^  42BLOOD TESTS  43EXERCISE PERFORMANCE  43SUMMARY ^  48REFERENCES  50APPENDIX A. REVIEW OF LITERATURE ^  59NATURE OF THE PROBLEM/IMPORTANCE OF TOPIC^ 59EFFECT OF THE MENSTRUAL CYCLE ON PERFORMANCE^ 63BACKGROUND AND EARLY STUDIES ^  63STUDIES WITHOUT HORMONAL DOCUMENTATION.^ 66STUDIES UTILIZING SERUM PROGESTERONE MEASUREMENTS ^ 69CARDIOVASCULAR AND HEMODYNAMIC RESPONSES ^ 71TEMPERATURE REGULATION AND HEAT EXCHANGE  74RESPIRATORY DRIVES AND VENTILATION ^ 75METABOLIC RESPONSES^  77EFFECTS OF ORAL CONTRACEPTIVES ON PERFORMANCE^ 80BACKGROUND^  80CARDIOVASCULAR AND HEMODYNAMIC RESPONSES ^ 81RESPIRATORY DRIVES AND VENTILATION ^ 81METABOLIC RESPONSES^  82EFFECTS OF ORAL CONTRACEPTIVES ON EXERCISEPERFORMANCE  83APPENDIX B. RAW DATA ^  86LIST OF SYMBOLS:ADH^•.^antidiuretic hormoneAST^•.^anaerobic speed testATP^•.^adenosine triphosphateBBT^•.^basal body temperaturebpm^•.^beats per minuteC CentigradeCl'^•.^chloride ionCO2^•.^carbon dioxideCP^•.^creatine phosphateECG electrocardiogramET^ endurance time to fatigueF follicular phaseFFA^ free fatty acidsFO force outputGH^ growth hormoneIr hydrogen ionHct^ hematocritHCVR hypercapnic ventilatory responseHg^•^mercuryHgb hemoglobinviiHR(max)^• maximum heart rateHVR^• hypoxic ventilatory responseIOC^• International Olympic CommissionL • luteal phaseLH^• luteinizing hormoneMPA medroxy-progesterone acetateMVC^maximal voluntary contractionNa+^sodium ion/i•n newton meter02^oxygenOCA oral contraceptive agentpH^ negative logarithm of 11+ concentrationRER(max)^maximum respiratory exchange ratioRX treatmentSE^ standard error''CO2^carbon dioxide productionVE^expired minute ventilationVE(max) maximum minute ventilationVO2^oxygen uptakeV02. maximal oxygen consumptionviiiLIST OF TABLES:TABLE I. SUBJECT PROFILES AND HORMONAL VALUES ^ 18TABLE Ha. EFFECT OF MENSTRUAL CYCLE PHASE ON ANTHROPOMETRIC,HORMONAL AND HEMATOLOGICAL VARIABLES ^ 21TABLE Hb. EFFECT OF MENSTRUAL CYCLE PHASE ON PERFORMANCEVARIABLES ^  22TABLE Ella. EFFECT OF CYCLE PHASE AND OCA ON ANTHROPOMETRIC,HORMONAL AND HEMATOLOGICAL VARIABLES ^ 30TABLE Mb. EFFECT OF CYCLE PHASE AND OCA ON PERFORMANCEVARIABLES ^  31ixLIST OF FIGURES:FIGURE 1. EFFECT OF MENSTRUAL CYCLE PHASE ON V02,. ^ 24FIGURE 2. EFFECT OF TREATMENT ON SUM OF SKIN FOLDS  28FIGURE 3. EFFECT OF TREATMENT ON V02.,, ^  29xACKNOWLEDGEMENTS:The realization of a project of this magnitude seems viable when it is first conceived,totally insurmountable in the middle of it, and nothing short of miraculous when it is finallyachieved. I would like to gratefully recognize the contributions of the many people who haveencouraged me along the way, through numerous setbacks including personal injury and illness.Special acknowledgment must go to all of my advisors, but especially to my committeechairman, Dr. Don McKenzie, for his endless patience and guidance over the past five years. Iam deeply indebted as well to Dr. Jerilynn Prior, and to her research nurse, Yvette Vigna, fortheir advice and suggestions. Their enthusiasm for research on the female athlete, and theirexperience and knowledge on this subject were invaluable to me. Particular thanks also go to Dr.Jack Taunton for his cheerful optimism and his role as a mentor in sports medicine. Both he andDr. Stan Herring from Seattle deserve much credit for my continuing and improving good health.My close friends have played a singular role in this process, and I would like to thankAlison Forbes for her dependable good humor and continued belief in me, and my secretary PatMorgan for her wonderful ability to keep both me and my office functioning and my patientsplacated during my many absences. Dr. Bill Milsom also deserves very special appreciation forhis selfless and unquestioning moral support over the past year, and for his attempts to make meshare his ardour for the entire research process. Finally, I am totally indebted to all of mysubjects, who faithfully kept their basal body temperature charts and their training logs, and rantheir hearts out on the treadmill for me, not just once, but three times. This project was assistedby financial support from Sport Canada, and from Syntex, Inc. In addition, I am grateful toDusan Benicky and Dr. Ted Rhodes for their technical assistance and laboratory support.xiDEDICATION:This work is dedicated to my parents: to my mother, who is always interested in andsupportive of my many endeavors, even when they lie outside her realm of experience; and tomy father, from whom I must have inherited this penchant for higher education and academia.1EFFECTS OF THE MENSTRUAL CYCLE AND ORAL CONTRACEPTIVESON ATHLETIC PERFORMANCEINTRODUCTION:From the time of the ancient Greeks and Romans, the athletic arena has historically beenregarded as a male domain. Indeed, it has only been since the beginning of the 20th century thatwomen have been participating in both recreational and competitive sport in significant numbers.Today's female athlete is just as likely as her male counterpart to be testing the limits of herphysical capabilities, and engaging in strenuous and prolonged training programs in order toachieve her best performance in elite sport. While the mechanisms of pulmonary, cardiovascularand cellular adaptations to an exercise stimulus are continually being explored by the sportscientist, much less is known about how the special physiological and hormonal variations of thefemale athlete interact with these functions. The majority of research on the female athlete hasfocused on the links between rigorous physical training and delayed menarche, alteration ofnormal pubertal progression, shortened luteal phase, anovulation, athletic amenorrhea andreversible infertility (see Highet, 1989; Loucks and Horvath, 1985; Loucks, 1991; Prior andVigna, 1985; Prior and Vigna, 1991). By comparison, the influence of these hormonal cycles onphysiological and exercise variables has not been studied extensively (Albohm, 1976). The femaleathlete, from puberty through pregnancy and childbirth, to menopause and beyond, has to contendwith a shifting spectrum of hormonal alterations that have potential to affect performance,especially at the elite level.Considerable interest has also been generated lately in the usage of certain medications,2particularly anabolic steroids, for performance enhancement. Oral contraceptives contain potentsynthetic steroid hormones, albeit in minute quantities, yet relatively little is known about themetabolic consequences of their administration. A significant number of elite female athletes areprescribed the birth control pill at various times during their competitive careers, whether it befor purposes of contraception, cycle regulation, control of dysmenorrhoea, or more recently, forhormonal replacement in women with chronic amenorrhea (Shangold, 1988, 1990). Someconcerns have been expressed by others (Prior and Vigna, 1985) about this latter usage of OCAsin women who already have a suppressed hypothalamic-pituitary axis. Side effects such as weightgain and fluid retention, and long term risks related to cardiovascular disease, thromboembolism,and alterations in lipid profiles have been substantially reduced by the newer low-dose triphasicpreparations. The question of potential effects of oral contraceptive agents (OCAs) on athleticperformance has not been answered conclusively; given the common usage of OCAs by athletes,there may be profound implications for training and competition.Early studies of the influence of the menstrual cycle on sport performance are largelyretrospective and anecdotal. Furthermore, their classifications of menstrual cycle phase were donewithout any knowledge of actual levels of the ovarian hormones, and are consequently inaccurate,and potentially misleading. The assumption that ovulation, and therefore a luteal phase occur ifthe cycle is "regular" (i.e. 28 days long), is unfounded, but unfortunately widely held, even bysome modern-day researchers. With this in mind, in analyzing the impact of the "phase" of themenstrual cycle on physical performance, investigators have documented no perceived influenceof cycle phase in 37% to 63% of athletes surveyed (Erdelyi, 1962; Ingman, 1953; Kral andMarkalous, 1937; Zaharieva, 1965). Estimates of cycle phase detriment range from 8% during3the menstrual phase (Kral and Markalous, 1937) to a high of 59% during the premenstrual phase(Rougier and Linquette, 1962). In one study (Ingman, 1953), 24% of athletes did not ordinarilycompete during menses because of pain and/or fatigue. Performance was purportedly enhancedduring the menstrual phase in 13% (Erdelyi, 1962) to 29% (Kral and Markalous, 1937) of thewomen surveyed. These results are both interesting and contradictory, but it is important to keepin mind the notorious unreliability of such retrospective studies.Early attempts to quantify this perceived difference in performance are marked withdiscrepancies in the timing of the testing, as well as inadequate documentation (either by basalbody temperature monitoring or by serum progesterone measurements) of the cycle phase. Thetesting procedures have usually involved either treadmill or cycle ergometry, and have measuredV02  or submaximal cardiorespiratory responses employing a variety of protocols. Many of thestudies have used relatively untrained subjects, or extremely small numbers. Some investigatorshave found little or no difference in performance at various times during the menstrual cycle(Allsen et al., 1977; De Bruyn-Prevost et al., 1984; Doolittle and Engebretsen, 1972; Gamberaleet al., 1975; Garlick and Bernauer, 1968; Stevenson et al., 1982a, 1982b). Others havedocumented a decrement in performance in the premenstrual (Erdelyi, 1962) or menstrual phase(Wearing et al., 1972), and the best performances in the intermenstrual (Erdelyi, 1962; Wearinget al., 1972) or postmenstrual phases (Erdelyi, 1962, Fox et al., 1977). There have also beenseveral "field studies" (Bale and Nelson, 1985; Brooks-Gunn et al., 1986; Fomin et al., 1989;Quadagno et al., 1991) with inconclusive results.Of the studies that have utilized serum progesterone to confirm the luteal phase, only onegroup of investigators (Jurkowski et al., 1978, 1981) has shown a dramatically significant change4in any measurable test of performance. In 9 moderately trained females (mean V02  of 42.8± 1.7 ml•Ice•min-1), the time to exhaustion on a bicycle ergometer at 90% of 1102.„ wasincreased from 1.57 ± 0.32 to 2.97 ± 0.63 minutes in the luteal phase. Subsequent attempts toexplain this enhancement of endurance performance have focused on various aspects of substratemetabolism as reflected by measurements of blood lactate and glucose, free fatty acids, insulinand growth hormone (GH) responses, and glycerol and cortisol (Bonen et al., 1983; Lamont,1986; Lavoie et al., 1987; Reinke et al., 1972; Sutton et al., 1980). Glycogen uptake and storagein both liver and muscle have been shown to be facilitated by high concentrations of estradiol,both in animal studies (Ahmed-Sorour and Bailey, 1981; Kendrick et al., 1987; Matute andKalkhoff, 1973) and in humans (Nicklas et al., 1989). Other metabolic actions of estradiol witha potential impact on performance include effects on lipid availability and utilization, as well asgluconeogenesis (Bunt, 1990). Progesterone has been shown in both men and women to causea shift in substrate metabolism towards a greater dependence on fat, as manifest by lowerrespiratory exchange ratio (RER) values, and lower blood lactate levels during submaximalexercise (Dombovy et al., 1987). However, with the exception of one study (Nicklas et al., 1989)that found a strong tendency (p=0.07) towards an increase in endurance during the luteal phase,no other group has successfully replicated the findings of Jurkowski et al., (1977, 1981) ofenhanced luteal phase performance in athletes.Other researchers have examined the resting respiratory drives as a function of cyclephase (Schoene et al., 1981). It has been shown that an increase in both hypoxic and hypercapnicrespiratory drives, as well as in minute ventilation, occurs under the influence of the increasedprogesterone levels seen during the luteal phase (Schoene et al., 1981; Dombovy et al., 1987).5These changes can also be seen in men who are given a synthetic progesterone, medroxy-progesterone acetate (MPA) (Bonekat et al., 1987). Others (Regensteiner et al., 1989, 1990) havesuggested that the presence of estrogen potentiates these effects by its action on progesteronereceptors. Nevertheless, there have been no associated alterations in either V0 2,,,„x or enduranceperformance in the athletes, both male and female, involved in these studies. A recent study (DeSouza et al., 1990) reinforced the impression of no menstrual cycle influence on maximal andsubmaximal exercise performance in a group of elite female athletes, but contrary to these earlierstudies, did not find any variation in minute ventilation.Similarly, hormonally-mediated fluctuations have been documented throughout themenstrual cycle in plasma volume and hemoglobin concentration (Gaebelein and Senay, 1982;Jurkowski et al., 1981), as well as in body temperature (Hessemer and Bruck, 1985a, 1985b;Wells and Horvath, 1973, 1974), but without any significant corresponding impact onperformance. From these and other studies (Stephenson et al., 1982a, 1982b), there appears tobe a dissociation of the hemodynamic and thermoregulatory responses to exercise during themenstrual cycle from specific metabolic aspects of athletic performance.Most of the research to date has concentrated on cardiopulmonary changes, and very littleinformation exists on any differential strength gains as a function of cycle phase. The studies thathave been carried out, as a rule, have not used either basal body temperature (BBT) monitoringor measurement of serum progesterone to accurately document the cycle phase. The evidence todate, albeit somewhat limited, suggests that isometric strength, as measured by maximumvoluntary contraction (MVC) of grip strength, is actually decreased during the luteal phase (Wirthand Loman, 1982), and that there also appears to be a decrease in isometric endurance potentially6related to an increase in deep muscle temperature during this phase of the cycle (Petrofsky et al.,1975, 1976). Other more recent studies (Dibrezzo et al., 1991, Quadagno et al., 1991) have failedto demonstrate any meaningful changes across the menstrual cycle in either isokinetic strengthor maximal weight for bench press or leg lifts.Surprisingly, even less is known about the effects of OCAs on any of the common indicesof athletic performance. The few anecdotal or retrospective studies that have been carried out areinconclusive, and one even reported a performance enhancement in 8% of respondents (Bale andDavies, 1983). Early controlled trials are difficult to interpret because of the diversity in both theestrogen and progestin components of the OCA used, as well as in the range of fitness of thesubjects involved. It has been suggested by some that there is a decrease in VO2mu in subjectstaking an OCA (Daggett et al., 1983), in conjunction with a significant reduction in mitochondrialcitrate, but no associated alterations of post-exercise muscle glycogen or lactate. Other groupsof investigators maintain that there is no significant effect of OCAs (Huisveld et a., 1983;McNeil and Mozingo, 1981), but they have only studied cross-sectional populations of exercisingfemales. Furthermore, none of these early studies have been carried out with the OCA mostfrequently utilized today, a low-dose triphasic formulation. The only prospective investigationto date involving such an OCA has also shown a slight, but statistically significant reduction infunctional aerobic capacity after a 6 month period on a low-dose monophasic OCA, that wasreversible upon discontinuation of the medication (Notelovitz et al., 1987). In terms of musclestrength, extrapolation from the known effects of anabolic steroids might suggest that theandrogenic component of OCAs could have some positive effects, but the studies to date(Petrofsky et al., 1976; Wirth and Loman, 1982) do not substantiate this premise, and in fact,7refute it to some degree.Thus it can been seen that investigators are not in agreement on the effects of either thephase of the menstrual cycle, or the administration of OCAs, on athletic performance. This studywas therefore undertaken to examine the performance of a group of elite female athletes usingfour commonly utilized physiological measures: aerobic capacity (maximum oxygen consumptionor V02.), anaerobic capacity, aerobic endurance at 90% of V0 2., and isokinetic strength. Thepurpose was to document whether or not the results of these tests are influenced by either theendogenous hormonal variations during the phases of a normal menstrual cycle, and/or theexogenous administration of a low-dose triphasic oral contraceptive containing both norethindroneand ethinyl estradiol.8METHODS AND MATERIALS:SUBJECTS:Female subjects between the ages of 18 and 40 were recruited by means of advertisementand word of mouth. Ethical approval was obtained from the Committee on HumanExperimentation of the University of British Columbia, and all subjects signed a written informedconsent. All of the women were having regular menstrual cycles from 24-35 days apart, and hadnot taken oral contraceptives for at least three months prior to entering the study. Evidence forovulatory cycles was initially obtained by a menstrual history questionnaire determining theexistence of symptoms such as breast tenderness, fluid retention, appetite change, and moodswings in the one to two weeks preceding a normal menstrual flow. The presence of suchsymptoms has been shown to be due to, and thus be an indicator of the luteal phase elevationin estrogen and progesterone (Prior and Vigna, 1987a). All subjects were "trained", andparticipating in some type of regular intensive aerobic activity on a regular basis. In order tomore accurately document small differences in performance attributable to the experimentalconditions, the population of subjects studied was limited to elite female athletes, as defined byan entrance V02  equal to or greater than 50 ml•kg i•nin-1 . Volunteers were recruited from avariety of sports including running, cycling, triathlon, squash, cross-country skiing, ultimateFrisbee, and rowing. An initial screening assessment of the level of their training activities wascarried out at the time of entrance into the study, and fitness level was confirmed at the time ofthe first testing. Subjects who, on the first testing, did not meet the required aerobic capacitywere eliminated from the study.9A questionnaire was also administered to determine the general health of the subjects, andto eliminate any potential risk factors for the administration of oral contraceptives. Subjects wereexcluded if they were smokers, or if they had any significant past medical history, or were takingany medication that might interfere with the exercise testing. Those who were on vitaminsupplements, or iron therapy, were asked to maintain the exact dosage throughout the entirelength of the study. Subjects were also required to have a physical examination, including apelvic examination and Pap smear, carried out by their own physician. If they experienced anysignificant or untoward side effects from the oral contraceptive, they were free to discontinue it,and withdraw from the study at any time.Subjects were required to maintain a steady-state level of aerobic training throughout theexperimental period. They were asked to record a daily training log, as well as their basal bodytemperature, menstrual and ovulatory symptoms, resting heart rate, weight, and subjectivesensations of performance. Basal body temperature was taken orally, before rising at the sametime of day, and recorded on a standard form, with comments in a separate column to explaindifferent times or concurrent illness or fever. The intensity and amount of training were reviewedto ensure that there was no substantial training stimulus over the duration of the study.Physiological testing was carried out in the midfollicular phase (between days 3 and 8 ofa normal cycle), and in the midluteal phase (between days 4 and 9 after ovulation, as determinedby a sustained rise in basal body temperature of 0.2 to 0.3 degrees Centigrade). These resultswere later analyzed by a computerized (Maximina R) least mean squares technique (Prior et al.,1990b) to determine day of ovulation and length of luteal phase. The estimated phase of the cyclewas verified by comparing the obtained measurements of ovarian hormones to normal values, as10follows:Estradiol (pmo1•1 -1):^follicular range: 37-734 pmo1•1 -1midcycle range: 440-1375 pmo1.1 -1 'luteal range:^55-955 pmo1•14Progesterone (nmo1•1-1):^follicular range:0.3-4.8 nmo1•1-1luteal range:^8.0-89 nmol•r imid-luteal range: 12.1-89 nmol•1-1However, the level of serum progesterone at rest that was required for absolute confirmation ofthe luteal phase was greater than 16 nmo1•1 -1 (Abraham, 1974). Subjects who did not ovulateduring one cycle were followed through the next cycle and tested then after ovulation. If theydid not ovulate during the second cycle, then the first testing (midfollicular phase) was repeatedagain prior to testing during the luteal phase. The order of testing during a normal cycle wasrandom, depending upon when subjects were enrolled in the study.Following these two tests performed during the menstrual cycle, subjects were randomlyassigned in a double blind fashion to either an OCA (n=8) or a PLACEBO (n=9) group for atotal of two months. The oral contraceptive used in this study was a triphasic formulation(Synphasic, Syntex, Inc.) and contained two different combinations of ethinyl estradiol andnorethindrone as follows: days 1-7: norethindrone 0.50 mg; days 8-16: norethindrone 1.0 mg.;and day 17-21: norethindrone 0.50 mg; in combination with a constant concentration of 0.035mg of ethinyl estradiol from days 1-21. This OCA was chosen because it conformed to prevailingrecommendations of Health and Welfare Canada (1985) in terms of starting patients on a low-dose triphasic preparation. Of the OCAs available at the time that the study was initiated,11Synphasic contained the lowest total norethindrone dose (15.0 mg over the 21 day cycle).Moreover, for purposes of this study, it was deemed more appropriate to utilize an OCA witha constant estrogen component, and only two different dosages of the progestin, in order to moreclosely approximate the two phases of the menstrual cycle that were being studied.All subjects took an unmarked lactose capsule containing either OCA or placebo, dailyfor three consecutive weeks, and then stopped for a week, to simulate regular administration ofthe oral contraceptive. This was carried out for a total of two months. They continued to recordboth a training log, and their basal body temperature during this time. A third testing (treatmentor RX test) was carried out between days 14 and 17 of the second cycle of the OCA/placebo.For subjects who were taking the OCA, this corresponded to the higher dose of norethindrone.For subjects who were taking the placebo, however, this third test could have potentially takenplace during the follicular or luteal phase, or even during the mid-cycle estrogen peak. Theinvestigators were not aware to which group the subjects had been assigned.EXPERIMENTAL PROTOCOL:The experimental protocol was carried out on two successive days, and was virtuallyidentical for each testing. For the first day of testing, subjects were asked to refrain from anyvigorous exercise during the previous 24 hours, and to report to the laboratory in a rested state,having fasted and abstained from any caffeine-containing compounds for at least three hours priorto testing. The height and weight of each subject was measured. Room temperature andbarometric pressure were also recorded. Prior to warm-up, venous blood samples were taken(Becton-Dickinson EDTA K3 tubes), and subsequently analyzed for estradiol and progesterone,12and a complete blood count, as described later. Aerobic capacity (V02,..) and anaerobicperformance (AST) were assessed. The second day of testing involved the measurement ofisokinetic strength, aerobic endurance, sum of skinfolds and percent body fat by underwaterdensitometry.BODY COMPOSITION:Anthropometric measurements included height and weight (Detecto industrial scale),measurement of skinfold thickness at six different sites (biceps, triceps, subscapular, suprailiac,anterior thigh and medial calf) with a Harpenden skinfold caliper (John Bull, British IndicatorsLtd); and underwater densitometry using a hydrostatic weighing tank. Skinfold measurementswere simply summed Percentage of body fat was calculated by the method of underwaterdensitometry (Brozeck et al., 1963) using the Sin formula (Siri, 1961).BLOOD SAMPLES:Venous blood samples were taken prior to any warm-up exercise. They were kept cool(not refrigerated) for the duration of testing, and then processed as follows at the completion ofthe testing: one tube was taken to the Laboratory at the University Hospital, U.B.C. Site, fordetermination of an automated blood count (CoulterS + STKR). The remaining blood was spundown in a refrigerated centrifuge (Damon/IEC Clini-Cool) for 10 minutes at 3000 rpm. Theplasma was then removed and stored in Venoject plain silicone-coated glass tubes at -20 degreesC until it was subsequently analyzed in the laboratory at the Vancouver ni-nPral Hospital, usingcommercially available no-extraction solid-phase ' 251 radioimmunoassays ,.t-A-Count Estradiol13and Coat-A-Count Progesterone, Diagnostic Products Corporation). To minimize interassayvariability, samples were coded and analyzed in three separate batches by an independentobserver. All samples from one subject were analyzed together, and at least one subject fromeach of the two experimental groups was included in each assay. The intra-as say coefficient ofvariations (CV) were 10.6% for estradiol and 10.3% for progesterone. Interassay CV's rangefrom 4.2% to 8.1% for estradiol and from 7.2% to 10.0% for progesterone (Diagnostic ProductsCorporation). The sensitivities of these assays are 2.9 pmo1•1 -1 for estradiol and 0.16 nmo1•1 -1 forprogesterone.AEROBIC CAPACITY:Following a 5 to 10 minute warm-up at a speed of between 2.2 m•s'' and 2.7 m•s -1 , themeasurement of V02,nu was carried out on a Quinton 24-72 treadmill. The protocol utilized acontinuous progressive workload on a level grade, beginning at a speed of 2.2 m•s', andincreasing by 0.22 m•s -1 each minute until fatigue (as previously described by Parkhouse et al.,1985). Heart rate was monitored with either an ECG tracing on a Burdick EKI5Aelectrocardiograph, or a Polar Vantage heart rate monitor; and was recorded at 45 seconds intoeach stage. Expired gases were continuously sampled and analyzed utilizing a BeckmanMetabolic Measurement Cart (0M-11 oxygen analyzer and LB-2 carbon dioxide analyzer), andtabulated by a data acquisition system (Hewlett-Packard 3052A) that determined respiratory gasexchange variables every 15 seconds. Calibration of the volume transducer was performedutilizing a 1.0 liter syringe, and both gas analyzers were calibrated with standardized calibrationgases and room air prior to each test. A maximal test was defined by achievement of at least two14of the following three criteria: a plateau or decrease in V02  despite an increase in work load,a respiratory exchange ratio (RER) greater than or equal to 1.1, or attainment of at least 90% ofpredicted maximum heart rate. If a subject did not complete a satisfactory maximal test, thetesting procedure was repeated, following a short rest, but starting at a velocity of 3.08 ti•s'.ANAEROBIC PERFORMANCE:Subjects were allowed to rest for at least 1 and 1/2 hours following the V02 . test beforemeasurement of their anaerobic performance took place. High intensity running performance wasassessed by the anaerobic speed test (AST) of Cunningham and Faulkner (1969) employing timein seconds to fatigue as the performance index. Fatigue was defined as an inability of the subjectto continue at the set treadmill speed. Following an adequate warmup, subjects performed the runat 8 mph (3.52 m•s -1) at a 20% incline until fatigue. Subjects were aware of the elapsed time. Thetest-retest reliability of this test has been documented as r = 0.76 to 0.91 (MacDougall et al.,1991).ENDURANCE PERFORMANCE:The results of the V02.. were used to calculate a treadmill velocity representingapproximately 90% of the maximal oxygen uptake. In fact, this workload was determined bytaking 90% of the treadmill speed at which the subject completed their last complete minute ofrunning before stopping the test. Therefore, because of the different lengths of time that thevarious subjects were able to continue running in an anaerobic state, this value actually rangedfrom 90 to 95% of their V02... Once set, this workload speed remained constant for the next15two testing sessions, regardless of any subsequent variations in the actual V0 2  measurement.Endurance performance was assessed as the treadmill running time in seconds to fatigue.ISOKINETIC STRENGTH:Isokinetic strength was measured as peak torque in newton meters (N•m) generated byknee flexion and extension on a Cybex H isokinetic dynamometer at a velocity of 30 degrees•s -1 .The subjects were positioned on the Cybex table so that the lateral femoral condyle was alignedwith the axis of rotation of the isokinetic dynamometer. Subjects were secured to the backrestby a seat belt at the waist, and the leg to be tested was stabilized with a strap above the knee atmid-thigh. After a short warmup at a velocity of 240 degrees•s -1 , the best values of three differentattempts with each leg were taken. The coefficient of variation of this single joint test performedat this velocity has been reported as 5.9% (MacDougall et al., 1991).STATISTICAL ANALYSIS:The data from different phases of the menstrual cycle were analyzed using pairedStudent's t tests for dependent means. The data from the experimental protocol were analyzedusing a 2x3 analysis of variance (ANOVA) with repeated measures on the second factor. Theindependent variables were treatment protocol (RX = OCA or PLACEBO) and test (follicularphase, luteal phase, and test on OCA or placebo). The dependent variables analyzed in eachANOVA were maximum aerobic consumption (V0 2 ), anaerobic capacity (AST), isokineticstrength (Cybex II measurement of peak torque of knee flexion and extension), and aerobicendurance (time to exhaustion at 90% of VO2m.). The baseline variables of age, height, weight,16percentage body fat and VO2  were reviewed to ensure that the subjects in each group werehomogeneous. At subsequent testing sessions, weight, sum of skin folds and percentage body fatwere remeasured and also analyzed for changes over time as a result of treatment protocol. Theresults from the blood tests for estradiol, progesterone, hemoglobin concentration and hematocritwere also analyzed in this manner.Ideally, because of the multiple analyses that were performed, both Hotellings T 2, andmultivariate analysis of variance (MANOVA) should be carried out, prior to exploring significantdifferences between the two groups on any one variable. This was not possible, however, becauseof the nature of the study and the small number of subjects involved in comparison to thenumber of dependent variables. Therefore, to protect against an inflated Type I error rate, anabsolute level of significance that was acceptable was set at p<0.01. For purposes of analysis oftrends however, all p values up to 0.15 are reported and discussed. This was done to gain anunderstanding of any potential effects of either the phase of the menstrual cycle or administrationof OCA that might be statistically significant in future studies, given a larger sample size anddecreased variability in the population studied. Furthermore, since the treatment was not initiateduntil after both groups had completed both follicular and luteal phase tests, the F ratios and pvalues that are reported refer for the most part to the interaction between the two independentvariables (treatment protocol and test). The only exception to this are the ANOVA results forestrogen and progesterone values between all tests. Significant interactions were further exploredby graphing the means of each group over time. The statistical package utilized was Systatversion 5.01. All values are expressed as means + SE.17RESULTS:SUBJECTS:A total of 51 women were initially enrolled in the study based on predicted level offitness and a menstrual history suggestive of regular ovulation. Of these, 33 were actually testedin order to obtain 27 subjects who satisfied the entry requirement of a V0 2„,,„ greater than orequal to 50 ml•Ice•min -1 . A final sample of only 19 women were determined to have ovulatedaccording to nonquantitative assessment of their BBT measurements. All of these subjectssuccessfully completed at least two parts of the study. The entry level data for these women (atthe time of the follicular phase test) and their plasma estradiol and progesterone levels (for allthree tests) are presented in Table I.GROUPS:EFFECT OF MENSTRUAL CYCLE PHASE:Menstrual cycle phase was verified by comparison of the obtained measurements ofovarian hormones to those previously reported in the literature. The absolute level ofprogesterone accepted for confirmation of the luteal phase was 16 nmo1.1 -1 (Abraham, 1974). Twoof the women who did ovulate (VA and MO) were tested during both the follicular and the lutealphases, but dropped out of the study prior to being assigned to a treatment protocol. Their data,therefore, was included in the analysis of the effects of the menstrual cycle phase onperformance. Using the above criteria, it can be seen from Table I, that three of the subjects (SB,DH, and EB) were not actually in the luteal phase of their cycle at the time of testing for this18TABLE I. SUBJECT PROFILES AND HORMONAL VALUES:^Subj Age^Height^Weight^V02mai^Estradiol^Progesterone(yrs)^(cm) (kg)^(ml•kg-l•min-1)^(pmo1.14) (nmo1•1-1)F L RX F L^RXNO TREATMENT:VA' 27 169.4 53.0 54.7 255 497 --- 0.9 55.0 ---MO' 27 159.0 59.0 50.5 101 697 --- 1.6 37.0 ---PLACEBO GROUP:S132 25 169.4 53.0 53.2 61 348 1043 1.2 1.8 1.8JF 34 166.3 58.6 50.6 77 256 298 1.0 17.5 1.0JH 29 159.2 44.3 58.6 131 665 397 1.2 65.0 43.0PW 32 167.1 56.3 52.1 188 536 517 1.6 73.0 63.0JR 26 177.8 74.0 52.1 126 238 370 1.1 45.0 8.6TE 25 171.4 63.5 52.3 115 308 174 1.1 34.0 1.3SJ 30 169.2 57.3 55.2 109 254 340 0.6 24.0 11.5ES 22 167.4 65.3 50.2 190 631 455 1.4 41.0 8.2DIP 30 178.6 60.0 56.8 75 184 122 1.4 0.9 1.0OCA GROUP:CL 32 172.5 64.7 51.3 47 437 31 1.3 25.0 0.8AM 23 172.9 61.1 55.2 178 558 548 1.5 40.0 27.0CS 26 169.2 60.1 51.4 154 433 926 2.0 34.0 63.0KD 22 159.9 51.8 52.4 280 414 241 1.2 46.0 52.0MM 25 172.5 64.5 53.1 102 376 70 1.2 51.0 0.8MC 30 168.5 58.5 64.2 88 581 75 1.2 28.0 0.6IL 32 164.1 61.1 55.3 122 501 36 0.6 34.0 1.2EB3 23 155.6 55.8 52.2 83 632 87 1.5 3.1 1.4SUBJ, subject; F, follicular phase; L, luteal phase; RX, treatment; OCA, oral contraceptive agent'Subjects only completed menstrual cycle part of study.2Subject did not ovulate, so excluded from menstrual cycle part of study; third test was duringmidcycle estrogen surge, so excluded from oral contraceptive part of study.3Subjects did not ovulate, so data excluded from menstrual cycle part of study.19phase. This occurred despite biphasic BBT charts suggestive of ovulation, at least bynonquantitative analysis. The patterns of their cycles, as later analyzed by the computerizedMaximina R program (Prior et al., 1990b) showed that they had varying degrees'of luteal phasedysfunction. One of these athletes (EB) was tested on days 23 and 24 of her cycle, followingvisual estimation of the day of ovulation from her BBT charts as occurring on day 19. However,the statistical computer analysis of her BBT data (which is of necessity done retrospectively)showed that she did not actually ovulate until about day 25. Another athlete was tested duringthe luteal phase, according to the quantitative analysis of her temperature data, but had a lutealphase length of only 12 days. The third athlete probably did not ovulate, as even assessment ofher BBT pattern by the Maximina R program failed to give a result for the most likely day ofluteal phase onset. As a consequence, the data from these women was also excluded from theanalysis of the menstrual cycle phase effects on performance.EFFECTS OF THE ORAL CONTRACEPTIVE:Seventeen women participated in this part of the study. They were randomly assigned toeither PLACEBO (n=9) or OCA (n=8). The three women who did not show objective hormonalevidence of ovulation were excluded from the final analysis. It is interesting to note that one ofthese subjects, (SB) in the PLACEBO group appeared to be in the midcycle estrogen surge at thetime of her third test (i.e. high estradiol and low progesterone). The remainder of the subjectsin the PLACEBO group, could be classified as either being in the follicular (low estradiol, lowprogesterone) or the luteal (high estradiol, high progesterone) phase during their third test, basedon their hormonal data. Further examination of the hormonal values for the third and final test20indicated that 5 of 8 subjects taking the OCA had suppression of their endogenous ovarianhormones to varying degrees. This was not true however, for 3 of them (AM, CS, and KD), whohad values of both estradiol and progesterone equivalent to luteal phase levels. This was anunexpected finding, and may indicate incomplete or inadequate suppression of ovulation by theOCA in these subjects. Plasma levels of the synthetic steroid hormones in the OCA (ethinylestradiol and norethindrone) were not measured, but were assumed to be high during this test.EFFECT OF MENSTRUAL CYCLE PHASE:The data from both the OCA and placebo group were pooled to obtain a total of 16subjects (mean ± SE; age = 27.6 ± 3.8 yr; height = 167.9 + 5.3 cm; follicular phase weight =59.6 + 6.7 kg; VOA. = 53.7 ± 0.9 ml•kg -1 •min-1 ) who demonstrated both subjective(nonquantitative assessment of BBT charts) and objective (plasma estrdiol and progesteronevalues in the mid-luteal range) evidence of ovulation. Their body composition measurements andthe results of their blood tests and exercise performance tests are presented in Tables Ha and Ilb.Testing took place during the midfollicular phase (day = 5.7 + 0.5) and the midluteal phase (day= 23.3 + 0.9). Room temperature was 22.9 + 0.4 degrees Centigrade and barometric pressure was760.9 ± 0.7 mm Hg.BODY COMPOSITION:There were no significant differences found between the two tests (i.e. between thefollicular and luteal phases of the cycle in the same subject) with regards to weight, percent bodyfat or sum of skinfolds.21TABLE Ha. EFFECT OF MENSTRUAL CYCLE PHASE ON ANTHROPOMETRIC,HORMONAL AND HEMATOLOGICAL VARIABLES:VARIABLEWeightkgBody Fat%Sum ofskinfoldsEstradiolpmo1•1-1Progesteronenmo1•1-1Hemoglobingin.1-1Hematocrit%MCVfLPHASE OF CYCLEFOLLICULAR^LUTEALPAIRED t-TEST(df = 15)59.6 ± 1.7 59.5 ± 1.8 NS17.4 ± 0.3 17.1 ± 1.0 NS75.2 ± 3.9 76.1 + 3.7 NS141.4 ± 15.8 461.4 + 36.9 T=8.58, p<0.01122 ± .09 40.6 + 3.7 T=10.57, p<0.01131.4 + 1.5 133.2 + 1.2 T=1.72, p=0.1138.5 ± 0.4 39.2 ± 0.3 T=1.98, p=0.0791.8 + 0.9 91.8 + 0.9 NSValues are means ± SE. (n=16)Sum of skinfolds = total in mm; MCV, mean cell volume.No other significant differences were observed.22TABLE Hb. EFFECT OF MENSTRUAL CYCLE PHASE ON PERFORMANCEVARIABLES:VARIABLE PHASE OF CYCLEFOLLICULAR^LUTEALPAIRED t-TEST(df = 15)V02.l•min-13.19 ± .09 3.13 + .08 T=2.28, p=0.04V02,,.ml•kg i•nie53.7 ± 0.9 52.8 ± 0.8 T=2.04, p=0.06HR(max)bpm189.4 + 2.3 189.5 ± 2.6 NSRER(max) 1.17 ± 0.01 1.15 ± 0.01 NSVE(max) 105.4 + 2.3 106.3 ± 2.4 NS1•min-1(BTPS)ASTseconds28.5 ± 2.2 28.3 + 2.3 NSETseconds753.8 + 58.8 769.3 + 64.1 NSR Quadriceps 143.9 ± 7.9 142.4 + 6.1 NSN•mR Hamstrings 80.5 ± 4.5 83.3 + 4.8 NSIsT•mL Quadriceps 144.4 ± 8.2 141.7 ± 7.2 NSN•mL Hamstrings 82.5 ± 5.6 83.6 + 4.4 NSN•mValues are means ± SE. (n=16)V02,. •, maximum oxygen consumption; VE(max), maximum recorded minute ventilation;HR(max), maximum heart rate; RER(max), maximum respiratory exchange ratio; AST,anaerobic speed test; ET, endurance time; R, right, L, left; (measurements of muscle strength arepeak torque, measured at 30 degrees•s-1 , best of three trials).No other significant differences were observed.23BLOOD TESTS:The levels of both estradiol (mean follicular = 141.4 + 15.8 pmo1•1 -1; mean luteal = 461.4+ 36.9 pmo1•1 -1) and progesterone (mean follicular = 1.22 + 0.09 nmo1•1-1; mean luteal = 46.6 +3.7 nmo1•1-1) were significantly different (p<0.01) between the two phases, as would be expectedin women with ovulatory cycles. Mean red cell volume did not change from the follicular toluteal tests. There was a trend towards a slightly increased hemoglobin (mean follicular = 131.4+ 1.5 gm•1-1 , mean luteal = 133.2 + 1.2 gm•1 -1) and hematocrit (mean follicular = 38.5 ± 0.4percent, mean luteal = 39.2 ± 0.3 percent) during the luteal phase, although the increase did notreach statistical significance.EXERCISE PERFORMANCE:In examining the effects of cycle phase on athletic performance, the data show thatabsolute VO L,2  decreased slightly from 3.19 + 0.09 limin -1 to 3.13 + 0.08 l•mie from thefollicular to luteal phase (p=0.04), while relative V0 2. also decreased in parallel, from 53.7 +0.9 ml•kg-l•mie to 52.8 + 0.8 ml•keirnin-1 (p=0.06). These changes are represented graphicallyin Figure 1 for all subjects. There were no significant alterations in maximum VE (highestrecorded minute ventilation), maximal heart rate, or maximum RER attributable to phase of thecycle. The remainder of the tests of performance: the anaerobic speed test (AST), the endurancerun at 90% V02., and the Cybex II measurements of isokinetic strength of quadriceps andhamstrings; were also not influenced by the menstrual cycle phase to any significant degree inthese 16 subjects.Figure 1: Effect of Menstrual Cycle Phaseon VO2max65so55EL 5045Follicular^Luteal2425EFFECT OF THE ORAL CONTRACEPTIVE:A subgroup of 14 of the original 19 subjects successfully completed all three parts of thestudy, and it was thus possible to compare their results from the follicular, -luteal and theTREATMENT tests. The effect of administration of the triphasic OCA (Synphasic) wascompared to a PLACEBO, (OCA n=7; PLACEBO n=7) for differences in the trends across bothgroups. The descriptive statistics for both groups during the follicular phase were similar (mean+ S.E.; PLACEBO: age = 28.3 ± 1.58 yr, height = 168.6 + 2.0 cm, weight = 60.0 + 3.5 kg;OCA: age = 27.1 ± 1.6 yr, height = 168.5 + 1.9 cm, weight = 60.2 + 1.7 kg). The measurementsof body composition, and the results of the blood tests, and tests of exercise performance for bothgroups are presented in Tables Ma and DD. Testing took place during the midfollicular andmidluteal phases, as previously described and then at approximately midcycle (day 14.4 ± 0.5)during the second month of administration of the treatment. Testing conditions were similar tothose for the first part of the study.BODY COMPOSITION:There were no significant overall mean differences between the two groups in weight orpercentage body fat for the follicular and luteal phase tests, and the treatment tests. There wasa tendency for a slight increase in weight (mean follicular = 60.2 + 1.7 kg to mean treatment =61.2 ± 1.6 kg) in the group on OCA, compared to the PLACEBO group. There was also a slightincrease in body fat in the OCA group from 16.5 ± 1.6 percent in the follicular phase to 17.5 +1.6 percent on treatment, and a concomitant decrease in the PLACEBO group from 17.4 + 1.9percent in the follicular phase to 16.9 ± 1.9 percent over the same time frame. These results,26however, did not quite attain statistical significance. There was an overall significant differencebetween the two groups (p<0.01) in the change in the sum of the skinfolds. The OCA groupincreased from 68.8 + 5.3 mm in the follicular phase to 73.1 + 4.1 mm in the luteal phase to79.2 + 6.2 mm on treatment, while the PLACEBO group decreased slightly from 80.1 + 6 6 mmin the follicular phase to 78.9 ± 7.5 in the luteal phase to 76.3 ± 8 0 mm on treatment. Theseresults are presented graphically in Figure 2.BLOOD TESTS:There was a significant difference in the estradiol values obtained in the follicular, luteal,and treatment tests for all subjects (p<0.01), but this effect was to be expected, and did not varyas a function of the treatment. Likewise, progesterone values varied between each test for bothgroups (p<0.01), but there was no significant difference between the two groups as a result ofthe treatment protocol. Hemoglobin and hematocrit values and mean red cell volume did not varysignificantly either between the two groups, or within each group across the three tests.EXERCISE PERFORMANCE:There was an overall difference in response between the OCA and PLACEBO group inboth the absolute V02  (p4.05), and the relative V02. (p=0.02). This occurred between theluteal phase and the treatment test measurements (i.e. when the athletes were taking themedication). Absolute V0 2. continued to decrease in the OCA group from the follicular to theluteal phases (3.29 + 0.12 1.min -1 to 3.26 + 0.11 1•min" 1 ), to the treatment tests (3.18 ± 0.09l•min-1); while in the PLACEBO group, there was a slight decrease between the follicular and27luteal phase tests (3.16 ± 0.15 l•min -1 to 3.08 ± 0.13 l•min-1), but an increase in the third test (to3.18 + 0.13 1.min"). Relative V0 2. followed the same pattern in the OCA group with follicularto luteal phase decreases (from 54.7 + 1.7 ml•kg -l inain-1 to 53.7 + 1.2 ml•lcesmin -1) followed bya further decrease on OCA (to 52.0 ± 1.0 ml•kg -1 •min-1); while the PLACEBO group decreasedconcomitantly from the follicular to luteal phases (53.0 ± 1.1 ml•lcg 1•min-1 to 51.9 ± 1.3 ml•kg-1•min-1) and then increased again during the third test (to 53.8 + 1.7 m1.14 1 .min-1). Thesechanges are depicted graphically in Figure 3. There were no significant accompanyingfluctuations in maximum recorded minute ventilation (V E), maximum heart rate or maximumrespiratory exchange ratio (RER).Follicular Luteol Rx9050V)60Figure 2: Effect of Rx on Sum of Skin Folds28Figure 3: Effect of Rx on VO2max5856xoo54oc%) 52050Follicular Luteal^Ex2930TABLE ma. EFFECT OF CYCLE PHASE AND OCA ON ANTHROPOMETRIC,HORMONAL AND HEMATOLOGICAL VARIABLES:VARIABLEFPLACEBO (n=7)L RXORAL CONTRACEPTIVE (n=7)F^L RXWeight 59.9 59.9 59.8 60.2 60.6 61.2kg ±3.5 ±3.6 ±3.8 ±1.7 ±1.7 ±1.6Body Fat 17.4 17.1 16.9 16.5 16.5 17.5±1.9 ±1.5 ±1.9 +1.6 ±1.4 ±1.6Sum of 80.1 78.9 76.3 68.8 73.4 79.21skinfolds +6.6 +7.5 +8.0 +5.3 +4.1 +6.2Est 133.7 412.7 364.4 138.7 471.4 275.3*pmo1•1-1 ±15.7 ±72.0 +41.9 ±28.6 ±29.1 +128.9Progest 1.14 42.8 19.5 1.29 36.9 12.7*nmol•rl +.12 +7.7 +9.0 +.16 +3.6 +7.5Hgb 133.1 134.4 135.7 131.3 132.6 130.7gm•1-1 ±1.9 ±1.9 ±1.7 ±2.3 ±1.8 +1.8Hct 39.0 39.3 39.9 38.5 39.2 38.7+0.6 +0.4 +0.5 +0.5 +0.4 +0.6MCV 92.0 91.7 92.9 91.9 92.3 91.8fl. +0.6 +0.9 +1.0 +1.8 +1.8 +1.9Values are means + SE.F, follicular phase; L, luteal phase; RX, treatment.Est, estradiol; Progest, progesterone; Hgb, hemoglobin; Hct, hematocrit; MCV, mean cellvolume.significant F(2,24)=6.94, p<0.01.* significant between phases, but not between groups: estradiol F(2,24)=13.58, p<0.01;progesterone F(2,24)=34.18, p<0.01.No other significant differences were observed for the interaction.31TABLE Mb. EFFECT OF CYCLE PHASE AND OCA ON PERFORMANCEVARIABLES:VARIABLEFPLACEBO (n=7)L RXORAL CONTRACEPTIVE (n=7)F^L^RXV02„,,„^3.16 3.08 3.18 3.29 3.26 3.18'l•mind^+.15 +.13 +.13 +.12 +.11 +.091702,„.^53.0 51.9 53.8 54.7 53.7 52.02ml•ke•miril ±1.1 ±1.3 ±1.7 +1.7 ±1.2 ±1.0VE(max)^108.4 109.3 107.6 104.5 105.2 102.6l•minABTPS) +4.2 ±3.8 ±5.2 ±3.0 ±3.5 ±2.4HR(max)^188.9 188.3 191.0 189.9 190.0 190.5BPM^+4.3 +5.1 +5.4 +3.3 +3.2 +4.6RER(max) 1.17 1.15 1.12 1.17 1.16 1.16±.02 ±.02 ±.02 ±.02 ±.03 ±.02AST 26.1 24.9 26.6 33.0 33.0 33.0seconds +3.2 +2.8 +3.4 +3.0 +3.2 +2.8ET 790.4 761.7 842.4 753.6 781.6 703.1seconds +83.8 +95.0 +120.7 +88.9 +111.0 +148.9RQuad 138.7 135.2 140.2 161.5 157.8 149.1N•m +9.8 +9.4 +12.7 +10.2 +5.5 +4.7RHs 77.1 76.9 78.8 89.9 94.5 93.0N•m +6.5 +5.6 +6.0 +5.8 +7.7 +7.5LQuad 146.4 148.1 138.3 154.5 148.0 141.0N•m +10.9 +9.7 +12.8 +12.7 +9.2 +8.0LHs 75.9 80.9 75.9 98.0 92.0 86.0N•m +5.7 +6.6 +6.8 +7.2 +5.7 +5.5Values are means ± SE.F, follicular phase; L, luteal phase; RX, treatment.V02,„.., maximum oxygen capacity; V E(max) maximum minute ventilation; HR(max), maximumheart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET,endurance time; RQuad, right quadriceps; RHs, right hamstrings; LQuad, left quadriceps; LHs,left hamstrings; measurements are peak torque at 30 degrees•s 1 .significant F(2,24)=3.39, p=0.05^2 significant F(2, 24)=4.91, p=0.02No other significant differences were observed for the interaction.32There was an initial slight dissimilarity between the two groups in the anaerobic speedtest (26.1 ± 3.2 seconds for the PLACEBO group, compared to 33.0 + 3.0 seconds in the OCAgroup), but neither group varied in their performance to any significant degree across all threetests, or as a function of treatment. There was no significant alteration in endurance performancedue to the treatment protocol, although there was a trend towards a decrease in the OCA groupfrom 753.6 + 88.9 seconds in the follicular phase to 703.1 + 148.9 seconds while on treatment,while the performance in the PLACEBO group increased from 790.4 ± 83.8 seconds in thefollicular phase to 842.4 + 120.7 seconds on treatment. Similarly, there was an initial discrepancyin the left hamstrings peak torque measurements (75.9 ± 5.7 N•in in the PLACEBO group vs.92.0 ± 5.7 N•m in the OCA group) but no overall significant difference in the performance overtime. There was a trend for all measurements of strength to decrease slightly in the OCA groupfrom follicular to treatment tests, and to stay relatively the same in the PLACEBO group, but thisdid not reach statistical significance.33DISCUSSION:EFFECTS OF MENSTRUAL CYCLE PHASE:Menstrual cycle phases were confirmed by measurement of plasma estradiol andprogesterone levels taken before exercise for each test. The wide range of values found withineach phase attests to both the interindividual and intercycle variability. Some studies (Prior andVigna, 1991, Shangold et al., 1979) have suggested that trained subjects who are menstruatingmay have a shortened luteal phase with lowered progesterone levels. Many of the subjects in thisstudy, however, despite V02.. values in excess of 50 mg•kg- '•inin-' that would define them aselite athletes, had normal progesterone levels, indicating that low concentrations of progesteroneare not a consistent finding in accomplished athletes. Nor is there necessarily an association ofaltered menstrual status with low body weight, as initially suggested by others (Frisch 1974,1987). Nevertheless, this level of aerobic training is still associated with a fairly high degree ofluteal phase dysfunction, as evidenced by quantitatively determined luteal phase lengths between9 to 14 days in this group of elite female athletes. Furthermore, most athletes with "regular"menstrual cycles would not likely be aware of this process without monitoring of their BBTand/or premenstrual symptoms.The fact that three of the subjects were not actually in the luteal phase at the time of thistest, despite nonquantitative BBT evidence to the contrary, underscores the importance ofaccurate measurements of plasma levels of ovarian hormones in any research involving phasesof the menstrual cycle. Quantitative computer analysis of BBT patterns by programs such asMaximina R (Prior et al.,1990) can further add to the accuracy of timing of luteal phase tests,34as can newer assays to detect the midcycle urinary peak of luteinizing hormone (LH). Neithertechnique is completely infallible, and the accuracy of each method increases with the user'sfamiliarity with the procedures. The former program is helpful also to document the length ofthe follicular and luteal phases, as determined by the least mean squares method. However, priorto comparative analysis of data from different phases of the menstrual cycle, it is still essentialto know the resting plasma levels of estradiol and progesterone values at the time of testing, inorder to accurately ascertain the menstrual cycle phase.BODY COMPOSITION:There were no significant alterations in body weight, percentage body fat, or sum ofskinfolds between the two phases of the cycle in this group of 16 subjects. Many womencomplain of a subjective feeling of weight gain in the premenstrual phase but there is evidence(Prior and Vigna, 1987b) that regular physical exercise can ameliorate some of the symptoms ofpremenstrual syndrome, including fluid retention. This group of athletes was engaged in regularaerobic training, and this factor may have accounted for the lack of variation in their weight.Recent work by Bunt et al., (1989) has questioned the validity of underwater bodydensitometry measurements in women at various phases of the menstrual cycle, because themenstrual cycle changes in plasma volume and total body water may lead to errors in thedetermination of the percentage of body fat using conventional formulas. There also exists acurrent controversy about the reliability and reproducibility of the usage of skinfoldmeasurements in determining body fatness (for review, see Lohman, 1981). Many of theregression formulas use varying combinations of the skinfold measurements in their calculations,35and this may limit comparison of values between different studies. Furthermore, there is markeddisparity between men and women, as well as between young and old individuals in thedistribution of their subcutaneous fat. Therefore, formulas that are derived for a population ofmen or middle-aged women, are totally inaccurate and unacceptable for usage in a selected groupof young athletic women, such as were involved in this study. It is thus more appropriate to usethe sum of the obtained skinfold measurements for comparative purposes, rather than alter thesevalues by any complex mathematical transformations that have the inherent potential forerroneous assumptions.BLOOD TESTS:There was a slight, but nonsignificant increase in both hemoglobin concentration andhematocrit in the luteal phase as compared to the follicular phase of the menstrual cycle. Thisis in disagreement with the results of a very early study (Vellar, 1974), which reportedsignificantly lower hematocrits and hemoglobin concentrations during the premenstrual phase,as a consequence of the plasma volume shifts that occur from the physiological actions ofestradiol. Both hemoglobin concentrations and hematocrit values reached a peak at about the 18thday of the cycle, a time which Vellar termed the postovulatory phase. However, in that study,the blood samples were drawn from women at unsubstantiated phases of the cycle, and bloodestrogen concentrations were not measured. A recent study (Fortney et al., 1988) suggests thatblood progesterone levels must be low in order to see this estrogenic effect. In the present study,both estradiol and progesterone levels were high during the luteal phase. Other investigators havealso noted a slight increase in resting hemoglobin concentration (Jurkowski et al., 1978) and36hematocrit (Fox et al., 1977) during the luteal phase, but have not offered any biologicalexplanation for this phenomenon, nor have they linked it to any alteration in performance.EXERCISE PERFORMANCE:AEROBIC CAPACITY:Both absolute and relative V02,. declined slightly during the luteal phase, (p=0.04 and0.06 respectively). This is of borderline significance, bearing in mind the small number ofsubjects and the number of tests that were carried out, and should therefore be interpreted withsome caution. Because of the multiple comparisons involved in this study, the fiduciary level ofconfidence was set to p<0.01. However, it is still important to consider this as a potentiallymeaningful trend, that may be significant in a larger study with more subjects. To date, thisrepresents the largest series of this nature that has been carried out in elite level athletes, withproper documentation of menstrual cycle phases. In comparison, the most recent study by DeSouza et al., (1991) did not find any significant differences in VO2max between the follicular andluteal phases in their group of 8 eumenorrheic subjects. It does emphasize the fact, however, thatinvestigators doing studies on female athletes should be careful to standardize the phase of thecycle in which testing is being carried out, i.e. 3-8 days post menses, in order to eliminate theconfounding factor of these possibly significant changes in V02.,. between the two phases of themenstrual cycle. It is also quite conceivable, that given the different hormonal milieu at midcycle(high estradiol, low progesterone), that aerobic capacity might be altered as well, potentially ina different fashion. There has been no well-documented research to date on performance duringthis part of the menstrual cycle.37None of the other measurements taken during exercise in this group of athletes showedany variation between the follicular and luteal phases. Again, these findings corroborate theconclusions reached by previous investigators. Both early studies without hormonal measurements(Fox et al., 1977, Garlick and Bernauer, 1968; Wells and Horvath, 1974) and more recent workutilising progesterone and estradiol levels for confirmation of cycle phase (Jurkowski et al., 1978,Shoene et al., 1981, De Souza et al., 1990) have failed to document any significant alterationsin maximum heart rate or respiratory exchange ratio related to phase of the cycle.The lack of change in maximum minute ventilation in this study is also in agreement withthe results of Schoene et al. (1981), who found changes in normally menstruating nonathletes,but not in normally menstruating athletes or amenorrheic controls. Progesterone is thought tostimulate respiration through a central mechanism during both the luteal phase of the menstrualcycle (England and Fahri, 1976), and during pregnancy (Moore et al., 1987; Pernoll et al., 1975).This hyperventilation has also been seen in men given medroxy-progesterone acetate (MPA), asynthetic progesterone (Dombovy et al., 1987; Skatrud et al., 1978) and is thought in part to bedue to increased metabolism, as reflected by increased body temperature after ovulation. The lackof a significant progesterone effect on ventilation in athletes, however, is consistent with theobservation that outstanding endurance athletes have a decreased ventilatory drive in responseto chemotactic stimuli (Byrne-Quinn et a., 1971; Martin et al., 1979). This characteristic isinherited to a certain degree (Martin et al., 1979), and may be a contributing factor in their abilityto successfully compete at an elite level.38ANAEROBIC PERFORMANCE:Little information exists in the literature on the effects of cycle phase on anaerobicperformance. In this study, there was no significant variation in the anaerobic -speed test as afunction of phase of the cycle. The metabolic effects of estradiol on substrate utilization mostlycome into play in prolonged exercise, and therefore would not be expected to have any effect onshort term (around 30 seconds) anaerobic metabolism which relies more on ATP and creatinephosphate. Likewise, elevation of progesterone levels in the luteal phase do not seem to have anyconsequences on this type of energy turnover. The variation and the range of values seen in thesubjects in this study can most likely be attributed to sport-specific training, and the energydemands of the various sports that these subjects were participating in (i.e. the squash playershad the highest time for the anaerobic speed test (35-40 seconds). These AST values are onlyindicative of their anaerobic capacity, and do not reflect the state of their aerobic fitness. Inactual fact, low anaerobic performance is a common finding in aerobically or endurance trainedathletes, such as those involved in this study.ENDURANCE PERFORMANCE:With regards to the effects of phase of the cycle on aerobic endurance performance, incontrast to the work of Jurkowski et al., (1978, 1981), the present study did not demonstrate anysignificant differences relative to the two phases of the cycle. Their group documented a doublingin endurance time at 90% V02„, between the follicular and luteal phases; from 1.57 minutes to2.97 minutes. They postulated a shift in metabolism towards free fatty acids (PM), and aglycogen sparing effect secondary to the increased estradiol and progesterone in this phase of the39cycle. They also measured a higher blood lactate in the follicular phase during heavy andexhaustive exercise. To substantiate their hypothesis of a decrease in lactate production duringthe luteal phase, they further confirmed no effect of the cycle phase on the disappearance of abolus of infused lactate (Jurkowski et al., 1981). Similarly, other investigators (Dombovy et al.,1987) found a decrease in blood lactate and respiratory exchange ratio under the influence ofendogenous progesterone during the luteal phase in women, and also in men given medroxy-progesterone acetate. Earlier studies (Reinke et al., 1971; Lamont, 1986) and work by Bonen etal. (1983, 1991) and Nicklas et al., (1988) have not substantiated these findings. In addition, thereis some disagreement about whether or not there actually is an increment in circulating FFAduring the luteal phase (Reinke et al., 1971; Bonen et al., 1991).One of these groups of researchers (Nicklas et al., 1989) has actually performed musclebiopsies in both the follicular and luteal phases following a bout of depletion exercise on abicycle ergometer (90 minutes at 60%V0 2. and 4 x 1 minute at 100% VO2 ), and then beforeand after exercise to exhaustion three days later. During the three days between these exercisetests, the subjects consumed a controlled diet of 60% carbohydrate in order to maximize repletionof glycogen stores. Although there was no difference in glycogen utilization per se, duringexercise in either phase of the cycle, muscle glycogen repletion was greater in the luteal phasefollowing depletion exercise. Furthermore, even though the change did not attain statisticalsignificance, there was a strong tendency (p<0.07) towards a longer duration of enduranceexercise during the luteal phase. Other authors have found either no phase difference inendurance performance (Stephenson et al., 1982a; Dombovy et al., 1987), or even a longer worktime during the follicular phase, albeit in nonathletes only (Schoene et al., 1981).40One possible explanation for the inconsistency in results is the difference in the variousprotocols used to assess endurance performance. The subjects in this study performed theendurance run on the second day of testing, and had only completed the strength tests, and ashort warmup prior to beginning this test. In the study of Jurkowski et al., (1978) enduranceperformance was tested on a bicycle ergometer as part of a continuous progressive protocol,where the subjects had already completed 20 minutes at 33% of VO2m„x, and 20 minutes at 66%of V02,.. prior to being tested at 90% V02„,„. Furthermore, one of their subjects was unable tocomplete any work at the highest intensity of the protocol during the follicular phase, and withonly 9 women in the study, this may have biased the results. It may be that the progressiveprotocol is a more sensitive test of changes in aerobic endurance; nevertheless, the fact remainsthat the subjects in the present investigation were able to maintain an output of at least 90% ofV02. 0 for anywhere from 4.5 to 22 minutes independent of menstrual cycle phase. The subjectsin the study of Nicklas et al., (1989), on the other hand, were tested at 70% of VOzn., and wereable to sustain this somewhat lower exercise intensity for up to 150 minutes.ISOKINETIC STRENGTH:Studies on strength performance throughout the menstrual cycle are sparse and employa variety of strength tests. In the current protocol, there were no differential effects on isokineticstrength of knee flexion or extension attributable to the phase of the cycle. The majority ofprevious investigators did not confirm menstrual cycle phases with estradiol and progesteronemeasurements, so interpretation of their findings must be made with caution. None-the-less,Quadagno et al., (1991), studied twelve recreational weight-lifters, and found no differences in41their performance in lifting 70% of their maximum weight for bench and leg press at any timeduring the menstrual cycle, as monitored by menstrual cycle charts only. Dibrezzo et al., (1991)found little or no effect of the menstrual cycle phase upon the relationships among body weight,percent body fat, knee extension and flexion strength or endurance (tested on the Cybex IIdynamometer at 60, 180 and 240 degrees•s -1). The definitions of menstrual cycle phases (mensus,ovulation and luteal) in that study were, however, based only on assigned days of an ideal cycle.Wirth and Loman (1982), on the other hand, measured handgrip endurance time and forceoutput at 50% of a maximal voluntary contraction. They found that the maximal voluntarycontraction (MVC) was significantly greater during the follicular phase, but there was nodocumentation of the luteal phase in their subjects by either BBT measurements or serumprogesterone. In another study, Petrofsky et al., (1976) noted a decrease in maximal enduranceof isometric forearm contraction during the luteal phase compared to midway during theovulatory phase (as determined by a rise in BBT temperature), suggesting an inverse relationshipbetween muscle temperature and isometric endurance. This tendency was reversed when thetemperature of the muscle was held constant at 37 degrees Centigrade. The increased bodytemperature in the luteal phase that occurs as a result of the elevation in progesterone has beenshown by others (Quadagno et al., 1991; Wearing et al., 1972) not to have any substantialadverse effects on either the speed or force of muscle contraction. Thus the findings in thecurrent study are in agreement with most of the previous studies, despite the fact that these havenot been carried out with accurate documentation of the cycle phase.42EFFECTS OF THE ORAL CONTRACEPTIVE:BODY COMPOSITION:Early studies using the original high-dose oral contraceptive formulations havedocumented many potentially detrimental side effects, including fluid retention and weight gain,whereas today's new biphasic and triphasic pills contain between 30% to 40% less hormone andcan thus be expected to have a corresponding decrease in adverse effects (Greenblatt, 1985).There was a slight weight gain of about 1 kg in the subjects on the OCA as compared to theplacebo group, but these athletes were only followed for two months. It is possible that this effectwould stabilize over time with continued administration of the OCA, but it is equally conceivablethat this metabolic influence of the synthetic steroid hormones would be cumulative. Whetherthe increased weight is fat, muscle or water is somewhat difficult to ascertain. If the weight gainwas muscle, then one might expect a slight increase in absolute, but not in relative V0 2,.., asa function of increased metabolically active tissue. The increase in the sum of skinfolds wouldsuggest that it was primarily fat or water, but the lack of associated change in percentage bodyfat does not substantiate this entirely.Furthermore, it has been suggested that variations in bone mineral content in young adultwomen may also have an impact on the estimation of percent body fat (Bunt et al., 1990) byunderwater densitometry methods. It has been shown that women with episodic amenorrhea maybe at risk of lowering their bone density in proportion to the number of missed cycles(Drinkwater et al., 1990) It is also quite probable that a group of elite female athletes such aswere involved in this study, experience frequent anovulatory cycles and luteal phase disturbances,despite having seemingly "regular" menstrual bleeding (Bonen and Keizer, 1984). It has recently43been documented (Prior et al., 1990a) that this may, over time, also have an insidious influenceon their bone density that they may not be aware of. Therefore, in terms of the impact of thesevariations in bone density on the determination of body density using underwater densitometry,it would require an extremely large change in percentage of body fat to exceed the limits of bothexperimental and calculation error. These factors need to be kept in mind when doingcomparative research on similar groups of exercising females (see Martin and Drinkwater, 1991).BLOOD TESTS:Some of the potential benefits of oral contraceptives for athletic performance include anamelioration of dysmenorrhea, and a reduced risk of both iron deficiency and anemia. None ofthe subjects in this study were clinically anemic (ie. hemoglobin concecntration < 120 gm•1 -1),but iron status was not determined. Nevertheless, there were no significant changes in eitherhemoglobin concentration or hematocrit as a result of OCA treatment compared to placebo. Thisis in agreement with other studies (Notelovitz et al., 1987).EXERCISE PERFORMANCE:AEROBIC CAPACITY:A slight decrease in V02. was measured in the subjects on OCA as compared to thesubjects on placebo, with no alteration in any of the other cardiorespiratory measures. This is inconcordance with several of the previous investigations. One study (Daggett et al., 1983) hasshown a slight but statistically significant (p<0.05) reduction in V0 2.. (from 44.6 to 39.8 nal•kg -'.miri l) in a group of seven relatively untrained subjects after 1 to 2 months use of an44unspecified oral contraceptive. Another study (Notolovitz et al., 1987) used a design similar tothe present investigation, with both a control group (n=6) and an OCA group (n=6). They hadsimilar findings, but to a lesser degree following a 6 month usage of a lower dose monophasicpreparation. The control group increased their V02. values from a mean ± SD of 42.6 ± 2.8to 45.9+ 5.8 ml•kg-1•min-1 over the duration of the study, but in contrast, the oral contraceptiveusers decreased from 41.2 ± 11.8 to 38.4 ± 9.8 ml•kg -I •min-1 (a 7% difference in aerobic capacityrelative to body weight). This was associated with an 8% decrease in the absolute oxygen uptake(from 2.34 ± 2.17 limin -1), and in the oxygen pulse (12.1 ± 3.2 to 11.2 + 2.2 ml per beat). Thesechanges were reversible on discontinuation of therapy. It may well be that there is a continuumof effects of OCA on aerobic capacity, and as the concentrations of hormones decrease (with acorresponding decrease in most of the other side effects), the effects on V02. become lesssignificant. As these decreases in V02. have not been linked with any significant alterations in02 carrying capacity of the blood (hemoglobin concentration or hematocrit), or the majority ofthe other physiological measurements influencing 02 uptake or delivery to the tissue (such asminute ventilation, heart rate or cardiac output), there may be significant changes at the cellularlevel. The study by Daggett et al., (1983), for example, found a decrease in muscle mitochondrialcitrate in their subjects on OCA. It is worth emphasizing, however, that even a small variationin performance, even though it does not quite reach statistical significance, may be of tremendousimportance to the high performance athlete, where success or failure is frequently measured intenths of a second.Another caveat in research of this nature is the relative impossibility of carrying outdouble blind studies in this type of situation. Approximately half of the subjects in this study45were aware that they were taking the OCA by the alteration in the pattern of their normalmenstrual cycles, and frequently by nuisance side effects such as breakthrough bleedingthroughout the cycle. It is also important to point out that at the time of the third test, 2 of thesubjects on the placebo were actually definitely in the follicular phase, and 2 of them were inthe luteal phase, while the remaining 3 subjects were possibly just entering or finishing the lutealphase of their cycles. Therefore no substantial generalizations or comparisons can be made withregards to the means of these results with their performance on the earlier tests. Nevertheless,the fact remains that overall, the placebo group increased their V0 2. from the baseline follicularphase measurements, as compared to the subjects on the OCA who had a mean slight decreaseover the same time frame. Furthermore, although the mean values for the OCA group onlydeclined from 54.7 ± 1.7 to 52.0 ± 1.0 ml•kg-l •min-1 from the follicular phase test to thetreatment test, 6 out of the 7 subjects showed at least a minimal decrease in V0 2„,,,, over thisperiod, and two subjects had dramatic decreases, in the range of 4 to 9 ml•kg-l•Miti l . There isthus a degree of intersubject variability in this response to exogenously administered hormones.ANAEROBIC PERFORMANCE:There was no alteration in the capacity of the subjects to carry out the anaerobic speedtest, as a function of administration of the OCA or placebo. There does not appear to be anyimpact of OCA on energy metabolism for short term anaerobic work. The scores for this testwere relatively low in the majority of the athletes, indicating a low anaerobic capacity. This isconsistent with the fact that these subjects were well trained for predominantly aerobic-typeactivities.46ENDURANCE PERFORMANCE:There were no significant differences between the two groups with respect to theirperformance on the endurance run, although there was a trend towards a slight decrease in thegroup on OCA. This may be related to some influence of the OCA on substrate metabolism, suchas alteration in carbohydrate or lipid metabolism (Beck, 1973; Bonen et al., 1991). Oralcontraceptives are known to potentiate diabetes and have also been shown to cause a decreasein blood glucose with heavy exercise as compared to a eumenorrheic control group (Bonen etal., 1991). This action would be more likely to decrease endurance performance, than to enhanceit, by decreasing the available fuel for the exercising muscles. Blood glucose was not measured,but this may have been one of the mechanisms accounting for the dramatic difference inendurance performance in some of the subjects. All subjects had fasted for at least three hoursprior to the testing, and they were not allowed to take anything other than water until completionof the endurance run.ISOKINETIC STRENGTH:Likewise, there was a trend for all strength measurements in the OCA group to decreaseover time, as compared with the subjects on placebo, but this did not reach statistical significanceeither. With regards to the effects of OCA on strength, only one study (Petrofsky et al., 1976)has looked at this in any detail. They found that the isometric endurance of subjects on oralcontraceptives did not vary during the course of a cycle, compared to normal controls who didshow an alteration in isometric endurance in response to different times during the menstrualcycle, with a decrease during the luteal phase. They postulated that this latter trend was due to47the increase in deep muscle temperature occurring in the luteal phase of the cycle. The womenon the OCA did not show any variation in their core temperature over the course of a cycle.Unfortunately, they did not test women before putting them on an oral contraceptive to determinethe effect of the medication itself in the same subject. The oral contraceptives certainly providea relatively stable hormonal milieu, as compared to the variations within a normal cycle, but theimportant question of their overall effect on strength still remains unanswered.48SUMMARY:The results of this study demonstrate that although there are small decreases in bothabsolute and relative V02. during the luteal phase of the menstrual cycle in" trained femaleathletes, these do not impact to any significant degree upon commonly utilized measurements ofanaerobic performance, aerobic endurance performance, or isoldnetic muscle strength .Furthermore, there are no associated alterations in maximum minute ventilation, maximum heartrate, maximum respiratory exchange ratio, body composition or any hematological variables toexplain these changes in aerobic capacity. The administration of a low-dose triphasic oralcontraceptive pill (Synphasic), over a one and one half month time span resulted in a smallincrease in the sum of skin folds and a lesser (nonsignificant) increase in weight, as well as aslight decrease in both absolute and relative V0 2.., as compared to a similar group of subjectson placebo. There were no statistically significant changes in any of the other measures ofperformance, or physiological variables.Therefore the results of this study indicate that neither phase of the menstrual cycle ornor administration of a low-dose triphasic oral contraceptive have any apparent or measurableeffects on certain aspects of athletic performance in this group of elite female athletes. 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Mirkin (Eds.): Women & Exercise: Physiology & Sports Medicine.Philadelphia, FA Davis Co., 1988.Shangold, M. M., R. W. Rebar, A. C. Wentz, and I. Schiff. Evaluation and management ofmenstrual dysfunction in athletes. JAMA 263(12):1665-1669, 1990.W.E. Body composition from fluid spaces and density analysis of methods. In J. Brozek &A. Henschel (Eds.), Techniques for measuring body composition. Washington, DC: NationalAcademy of Science and National Research Council, 1961.Skatrud, J. B., J. A. Dempsey, D. G. Kaiser. Ventilatory response to medroxy-progesteroneacetate in normal subjects: time course and mechanism. J. Appl. Physiol. 44:939-944, 1978.Sport Canada Policy on Women in Sport. Minister of State, Fitness and Amateur Sport. Ministerof Supply and Services Canada, 1986.Southam A. L., and F. P. Gonzaga. Systemic changes during the menstrual cycle. Am. J. Obst.and Gynec. 91(1):142-165, 1965.Stevenson, L. A., M. A. Kolka, and J. E. Wilkerson. Perceived exertion and anaerobic thresholdduring the menstrual cycle. Med. Sci. Sports Exerc. 14(3):218-222, 1982a.58Stevenson, L. A., M. A., Kolka, and J. E. Wilkerson. Metabolic and thermoregulatory responsesto exercise during the human menstrual cycle. Med. Sci. Sports Exerc. 14(4):270-275, 1982b.Sutton, J. R., J. E. Jurkowski, P. Keane, W. H. C. Walker, N. L. Jones and C. J. Toews. Plasmacatecholamine, insulin, glucose and lactate responses to exercise in relation tO the menstrualcycle. (Abstract) Med. Sci. Sports Exerc. 12(4):83-84, 1980.Vellar, 0. D. Changes in hemoglobin concentration and hematocrit during the menstrual cycle.Acta. Obstet. Gynec. Scand. 53:243-246, 1974.Vollman, R. F. The menstrual cycle. In: Friedman, E. A., Ed. Major problems in obstetrics andgynecology. Vol 7. Toronto: W.B. Saunders Co., 1977:1.Wearing, M. P., M. Yuhosz, R. Campbell, and E. Love. The effect of the menstrual cycle on testsof physical fitness. J. Sports Med. Phys. Fitness 12:38-41, 1972.Wells, C. L., and S. M. Horvath. Heat stress responses related to the menstrual cycle. J. Appl.Physiol. 35(1):1-5, 1973.Wells, C. L., and S. M. Horvath. Responses to exercise in a hot environment as related to themenstrual cycle. J. Appl. Physiol. 36(3):299-302, 1974.Wirth, J. C., and T. G. Lohman. The relationship of static muscle function to use of oralcontraceptives. Med. Sci. Sports Exerc. 14(1):16-20, 1982.Zaharieva, E. Survey of sportswomen at the Tokyo Olympics. J. Sports Med. Phys. Fitness.5(4):215-219, 1965.59APPENDIX A. REVIEW OF LITERATURE:NATURE OF THE PROBLEM/IMPORTANCE OF TOPIC:Women have been an integral part of the work force for hard manual labour for centuriesand they continue to labour in this capacity in underprivileged and third world countries.Nevertheless, little research exists on the physical effects of such toil on their reproductivesystems, or on their physical work capacity as affected by their hormonal status (Gamberale etal., 1975). In more affluent and developed countries, women have ever-increasing opportunitiesto challenge themselves outside the workplace, in both competitive and recreational sport.Considering that women have only been allowed to compete in the Olympic Games since 1912,and that events such as the women's marathon were just added in 1984, it is easy to see whatgiant strides women have taken, both physiologically and psychologically, over the past fewdecades. The momentum is not likely to abate; more and more sports such as hockey, rugby, etc.continue to expand to include women's teams, and the International Olympic Committee itselfdesignated 1990 as the year of "Women in Sport", as well as announcing that their goal was toinclude more womens' sports in 1996 and beyond. In Canada, the Sport Canada branch of thefederal government has issued a policy paper focusing on strategies to ensure equity for womenin sport (Sport Canada Policy on Women in Sport, 1986).Concomitant with this rise in popularity of physical recreation and sport for women hasbeen a concern about the effects of strenuous exercise on their reproductive and neuroendocrinesystems. Menstrual irregularities such as delayed menarche, primary and secondary amenorrhea,shortened luteal phase, oligomenorrhea and infertility, once thought to be purely a result of acritical set point of percentage body fat (Frisch, 1974, 1987) have been shown to have60multifactorial causes. Family history, previous menstrual history, nutrition and body compositionhave all been implicated in these hormonal disruptions, and so have sport specificity (with aheavy emphasis on aerobic type activities such as running, aerobics and gymna .stics or ballet),rigorous training programs, excessive mileage and psychological stress of training andcompetition (for a review of athletic amenorrhea, see Bonen and Keizer, 1984; Highet, 1989).Hans Selye (1939) demonstrated that it was possible to induce changes in the estrous cycle offemale rats with a program involving abrupt onset of intense exercise. Bullen et al., (1985) wereable to reproduce these findings in women, causing menstrual dysfunction such as altered lutealphase and anovulation which were reversible on discontinuing the exercise stimulus. Numerousother studies have also substantiated these fmdings (see Shangold et al., 1979; Shangold andLevine, 1982, Keizer and Rogol, 1990, Prior and Vigna, 1991).Conversely, relatively little work has been done on the influence of hormones such asestrogen and progesterone on various components of athletic performance. There is much indirectevidence to suggest that they should have some impact. In pregnancy, profound alterations inbody composition, cardiorespiratory function, hemodynamics and exercise performance are knownto occur in different trimesters (Arta! et al., 1981, 1986). There are also volume andbiomechanical changes as well as significant hormonal shifts. Estrogen and progesterone, whenadministered therapeutically, either together or separately, can influence a variety of metabolicprocesses. Estradiol, for example, has been shown to directly impact upon substrate utilizationby increasing lipid availability and utilization, and by decreasing gluconeogenesis andglycogenolysis (for a review, see Bunt, 1990). It also has profound effects on plasma volume(Fortney et al., 1988). Progesterone, either endogenous (Schone et al., 1981) or synthetic61(Dombovy et al., 1987) causes an increase in ventilation, and an alteration in respiratory drives.Therefore, it is highly conceivable that the fluctuations in hormonal concentrations that occurduring both normal and abnormal menstrual cycles might have effects of some consequence tothe competitive athlete.Oral contraceptive agents (OCAs) were initially developed to prevent pregnancy, but theirpredictable control of the menstrual cycle and the decrease in cramps and menstrual flow haveprompted their use in many other clinical situations. Elite athletes troubled by dysmenorrhea mayutilize them for manipulating both the timing and the symptoms of their normal menstrual cycles(Shangold, 1988). More recently, concerns have surfaced about the effects of altered menstrualfunction on bone density and subsequent problems with premature osteoporosis (Drinkwater etal., 1981, 1990; Prior et at, 1990a). The majority of investigators believe that lack of estrogenis the determining factor in rate of bone turnover (similar to the postmenopausal woman), andtherefore recommend the utilization of estrogen for therapy (Drinkwater et al., 1981, Shangold,1982, Shangold et al., 1990). Another school of thought believes that progesterone is the principalbone-trophic hormone (Prior et al., 1990). Clinically, both hormones are frequently used togetherin estrogen replacement therapy in postmenopausal women, or in the combination oralcontraceptive pill in younger women. Side effects of OCAs have been reduced or eliminated bya gradual decrease in the concentration and composition of both the estrogen and theprogestational agents in the pills currently on the market (Greenblatt, 1985; Percival-Smith et al.,1990). However, there is little or no accurate information on the influence of OCAs on any ofthe many components of athletic performance (Schelkun, 1991).62Performance is multi-faceted and sport-specific, and difficult to predict with any degreeof accuracy. Furthermore, there are many different criteria that may be measured. Events suchas long-distance running require a well-trained cardiovascular system, and a high aerobiccapacity. Other sports, such as squash, demand a high degree of anaerobic fitness for the shortbursts of intense activity during rallies. Still others, such as judo, rowing, and the field eventsin athletics, are weight and strength-dependent. The majority of sports also require a refined levelof hand-eye coordination and quick reaction time, and more and more sports rely on sportspsychology and visualization techniques to enhance performance. To date, there is no singleaccurate method of predicting performance; there are just too many factors to take into account.Nevertheless, there are some physiological tests of performance that have beenconsistently utilized in the laboratory setting. Aerobic capacity, anaerobic capacity and isokineticmuscle strength can be measured reliably, accurately, and with a high degree of intersubjectreproducibility (MacDougall et al., 1991). Aerobic endurance can be determined by recording thelength of time that an athlete can sustain a continuous effort at a given percentage of VO2m,x ,usually from 70 to 90%. Body composition and percentage of body fat are conventionallyassessed using skinfold calipers and the underwater densitometry method (Brozek et al., 1963;Lohman, 1981; Ski, 1961). These, and other measures can be utilized to help predict sportperformance in the athlete, both male and female.63EFFECT OF THE MENSTRUAL CYCLE ON PERFORMANCE:BACKGROUND AND EARLY STUDIES:Early studies dealing with the influence of the menstrual cycle on performance were basedon retrospective surveys. Furthermore, definitions of cycle "phase" were not documented byhormonal measurements, and are thus more accurately interpreted using the specific name of thestage, such as "post menses", "premenstrual" or "menstrual flow". A report from Kral andMarkalous (1937) involving an unspecified number of athletes found that 63% did not notice anydifferential effects during the menstrual cycle. Despite the fact that 8% reported a decrement inperformance during menses, another 29% found that their performance was enhanced during thistime. Ingman (1953) surveyed 104 Finnish athletes with regards to their performance. There wasno perceived effect in 43% of this group, while 19% actually reported enhanced performanceduring the time of menstrual flow. Another 38% of the women described the oppositephenomenon - performance decrement during their menses, and in fact, a significant number ofthese women (24%) did not normally compete during their menses because of pain and/orfatigue. Erdelyi (1962) studied 557 Hungarian female athletes from a variety of sports. Onaverage, 48.2% of these women did show any change in their performance during the menstrualflow, 30.7% showed worse performance and 13% showed better performance that their usualaverage. The results of his survey were consistent with the findings of other authors of that era(see Erdelyi, 1962). The "best" performances were generally reported during the immediate"postmenstrual" days, while the worst performances were in the "premenstrual" interval, andduring the first few days of menstrual flow. It is important to remember, however, that althoughthe timing of these "postmenstrual" and "premenstrual" stages may correspond to the timing of64"follicular phase" and "luteal phase", current definitions of these phases includes accuratedocumentation by serum hormone measurements (Abraham, 1974).Rougier and Linquette (1962) had the largest series of respondents, and compared 1435athletes of varying calibre. Of the 553 engaged in regular intensive exercise, 59% noticed animpairment in their performance during the premenstrual time concomitant with an increase intheir premenstrual symptoms. Another 309 women only exercised for 2-4 hours per week, and11% of these related the same decrement, but without any increase in their symptoms. A further1% who suffered no recognizable symptoms also showed a definite decrease in performance asregards speed, accuracy, strength and fatigue in the pre-menstrual and menstrual phase. Thissuggests that the elite female athlete may be more sensitive to and cognizant of any variation inher athletic efficiency. Conversely, small differences in performance are significantly moreimportant to this group of women, especially considering the importance of their competitivecareers.Zaharieva (1965) found that amongst 66 Olympians from a variety of sports surveyed atthe Tokyo Olympics, 34% of the women continued to train during the menses, but 12% of theathletes overall, and an astonishing 33% of the swimmers always interrupted their training duringthe menstrual flow. It is possible that this may have been associated with the prevailing customsof the times when tampons were not yet popular or acceptable, and there were still a largenumber of superstitious beliefs about menstrual flow. Of the sportswomen competing duringmenstruation, 36.9% noticed no difference in their performance, 27.7% stated that the effectvaried, but 17% found that their performance was worse. With regards to the feeling of fitness,46% of these Olympians did not notice any change, but 32% felt weaker during the menstrual65flow. Bale and Davies (1983) administered a questionnaire to 109 specialist physical educationstudents, and found that 45% of women not taking the contraceptive pill felt that menstruationaffected their performance, as compared to 31% of women taking the pill. The other studies aresimilarly inconsistent, but it has been generally recognized and accepted that gold medals havebeen won and world records set during any part of the menstrual cycle.Menstrual symptoms such as dysmenorrhea, fatigue, fluid retention and weight gain arepostulated to have potential adverse effects on sports activity and performance. Indeed, thesesymptoms were noted by many of the women surveyed in these retrospective studies. Anotherfactor that is more difficult to quantify is the possible negative impact on performance of earliermisconceptions about menstrual flow. A more recent prospective study (Moller-Nielsen andHammar, 1989) has suggested that women soccer players were more susceptible to traumaticinjuries during the premenstrual and menstrual period than during the rest of the menstrual cycle,especially amongst players with premenstrual symptoms such as irritability/irrascibility,swelling/discomfort in the breasts, and swelling/discomfort in the abdomen. However, despitecurrent knowledge about the variability of menstrual cycles in athletes, this study approximatedthe length of the menstrual cycles to be 28 days (14 day duration of premenstrual and menstrualperiod, and 14 day duration for the rest of the cycle). Thus, the investigators did not adequatelydocument the existence of ovulatory cycles, and furthermore, may have under or overestimatedthe length of the premenstrual phase of the cycle. These results therefore, should be interpretedwith caution. The authors also found that women using oral contraceptives had a lower rate oftraumatic injuries as compared to women who were not on OCAs. They postulated that oralcontraceptives might exert a protective effect by ameliorating some symptoms of the66premenstrual and menstrual period which might affect coordination and hence the risk of injury.Other studies (Dalton, 1960, Posthuma et al., 1987, Wearing et al., 1972) have also investigatedgeneral accident proneness, neuromuscular coordination, and reaction time and manual dexterityat different times during the cycle. In general, women with premenstrual symptoms have showeda decrement in these indices of performance during the premenstrual stage of their cycles andhave performed best in the "intermenstrual phase".STUDIES WITHOUT HORMONAL DOCUMENTATION:The majority of the early clinical studies which attempted to document aerobicperformance during different times in the menstrual cycle did not include ovarian hormonemeasurements. Furthermore, the definitions of cycle "phase", and the range of days over whichtesting was carried out, make accurate interpretation of the results both confusing and hazardous.Doolittle and Engebretsen (1972) tested 16 university women during four different stages:"follicular" (day 7-10 of the cycle), "ovulatory" (day 13-15),"luteal" (day 18-20) and "premenses"(day 23-26); and found no performance variations due to the menstrual cycle in the maximum02 consumption, the 12 minute run-walk, the 600 yard run-walk or the 1.5 mile run-walk tests.They were the earliest group of investigators to even think of documenting the cycle phase byserum progesterone levels. However, their blood test results for progesterone showed that onesubject may not have ovulated, and two others may have ovulated late or not at all. Furthermore,the blood samples were drawn between five and seven minutes after exercise. It has since beenshown that both estrogen and progesterone levels increase with exercise over resting values.These increases appear to be independent of pituitary control, and are dependent upon exercise67intensity, and phase of the cycle, being higher in the luteal than in the follicular phase of themenstrual cycle (Jurkowski et al., 1978). Other authors have documented similar changes in oneor both female steroid hormones (Bonen et al., 1979; Shangold et al., 1980; Sutton et al., 1980).These increases likely occur as a result of decreased metabolic clearance (Keizer et al., 1981),although recent work suggests that there may actually be increased secretion of these ovarianhormones with exercise (Bonen et al., 1991).Gamberale and his group (1975) tested 12 subjects with severe menstrual distress at threedifferent intervals during the cycle, the 1st or 2nd day of menstruation ("menstrual"), 10-18 daysafter the start of menstruation ("postmenstrual") and 6-2 days prior to the estimated start ofmenstruation ("premenstrual"). Testing was carried out on a bicycle ergometer for 6 minutes at40% and 70% VO2inaz. They did not find any significant change in either heart rate or 0 2 uptakeat any phase of the cycle. Interestingly, however, at the same heart rate, exercise was perceivedas more exerting in the menstrual stage than in either the premenstrual or postmenstrual stages.Another study that was reported in abstract form only (Fox et al., 1977) involved trainedand untrained women tested on a treadmill at three specific points in the cycle: 13 days after theonset of menstruation ("postmenstrual"), 7 days after ovulation ("premenstrual"), and 3 days afterthe onset of menstruation ("menstrual"). Of note is the fact that, according to this classificationsystem, the women in the "postmenstrual phase" could potentially have been ovulating. Theyfound that in the trained group, the submaximal VO2 was highest 13 days after the onset of men-struation, but that there were no differences in the untrained group. In contrast, Allsen et al.,(1977) tested 10 trained women on a treadmill at four different times in the cycle across fourcycles and were not able to demonstrate any differences in maximal aerobic capacity. Their tests68included Phase I: 24 hours after the onset of the menstrual period, Phase II: within 24 hours ofPhase I, Phase III: 10 days from the Phase II test; and Phase IV: 10 days from the Phase III test;and again, did not include verification of the cycle phase by serum progesterone.Some investigators (Stevenson et al., 1982a, 1982b) have even monitored their subjectsat 5 different points during the cycle (days 2, 8, 14, 20 and 26), and failed to demonstrate anysignificant variations in peak 0 2 uptake or submaximal cardiorespiratory responses to exerciseon a bicycle ergometer. However, mean core temperature was elevated on day 14 and 20, ascompared to days 2 and 8. They thus postulated a dissociation of the metabolic responses fromthe thermoregulatory responses to exercise during the menstrual cycle (1982b). In a separatepaper, (1982a), they also noted that there was no difference in either the anaerobic threshold orin the level of perceived exertion at any exercise level that they could attribute to the timing ofthe test within the menstrual cycle.In contrast, a recent "field" study (Brooks-Gunn et al., 1986) looked at the performancetimes of 6 adolescent swimmers over a 12 week period and found that they were slowest duringthe premenstruum, and fastest during the menstrual phase. Menstrual phase was determined bya biweekly questionnaire (the Moos Menstrual Distress Questionnaire), and oral basal bodytemperature. However subsequent analysis of the basal body temperature data of the cycles, bythe method of Vollman (1977), showed that 5 of 10 cycles were biphasic, 2 of the 10 weremonophasic, and 3 were biphasic with a short luteal phase.A group of investigators in the USSR (Fomin et al., 1989) assessed the working capacityof 164 female cross-country skiers by testing their performance during a 5-km test race on thestandard track and during a 12.5-km test race on ski rollers. They also analyzed personality and69reactive anxiety at different times during the menstrual cycle. They divided the biologic cycleinto 5 stages including menstrual, postmenstrual, ovulatory, postovulatory, and premenstrual, (butagain without documentation by either BBT or serum progesterone). The best test results wereachieved by women who were in the postovulatory and postmenstrual stages. Their conclusionswere that in order to achieve maximum benefit, training loads should be selected with specialattention to volume and intensity, based on the phase of the cycle.STUDIES UTILIZING SERUM PROGESTERONE MEASUREMENTS:A few investigators have adequately documented cycle phase by serum progesteroneand/or estradiol concentrations, and therefore, their findings can be considered as morescientifically acceptable. Jurkowski et al., (1978, 1981) looked at the performance of 9moderately trained women (mean 1.102,„. 42.8 + 1.7 ml•ke•min -1) on a bicycle ergometer.Testing was carried out in the midfollicular phase (6-9 days after beginning of menstruation), andin the midluteal phase (6-9 days after ovulation as determined by a sustained rise in BBT of 0.3degrees Centigrade. The procedure involved a predetermination of V02 O L, and then a progressiveincremental exercise protocol of sustained testing for 20 minutes at 33% and then at 66% of thislevel of exertion, followed by time to exhaustion at 90% of this value. The first two exerciseloads were termed light and heavy exercise respectively. There were no significant differencesin maximum work load, heart rate, cardiac output or ventilation between the two phases at lightand heavy exercise, or in heart rate at exhaustion; but time to exhaustion doubled in the lutealphase from 1.57 ± 0.32 minutes to 2.97 + 0.63 minutes (p<.02). There were no significantdifferences in 02 uptake, CO2 output, cardiac output or stroke volume to account for this marked70improvement in endurance performance. There was, however, an increase in maximuminspiratory ventilation (VI) during the luteal phase, from 80 +5.4 limin -1 to 88 + 5.6 and,as will be discussed later, differences in venous blood lactate between the two phases.Schoene et al., (1981) also tested women in the midfollicular phase (6-10 days after theonset of menstruation) and the midluteal phase (4-9 days after ovulation), and measured serumprogesterone, both before and after the exercise protocol. They compared three groups of women:6 nonathletic women with normal cycles, 6 athletic women with normal cycles, and 6 athleticwomen who were also amenorrheic. Interestingly, there were no significant differences inperformance or in the time to onset of the anaerobic threshold in the athletic women, irrespectiveof their menstrual status. In the nonathletic group, however, maximal exercise response,expressed either as total exercise time or maximum VO2  or CO2 production, was better in thefollicular phase than during the luteal phase. They postulated that in the nonathletes there mightbe some effect of subjective dyspnea, possibly associated with the increase in VE, or change inrespiratory drives during this part of the cycle, which limited maximal exercise performance. Theathletes, on the other hand, did not have any associated alterations in their ventilatory responsesdue to the menstrual cycle phase.Hessemer and Bruck (1985a, 1985b) investigated the influence of the menstrual cycle onthermoregulatory, metabolic and heart rate responses to exercise at night. They studied 10 womenwith normal cycles during the follicular phase (4-7 days after the onset of menses) and the lutealphase (4-8 days after a sustained rise in BBT) Both phases were properly substantiated by serumprogesterone measurements. Along with their other findings they did note a 5.2% increase inmean V02 during the luteal phase as compared to the follicular phase. Metabolic rate actually71increased by 5.6% in the luteal phase, but surprisingly, net efficiency was 5.3% lower. They didnot document significant differences in any other exercise variables to explain these results; andthus postulated that it was the elevated body core temperature during the postovulatory phase thathad a negative influence on exercise efficiency.CARDIOVASCULAR AND HEMODYNAMIC RESPONSES:Investigators have attempted to implicate hormonally mediated shifts in plasma volume,hemoglobin concentration and hematocrit, and cardiac output at different phases of the menstrualcycle in these variations in performance. It has been well documented that one of the long-termadaptations to endurance exercise is a significant increase in plasma volume. There is aconcomitant but proportionately smaller increase in the red blood cell volume leading to asubsequent fall in hematocrit termed the "runner's anemia". This phenomenon is postulated tobe effective in lowering blood viscosity, thus facilitating movement of the blood through thesystem of vessels and capillaries. It is possible, that this is a "preadaptation" to exercise, as thecommencement of exercise from rest causes a fairly immediate decrease in plasma volume thatcontinues as exercise is prolonged. This loss of fluid occurs primarily through sweating, buttranscapillary fluid flux in exercising muscle also plays a role in this process.Significant alterations in the distribution of body fluids occur throughout the normalmenstrual cycle. During the luteal phase, the increase in progesterone acts at the level of thekidney to block the action of aldosterone resulting in loss of Na + and H20. This stimulates therenin/angiotensin system to increase aldosterone secretion, and also promotes an increase inantidiuretic hormone (Gaebelein and Senay, 1982). This is one of the mechanisms felt to be72responsible for the fluid retention reported in the postovulatory phase. Estrogen has also beenshown to have a water-retaining effect, potentially due to either an effect on the kidneys, or analteration in the synthesis or release of antidiuretic hormone (ADH). The effect on plasmavolume is more pronounced with exogenously administered estrogens (Fortney et al., 1988),especially in the presence of low blood progesterone concentrations. It appears that estrogen andprogesterone may have opposing influences on the control of body fluids, and this may thenpotentially be of significance to the exercising woman both during the course of a normalmenstrual cycle, or during the administration of a combination oral contraceptive agent.In resting subjects, the luteal "phase" has been associated with decreases in bothhemoglobin and hematocrit (Vellar, 1974). In this study, however, the phase of the cycle was notaccurately determined, and serum estrogen was not measured. Measurements during exercise ofplasma volume, cardiac output, hemoglobin concentration and hematocrit have intermittentlydocumented significant differences between phases of the menstrual cycle, but there has been noassociated alteration of any of the measurements of performance. Wells and Horvath (1973),studied the effects of heat stress responses in 7 untrained and unacclimatised subjects at threetimes during the cycle: within 36 hours of commencement of menstrual flow, at the estimatedtime of ovulation, and midway between ovulation and the day of the next expected menstrualflow. The time of estimated ovulation was determined on the basis of early morning rectaltemperature recordings taken over a period of 4-5 months. Unfortunately, there was nodocumentation by steroid hormone measurements. They found a higher hemoglobin concentrationand hematocrit in the ovulatory tests, and the lowest values during the menstrual flow. There wasessentially no difference in serum electrolytes (except for a higher serum Cr) or plasma proteins.73However, total body sweat losses of Na* and C1 were lower during heat exposure in the testsconducted between the time of supposed ovulation and menstrual flow, suggesting that highlevels of both female sex hormones decreased electrolyte loss in sweat. However, as previouslymentioned, there is no assurance that either estrogen or progesterone were high during this timeperiod. Interestingly, though, with the addition of moderate exercise to the heat stress, theseeffects were no longer observed to any significant extent. Fox et al., (1977) noted an increasedhematocrit in conjunction with an increase in submaximal mean Vol at 13 days after the onsetof menstruation, as compared to measurements obtained 7 days after ovulation, and 3 days afterthe onset of menstruation. They did not document any differences in other cardiorespiratoryvariables relative to time during the cycle, either at rest or during exercise.The hydration status of the subjects has also been shown to have a significant effect onthese hemodynamic alterations. Gaebelein and Senay (1982) studied 5 women on a bicycleergometer, early in the follicular phase, and in the mid-luteal phase, as documented by anincrease in serum progesterone. They observed a more rapid increase in hemoglobinconcentration and osmoconcentration as well as decreases in plasma volume during exercise inthe follicular phase, especially following hypohydration. Their data are more convincing, andsuggest that both the phase of the menstrual cycle, and the pre-exercise fluid status may beimportant determinants of vascular volume dynamics during exercise.74TEMPERATURE REGULATION AND HEAT EXCHANGE:It has been shown that women are less tolerant of heat stress than men, but controversystill exists regarding the effects of the different phases of the menstrual cycle onthermoregulation, and there is even more debate as to whether or not there are any significantimplications for performance. Wells & Horvath (1973) investigated the effects of heat stressresponses at 48 degrees Centigrade and 11 mm. Hg water vapor pressure, during three separatetimes of the cycle in 7 subjects with "normal" menstrual cycles. They were tested within 36hours of commencement of menstrual flow, at the estimated time of ovulation (as determined bybasal body temperature recordings), and midway between ovulation and the day of the nextexpected menstrual flow. Although there was a tendency towards a higher heart rate and lowerventilation volumes in the ovulatory tests, there were no differences in core or skin temperature,02 consumption, or total body sweating rate; and they concluded that cycle phase had nosignificant effects on generalized thermoregulatory or metabolic responses to acute short-termheat exposure. Even the addition of an exercise stress (a 40 minute treadmill walk at 50% ofroC)2z..x) exercise to that of the hot environment did not potentiate any differences in thesevariables across the different times of the cycle (Wells & Horvath, 1974). These findings are inkeeping with a previous study by Sargent and Weinman (1966) where the activity of the eccrinesweat glands was not significantly affected by the stage of the menstrual cycle. Otherinvestigators (Frye and Kamon, 1981) have also not been able to document any significantvariation in heat stress responses in women in relation to any "phase" during the menstrual cycle.In contrast, Hessemer and Bruck (1985a, 1985b) documented the cycle phase bymeasurement of serum progesterone, and tested their subjects between 3:00 and 4:00 am. when75the difference between the temperature in the luteal and follicular phases is at its maximum. Theydid demonstrate a higher pre-exercise and postexercise core temperature during the luteal phase,as well as an elevation in the thresholds for shivering, chest sweating, and cutaneous vasodilation.There was also a luteal phase increase in the above threshold of chest sweat rate and cutaneousheat clearance. Others (Stephenson et al., 1982a, 1982b) have 4hown the variation in coretemperature, but have not found any significant variation in performance. They have thuspostulated a dissociation of the metabolic responses from the thermoregulatory responses to exer-cise during the menstrual cycle.RESPIRATORY DRIVES AND VENTILATION:Progesterone has been implicated as a causative factor in the hyperventilation seen duringpregnancy (Moore et al., 1987; Pernoll et al., 1975) and the luteal phase of the cycle (Dombovyet al., 1987); and a synthetic progestin, medroxyprogesterone-acetate (MPA), is oftenadministered to patients with central hypoventilation syndromes in order to stimulate ventilation.It has been shown that giving this same hormone to men will induce all of the ventilatorychanges seen during the luteal phase of the menstrual cycle, but does not cause any significantalteration in overall exercise performance as measured on a bicycle ergometer (Bonekat et al.,1987).It is currently widely held that highly accomplished endurance athletes commonly havealtered respiratory drives, in terms of a decreased ventilator)/ response to hypoxia andhypercapnia (Byrne-Quinn et al., 1971, Martin et al., 1979). Decreased hypoxic and hypercapneicventilatory responses are postulated to have a positive effect in endurance athletes, by decreasing76the subjective sensation of dyspnea that may be a factor in limiting maximal exerciseperformance, as well as allowing them to continue exercising despite the onset of hypoxia. It hasbeen suggested that the endogenous surge of progesterone during the menstrual cycle may exerta deleterious effect on performance due to alterations in these respiratory drives. It is alsopossible, that in the luteal phase, the effects of an increased sensitivity of the respiratory centerand a lower W ion concentration may combine to account for a lack of difference in ventilationduring exercise. England and Fahri (1976) noted a decrease in end tidal P an (from a mean valueof 39.8 torr to 36.7 torr) and in base excess during the luteal stage, but failed to measure serumprogesterone, and in fact, calculated the probable time of ovulation by subtracting 14 days fromthe date of the first menstrual bleeding.There are relatively few studies of this nature with accurate hormonal documentation ofthe phase of the menstrual cycle. Schoene et al., (1981) examined the relationship betweenrespiratory drives and exercise performance during different phases of the menstrual cycle (asdetermined by serum progesterone measurements) in 6 eumenorrheic athletes, 6 amenorrheicathletes and in 6 nonathletic controls. They documented an increase in both the hypoxic andhypercapnic ventilatory responses in the luteal phase in all groups, with the hypoxic ventilatoryresponse being lower in the athletes in both test periods. Maximal exercise response, expressedeither as total exercise time or maximum 02 consumption was significantly decreased during theluteal phase in the nonathietes only. Ventilatory equivalent was also increased during the lutealphase. The amenorrheic athletes, on the other hand, showed no changes between the two testperiods on any of the parameters including serum progesterone. Although this study did notdemonstrate an overall difference between the two phases of the cycle in the athletic group, it77is interesting that the three athletes who did show luteal increases in hypoxic ventilatoryresponses, and hypercapnic ventilatory responses, as well as substantial luteal phase decreasesin V02. related poor performance in training and national competition with the-luteal phase oftheir cycle. There was thus a suggestion of a correlation between augmentation of drives anda decrease in performance as measured by V02„.„ and maximal exercise time, at least in thenonathletic group. In contrast, other investigators (Chen and Tang, 1989) have documented aninteresting finding, that of increased inspiratory muscle endurance (by 26%) in the luteal phase,and postulated that this was due to a higher level of circulating progesterone, as measured in theirstudy. Obviously the responses of the ventilatory system to endogenous variation in the femalesteroid hormones during the menstrual cycle are myriad and extremely complex.METABOLIC RESPONSES:The luteal phase elevations in progesterone and estrogen may in some way impact uponeither substrate utilization or hormonal response patterns during exercise. Glucose uptake andstorage in the liver and muscle is known to be facilitated by estrogens (Bunt, 1990) andprogesterone (Matute and Kalkhoff, 1987); both in animals (Ahmed-Sorour and Bailey, 1981;Kendrick et al, 1987; Matute and Kalkhoff, 1987), and also in humans (Nicklas et al., 1989).During prolonged exercise, glycogen is spared when estrogen levels are high. Furthermore, theseresponses may be altered or affected by the pre-exercise nutritional status of the subjects, inaddition to the phase of the menstrual cycle. Bonen et al., (1983) tested 19 subjects on atreadmill under fasting (n=6), glucose-loaded (n=5) and control (n=8) conditions, and found thatfor all the groups, the metabolic and endocrine responses to exercise were similar in both the78follicular and the luteal phase for glucose, lactate, glycerol, LH, FSH, and cortisol. However, inthe glucose group, the FFA response was lower in the luteal phase, while in the fasted group, theinsulin and GH responses were elevated in the luteal phase. The progesterone response toexercise in both the control group and the glucose group was found to be greater in the lutealphase. In the fasted group, there was no alteration in progesterone response in either phase.Furthermore, this group had a lower LH response and a greater GH response than the othergroups. Earlier studies (Bonen et al., 1979) have also shown that the progesterone and estradiolincrement induced by exercise is relatively greater in the luteal than in the follicular phase. Theypostulated that a greater reliance on fat metabolism through oxidation of fatty acids may resultin retardation of the rate of utilization of glycogen and therefore production of lactate.Several experiments by Jurkowski et al., (1978, 1981) tested trained female athletes duringboth the midfollicular phase (6-9 days after the beginning of menstruation, and the midlutealphase (6-9 days after ovulation). Ovulation was documented by a sustained rise in basal bodytemperature of at least 0.3 degrees Centigrade, and cycle phase was subsequently confirmed byan increase in serum progesterone from a mean of 0.58 ng•mr 1 to 8.8 ng•rn1 -1 . At work loads ofapproximately 33%, 66% and 90% of V0 2., there were no significant differences in maximumwork load, heart rate or ventilation between the two phases, but the time to exhaustion at 90%of V02.„. was increased in the luteal phase from 1.57 + 0.32 to 2.97 + 0.63 minutes. It wasfurther noted that the exercise-induced increase in plasma lactate during heavy and exhaustiveexercise was greater during the follicular phase than in the luteal phase. A hormonally-mediatedshift towards a greater reliance on free fatty acid metabolism during exercise was postulated toaccount for the lower respiratory exchange ratio and the delayed appearance of plasma lactate79during the luteal phase. In a separate part of the study, they showed that the phase of the cyclehad no effect on the disappearance of a bolus of infused lactate, thus implying that the differenceduring exercise somehow reflected a true difference in production. As these studies were not ableto document any differences in central components of performance such as heart rate, ventilationand cardiac output, perhaps the variation in performance can be attributed to contributions at themetabolic and cellular levels.The only other study to show a potentially significant increase in endurance time duringthe luteal phase was also carried out utilizing plasma estradiol and progesterone concentrationsto confirm the phase of the cycle. In their study, Nicklas et al., (1989) performed muscle biopsieson a group of six eumenorrheic athletes after a bout of depletion exercise on a bicycle ergometer.Following three days of rest and diet control, these subjects carried out an endurance test tofatigue (at a workload of 70% of V02.), with pre and post exercise muscle biopsies taken fromthe vastus lateralis. These authors were able to document a strong tendency (p=.07) for anincrease in endurance time during the luteal phase (139.2 + 14.9 minutes as compared to 126 ±17.5 minutes during the follicular phase). This was accompanied by, and potentially due to, agreater glycogen repletion in the three days following the depletion exercise test during the lutealphase, but was not associated with any significant alterations in glycogen utilization. Thus, theinteractions of both estrogen and progesterone at the substrate level, are intricate, and as yet,incompletely understood.80EFFECTS OF ORAL CONTRACEPTIVES ON PERFORMANCE:BACKGROUND:In terms of the effects of the oral contraceptive agents (OCA) on performance, the evidencepresented so far has been contradictory. Again, the early studies were mostly anecdotal orretrospective surveys. Bale and Davies (1983) administered a questionnaire to 109 specialistphysical education students. Of these, 69.7% felt that menstruation adversely affected theirperformance. They complained of feelings of lethargy and tiredness, and a lack of interest inphysical activity during this time. Of the 50 girls (46%) that were on the birth control pill, it isinteresting that no student thought that her performance had deteriorated as a result, and in fact8% even felt that their performance had improved. As previously mentioned, Moller-Nielsen andHammar (1989) prospectively followed 86 female soccer players over a one year period. Theyfound a decreased incidence of traumatic injuries in the women who were taking oralcontraceptives as compared to the women who were not (P< 0.05). They attributed-these findingsto an amelioration of premenstrual symptoms such as fluid retention, mood swings, breasttenderness, etc., that might influence neuromuscular coordination, and thus reduce the rate ofinjury. However, an assumption in their statistical analysis was that the cycles were all exactly28 days in length. This is unlikely to have occurred, and furthermore, without hormonaldocumentation of the cycle phases, it cannot be assumed that all of the women in the controlgroup were even ovulatory.81CARDIOVASCULAR AND HEMODYNAMIC RESPONSES:Various controlled studies have looked at the different components of the cardiovascularand pulmonary systems. Littler et al., (1974) measured pulmonary blood flow and cardiac outputusing N20 whole body plethysmography, and found no significant difference in cardiac index,pulmonary arterial distensibility, heart rate or systemic blood pressure in any phase in womenon a combined estrogen-progestin pill, a progestin only pill or on no pill at all. When expressedas cardiac output, however, the estrogen-progestin group had a significantly greater cardiacoutput, followed by the progestin only group, as with the control group being the lowest. Inanother study, Lehtovirta et al., (1977) also documented a higher blood volume, stroke volumeand cardiac output during exercise, as well as an increase in blood volume at rest, in a group of13 women taking an OCA containing 0.075 mg of mestranol and 2.5 mg of lynestrenol for 1 to2 months.There have been relatively few studies specifically on alterations in either hemoglobin orhematocrit in women taking OCAs, but since they decrease menstrual blood loss, they are knownto decrease the risk of iron deficiency and anemia, so there may be a differential effect of OCAson performance simply by enhancement of the oxygen-carrying capacity of the blood.RESPIRATORY DRIVES AND VENTILATION:Just as endogenous progesterone has significant effects on respiratory drives in women,and medroxy-progesterone acetate (MPA) has been shown to induce similar changes in men; thepossibility exists that synthetic progestins in OCAs may also have deleterious effects. Montes etal., (1983) examined the effects of oral contraceptives on respiration and found an increase in82VE, and VCO2 (but no change in V02, either at rest, or during exercise) in subjects taking OCA.This effect was shown to be greater at three months than after six months of use, suggesting thatsome respiratory or metabolic adaptations may take place.METABOLIC RESPONSES:Others have also investigated the potential effects of oral contraceptive agents on substratemetabolism. Bonen et al., (1991) have documented an increase in FFA concentrations during mildexercise, and a lower glucose both at rest and during exercise in subjects taking OCAs. Manyother studies have yielded conflicting reports on the effect of OCAs on glucose and insulinproduction or metabolism during exercise (see Bonen et al., 1991). Extrapolation of these resultsto the level of muscle metabolism is limited. However, the majority of investigators infer thata higher concentration of FFA in the blood means that more of this substrate is beingmetabolised by the exercising muscle. Furthermore, greater availability of FFA can inhibitcarbohydrate metabolism in skeletal muscle. Conversely, during heavy exercise, muscle glycogenis metabolised to a greater degree, resulting in higher circulating lactate concentrations, whichin turn, reduce the concentration of FFA. The study of Bonen et al., (1991) however, did notdocument any alterations in lactate response in the subjects on OCA.Another group, (McNeill and Mozingo, 1981) exercised a group of nonathietes on abicycle ergometer on the 4th, 10th, and 26th day of their menstrual cycle before taking OCA(Norlestrin 21 1 mg), and then again during the second cycle of OCA. They demonstrated asignificant increase in the oxygen consumption for standardized work loads of 300 and 600 kpmwhen the subjects were taking OCA. They hypothesized a shift in the mixture of substrates83utilized in submaximal work towards an increased dependence upon triglycerides and a decreaseddependence on glycogen as a result of taking OCA. Since more oxygen is required to releaseeach calorie of energy from the triglyceride molecule than from the glycogen -molecule, 'theyfurther postulated that such a shift in substrate utilization should be manifested by a concomitantincrease in the energy cost of standardized work, in keeping with their findings.EFFECTS OF ORAL CONTRACEPTIVES ON EXERCISE PERFORMANCE:Investigators are not in agreement on either the quantitative or directional effects of OCAon various physiological tests. Interpretation of these studies is further complicated by thediversity in both the estrogen and progestin components of the OCAs used, as well as in therange of fitness of the subjects involved. Attempts have been made to examine the effects ofOCA on maximal aerobic capacity, but most studies have been carried out either with the higher-dose OCAs, or with relatively untrained subjects. An abstract by Daggett, Davies and Boobis(1983) has reported that there is a decrease in VO2max (from a mean of 44.6 ml•kg-l •min-1 to 39.8ml•kg-l•min-1), as well as a decrease in muscle mitochondrial citrate during OCA use. Theystudied 7 active females prior to, one and two months during, and six weeks following oralcontraceptive use, although there is no mention as to which OCA they were utilizing. There wereno fluctuations in post-exercise muscle glycogen and lactate as determined from muscle biopsies.They did not find any change in respiratory quotient, blood lactate or blood glucose responsesto 60 minutes of exercise at 10% above the lactate inflection point between the two conditions,but there was a significant increase in ventilatory equivalent during OCA use. They followedtheir subjects through two months on OCA and found that the differences returned to normal by846 weeks post-cessation of the medication.In contrast, De Bruyn-Prevost et al., (1984) used a cross-sectional sample and tested twodifferent groups of subjects (a control group, and a group on OCA) on a bicycle ergometer forboth aerobic and anaerobic endurance at three times during the cycle: the 1st or 2nd day ofmenstruation, at the ovulatory period (or the 14th day of the cycle for the OCA group) and atthe end of the cycle, one to two days before menstruation. There was no documentation as to thecontent or composition of the OCAs that the subjects were taking. They concluded that therewere no significant differences either between the groups, or at different phases of the cycle, butagain, phase of the cycle was not identified by measurement of serum progesterone. Furthermore,the subjects on OCA did not have any pre-OCA results to compare to, to assess any significanteffects in the same subject. Another study with a similar comparative design (Huisveld et al.,1983) also did not find any significant differences in VO2m., maximal respiratory exchange ratio,maximum heart rate or the duration of the exercise test on a bicycle ergometer between 10 usersof OCA and 10 nonusers. It is obviously dangerous and incorrect to make any generalizationsfrom this type of study to the general population of exercising women.There has been only one prospective trial carried out to date with a low-dose oralcontraceptive. Notelovitz et al., (1987), examined the effects of 6 months of administration ofOvcon 35 (35 micrograms of ethinyl estradiol and 0.4 mg of norethindrone) in 6 subjects ascompared to 6 controls. The controls were fitted with diaphragms and/or IUD's. The VO2,.0 inthe OCA users declined significantly from 41.2 + 11.8 ml•kg -l •miti l to 38.4 + 9.8 ml•kg -l •rnin-1(a 7% difference) while the control group increased from 42.6 + 2.8 ml•kg -l •min-1 to 45.9 + 5.8mlike•min1 over the same time frame (p<.03). There was an increase in weight on OCA from85a baseline of 57.5 ± 6.5 kg to 59.3 ± 6.3 kg. They also found an 8% decrease in both theabsolute oxygen uptake (2.4 ± 0.67 1.min' to 2.2 ± 0.5 1.min') and the oxygen pulse (the volumeof oxygen consumed per heart beat (12.2 ± 3.2 ml•bear l to 11.2 + 2.2 ml•bear l). The controlgroup, in contrast, increased their values by 9%, from 12.3 ± 2.3 to 13.4 ± 2.2 ml•bear i (p<.02).All values returned to baseline levels 1 month after stopping the oral contraceptives.There have been few studies to date on the effects of OCAs on muscle strength, and thesesuffer as well from problems of design, and small numbers of subjects. Petrofsky et al., (1976)tested 7 women, 3 of whom were on two different OCAs; and found that although static musclestrength on a hand-grip dynamometer was not different between the two groups, OCA use hada significant deleterious action on isometric endurance. Wirth and Lohman (1982) measuredhandgrip endurance time (ET) and force output (FO) at 50% of a maximum voluntary contractionin three groups of subjects: nonusers, females on OCA, and females taking OCA and VitaminB6, at two different phases in the cycles. The MVC was significantly greater during the follicularphase in the control subjects, and both the ET and FO were lower in the subjects on OCA, withno variation during the pill cycle. Unfortunately, neither author was able to offer a convincingphysiological explanation for any of these observed differences.Thus, the studies to date suggest that there may be subtle variations in performancethroughout the normal menstrual cycle, and that the administration of oral contraceptive agentsto female athletes may potentially have undesirable effects in terms of aerobic capacity andmuscle strength and endurance. What has been lacking is a prospective controlled study involvingathletes at an elite level, using proper documentation of cycle phase by serum progesterone, andutilizing a single OCA, preferably one of the new low-dose triphasic preparations.86APPENDIX B. RAW DATA:SUBJECT: VA GROUP: N/AVARIABLE FOLLICULAR^LUTEAL^TREATMENTWeightkg53.0 53.1Body fat 15.1 14.5%Sum ofskinfoldsmm76.4 67.6Estradiolpmo1•11255 497Progesteronenmo1•140.9 55.0Hemoglobingin•r i131 134Hematocrit 38.7 40.0%MCVfL86 87V02.l•min-12.90 2.94V02.ml•kg-l•inizi l54.71 55.29V5(max)l•min-1 BTPS99.1 104.7HR(max)bpm187 188RER(max) 1.14 1.14ASTseconds27 35ET-90% V02.seconds343 542R Quadriceps 89 100N•mR Hamstringsli•m57 62L Quadriceps 92 84N•mL Hamstrings 49 60/i•mMCV, mean cell volume; V0 2., maximum oxygen capacity; VE(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s -1 , best of three trials)87SUBJECT: MO GROUP: N/AVARIABLE FOLLICULAR^LUTEAL^TREATMENTWeightkg58.0 55.7Body fat 25.4 23.6%Sum ofskinfolds85.1 85.6Estradiolpmo1.1-1101 497Progesteronenmo1•1-11.6 55.0Hemoglobingm•1-1120 128Hematocrlt 34.9 36.7%MCVfa,V02.962.93942.761•min-1V02.ml•kg i•miri l50.45 49.62Vs(max)l•min-1 BTPS97.0 94.1HR(max)bpm192 196RER(max) 1.16 1.12ASTseconds15 14ET-90% V02.,seconds909 963R Quadriceps 111 127N•inR Hamstrings 62 70N•inL Quadriceps 111 111N•inL Hamstrings 54 68N•nMCV, mean cell volume; V02., maximum oxygen capacity; V E(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s4 , best of three trials)88SUBJECT: IF GROUP: PlaceboVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg58.6 57.5 56.5Body fat 19.4 17.0 17.1%Sum ofskinfolds90.0 89.0 90.0Estradiolpmol•r l77 256 298Progesteronenmol•r i1.0 17.5 1.0Hemoglobingm•1•128 133 135Hematocrit 37.0 38.7 39.2MCV 92 95 96ILV02. 2.96 2.93 3.031•min-1V02.ml•kg-i•min-i50.57 50.91 53.50V$(max) 105.7 110.7 105.01•min' BTPSHR(max)bpm180 180 180RER(max) 1.16 1.17 1.06ASTseconds23 18 18ET-90%1/02.seconds798 677 893R Quadriceps 138 125 155N•mR Hamstrings 60 65 84N•mL Quadriceps 133 138 149InnL Hamstrings 62 65 70MCV, mean cell volume; V0 2.,, maximum oxygen capacity; VE(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s -1, best of three trials)89SUBJECT: III GROUP: PlaceboVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg443 44.2 44.0Body fat 10.0 112 10.1%Sum ofskinfolds44.4 35.8 36.0Estradiolpmo1•1: 1131 665 397Progesteronenmol•r i1.2 65.0 43.0Hemoglobingrn•l129 128 138Hematocrit 37.8 37.6 39.1%MCV 92 89 91ILV02.l•min-12.60 2.63 2.75V02.ml•ke•nie58.56 5958 62.16VE(max) 88.6 90.5 89.31.min' BTPSHR(max)bpm187 185 190RER(max) 1.16 121 1.09ASTseconds21 26 34ET-90% V0,,seconds1005 1083 951R Quadriceps 106 92 75INI•inR Hamstringsli•m65 57 49L Quadriceps 117 103 87N•tnL Hamstrings 68 62 46IsI•nMCV, mean cell volume; V0 2., maximum oxygen capacity; VE(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s-1 , best of three trials)90SUBJECT: PW GROUP: PlaceboVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg56.3 55.4 55.1Body fat 14.6 12.6 10.6Sum ofskinfolds85.4 81.6 65.4Estradiolpmol•I' l188 536 517Progesteronenmo1•1-11.6 73.0 63.0Hemoglobingm•r1134 143 140Hematocrit 38.8 41.4 413%MCVfL93 93 93VOzi.„„l•min' l2.94 2.84 2.94V02.ml•kg-l •min452.14 51.33 53.44VE(max)l•rnin' l BTPS104.0 104.9 105.5HR(max)bpm176 176 176RER(max) 1.17 1.10 1.21ASTseconds39 33 37ET-90% V02.seconds1015 1082 1201R Quadriceps 152 152 149N•rnR Hamstrings 92 92 89N•inL Quadriceps 184 184 157N•mL Hamstrings 103 103 98N•nMCV, mean cell volume; V0 2., maximum oxygen capacity; VE(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s'', best of three trials)91SUBJECT: JR GROUP: PlaceboVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg74.0 74.5 74.4Body fat 18.8 18.5 17.2%Sum ofskinfolds99.8 97.8 101.2Estradiolpmo1•1-1126 238 370Progesteronenmo1•1-11.1 45.0 8.6Hemoglobingm•1" 1136 137 136Hematocrit 39.0 39.5 39.5%MCVfi.,V02.933.85933.62953.721•min-1V02.ml•kg-i•mie52.10 48.76 50.03VE(max) 121.6 116.5 116.31•min-1 BTPSHR(max)bpm185 175 180RER(max) 1.19 1.15 1.14ASTseconds30 26 26ET-90% V02,seconds999 771 1205R Quadriceps 176 163 182Isi•nR Hamstrings 106 88 98N•mL Quadriceps 163 169 182N•rnL Hamstrings 87 95 89N•inMCV, mean cell volume; V0 2., maximum oxygen capacity; V E(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s 4 , best of three trials)92SUBJECT: TE GROUP: PlaceboVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg63.5 64.6 66.5Body fat 13.1 17.3 18.9Sum ofskinfolds77.8 81.2 82.6Estradiolpmo1•1-1115 308 174Progesteronenmo1.1-11.1 34.0 1.3Hemoglobingm•r i139 136 138Hematocrit 41.3 39.4 40.7MCVtL89 88 881/02,..l•min-13.32 3.29 3.18V02,„,„ml•kg innin' i52.31 50.83 47.78VE(max) 117.5 116.3 107.41•min' BTPSHR(max)bpm210 205 215RER(max) 1.21 1.16 1.11ASTseconds33 33 28ET-90% V/02,„„seconds484 380 328R Quadriceps 138 149 146N•inR Hamstrings 73 87 81Isi•nL Quadriceps 168 149 149/i•nL Hamstrings 81 95 84N•mMCV, mean cell volume; V02,„,„„ maximum oxygen capacity; VE(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s1, best of three trials)93SUBJECT: S/ GROUP: PlaceboVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg57.3 57.4 56.1Body fat 21.6 21.1 23.7%Sum ofskinfolds77.0 83.4 73.6Estradiolpmo1•14109 254 340Progesteronenmol•ri0.6 24.0 11.5Hemoglobingm•1-1139 134 137Hematocrit 41.1 39.5 41.8%MCVa,*02„.943.16932.95943.111•min-1*02,...ml•ke•nie55.17 51.37 55.46V$(max) 105.8 105.6 97.41•min-1 BTPSHR(max)bpm197 208 204RER(max) 1.07 1.09ASTseconds14 13 12ET-90% V02„,.seconds628 709 713R Quadriceps 106 117 119N•rnR Hamstringsisi•n65 62 69L Quadriceps 106 144 98Isi•nL Hamstringsli•n62 62 60MCV, mean cell volume; VO 2., maximum oxygen capacity; iymax), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s -1 , best of three trials)94SUBJECT: ES GROUP: PlaceboVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg653 65.6 65.8Body fat 24.3 21.8 20.5%Sum ofskinfolds86.2 83.8 85.6Estradiolpmo1•1-1190 631 455Progesteronenmo1•1-11.4 41.0 8.2Hemoglobingm•t i127 130 126Hematocrit 37.7 39.2 37.8MCVfL91 91 93V02.l•min-13.28 3.31 3.56V02,..,ml•kg i•nie50.16 50.48 54.11Vz(max)l•min-i BTPS115.02 120.3 132.6HR(max)bpm187 189 192RER(max) 1.23 1.20 1.13ASTseconds23 25 31ET-90% V02.,seconds604 630 606R Quadriceps 155 149 155Isi•nR Hamstrings 81 87 81N•rnL Quadriceps 155 149 146N•mL Hamstrings 68 84 84N•mMCV, mean cell volume; V02„„,., maximum oxygen capacity; Vz(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s -1 , best of three trials)95SUBJECT: CL GROUP: OCAVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg64.7 64.6 65.2Body fat 14.8 15.7 15.5Sum ofskinfolds63.4 65.8 69.8Estradiolpmo1•1-147 437 31Progesteronenmo1•1-11.3 25.0 0.8Hemoglobingm•r1138 140 135Hematocrit 39.5 40.8 38.9%MCVfL89 90 91V02,..l•min-13.32 3.47 3.41V02,..,ml•ke•nie51.26 53.67 52.35V1 (max) 116.4 121.1 109.41•min-1 BTPSHR(max)bpm188 186 190RER(max) 1.25 1.28 1.22ASTseconds42 46 46ET-90% V02.,seconds424 486 421R Quadriceps 171 134 141N•mR Hamstrings 106 113 106N •rnL Quadriceps 179 136 152N•ntL Hamstrings 122 110 95N•mMCV, mean cell volume; 1702,u, maximum oxygen capacity; VE(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s -1 , best of three trials)96SUBJECT: AM GROUP: OCAVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg61.1 61.2 61.2Body fat 12.9 14.3 13.9%Sum ofskinfolds77.3 84.8 83.8Estradiolpmo1•1-1178 558 548Progesteronenmo1•141.5 40.0 27.0Hemoglobingm•1-1137 136 139Hematocrit 39.8 39.8 41.2%MCVa.91 91 89V02.l•min-13.38 3.24 3.26V02.ml•ke•rnie55.22 52.95 53.29Vs(max)l•min' i BTPS102.3 101.9 98.3HR(max)bpm203 205 205RER(max) 1.18 1.13 1.12ASTseconds45 39 35ET-90% V02.,seconds716 740 651R Quadriceps 152 165 138/*I•nR Hamstrings 68 79 65/i•nL Quadriceps 160 171 141N•tnL Hamstrings 79 87 65N•mMCV, mean cell volume; V02„,., maximum oxygen capacity, VE(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s-1 , best of three trials)97SUBJECT: CS GROUP: OCAVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg60.1 59.9 60.6^.Body fat 24.1 22.6 22.1Sum ofskinfolds63.4 73.0 79.6Estradiolpmo1•1-1154 433 926Progesteronenmo1.1-12.0 34.0 63.0Hemoglobingm•1-1129 133 130Hematocrit 38.6 40.2 38.3MCVfL88 89 90V03.,l•min-13.08 3.01 2.96V02,„,„ml•kg innind51.41 50.29 48.86Vs(max) 93.1 91.79 92.341.min-1 BTPSHR(max)bpm184 187 180RER(max) 1.19 1.25 1.20ASTseconds23 19 21ET-90% V02„,,,,seconds834 695 721R Quadriceps 106 152 152R Hamstringsbi•n73 62 73L Quadriceps 111 136 155L Hamstrings 73 65 76ZinnMCV, mean cell volume; V0 2., maximum oxygen capacity; 'V E(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s" 1, best of three trials)98SUBJECT: KD GROUP: OCAVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg51.8 51.6 53.4Body fat 20.5 20.4 23.2Sum ofskinfolds76.2 72.4 86.2Estradiolpmol•l' i280 414 241Progesteronenmo1•1-11.2 46.0 52.0Hemoglobingm•1• 1135 129 126Hematocrit 39.0 37.4 36.7MCVfi,V02.l•min-1992.72992.76982.73V02.ml•kg-i•min-152.44 53.51 51.04Vz(max) 96.7 100.9 99.71.min-1 BTPSHR(max)bpm194 198 198RER(max) 1.12 1.11 1.12ASTseconds29 34 30ET-90% V02.seconds723 905 405R Quadriceps 163 155 146!i•mR Hamstrings 108 122 78N•inL Quadriceps 155 155 127N•inL Hamstrings 103 106 76MCV, mean cell volume; V0 2„,., maximum oxygen capacity; V E(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•s -1 , best of three trials)99SUBJECT: MM GROUP: OCAVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg64.5 65.3 66.3Body fat 16.4 16.9 20.1Sum ofskinfolds92.4 89.9 109.4Estradiolpmo1•1-1102 376 70Progesteronenmo1•1-11.2 51.0 0.8Hemoglobingm•r 1131 134 130Hematocrit 38.5 39.6 39.8MCVfi.,Vo2.,l•min4883.4387337853.24V02„.„ml•kg-l•min-153.20 51.64 48.90Vz(max) 107.2 102.6 103.71•min -1 BTPSHR(max)bpm198 190 195RER(max) 1.18 1.14 1.13ASTseconds35 29 33ET-90% V01seconds537 451 261R Quadriceps 179 163 174N•inR Hamstrings 87 102 114IsI•nL Quadriceps 198 149 163N•nL Hamstrings 119 98 108N•mMCV, mean cell volume; V02„., maximum oxygen capacity; V E(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degree•s -1 , best of three trials)100SUBJECT: MC GROUP: OCAVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg58.4 60.5 59.7Body fat 14.8 15.8 15.3^-Sum ofskinfolds49.9 67.4 59.0Estradiolpmo1•1-188 376 581Progesteronenmo1•111.2 51.0 28.0Hemoglobingm•ri128 130 128Hematocrit 38.1 38.9 38.2%MCV 90 91 91IL1/02. 3.75 3.65 3.311•min-1V02.ml•kgi•miri l64.22 60.36 55.52V1(max)l•min-I BTPS110.9 110.6 104.6HR(max)bpm181 182 205RER(max) 1.08 1.18ASTseconds29 29 34ET-90% V02.,seconds1133 876 1285R Quadriceps 174 182 155Isl•nR Hamstrings 98 98 108N•mL Quadriceps 171 182 149/i•nL Hamstrings 103 95 92N•mMCV, mean cell volume; V0 2., maximum oxygen capacity; VE(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degrees•g i , best of three trials)101SUBJECT: IL GROUP: OCAVARIABLE FOLLICULAR^LUTEAL TREATMENTWeightkg61.1 61.3 62.3Body fat 12.2 12.9 12.3^-Sum ofskinfolds59.0 58.7 66.6Estradiolpmol•r1122 501 36Progesteronenmol•ri0.6 34.0 1.2Hemoglobingm•1-1121 126 127Hematocrit 35.9 38.0 37.6MCVn.98 99 99V02„,„i•nin-13.38 3.30 3.38V02„„,ml•lce•min' i55.34 53.76 54.31V1(max) 104.8 107.9 109.91•min-1 BTPSHR(max)bpm181 182 175RER(max) 1.08 1.14 1.14ASTseconds28 35 31ET-90% V02,,,„seconds908 1318 1178R Quadriceps 187 155 138N•mR Hamstrings 89 87 106N•inL Quadriceps 108 108 100N•mL Hamstrings 87 84 89N•mMCV, mean cell volume; V0 2„„„, maximum oxygen capacity; VE(max), maximum minute ventilation; HR(max),maximum heart rate; RER(max), maximum respiratory exchange ratio; AST, anaerobic speed test; ET, endurancetime; R, right; L, left (peak torque measured at 30 degree•s -1, best of three trials)

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