16 Effects of Female Reproductive

Transcription

1 16 Effects of Female Reproductive Hormones on Sports Performance Constance M. Lebrun, MDCM, Sarah M. Joyce, BEXSC, and Naama W. Constantini, MD CONTENTS Introduction Physiology of the Menstrual Cycle Oral Contraceptives Physiological Effects of the Female Sex Steroid Hormones Female Reproductive Hormones and Athletic Performance Female Reproductive Hormones and Sports Injuries Summary References INTRODUCTION Over the past 30 years, the involvement of women and girls in physical activities and competitive sport has increased exponentially. This is largely a consequence of Title IX of the United States Educational Assistance Act (enacted in 1972), which mandated institutions receiving federal monies to provide equal access for women to funding for extra curricular activities, including opportunities for participation, fi nancial resources for scholarships, and quali fi ed coaching. Equally as important, there have been progressive changes in societal and cultural views worldwide toward the acceptance of female athletes into the sporting arena historically and traditionally a male bastion. Women From: Endocrinology of Physical Activity and Sport: Second Edition Edited by: N. Constantini and A.C. Hackney, DOI / _16 Springer Science+Business Media New York

2 282 Lebrun, Joyce, and Constantini now compete at the highest levels in most sports, some of which were previously played by men only, such as ice hockey, wrestling, and rugby. The 2012 Summer Olympic Games in London marked the introduction of women s boxing as a full-participation sport. Yet scienti fi c knowledge regarding a woman s unique physiology from childhood through puberty and adolescence, across the reproductive lifespan, and into the postmenopausal years has not kept pace with this explosion in sport participation by girls and women. In particular, there still remains a multitude of unanswered questions about the effects of the female reproductive hormones estrogen and progesterone on various aspects of athletic performance. Athletic performance itself is a multifaceted entity a complex and intricate kaleidoscope of cardiovascular, respiratory, metabolic, endocrinological, and psychological factors that all must interact to enhance and facilitate sporting success. The relative importance of each varies with the speci fi c demands of the particular discipline. Athletes and coaches have long postulated that altered athletic performance might result from the hormonal swings of the female menstrual cycle (MC). Early studies were retrospective and nonspeci fi c, with substantial recall bias in terms of MC phase and status ( 1 3 ). Researchers have investigated the in fl uence of the MC on substrate metabolism, cardiorespiratory function, thermoregulation, psychological factors, and musculoskeletal injury rates. The individual sex steroids estrogen and progesterone can have antagonistic, synergistic, or additive effects, and furthermore, their relative concentrations change during the course of an ovulatory menstrual cycle ( 4, 5 ). In addition, hormonal levels have been shown to increase with exercise ( 6 8 ). Both oral contraceptives (OCs) and hormone replacement therapy (HRT) can provide a stable and controllable hormonal milieu for training and competition. However, the combinations of exogenous hormones in these formulations introduce yet other potential modifying factors. This chapter will integrate what is already known in this somewhat controversial fi eld of inquiry ( 9 16 ), with new emerging evidence and interesting future directions. The reader is referred to summative reviews ( ) for further details on the individual investigations. PHYSIOLOGY OF THE MENSTRUAL CYCLE A well-de fi ned, predictable pattern of hormonal fl uctuations takes place over the course of an ovulatory menstrual cycle ( 23, 24 ). In eumenorrheic females, an average menstrual cycle (MC) lasts 28 days, but may range from 20 to 45 days. The three main phases follicular, ovulatory, and luteal are based on ovarian function and controlled by pituitary hormonal signals (Fig. 1 ) ( 4 ). Intricate feedback mechanisms involve the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and the female sex steroids. Some studies further divide the cycle into fi ve discrete phases, including an early and late follicular phase and an early, middle, and late luteal phase (see Chap. 8 by Petit and Prior) ( 25 ). Varying concentrations of estradiol and progesterone differentiate the phases of an ovulatory MC: both are low during the follicular phase (FP), estrogen is high and progesterone low during the ovulatory phase (OP), and both are high in the luteal phase (LP).

3 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 283 Fig. 1. Hormonal changes and phases of the menstrual cycle. FSH follicle-stimulating hormone; LH luteinizing hormone. ORAL CONTRACEPTIVES Oral contraceptive pills provide steady levels of exogenous estrogen and progestin, which act primarily by disrupting the normal hypothalamic-pituitary-ovarian (HPO) axis to suppress ovulation (Fig. 2 ). Current recommendations state that age alone does not constitute a medical reason for denying any contraceptive method including OCs and progestogen-only injectables, as this concern must be balanced against the advantages of avoiding pregnancy in adolescents below 18 years ( 26 ). OCs can be safely prescribed right up until the perimenopausal years in nonsmoking women. In addition to the prevention of pregnancy, OCs are sometimes utilized by female athletes to manipulate timing of menses around important competitions. However, it is estimated that the prevalence of OC usage in the athletic population matches that within the general community ( 27 ). Newer formulations such as Seasonale even make it possible to even completely withhold menstruation. This OC is administered continuously for 3 months, allowing only four periods or withdrawal bleeds per year, thereby decreasing premenstrual syndrome (PMS) and concomitant menstrual discomfort and pain, as well as blood loss and iron de fi ciency ( ). Contemporary low-dose combination pills have a three- to fourfold decrease in estrogen content and a tenfold decrease in progestin compared with earlier generation OCs, usually containing between 15 and 35 μ g ethinyl estradiol (EE) and less than 1 mg progestin ( 31 ). In monophasic preparations, estrogen and progesterone doses are fi xed

4 284 Lebrun, Joyce, and Constantini Fig. 2. Suppression of endogenous female sex steroid hormones by combined oral contraceptives (OCs). FSH follicle-stimulating hormone; LH luteinizing hormone; EE ethinyl estradiol. over the entire pill cycle, while in biphasic or triphasic formulations, amounts vary to mimic normal physiologic cyclical patterns. Most OCs incorporate EE as the synthetic estrogen, although some older formulations contained mestranol. Synthetic progestins, derived either from 19-nortestosterone or from 17-OH progesterone derivatives and 19-norprogesterone derivatives, have been chemically re fi ned to decrease unwanted side effects. First-generation progestins include norethindrone and norethindrone acetate, norethynodrel, and ethynodiol diacetate. Levonorgestrel and norgestrel are second-generation drugs from the gonane group, with norgestrel the more potent and the more androgenic. The estrane group comprises norethisterone and its metabolites, as well as norethisterone pro-drugs: norethynodrel, lynestrenol, and ethynodiol acetate. Third-generation progestins are deliberately more selective for progestin receptors, with consequently a less negative impact on lipoproteins and atherogenesis of vessel walls. These include desogestrel (and its active metabolite 3-keto-desogestrel or etonogestrel), norgestimate, and gestodene. Fourth-generation progestins are dienogest (a hybrid progestin, with antiandrogenic actions) and drospirenone (derived from spironolactone, giving it anti-mineralocorticoid and progestogenic properties not found in most synthetic progestins). There are other new progestins, with varying pharmacological pro fi les and activities ( 32 ). For women unable to tolerate these combined regimens or for those with medical contraindications to estrogen use, there are progestin-only preparations, such as progestin-only minipills, or injectable depot medroxyprogesterone acetate (DMPA) or Depo-Provera ( 33 ). Subdermal slow-release capsules containing levonorgestrel (Norplant) or etonogestrel (Implanon) provide rapidly reversible contraception for up to 5 years with only a 1% failure rate, but require special physician training on implantation and removal of the capsules. Increased and irregular intermenstrual bleeding

5 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 285 with progestin-only preparations may, in itself, be disruptive for athletic training and competition. There is little existing information on the use of these contraceptive methods in adolescent athletes and/or any associated effect on performance. Additional methods of long-acting reversible contraception include intrauterine devices (IUDs) containing either copper or levonorgestrel (Mirena), and the contraceptive vaginal ring or transdermal patch ( 34 ). PHYSIOLOGICAL EFFECTS OF THE FEMALE SEX STEROID HORMONES The female sex steroid hormones are all derivatives of cholesterol. Within the estrogen group of 18-carbon steroids, 17 b estradiol is the major form, and estrone and estriol are less potent. In women, they are secreted primarily by the ovaries, and to a lesser extent by the adrenals ( 35 ). As discussed, synthetic forms include ethinyl estradiol and mestranol. The other major female hormones are the progestins : endogenous progesterone and first-, second-, third -, and now fourth-generation synthetic progestins in OCs. The various female sex steroids (endogenous and exogenous) exert a myriad of diverse and complex effects on multiple physiologic parameters, with the potential to in fl uence athletic performance. Considerations for exercise performance in women therefore differ signi fi cantly from men ( 36 ). Cardiovascular Function All estrogens are known to have important actions on the cardiovascular system ( 37, 38 ). They alter plasma fi brinolytic activity and platelet aggregation, resulting in a detrimental increase in thrombosis. Conversely, they also confer protection against atherosclerosis by decreasing total cholesterol and low-density lipoprotein (LDL) levels and increasing high-density lipoproteins (HDL). Estrogen enhances vasodilation of the vascular smooth muscle of coronary arteries and peripheral vascular beds ( 39, 40 ), in turn increasing blood supply to the heart and muscles. At least theoretically, there is potential here for enhancement of cardiac function and aerobic performance. Estrogen controls production and release of nitric oxide (NO), now known to be the endotheliumderived relaxation factor ( 41 ), and can act as a calcium channel blocker ( 42, 43 ). In addition, estrogen is thought to be protective against in fl ammation ( 44, 45 ). Many of these actions are antagonized by progesterone, making this an extremely complex area of physiology ( 46 ). Overall, estrogen is viewed as protective against cardiovascular disease and hypertension ( 47 ). Therefore, there is mounting concern that women with functional hypothalamic amenorrhea (and consequently low estradiol levels) have an increased risk of cardiovascular disease, through changes in the above mechanisms ( ). Amenorrhea in female athletes is associated with endothelial dysfunction and an unfavorable lipid profile ( ). One study showed that folic acid supplementation improved vascular function in amenorrheic athletes ( 58 ). By replacing estradiol with an exogenous form of estrogen, OCs may ameliorate this endothelial (and vascular) dysfunction and, by extension, potentially modify this increased risk ( 59 ).

6 286 Lebrun, Joyce, and Constantini Fig. 3. Overview of the effects of estrogen (E) and progesterone (P) on pathways of carbohydrate and fat metabolism;, increased fl ux through pathway;, decreased fl ux through pathway; TG triglycerides; FFA free fatty acids; LPL lipoprotein lipase; GLUT-4 glucose transporter type 4; CAT 1 mitochondria carnitine acyltransferase 1. Respiratory Function Sex hormones are involved in central neural control of breathing ( 60 ), and can also affect the lungs and the airways. Investigations have consistently shown increased minute ventilation (VE) and augmented ventilatory response to hypoxia and hypercapnia during the LP, when hormone levels are highest ( 61, 62 ). Other researchers have documented changes in carbon dioxide (CO 2 ) sensitivity ( 63 ) and pulmonary carbon monoxide diffusing capacity ( 64 ). Similar changes in ventilation and respiration are seen in pregnancy ( 65, 66 ), due to elevated progesterone levels (see Chap. 17 by Bessinger). Different exogenous synthetic progestins in OCs may also have some in fl uences on the respiratory system ( 67 ). Substrate Metabolism and Energy Sources Estrogen (and progesterone to a lesser extent) promotes glycogen uptake and storage in the liver and muscle (mostly type I fi bers), and during exercise spares glycogen stores by shifting metabolism toward free fatty acids (FFA) ( ). This occurs by increased lipid synthesis, enhanced lipolysis in muscle through induction of lipoprotein lipase (LPL), and greater utilization of FFA (Fig. 3 ). Such metabolic adaptations may be advantageous for women during ultraendurance exercise in comparison with their male counterparts ( 75, 76 ), by reducing reliance on muscle glycogen and increasing oxidative capacity ( 68 ). Women respond similarly to men to a protocol of carbohydrate (CHO) loading to supercompensate muscle glycogen stores, when fed the same relative amount of CHO ( 77 ).

7 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 287 Glycogenolysis (hepatic release of glucose) and gluconeogenesis help to control blood glucose levels along with peripheral glucose uptake. Progesterone may promote translocation of the GLUT-4 glucose transporter to the plasma membrane ( 73 ). It has been hypothesized that the drop in blood glucose represents an inability to maintain blood glucose homeostasis, rather than increased utilization ( 78 ). Paradoxically, however, both estrogen and progesterone suppress gluconeogenic output during exercise, which may potentially compromise performance in the latter stages of ultralong events, unless energy replacement supplements are adequate ( 22 ). Some have suggested that it may be more relevant to supplement energy intake during exercise with protein when progesterone is elevated, compared with estrogen, because progesterone promotes protein catabolism, while estrogen suppresses it ( 79 ). Similarly, estradiol and progesterone seem to have opposing effects in terms of lipid metabolism, with greater lipid oxidation when estradiol is used alone (Fig. 3 ). A detailed review of these complex metabolic processes, and the relative roles of hormones in regulating CHO and fat utilization at rest and during exercise, is beyond the scope of this chapter but is available elsewhere ( 73, 80 ). Estrogen also acts in concert with growth hormone (GH), catecholamines, and insulin to regulate glucose metabolism ( 81 ) by decreasing insulin-binding capacity, resulting in deterioration in glucose tolerance and insulin resistance ( 82 ). Transdermal estradiol has been shown to change glucose metabolism, through decreased gluconeogenesis and changes in epinephrine secretion and glucose transport ( 83 ). Metabolic effects of progesterone include relative glucose intolerance and insulin resistance during the LP and pregnancy (when progesterone is high), with greater dependence on fat as a substrate, as shown by higher circulating FFAs ( 84 ), lower respiratory exchange ratios (RERs), and lower blood lactate levels during submaximal exercise ( 71, 85 ). Progesterone also appears to induce peripheral insulin resistance through actions on insulin receptors ( 81, 82 ), facilitated by the presence of estrogen. Female athletes with diabetes may need to be cognizant of such menstrual cycle in fl uences, in order to optimize glucose control during training and competition. There are varying concentrations and types of synthetic progestins in OCs, which also have the potential to impact hormonal responses and substrate utilization during exercise. The more androgenic progestins (norgestrel and levonorgestrel), in combination with ethynodiol diacetate, cause a decrease in glucose tolerance and an increase in insulin levels, but ethynodiol diacetate and norethindrone do not seem to have this effect. The newer third-generation progestins (i.e., desogestrel, gestodene, and norgestimate) have been designed to have less impact on glucose tolerance and insulin levels, as have fourth-generation progestins ( ). Deterioration of glucose tolerance and hyperinsulinemia are seen with DMPA, but norethindrone alone does not seem to have any signi fi cant effects. Approximately 25 50% of insulin-dependent diabetics will have an increase in insulin requirements while taking OCs, although there is great intraindividual variability ( 89 ). Low-dose monophasic OCs, limiting the amount of androgenic activity of the progestin, may be the best choice for women with insulin-dependent diabetes mellitus (IDDM). More information is needed on the impact of third- and fourth-generation progestins on glucose tolerance, insulin responses, and any clinical implications for exercising females.

8 288 Lebrun, Joyce, and Constantini Body Composition, Weight, and Bone Mineral Density Other actions of estrogen include deposition of fat into the breasts, buttocks, and thighs, typically female characteristics. In terms of fl uid balance and plasma volume, estrogen causes sodium and chloride retention, resulting in edema, weight gain, and an increase in blood pressure. Levels of both estrogen and progesterone are high in the end-luteal phase (i.e., immediately premenstruation). Through a complex feedback mechanism involving the renin-angiotensin system and aldosterone, progesterone in particular can cause fl uid retention and increased body weight, possibly hindering performance ( 90 ). In one study, however, sodium retention during the LP did not correlate signi fi cantly with the typical premenstrual symptoms of subjective breast tenderness and bloating ( 91 ). In another 1-year prospective cohort study, monitoring of fl uid retention during the MC in 62 healthy women revealed a peak on the fi rst day of fl ow (when estradiol and progesterone levels are low), rather than premenstrually, possibly suggesting a lag of fl uid dynamics in response to previous higher hormone levels ( 92 ). Administration of OCs has variable effects on weight, body composition ( 93 ), and fl uid dynamics, depending on the relative androgenicity of the progestin used ( 94 ). Importantly for bone mineral density (BMD), estrogen facilitates both gastrointestinal calcium absorption and calcium uptake into bone. Chronic estrogen-de fi cient states (such as menopause or amenorrhea and other forms of menstrual dysfunction) increase susceptibility to alterations in BMD. This can lead to either osteopenia or frank osteoporosis, with an increased risk for fractures, including stress fractures in younger individuals (a de fi nite hindrance to training and competition!). The problem here is really twofold: lack of estrogen causes increased bone resorption, but equally and even more importantly, low energy availability (intentional or inadvertent) leads to menstrual dysfunction ( 95, 96 ). Low energy availability interferes with bone formation through the insulin growth factor-growth hormone (IGF-GH) axis (see Chap. 11 by Anne Loucks). This is most worrisome in the young adolescent athlete, who should be building up peak BMD during the critical years of rapid growth; even endurance training or weight-bearing exercises are not completely protective ( 97 ). There is an ongoing need to educate athletes, coaches, and physicians about this important issue ( 98 ). Traditional postmenopausal HRT has been designed to counteract this process and replace the bene fi cial effects of estrogen in maintaining BMD. Because of the other energy-dependent mechanisms involved, it remains controversial whether or not administration of OCs is protective in younger women with functional hypothalamic amenorrhea ( ), or if the length of previous exposure is a factor ( 102, 103 ). In fl uences of synthetic progestins on bone density are dependent on biochemical con fi guration and relative potency. Progesterone injections (DMPA) induce amenorrhea, with detrimental effects on BMD, which have been shown to be only partially reversible on discontinuation ( 104 ). It therefore behooves health-care providers to be aware of such potential effects, especially in younger female athletes, for whom stress fractures (especially in high-risk areas, such as the femoral neck) can be catastrophic. Little to no research has been done on BMD and contraceptive hormone-releasing patches, IUDs, or vaginal rings.

9 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 289 Thermoregulation Progesterone has long been recognized to have thermogenic action. It causes an increase in basal body temperature (BBT) of C during the LP ( ) and during pregnancy ( 108 ), (see Chap. 17 by Bessinger) through a central action on the preoptic neurones ( 109 ). This central effect on body temperature also increases minute ventilation ( 110 ). There are numerous associated physiological mechanisms: altered skin blood fl ow ( 111, 112 ), a higher threshold for cutaneous vasodilatation, delayed onset of sweating ( 113, 114 ), and decreased thermal conductance ( 115 ). The increased BBT is postulated to result from an alteration or shift in set-point temperature related to the MC ( 116 ), but there may be individual differences in these temperature changes ( 117 ). Estrogen modi fi es the temperature effects of progesterone ( 118 ). Exogenous progestins in OCs can also affect centrally thermoregulatory mechanisms, and shift baseline core BBT and the threshold for the active vasodilator system to a higher internal temperature, with associated implications for exercise performance in the heat ( 119 ). Psychological Factors: Estrogen and the Brain There is increasing evidence that estrogen mediates different aspects of cognition, alertness, and mood, possibly through changes in the availability of neurotransmitters in the brain, such as serotonin. This is especially important during competition, where peak mental functions are required. Alterations in 5-hydroxytryptamine (5-HT) and serotonin pathways may also play a role in dysphoric PMS ( 120 ), and there may be associated changes in functional ability ( 121 ), which might increase risk for musculoskeletal injury. There have been reports of MC alterations in color vision performance, sleep-related memory consolidation, etc., but only with small numbers of subjects and mostly without hormonal veri fi cation. Brain size and morphology have been found to change over the MC, with signi fi cant grey matter volume peak and CSF loss at the time of ovulation, but with no correlation to estradiol or progesterone hormone levels ( 122 ). It has also been proposed that estrogen bene fi ts cognitive function and verbal memory in postmenopausal women, again through an effect on neurotransmitters, such as serotonin ( 123 ). Recent research has shown an inverse relationship between blood glutamate levels (which have neurotoxic properties) and levels of plasma estrogen and progesterone ( 124 ). Several current reviews explore these concepts in more detail ( 125, 126 ). The potential effects, if any, of a prolonged hypoestrogenic state on cognitive function in amenorrheic athletes are purely speculative and hypothetical at this time. Researchers have linked gender differences in ischemic brain injury to estrogens ( 127 ), and have even examined clinical measures of concussion during the MC ( 128 ). Progesterone is also thought to possibly have neuroprotective bene fi ts ( 129 ). There is potential for OCs to positively affect cognition, attention, mood, and various other psychological parameters, such as mental rotation and verbal fl uency, depending on the speci fi c chemical formulation ( ). This is a fertile area for future research, especially since brain function under a varying human estrogenic environment is another source of modulation of exercise responses ( 133 ).

10 290 Lebrun, Joyce, and Constantini Strength & Power Psychomotor Hand eye coordination Cardiovascular Heart rate and rhythm Stroke volume Blood pressure Body fluid volume Coagulation Vascular function Sympathetic activity Anaerobic capacity Aerobic capacity Brain function Mood Arousal Cognition Athletic Performance Musculoskeletal Injury rate Ligament laxity Low back pain Sensory-motor Simple reaction time Sensory perception Pain threshold Metabolic Core body temperature Thermoregulation Resting O 2 consumption Substrate availability Substrate metabolism Acid-base balance Respiratory Ventilation Asthma Fig. 4. Components of physical performance that may be affected by menstrual cycle fl uctuations in endogenous hormones. FEMALE REPRODUCTIVE HORMONES AND ATHLETIC PERFORMANCE Physical fitness is frequently de fi ned in terms of aerobic capacity, anaerobic capability, muscle endurance and strength, fl exibility, and body fat percentage, but actual athletic performance is much more complex, with neuromuscular, sensorimotor, psychomotor, cognitive, and psychological functions all coming into play (Fig. 4 ). There are signi fi cant genetic inheritance effects on various components such as peak oxygen uptake and anaerobic power ( 134 ). Therefore, both nature and nurture (genetic factors and training) are involved in determining athletic prowess ( 135 ). Finally, the human spirit is of such tenacity that the ultimate determinate of success and athletic performance may actually reside within the brain according to the central governor model (CGM) of Noakes ( 136, 137 ). As detailed in previous sections, both estrogen and progesterone have signi fi cant effects on the metabolic, thermoregulatory, cardiovascular, and respiratory systems. Therefore, it is not unreasonable to conjecture that cyclical endogenous hormonal variations of the MC might in fl uence performance. When comparing research fi ndings, it is critical to consider the population being studied and the training status of the women (untrained, recreational, or elite athletes). Small subject numbers lead to inadequate power to detect signi fi cant differences, and individual variability could conceivably skew the results. Contradictory fi ndings may be explained by the variety of testing protocols, differences in exercise intensity levels used, wide circadian variation in hormonal secretion, and discrepancies in the timing of testing, as well as the state of hydration, nutrition, and fi tness, etc., of subjects. Much of the early research is fraught with methodological inaccuracies, the most signi fi cant being inconsistent de fi nitions and documentation of MC phases (see Chaps. X and X by Hackney and Petit).

11 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 291 Cardiovascular Function and Athletic Performance Cardiovascular Function and the Menstrual Cycle Some physiological parameters can potentially be affected during the MC by the different cardiovascular effects of estrogen and progesterone. There are transient changes in plasma volume (PV), peaking within 2 days of the estimated day of ovulation and progressively increasing during the LP ( 138 ). Hemoglobin concentration may affect oxygen delivery to the tissues, but studies have shown no change ( 9 ), increased resting hemoglobin ( 139 ), or a decrease in hemoglobin in the LP ( 140 ). Also, in terms of actual oxygen utilization, increased body temperature during the LP causes a rightward shift of the oxyhemoglobin dissociation curve, while the concomitant LP increase in ventilation shifts the curve leftward due to an increase in ph, quite probably leading to no net effect. Peripheral hemodynamics and renal function are affected through various mechanisms by both MC phase ( 141 ) and OC use, with additional effects during exercise ( 142 ). Measurements of tissue Doppler imaging derived myocardial performance index during the menstrual and the LP in 27 women aged documented that endogenous estrogen improved combined systolic and diastolic function in both the left and right ventricles ( 143 ). Another study tested 19 eumenorrheic women with two incremental tests to voluntary exhaustion on a cycle ergometer and did not show any differences in cardiorespiratory variables, substrate metabolism (lactate), or performance (de fi ned as power output and oxygen consumption or VO 2 ), but did fi nd a greater ventilatory drive in LP ( 144 ). Decreased estrogen levels increase peripheral resistance and decrease exercising muscle blood fl ow ( 37, 38, 43 ). Blood pressure is reduced and systemic vascular reactivity increased during the late FP, just prior to ovulation ( 145, 146 ). Both MC ( 147, 148 ) and OCs ( 148 ) alter sympathetic nerve activity during orthostatic stress in young healthy women. Conversely, higher estradiol levels have been shown to lower cardiovascular responses to stress, most likely through effects on arterial wall tone and a decrease in beta-receptor sensitivity to catecholamines ( 149 ). Progesterone may act to increase cardiac excitability during the LP, as documented by a greater number and duration of episodes of paroxysmal supraventricular tachycardia (SVT) ( 150 ). A higher heart rate (HR) and rating of perceived exertion (RPE), at the same intensity of exercise, have been seen in many studies, suggesting greater cardiovascular strain during the LP. However, given the overriding adaptations of the cardiovascular system to exercise, it is not surprising to fi nd few observed alterations in actual athletic performance, despite this increase in HR and RPE. Within the last decade, MC phase has been demonstrated to have an in fl uence on timing of acute coronary events, with increases during the early FP ( 151, 152 ), possibly due to alterations in adrenergic control. Additionally, estrogen may have a bene fi cial effect on myocardial ischemia in women with coronary artery disease (CAD) ( 153 ). Given the increasing numbers of masters-level female athletes training and competing, some of these fi ndings become more pertinent. Oral Contraceptives and Cardiovascular Function Synthetic hormones also have signi fi cant cardiovascular effects. This was suggested by very early studies in subjects taking higher-dosage OCs ( 154, 155 ). Theoretically, such estrogen-mediated cardiovascular changes (e.g., increases in preload and stroke volume caused by increased PV) might augment effective cardiac

12 292 Lebrun, Joyce, and Constantini output (CO) and enhance performance. Higher CO has been found at rest and during exercise, with or without concomitant alterations in blood pressure and vascular volume, in women on several different higher-dosage combination pills ( 90, 156 ). It is likely that the newer formulations of synthetic progestins in OCs have less impact, as they have fewer side effects. An echocardiographic study of 31 young women did not fi nd any differences in resting left ventricular structure and function attributable to either hormonal variation over the MC, or with a combined OC pill ( 157 ), although estradiol levels were not measured directly. Studies have also found no signi fi cant alterations in cardiac index or pulmonary artery distensibility in inactive women taking OCs ( 154, 158 ). Heart rates at rest and during exercise generally do not change with administration of OCs; however, increases in office blood pressure (from 2 to 7 mmhg systolic and from 1 to 3 mmhg diastolic) have been documented during the fi rst few months of use, diminishing over time and reversible on discontinuation of OCs. This fi nding has primarily been associated with low-dose monophasic OCs containing levonorgestrel, and not with triphasic preparations or OCs with the newer progestins. Detrimental changes in serum lipids are also minimized with the newer progestins, and are attenuated by regular exercise ( 159 ). Exercise has an anticoagulation effect, and has been observed to act synergistically with some OCs to increase fi brinolytic activity. However, estrogen also enhances platelet aggregation and increases various coagulation factors, facilitating thrombogenesis; this effect is decreased with formulations containing 35 μ g of EE or less ( 160 ). The newest progestins may be associated with a greater incidence of venous thromboembolism ( 161, 162 ), compounded in women with factor V Leiden thrombophilia. Because of the overall increased risk of cardiovascular disease in women using OCs, current prescribing guidelines should be carefully followed ( 163 ). Respiratory Function and Athletic Performance Respiratory Function and the Menstrual Cycle Minute ventilation (VE) and respiratory drive are generally increased under the in fl uence of higher progesterone levels during LP ( 63, 140 ). Curiously, more recent research has suggested that estradiol mediates cyclic changes in angiogenesis and causes neovascularization in the pulmonary vascular bed, leading to decreased diffusing capacity ( 164 ). In one early study, a higher ventilatory rate during the LP was associated with greater oxygen demand, subjective dyspnea, and perceived exertion, and a decrease in maximal exercise response during the LP, but only in the nonathletes ( 62 ), suggesting that these responses may be overcome with increased training. Conversely, another early study found no signi fi cant differences in VO 2 max, HR, time to exhaustion, or maximal ventilation between MC phases in fi ve moderately trained women ( 165 ). Relative ventilatory threshold (VT), however, occurred at a signi fi cantly higher percentage of VO 2 max in the early FP compared with the mid-luteal phase. Many others since then have documented either no MC variation in ventilation or mid-luteal elevation in resting minute ventilation (VE), but generally no changes in VE during submaximal exercise. These are well reviewed in a recent research publication ( 166 ). This latter group also did not fi nd any MC effect on sensitivity to chemical stimuli,

13 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 293 either isocapnic hypoxic ventilatory response (ihvr) or hypercapnic ventilatory response. They concluded that any hormone-mediated in fl uences are of insuf fi cient magnitude to exceed the inherent variation in these chemosensitivity measures, and that feedforward and feedback mechanisms during exercise override the effects of naturally occurring changes in sex hormones. It appears that neither exercise VE nor physical performance in women at altitude is affected by MC phase ( 167 ), possibly for similar reasons, although some have found ventilatory alterations with higher work output, but no change in VO 2 max ( 168 ). Menstrual cycle-induced modulation of the ventilatory responses to exercise may be altered under acute hypobaric-hypoxic conditions ( 169 ). There is also a documented link between female sex steroids and airway function: variously termed perimenstrual asthma ( 170 ), premenstrual asthma ( PMA ) ( 171 ), or menstrual-linked asthma (MLA). Overall, an estimated 33 52% of asthmatic women report premenstrual worsening of asthma symptoms, and an additional 22% report their asthma to be more severe during menses ( 172 ). This can have signi fi cant clinical impact for female athletes with asthma ( ). The role of endogenous and exogenous hormones in asthma is postulated to involve various mechanisms ( 177 ). Airway hyperresponsiveness is exacerbated during premenstrual phase, due to the withdrawal of high levels of progesterone (a smooth muscle relaxant) and estrogen, or both. In terms of airway tone, estrogens increase the production of nitric oxide (NO), an endogenous bronchodilator, in the human bronchial epithelium ( 178 ). Estrogens also have anti-in fl ammatory effects, so they can modulate the increased airway wall in fl ammation found in MLA ( 179 ). Recently, a large crosssectional population health questionnaire of women registered in an asthma database (540/1,260 43% response rate) found an 11% incidence of self-reported MLA (worse with menstruation) as well as an increased association with other autoimmune-type diseases, such as rheumatoid arthritis, eczema, and heart disease ( 180 ). In this study, women with MLA compared to women without MLA also reported more urgent/emergent asthma-related health-care visits per year, more emergency room visits, and higher asthma-related absenteeism, and used almost twice the number of β 2 agonist rescue doses per day. The multifactorial etiology of MLA has implications for pharmacotherapy ( 181, 182 ). Short- and long-acting β 2 agonists are helpful ( 183 ), as are leukotriene antagonists ( 184 ). OC use has been reported to reduce the prevalence of current wheeze in women with a history of asthma ( 185 ), with a signi fi cant trend linked to duration of use ( 177 ); conversely, however, OC administration has also been found to exacerbate MLA ( 186 ). Oral Contraceptives and Respiratory Function Ventilatory changes similar to those of the LP of the MC, along with increased oxygen consumption ( 187 ), have also been documented in women taking the older higherdose OCs, with some evidence for accommodation over time ( 188 ). However, studies using low-dose OCs did not show any associated ventilatory changes, but documented a slight decrement in aerobic capacity ( 189, 190 ). A recent pilot study of cardiorespiratory fi tness in 12 endurance-trained runners suggested that OC use might attenuate MC-induced ventilatory changes as compared with non-oc users ( 191 ), thus allowing for more consistent cardiorespiratory fi tness throughout the (arti fi cial) cycle.

14 294 Lebrun, Joyce, and Constantini Substrate Metabolism Estrogen and progesterone promote glycogen uptake and storage. Muscle biopsies have documented increased muscle glycogen storage during the LP ( 192 ), with greater fat use and oxidation at ovulation postulated to be due to higher estrogen levels. Glycogen repletion after exhaustive exercise has been noted to increase during the FP ( 68 ). Some investigators have found a lower RER during the LP, suggesting increased reliance on FFA for fuel ( 68, 139 ) ; however, most have not found this to be the case ( 113, 114, ). This may be dependent on exercise intensity, which shifts the metabolic demands from aerobic to anaerobic fuel sources. For example, during the LP in nine eumenorrheic women, lower CHO use and oxidation rates, in association with greater lipid use and oxidation, were documented with 10-min submaximal treadmill exercise intensities at 35% and 60% VO 2 max, but not at 75% VO 2 max ( 70 ). Blood lactate generally increases in proportion to exercise intensity and the anaerobic contribution to glycolysis. A number of early studies with hormonal documentation suggested decreased lactate production during the LP ( 6, 78, 140 ), associated with an increase in endurance time ( 6, 139 ), but many others have not demonstrated any signi fi cant MC differences in lactate ( 144, 165, ), or any enhanced LP performance. In a study of nine athletes, no differences were found in resting blood lactate or in running time to exhaustion, but recovery lactate levels were signi fi cantly lower during the LP ( 197 ). This suggests preferential metabolism of lipids and a reduction in CHO metabolism, but confounding factors are energy demand and nutritional status. A CHO-loading diet can supercompensate muscle glycogen stores in the early FP to values attained in the LP ( ). There may also be mechanisms related to other hormones; for example, in a study of eight women performing three maximal exercise tests with simultaneous determination of lactate threshold during early and mid-fp, and mid-lp, there was no effect on lactate threshold, but there was a signi fi cant correlation between LT and the epinephrine breakpoint ( 201 ). Theoretically, endurance performance could also be enhanced during the LP, through increased muscle glycogen stores ( 68, 192 ) and the effects of MC on CHO and lipid metabolism ( 84 ). Consistent with these fi ndings, high estrogen levels during the LP are associated with sparing of muscle glycogen, in comparison to the FP ( 80 ). Hypothetically, such advantage might be lost in amenorrheic athletes ( 202 ). Dissociation of blood glucose homeostasis during exercise has also been shown to occur ( 78 ). An additional factor to consider is fl uctuation with the time of day ( 203, 204 ). Contradictory research (especially for endurance performance) can be explained by differences in de fi nitions and exercise protocols for endurance, variability in subject fi tness, pre-exercise hydration, nutritional status, and initial muscle glycogen stores ( 205 ). A different study found substrate oxidation and GH responses to exercise to be independent of MC phase and status ( 195 ). However, exercise-associated GH release is attenuated in amenorrheic athletes, due to decreased growth hormone-releasing hormone (GHRH) response to exercise, compared to eumenorrheic athletes This is particularly relevant to adolescent female athletes, since the prevalence of athletic (hypothalamic) amenorrhea among these athletes is 4 20 times higher than the general population, most frequently also associated with energy de fi ciency. Reduced exercise-induced GH response in these athletes may be important, since it potentially indicates reduced effectiveness to training stimuli.

15 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 295 Glucose tolerance deteriorates during the LP ( 81 ), but it has been suggested that the cyclic changes in metabolic control are attributable to mechanisms other than the variations in insulin sensitivity, such as energy intake and caloric expenditure. Other investigators have not shown a substantial change in blood glucose over the MC ( 68, 195, 206 ). It may be more appropriate to look at E/P ratio (pmol/nmol) during the LP as well as the absolute magnitude of increase in ovarian hormones. Substrate turnover studies using radioactive tracer isotopes have very precisely examined the kinetics of glucose and lipid metabolism, using glucose rate of appearance and glycerol appearance, respectively, and have found lower CHO utilization during the LP than the FP ( ). Another group did not fi nd any MC phase effect on glycerol or palmitate kinetics during 90 min of moderate exercise ( 210 ). This complex subject is well reviewed elsewhere ( 22 ). Synthetic steroids in OCs appear to increase glucose fl ux, but not overall CHO and lipid oxidation rates, during moderate-intensity exercise, with greater metabolic effects than endogenous ovarian hormones ( 211, 212 ). Increased TG mobilization is not matched by an increase in oxidation but rather by reesteri fi cation. When CHO use predominates (such as in a postprandial state or during moderate-intensity exercise), whole-body plasma FFA turnover does not appear to be affected by either MC or OC, suggesting that the hierarchy of regulators of fatty acid oxidation is: exercise intensity > recent CHO nutrition > synthetic > endogenous ovarian hormones. The interaction of OCs with energy metabolism systems is complex, and potential ergogenic or deleterious effects are not well de fi ned. Although glucose production is determined primarily by insulin, other hormones, such as thyroxine, catecholamines (epinephrine and norepinephrine), cortisol, and growth hormone (GH), can have a counterregulatory effect. GH levels are increased by high doses of estrogen, hypoglycemia, and endogenous opioids, and decreased by progestins. At rest, fasting blood glucose, serum triglycerides, basal serum prolactin, and GH may be higher in women taking combination OCs. Other studies have shown lower blood glucose levels at rest and during exercise in OC users, and an increase in FFA levels during mild exercise ( 206 ). During prolonged exercise, women on OCs have been shown to have an elevated GH response to exercise and lower glucose and CHO use, with a shift more toward metabolism of FFA ( 165 ). Overall, there appears to be a possible glycogen-sparing effect of OCs, with the magnitude dependent on the speci fi c chemical formulation. These alterations in substrate utilization, although minor, might still have an effect on aerobic performance, particularly in the elite female athlete. Thermoregulation Although some early studies did not show any cycle phase differences in response to short-term exercise or heat exposure ( 113, 114 ), others demonstrated that the normal hormonal fl uctuations of an ovulatory MC may increase the propensity for heat stress during the LP ( ). This can happen even at rest, i.e., with passive heat exposure ( 217 ), but can be somewhat ameliorated with acclimation and physical training ( 218 ). Shortterm endurance training in previously untrained subjects improves heat loss responses by decreasing the threshold temperatures, with this effect occurring within a month of training, and disappearing within a month of cessation of training ( 219 ). The degree of

16 296 Lebrun, Joyce, and Constantini increase in sweating with training differs among body sites (chest, thigh, back, and forearm), and might be affected by MC phase. The length of endurance performance in humans is related to a critical internal temperature ( 220 ), which is why precooling strategies before exercise, and in between bouts of exertion in the heat, are found to be physiologically advantageous ( 221, 222 ) and to decrease perceived exertion ( 223 ). A higher initial core body temperature during the LP may therefore theoretically increase the risk for heat accumulation when exercising in hot weather, thus decreasing time to fatigue ( 224, 225 ). An early study of seven eumenorrheic women ( 226 ) did not fi nd any variation in sweat loss, sweat rate, and steady-state exercise metabolism rate during a 2-h cycle ergometer exercise at 30% of maximal O 2 concentration in the heat, during mid-fp, menstrual fl ow, midcycle (including ovulation), and mid-lp. However, this heat stress test was conducted after heat acclimation. Elevated skin temperature also has an adverse effect ( 227 ), as does a high starting ambient temperature ( 228 ). Thresholds for shivering and sweating vary over the course of an ovulatory MC, with LP enhancement of the heat loss response, but with no associated impact on performance ( 113 ). Actual metabolic heat production does not seem to change from the FP to the LP, possibly due to decreased skin thermal conductance ( 115 ). A greater temperature threshold and larger gains for sweating have been reported during the LP compared with the FP ( 229 ), as well as a greater sweat rate ( 230 ). In the latter study, women exercising in a warm and humid environment (32 C and 80% humidity) with adequate water intake seemed able to adapt to the luteal phase increase of BBT, through reduced urinary volume and increased sweating rate. Plasma volume (PV) dynamics during passive heat stress and exercise are also affected by MC phase ( 231 ). In women exercising at 80% VO 2 peak on a cycle ergometer and passive heat stress of 50 C (dry environment), more fl uid shifted out of the vasculature during the LP, and there was a greater fl uid loss during exercise in the FP, yet the fi nal PV was not different between phases. It has been proposed that the thermoregulatory vasodilator response is attenuated by increasing exercise-induced vasoconstrictor tone in proportion to exercise intensity ( 111 ). Therefore, under extreme conditions, and at high ambient temperature and humidity, there may be signi fi cant implications for women participating in prolonged endurance activities (e.g., marathons, ultramarathons, and triathlons) during the LP ( 216 ). For unacclimatized game players, although the performance of intermittent, highintensity shuttle running in the heat was unaffected by MC phase, it was in fl uenced by OC use. Athletes on OC ran further (improved performance) on days compared to days 1 14, despite higher rectal temperatures, HR, and GH, but lower plasma glucose. However, the numbers were small 7 women studied during the MC and 8 on OC ( 232 ). Interestingly, OCs may also impact thermoregulatory responses to exercise ( 229, ) by increasing BBT by 0.2 C during the days on active OC pills, as compared with the days off OCs. There also appears to be an elevated HR during exercise ( 233 ). A potential advantage of OC use, then, is to make thermoregulatory responses more uniform across the cycle (at least for 21 days), thereby decreasing any cyclic performance alterations due to changes in core BBT. However, it appears that the administration of synthetic progestins in OCs still causes higher core BBT at rest and during exercise, similar to the in fl uence of endogenous progesterone during the LP.

17 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 297 Physical Capacity, Strength, and Reproductive Hormones Physical Capacity, Strength, and the Menstrual Cycle Physical work capacity during the MC has been investigated ( 196, 236, 237 ), but without hormonal documentation it is dif fi cult to give much credence to these studies. However, there is a suggestion from these early studies that HR response to repetitive lifting and an isometric endurance lift were both greater by 7 10 beats per minute in the postovulatory phase, possibly as a result of the elevation in temperature ( 237, 238 ). Superior achievement in hip strength ( fl exion and extension) and standing broad jump during the premenstrual phase ( 1 ), isometric handgrip endurance of forearm contraction during the ovulatory phase ( 239 ), maximal voluntary contraction of handgrip during the FP ( 240 ), and handgrip strength during menses ( 241 ) have all been reported in the past, but most investigators have not noted any signi fi cant MC effects ( 3, ). A prospective study with hormonal measurements did not fi nd any variations in isokinetic strength of knee fl exion and extension between FP and LP ( 245 ). Muscle strength decreases with the onset of menopause, and it is thought that estrogen may have an inotropic effect on muscle strength ( 246, 247 ). Estradiol promotes secretion of GH, a known anabolic hormone. Some early research suggests that estrogen increases the ability of muscles to contract by about 10%, with a peak in strength just before ovulation ( 239, 248 ). Contrary to this fi nding, women being treated with gonadotropin injections for in vitro fertilization did not have any change in maximal strength and fatigability of the fi rst dorsal interosseous muscle, despite the iatrogenic acute and massive fl uctuations in estrogen ( 249 ). One group did not fi nd any variation in either muscle strength or endurance with changing hormone levels across three MC phases ( 250 ). Others have documented maximal muscle contraction during the ovulatory phase, but without any signi fi cant changes in muscle strength, fatigability, or electrically stimulated contractile properties ( 251 ). Since then, a corroborating study ( 252 ) also found improved muscle strength at ovulation, with isokinetic peak torque knee fl exors improved by ~9 N m and maximum voluntary isometric contraction knee extensors by ~5 N m. There are no clear mechanisms for these noted effects, but a recent publication reviews this area in much more detail ( 253 ). In an elegant experiment sequentially assessing limb blood fl ow and skin and deep tissue temperature change during the MC, isometric endurance was shown to be lower during the end of the FP, due to (1) the cyclic variation in muscle temperature, (2) direct effects of the MC on circulation, and (3) direct effects of the MC on muscle ( 254 ). More recent work has attempted to link changes in electromyography variables over the MC to increased muscle fatigue ( 255, 256 ). Progesterone does not appear to have substantial effects on either muscle strength or function, but testosterone de fi nitely has anabolic actions in females ( 257 ). Although not systematically studied, testosterone varies over the MC under the control of luteinizing hormone (LH), and also from peripheral conversion of androstenedione, with very little actually produced by the ovaries. Concentrations are lowest in the early FP, highest just prior to or at the time of ovulation, and then fall during LP ( 258 ). Dehydroepiandrosterone (DHEA) and its sulfoconjugate DHEA-S, which are secreted by the adrenal glands, as well

18 298 Lebrun, Joyce, and Constantini as androstenedione, secreted by adrenals and ovaries, are all of physiological importance in women ( 259 ) and peak prior to or at the time of ovulation ( 35 ). Exhaustive physical exercise (an ergocycle test at 75% of their VO 2 max until exhaustion) induces an increase in circulating DHEA-S and testosterone in young women ( 260, 261 ). Studies looking at effects of resistance exercise on circulation of androgens in women are still contradictory: both estradiol and progesterone increase after a single bout of resistance exercise in mid-lp, but not in early FP ( 259 ). These different responses have prompted some investigators ( 262 ) to suggest periodization of training cycles during different phases of the MC to maximize anabolic effects. An early study modeled menstrual cycle-triggered training (MCTT) in seven healthy women every second day in the FP and once per week in the LP vs. regular training periodization (every third day over the entire MC without regard for cycle phase) for a total of 4 weeks ( 263 ). Trainability of isokinetic strength of one-leg knee extensor muscles was slightly greater during FP, compared to when the respective leg was trained for 4 weeks without regard for the cycle phase (33% increase vs. 13% increase). It is known that estrogen may govern the regulation of a number of downstream genes and molecular targets (264), improving the intrinsic quality of skeletal muscles by enabling fi bers to generate force through myosin binding to actin during contraction ( 265 ). Estrogen may reduce protein catabolism; in contrast, progesterone in fl uences amino acid oxidation and protein degradation with increased protein catabolism, greater in LP than in FP, both at rest and during exercise. Oral Contraceptives and Strength At one time it was hypothesized that the androgenic component of the OCs might be ergogenic and help to increase muscle strength. In 1987 the International Olympic Committee (IOC) actually contemplated banning compounds containing norethindrone, a more androgenic progestin. Fortunately, this situation was successfully challenged and overruled. An early study suggested that OCs might have an effect on static muscle function ( 240 ), but to date there is no consensus on this matter. Other studies did not fi nd any signi fi cant MC phase differences or changes with OCs in various strength parameters ( 239, 245, 248, ), even with OCs containing progestins of higher androgenicity ( 269 ). Similarly, a prospective study of strength and torque production in collegiate women softball and water polo athletes participating in a 12-week strength development program did not demonstrate any positive impact of taking combination OCs ( 270 ). The thermogenic effect of progesterone ( 229 ), which may have a detrimental impact on forearm isometric endurance and muscle force, is minimized in athletes taking OCs ( 240 ). Some researchers believe that increased GH response to exercise in women on OCs would potentiate the effects of a training program ( 271 ). However, recent work has questioned the effect of OC administration on serum androstenedione and the bioavailability of testosterone, and suggested a potential negative impact on the synthesis and breakdown of myo fi brillar proteins ( 272 ). This may also be related to the effect of MC and OCs to attenuate delayed onset muscle soreness (DOMS) 48 h postexercise ( 273 ), through a potential protective role of estrogen in decreasing production of prostaglandins ( 274 ).

19 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 299 Aerobic Capacity and Reproductive Hormones Aerobic Capacity and the Menstrual Cycle For the most part, aerobic performance, as measured by maximal oxygen capacity (VO 2 max ) and submaximal exercise responses, does not change signi fi cantly during an ovulatory MC ( 140, 144, 165, 168, 194, 201, 245, 275 ). Despite theoretical metabolic advantages, mostly to do with substrate metabolism, or enhanced glycogen stores during the LP ( 68 ), only a few studies have suggested enhanced endurance performance ( 68, 139 ). Earlier work, with hormonal documentation of MC phase, is well summarized elsewhere ( 253 ), with predominately comparable fi ndings. For example, a comparison of 8 eumenorrheic and 8 amenorrheic runners doing one maximal and one submaximal treadmill run (40 min at 80% VO 2 max treadmill run), during early FP and mid-lp (con fi rmed by urinary and serum hormone levels), did not fi nd any phase or group differences in oxygen uptake, minute ventilation, HR, RER, RPE, time to fatigue (maximal), or plasma lactate ( 194 ). A few small studies have measured a slight decrement in aerobic capacity ( 245 ) and exercise ef fi ciency ( 114 ) during high-intensity exercise in the LP. The latter paralleled a 5.2% increase in oxygen consumption, a 5.6% increase in metabolic rate, and a decrease in net ef fi ciency of 5.3% ( 114 ). Testing protocols differ, generally without any standardization of other variables, such as circadian rhythms, nutritional and hydration status, glycogen stores, caffeine ingestion, and exercise during the 24 h prior to testing. In all likelihood, these confounding factors contribute more to changes or enhancement of performance than hormonal in fl uences of either MC or OC. In addition, running economy (RE), de fi ned as the rate of oxygen consumption (VO 2 ) during a given submaximal steady-state running speed, has been suggested as a better measure of performance than VO 2 max ( 25 ). Investigations of work performance and MC have looked at physiological and psychological determinants, temperature, pain perception, and so on ( 237, 276, 277 ). There is an entire body of literature in this area ( 278 ). Most reports are based on surveys or cross-sectional data, without hormonal veri fi cation of cycle phase, but are thoughtprovoking, nonetheless. In a study of MC effects on exercise in sedentary young women, 14 subjects with a peak VO 2 max < 45 ml/kg/min were subjected to an incremental test to exhaustion and steady-state submaximal cycle ergometer during two phases ( 275 ). Time to exhaustion, maximum power output and total work done, absolute VO 2 peak, VE, respiratory frequency and HR, and lactate and lactate threshold did not differ between phases. However, as workload increased, plasma lactate, carbon dioxide output, and RER were all lower during LP, while oxygen uptake was higher. During the steady-state tests at submaximal intensities (at workloads of 25% and 75% of menstrual cycle phase-speci fi c VO 2 peak ), fi ndings were similar. Exercise performance did not change between MC phases, but metabolic responses suggested greater dependence on fat as the energy source during LP. Oral Contraceptives and Aerobic Capacity Performance enhancement has been reported anecdotally in 8% of women on OCs ( 2 ), but conversely a detrimental impact on VO 2 max was found after 2 months on a higher-dose

20 300 Lebrun, Joyce, and Constantini OC, reversible on discontinuation ( 279 ). Women taking a low-dose monophasic OC (0.4 mg norethindrone) for 6 months had a 7% decrease in maximal oxygen uptake and 8% deterioration in exercise performance (as measured by oxygen pulse or volume of oxygen consumed per heart beat) ( 189 ). In seven women taking a lower-dose triphasic OC for 2 months, compared with a similar group on placebo, there was a smaller decrement in VO 2 max (4.7%) not evident in the placebo group, who experienced a 1.5% increase over the same time period ( 190 ). Neither anaerobic capacity nor aerobic endurance was altered in this particular study. In another investigation of ten moderately trained women, prospectively randomized to placebo ( n = 3) or an OC containing 1 mg norethindrone and 35 μ g ethinyl estradiol ( n = 7) for 21 days, neither the cycle phase nor low-dose OC had any signi fi cant adverse effects on ventilatory measures or per formance during a maximal treadmill test or endurance run ( 280 ). A separate research group has been studying within OC differences: 13 female cyclists (mean peak VO ± 5.6 ml/ kg/min) had alterations in several physiological variables between the tests done during pill consumption, and during early and late withdrawal phases, but had no performance differences in a 1-h cycle endurance test ( 281 ). Others have looked at aerobic capacity during various MC phases (10 women) compared with low-dose OC (5 women) ( 282 ). Again, there were no differences between mid-fp and late LP or OC test results at two time points. However, there was altered metabolism between groups (plasma ammonium was higher in the non-oc group), and within the OC group (blood lactate and ammonium were higher within the fi rst week compared with the second week on OCs), believed to represent differences in substrate metabolism. Another study of ten women on a monophasic OC found a somewhat lower (3 5.8%) decrease in VO 2 when participants were on early and late OC use, compared to off OC, during a 12-min treadmill run (4 min each at 7, 8, and 9 km/h) ( 283 ). This was actually associated with an improved running economy. More contemporary work investigated peak exercise capacity in six moderately active women during the FP and LP, and after 4 months on the same triphasic OC ( 284 ). There were no signi fi cant MC changes, but all subjects experienced decrements in VO 2 peak (average: 11% L/min; 13% ml/kg/min), as well as decreased time to peak exercise (14%) and peak power output (8%). These were not different between tests during OC and the week off OC (low and high ethinyl estradiol levels), suggesting a persistence of OC effects. Finally, contrary to the above fi ndings, one study comparing two monophasic OCs with differing dosages of synthetic progestins (single-blind, randomized, counterbalanced, crossover study) suggested a higher VO 2 peak with usage of OCs for more than 6 months, with the effect more pronounced in the higher progestin OC ( 285 ). Obviously, much more accurate research is needed. Anaerobic Capacity and Reproductive Hormones Anaerobic Capacity and the Menstrual Cycle Anaerobic capacity refers to the maximal amount of adenosine triphosphate (ATP) resynthesized via anaerobic metabolism during a speci fi c bout of short-duration exercise. There is a paucity of research in this area, but for the most part there is either no

21 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 301 difference in anaerobic power output during the different phases of the MC, or greater anaerobic capacity and peak power during the LP. Older studies suggested no MC effects on an anaerobic endurance test on a cycle ergometer (no hormonal analyses of cycle phase) ( 286 ) or a 600-yd run test, with postexercise blood tests ( 287 ). Another investigation without hormonal veri fi cation measured mean power output and peak power output during a modi fi ed Wingate test as greater in MF than in either ML or menstrual phases ( 288 ). Others have reported poorer performances during the menstrual phase in a 50-m swim exercise ( 289 ) and standing broad jump ( 1 ). It appears that the activity and fi tness level of the women may be a factor. Previous studies (using cycle history only) have shown some decrement in performance during menstruation, but more active women (collegiate athletes) ( 290 ) were less in fl uenced by MC phase than women de fi ned as fairly active (11% less anaerobic capacity and 6% less anaerobic power in FP than in LP) ( 291 ) or healthy active women ( 242 ). Fifteen sedentary females (ages years) performed a Wingate test on a Monark 818E ergometer with 75 g/kg load on the 7th, 14th, and 21st cycle days randomly. There were no differences in peak power, mean power, and fatigue index, nor any correlations with estradiol or progesterone levels ( 292 ). Studies of fi t athletes (VO 2 max > 50 ml/kg/min) with more precise hormonal documentation showed no changes in the anaerobic treadmill speed test or AST (subjects run at 3.52 m/s at a 20% grade until unable to maintain the set pace average times approx s) between FP and LP ( 245 ). A small study of six women doing ten 6-s sprints on a cycle ergometer during the FP and LP revealed no differences in peak power, oxygen intake, or capillary blood lactate. However, average work was greater in LP, as was the recovery VO 2 between sprints ( 293 ). A different protocol tested eight females doing repeated 30-s sprints with 2-min rest periods at three phases FP, just prior to ovulation (midcycle), and LP (high endogenous hormones). There were no measured changes in peak power output, recovery, lactate, blood ph and ammonia, or estimated plasma volume ( 294 ). Maximal accumulated oxygen de fi cit (MAOD) was assessed in 12 women with an average VO 2 max of 34.9 ml/kg/min, during repeated submaximal cycling exercise at 50%, 60%, 70%, and 80% of VO 2 max for 10 min, followed by repeated sprint cycling for three times at 120% of VO 2 max, with 20-min rest between sprints. Again, no signi fi cant differences were found in any physiological parameters ( 295 ). Oral Contraceptives and Anaerobic Capacity In a model of performance using OCs to simulate the MC, fi ve female rowers were tested for anaerobic power (10-s all-out effort) and anaerobic capacity (1,000-m row) at two time points in each of three OC cycles: on OC days (high exogenous estrogen and progesterone levels) and OC days (i.e., during the week off OCs) ( 296 ). Peak power output was higher, and rowing performance better, at the low (exogenous) hormone levels. Pre- and postexercise glucose concentrations, plasma resting and postexercise TG were also lower at this time. Endogenous hormones were not signi fi cantly different between phases. A study using a multijump test, squatting jump test, and force velocity test on a cycle ergometer saw no differences between MC phases, consistent throughout three different time phases in a normal cycle menstruation (days 1 4), mid-fp (days 7 9), and mid-

22 302 Lebrun, Joyce, and Constantini LP (days 19 21) (con fi rmed by serum progesterone) or three testing times in a subsequent OC cycle; however, these particular tests might not have adequately stressed the lactic acid system (297 ). One of the largest studies examining the effects of reproductive hormones on anaerobic performance tested seven women with normal menstrual cycles during the menses and LP (documented by urinary LH levels), and 17 women on OCs (OCs) ( 268 ). No signi fi cant cycle phase differences were found in the women with regular cycles, or between active-pill (high hormone) and withdrawal phases in the OC users on the Wingate cycle test and associated parameters (such as peak power, anaerobic capacity, and power decline), or in power for the Margaria-Kalamen staircase test. Another group compared nine OC users and eight normally menstruating subjects (NM) in an all-out 30-s sprint on a treadmill, and did not fi nd any difference in peak and mean power output ( 298 ). However, the integrated GH was greater in the OC group, suggesting that the high-androgenicity OCs in this study caused a higher GH response to sprinting. Again, this begs the question of some type of anabolic effect of OCs through the effects on GH secretion during exercise. Of note in many of these studies, however, is that the women are on different OCs, both multiphasic and monophasic. One group of investigators ( 282 ) studied five recreationally active women doing an intermittent running protocol (20-s sprints of increasing speeds with 100-s passive recovery until fatigue). Performance was the same after 2 weeks of OC, but higher lactate levels were found during the fi rst week of testing, suggesting a possible alteration in metabolism with OC. Yet in a subsequent study of nine untrained women doing intermittent treadmill running followed by a run to exhaustion, there were no differences in performance or in energy metabolism between tests conducted during menstruation and after OC for days ( 299 ). In conjunction with anaerobic performance, the anaerobic threshold ( 300 ) appears to be affected by usage of low-dose OCs. Female Reproductive Hormones and Overall Sport Performance Menstrual Cycle and Overall Sport Performance Optimal sport-speci fi c performance is the primary goal of every athlete. Success in events such as long-distance running and cycling is more dependent on aerobic capacity, whereas sprinting activities require anaerobic capacity. Weightlifting obviously necessitates great strength, while fl uid retention might be critical for weight-dependent sports as well as for those where the body has to be lifted off the ground (high jumping, gymnastics, etc.). Early studies were based on subjective feelings, and relied on subject recall of menstrual status (a substantial source of error and bias), without measurement of hormone levels ( 301, 302 ). Many athletes described a decrement in performance during the premenstrual and menstrual phases, while others reported improved performance ( 303, 304 ). Perimenstrual symptoms, such as abdominal or low back pain, fatigue, or nervousness during menstruation, may also come into play. Survey questionnaires of NCAA athletes ( 305 ) and 241 Turkish athletes ( 306 ) did not yield any clari fi cations. Nevertheless, gold medals have been won and world records set at all different phases of the menstrual cycle.

23 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 303 Some previous studies have addressed MC and performance in speci fi c sports ( 9 ). For example, swimming speed was found to be highest during menstruation and lowest during the premenstrual period ( 289, 307 ); cross-country skiers performed better in the early LP and in the late FP ( 308 ); and in runners, no effect of MC phase on aerobic parameters or perceived exertion was identi fi ed ( 194 ). A more recent study of performance in a cycling time trial found it to be enhanced during the late FP, with the preovulatory surge in estradiol and suppressed progesterone ( 309 ). Several contemporary studies on rowers should be reassuring for elite female athletes in this sport: 11 rowers were tested on a 1-h ergometer exercise at 70% VO 2 max in the FP and LP, fi nding no effects on energy expenditure, heart rate, blood lactate, or substrate oxidation (RER) ( 310 ). Other work by this same group compared 24 rowers 8 competitive cyclic athletes, 7 recreationally trained cyclic athletes, and 9 recreationally trained rowers taking OC during 2 incremental tests to voluntary exhaustion. Higher values of VE/VCO 2 were documented during the LP at both intensities in the cyclic athletes, compared with FP in the group on OCs (not really phases then), but no other signi fi cant differences were found, particularly not in any performance variable ( 311 ). Oral Contraceptives and Overall Sport Performance The question of whether OCs help or hinder overall athletic performance still remains largely unanswered ( 21 ). Studies have documented fewer musculoskeletal injuries in women taking OCs, likely secondary to amelioration of PMS symptoms and dysmenorrhea ( ). Presently, extended- and continuous-use oral contraceptive regimens may give even better cycle control and reduce performance-disrupting dysmenorrhea and PMS symptoms, as well as the more severe premenstrual dysphoric disorder (PMDD). Current formulations include Seasonale, with 91 consecutive days of active OCs ( 315 ), and Lybrel (levonorgestrel/ethinyl estradiol), with continuous active OCs for 1 year. Both regimens are safe and ef fi cacious ( 316, 317 ), but current usage by athletes and any effects on performance are unknown. As mentioned above, endurance capacity (1-h rowing ergometer test at an intensity of 70% VO 2 max ) was not signi fi cantly different in eight rowers on a monophasic OC, during the active-pill and non-active-pill phases ( 318 ). Another study did not demonstrate any effects on an endurance test in women taking a triphasic OC, during similar testing phases ( 296 ). Several different performance tests were examined in ten female team sport players using a monophasic OC: during pill consumption and during early and late withdrawal phases ( 319 ). Only reactive strength during a drop jump landing from the 45-cm height varied; it was higher during the OC consumption phase. The authors postulated a possible implication of hormones on neuromuscular timing and the stretch-shortening cycle, which are both important for sprinting and jumping performance. The most recent research in this area raises some other interesting questions. Swimmers performed a 200-m time trial in three phases of a monophasic OC: during consumption and both early and late withdrawal phases. Swim times were not different, but there was decreased blood lactate and increased ph during the withdrawal phase, postulated to occur because of increase in fl uid retention, plasma volume, and cellular

24 304 Lebrun, Joyce, and Constantini alkalosis ( 320 ). There are potential implications for coaches and elite-level athletes when basing training programs on lactate levels. FEMALE REPRODUCTIVE HORMONES AND SPORTS INJURIES ACL Injuries The incidence of sports injuries in females is nearly tenfold that of males. This has been found in ball games, running, biking, military training, and other physical activities. Noncontact injuries to the anterior cruciate ligament (ACL) occur at a rate 4 6 times that of males participating in the same jumping and cutting sports, such as soccer and basketball. Postulated mechanisms that may be impacted by the female hormones (estrogen, progesterone, and relaxin) include anatomical and biomechanical factors, neuromuscular control, ligament laxity, knee instability, and others; these have been reviewed in detail by ACL research groups ( ) and even by the IOC Medical Commission ( 324 ). Most studies focus on knee injuries and the changes in ACL laxity throughout the MC. Estrogen and progesterone are believed to affect tensile properties of ligaments ( 325 ) as well as neuromuscular function. Estrogen has potential mechanical effects on the collagen-rich structures that contribute to joint stability. For example, increases in knee joint laxity at the time of ovulation have a detrimental effect on mediolateral knee joint loading during cutting maneuvers, which is subject speci fi c ( 326 ). This is thought to lead to increased joint loads ( 327 ). Both estrogen and progesterone receptors have been found in synoviocytes in the lining of the knee, fi broblasts in the stroma of the ACL ( 328 ), and cells in the blood vessel walls of the ligaments in both men and women ( ). There are also relaxin receptors in the ACL ( 331, 332 ). The importance of these fi ndings and any causal relationship to an increased incidence of ACL injury is still under debate, although a recent prospective study monitored 143 NCAA Division I athletes over their 4-year career. Those elite female athletes sustaining ACL injury had elevated serum relaxin levels, and therefore may have been at increased risk ( 333 ). Much of the early information came from animal studies ( 334 ), later replicated in humans ( 335 ). The results of in vivo assessment of knee joint laxity in humans are somewhat mixed ( ), documenting either no changes with MC or, similar to animal model studies, increased compliance at times of high estrogen (i.e., ovulation) ( 338 ) and/or during the LP ( 339, 340 ). No changes in ACL laxity were found among three phases of the MC in high school-aged girls ( 341 ), including at the time of ovulation (determined with the OvuQuick One-Step Ovulation Predictor (Quidel Corp., San Diego, CA)). However, because ovulation lasts h in a normally cycling female, this phase in the menstrual cycle is more correctly referred to as near ovulation to reflect this. Various investigators have attempted to characterize high- and low-risk MC phases (Table 1 ). An early study, using only interviewer-administered questionnaires to 28 women, reported a signi fi cant statistical association between the MC and likelihood of ACL injuries (greater during the ovulatory phase and less during the FP in 28 women) ( 342 ). Interestingly, a group of researchers reanalyzed the data and found a different chisquare value, which was not signi fi cant ( 343 ). The authors responded appropriately with

25 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 305 Table 1 Hormonal risk factors for ACL injury during the menstrual cycle Study design Injuries/subject High-risk phase Hormones References Questionnaire 28 Preovulatorya No ( 342 ) Case-series 65 Preovulatory Urine ( 344 ) Prospective cohort 46/69 Menstrual No ( 345 ) Prospective cohort 17/23 Late LP No ( 346 ) Unmatched case control 37/38 FP Salivary ( 335 ) Case-series 83 Preovulatory No ( 348 ) Matched case control 46/91 Preovulatory Serum ( 350 ) Descriptive 18/37 Ovulatory No ( 349 ) Matched case control 93/186 Preovulatory No ( 351 ) FP follicular phase; LP luteal phase a Later found not to be signi fi cantly different (see ref. (343)) a retraction, but maintained that there were fewer injuries than expected in the FP and more in the ovulatory phase. These original investigators published a later study using urinary hormone levels for cycle phase veri fi cations, and validated their hypothesis of greater than expected incidence of ACL injuries during midcycle (ovulatory phase), but less than expected during the LP ( 344 ). Other researchers have also shown the risk to be greater in the premenstrual period or late LP ( 345, 346 ), but there are little objective data using large numbers of subjects. There appears to be some periodicity to these serious injuries, regardless of OC status, but this is dependent on the method of analysis ( 347, 348 ). Teenaged female athletes have been shown to be more prone to ACL injuries during the FP ( 341, 349 ). More than half of the respondents in the fi rst study also reported feelings of diminished athletic performance during menstruation, which is in agreement with the fi ndings of greater variability during a cyclical athletic movement. Several studies in skiers found an increased incidence during the preovulatory phase: a matched case control study of alpine skiers (with veri fi cation of cycle phase) ( 350 ) and a self-reported questionnaire ( 351 ). Tissue qualities are also affected by estradiol concentrations ( 352 ). Using hormonal measurements, investigators found lower musculotendinous stiffness (MTS) during cyclical hopping tests at the ovulatory phase, in contrast to the menstrual phase and FP ( 353 ). They postulated that the resultant increase in compliance leads to greater reliance on re fl exive responses from the contractile component of the muscle, due to decreased contribution from passive elastic structures. This would increase electromechanical delay and therefore risk of injury. A reduction in knee stiffness of approximately 17% at ovulation was associated with increased knee laxity in another study ( 354 ). Such MC changes have not been found in other tissues, such as the gastrocnemius ( 355 ), patellar tendon ( 356 ), or Achilles tendon ( 357 ). Some researchers have found no changes in muscle and tendon properties in knee extensors and plantar fl exors ( 358 ). More recent work has examined variations in varus/valgus and internal/external rotational knee lax-

26 306 Lebrun, Joyce, and Constantini ity ( 359 ). Muscle stiffness of, and neuromechanics of, the hamstrings have also been studied at different MC phases and with OCs ( ). Various neuromuscular performance characteristics, such as gender differences in muscle strength, recruitment order, and peak torque production, also likely contribute to the higher ACL injury rate in women ( 363 ). Some have found no variation across MC ( 337, 364 ), while others have documented alterations in neuromuscular control patterns during landing or postural control ( 365 ). Knee joint kinesthesia, as measured by performance in a square-hop task, improved at ovulation when compared to the pre- and menstruation phases of the cycle (366 ). Sympathetic neural responses to upright tilt have also been noted ( 367 ). Given that muscle forces in fl uence knee joint dynamic restraint, neuromuscular control of the lower limb musculature will dictate the propensity for ACL injury ( 368 ). A previous study reported modi fi ed co-contraction patterns of the gluteus maximus and semitendinosus at different stages of the MC, with increased synchronicity of the contraction between the two muscle groups around ovulation ( 369 ). Knee joint position sense accuracy decreased during menses ( 370 ), but others have found no differences in knee or hip loading, using a variety of measures, during across MC phases or with OCs ( 371 ). Currently there is much ongoing sophisticated research on landing biomechanics ( 372 ). Additionally, PMS, with its effects on balance and motion perception, may be important. Motor skill performance may decrease during the premenstrual phase ( 121 ). A connection between the MC cycle and soccer injuries ( 313 ), with fewer injuries in women on OCs ( 314 ), has been reported, but these authors used a faulty calendar system for calculating MC phase, which may have underestimated the incidence of injuries. Other mechanisms of increased susceptibility to injury during speci fi c MC phases (and/or while taking OCs) include variations in muscle strength ( 266 ), neuroendocrine activation ( 373 ), motoneuron excitability and anterior tibial displacement ( 374 ), and, most recently, tibial acceleration variability ( 359, 375 ). Risks can be ameliorated with various neuromuscular training programs, including plyometrics, proprioceptive exercises, and correction of dynamic valgus (drop jumps). Improved knowledge of predisposing factors will also facilitate screening of athletes at increased jeopardy of sustaining ACL injuries (376 ). Keeping in mind the above mechanisms, OCs use may stabilize the hormonal milieu, and thus may function to either passively or actively stabilize the knee joint ( 377, 378 ). To this end, OC use was found to in fl uence injury risk in some ( 348 ), but not all, studies ( 379 ), in addition to neuromuscular properties ( 378, 380 ) and sporting performance ( 319 ). During steady-state running, female athletes who do not take OCs exhibit greater variability in gross mediolateral acceleration at the proximal tibia during menstruation compared to during ovulation ( 378 ). Given that mediolateral tibial acceleration can be used to represent varus/valgus movement of the knee, and that valgus collapse is a commonly cited gender-speci fi c risk factor for ACL injury, further research is needed to examine the ideal level of movement variability in this population around the time of menstruation. While OC ingestion may diminish the somewhat signi fi cant association between ACL injury and the ovulatory phase, there is no consensus on any proven protective effects ( 351 ). Much work remains to be done in the investigation of sex hormones and anterior knee laxity. Variations in the MC, with different hormonal pro fi les, will also have an

27 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance 307 impact ( 381 ). There is great dif fi culty with validated outcome measures using serum urine or salivary progesterone in combination with MC data ( 382 ). In addition, there may be a phase delay of hormonal effects, or they may be more cumulative and chronic, rather than acute. There are many excellent reviews on this important topic ( 323, 338, ). SUMMARY Although understanding of the unique physiology of the female athlete has increased, there are still many unanswered questions. Both endogenous and exogenous female sex steroids can in fl uence numerous cardiovascular, respiratory, and metabolic variables, but most likely have minimal impact on the athletic ability of most recreational athletes. In elite athletes, however, even a statistically nonsigni fi cant change can mean the critical difference between fi rst and second place. There appears to be individual variability in the response of different performance parameters to MC phase and/or OC administration. In particular, there may be subtle alterations in substrate metabolism, and increased susceptibility to heat stress under conditions of high heat and humidity. The latter is most important for female athletes competing in endurance events. Similarly, MC phase and OC use may have some implications in terms of management of MLA, prevention of ACL tears, and the response to periodized strength and endurance training. These areas warrant further scienti fi c investigation. Although the majority of research to date suggests that regularly menstruating female athletes do not need to adjust their MC to maximize performance, it is dif fi cult to extrapolate controlled laboratory fi ndings from a study population to an individual competitor on the playing fi eld. It is critical for each woman to monitor her own physiological responses and to listen to her body. For women with menstrual dysfunction and/or the need for contraception, OCs may provide a stable hormonal milieu for training and competition, and predictable onset of menstrual bleeding. Potential side effects (and any concomitant impact on performance) can be minimized with the lower-dose triphasic pills and the newer progestins. Continuous pills are another promising new option. Further large-scale, prospective, randomized clinical trials are needed on trained athletes, using accurate hormonal measurements for veri fi cation of MC phase, to further elucidate the short- and long-term effects of cycle phase and OCs in exercising women. REFERENCES 1. Wearing MP, Yuhasz M, Campbell R, et al. The effect of the menstrual cycle on tests of physical fitness. J Sports Med Phys Fitness. 1972;12: Bale P, Davies J. Effect of menstruation and contraceptive pill on the performance of physical education students. Br J Sports Med. 1983;7: Quadagno D, Faquin L, Lim G-N, et al. The menstrual cycle: does it affect athletic performance? Phys Sportsmed. 1991;19: Van Look PF, Baird DT. Regulatory mechanisms during the menstrual cycle. Eur J Obstet Gynecol Reprod Biol. 1980;11(2): Goodman LR, Warren MP. The female athlete and menstrual function. Curr Opin Obstet Gynecol. 2005;17(5): Jurkowski JEH, Jones NL, Walker WE, et al. Ovarian hormonal responses to exercise. J Appl Physiol. 1978;44:

28 308 Lebrun, Joyce, and Constantini 7. Bonen A, Lind WY, MacIntyre KP, et al. Effects of exercise on serum concentrations of FSH, LH, progesterone, and estradiol. Eur J Appl Physiol. 1979;42: Montagnani CF, Arena B, Maffuli N. Estradiol and progesterone during exercise in healthy untrained women. Med Sci Sports Exerc. 1992;24: Lebrun CM. Effect of the different phases of the menstrual cycle and oral contraceptives on athletic performance. Sports Med. 1993;16: Lebrun CM. The effect of the phase of the menstrual cycle and the birth control pill on athletic performance. Clin Sports Med. 1994;13: Frankovich R, Lebrun CM. Menstrual cycle, contraception, and performance. Clin Sports Med. 2000;19(2): Lebrun CM. Effects of the menstrual cycle and oral contraceptives on sports performance. In: Drinkwater BL, editor. Women in sport: the IOC encyclopedia of sports medicine. Oxford: Blackwell Science; p Reilly T. The menstrual cycle and human performance: an overview. Biol Rhythm Res. 2000;31: Lebrun CM, Rumball JS. Relationship between athletic performance and menstrual cycle. Curr Womens Health Rep. 2001;1(3): Constantini NW, Dubnov G, Lebrun CM. The menstrual cycle and sport performance. Clin Sports Med. 2005;24(2):e Constantini NW, Lebrun CM, Dubnov-Raz G. Menstrual cycle and sports performance. In: Micheli LJ, editor. Encyclopedia of sports medicine. 4 vols. Thousand Oaks, CA: Sage Publications; p Burrows M, Bird S. The physiology of the highly trained female endurance runner. Sports Med. 2000;30(4): Janse de Jonge XA. Effects of the menstrual cycle on exercise performance. Sports Med. 2003;33(11): Vanheest JL, Mahoney CE, Rodgers CD. Oral contraceptive use and physical performance (Chapter 19. The endocrine system in sports and exercise). In: Kraemer WJ, Rogol AD, editors. The encyclopaedia of sports medicine an IOC Medical Commission Publication. Malden, MA: Blackwell Publishers; p Burrows M, Peters CE. The in fl uence of oral contraceptives on athletic performance in female athletes. Sports Med. 2007;37: Rechichi C, Dawson V, Goodman C. Athletic performance and the oral contraceptive. Int J Sports Physiol Perform. 2009;4(2): Oosthuyse T, Bosch AN. The effect of the menstrual cycle on exercise metabolism: implications for exercise performance in eumenorrhoeic women. Sports Med. 2010;40(3): Owen JA. Physiology of the menstrual cycle. Am J Clin Nutr. 1975;28(4): Landgren BM, Unden AL, Diczfalusy E. Hormonal pro fi le of the cycle in 68 normally menstruating women. Acta Endocrinol. 1980;94(1): Williams TJ, Krahenbuhl GS. Menstrual cycle phase and running economy. Med Sci Sports Exerc. 1997;29(12): World Health Organization (WHO). Medical eligibility for contraception use. 4th ed. Geneva, Switzerland: WHO Press; Bennell K, White S, Crossley K. The oral contraceptive pill: a revolution for sportswomen. Br J Sports Med. 1999;33(4): Kaunitz AM. Choosing menstruation whether and when. Contraception. 2000;62: Archer DF. Menstrual-cycle related symptoms: a review of the rationale for continuous use of oral contraceptives. Contraception. 2006;74: Wiegratz I, Thaler CJ. Hormonal contraception what kind, when, and for whom? Dtsch Arztebl Int. 2011;108(28 29): doi: /arzebl Petitti DB. Combination estrogen progestin oral contraceptives. N Engl J Med. 2003;349: Sitruk-Ware R. Reprint of: Pharmacological pro fi le of progestins. Maturitas. 2008;61(1 2): Kaunitz AM. Long-acting injectable contraception with depot medroxyprogesterone acetate. Am J Obstet Gynecol. 1994;170:

29 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance Mestad RE, Kenerson J, Peipert JF. Reversible contraception update: the importance of long-acting reversible contraception. Postgrad Med. 2009;121(4): Longcope C. Adrenal and gonadal androgen secretion in normal females. Clin Endocrinol Metab. 1986;15(2): Charkoudian N, Joyner MJ. Physiologic considerations for exercise performance in women. Clin Chest Med. 2004;25(2): Collins P. Estrogen and cardiovascular dynamics. Am J Sports Med. 1996;24:S Collins P. Vascular aspects of oestrogen. Maturitas. 1996;23: Sarrel PM. Ovarian hormones and the circulation. Maturitas. 1990;590: Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999;340: Cicinelli E, Ignarro LJ, Lograno M, et al. Circulating levels of nitric oxide in fertile women in relation to the menstrual cycle. Fertil Steril. 1996;66: Collins P, Rosano GMC, Jiang C, et al. Cardiovascular protection by oestrogen: a calcium antagonist effect? Cardiovasc Res. 1995;30: Collins P, Beale CM, Rosano GMC. Oestrogen as a calcium channel blocker. Eur Heart J. 1996;17 (Suppl D): Straub RH. The complex role of estrogens in in fl ammation. Endocr Rev. 2007;28: Chakrabarti S, Lekontseva O, Davidge ST. Estrogen is a modulator of vascular in fl ammation. IUBMB Life. 2008;60: Xing D, Nozell S, Chen Y-F, et al. Estrogen and mechanisms of vascular protection. Arterioscler Thromb Vasc Biol. 2009;29(3): Reckelhoff JF. Sex steroids, cardiovascular disease, and hypertension: unanswered questions and some speculations. Hypertension. 2005;45: Friday KE, Drinkwater BL, Bruemmer B, et al. Elevated plasma low-density lipoprotein and highdensity lipoprotein cholesterol levels in amenorrheic athletes: effects of endogenous hormone status and nutrient intake. J Clin Endocrinol Metab. 1993;77: Solomon CG, Hu FB, Dunaif A, et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab. 2002;87: Bairey Merz CN, Johnson BD, Sharaf BL, et al. Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study. J Am Coll Cardiol. 2003;41: De Souza MJ, Williams NI. Physiological aspects and clinical sequelae of energy de fi ciency and hypoestrogenism in exercising women. Hum Reprod Update. 2004;10(5): Hoch AZ, Jurva JW, Staton MA, et al. Athletic amenorrhea and endothelial dysfunction. WMJ. 2007;106: O Donnell E, Harvey PJ, Goodman JM, et al. Long-term estrogen de fi ciency lowers regional blood fl ow, resting systolic blood pressure, and heart rate in exercising premenopausal women. Am J Physiol Endocrinol Metab. 2007;292:E Lanser EM, Zach KN, Hoch AS. The female athlete triad and endothelial dysfunction. PM&R. 2011;3: Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, et al. Amenorrhea in female athletes is associated with endothelial dysfunction and unfavorable lipid pro fi le. J Clin Endocrinol Metab. 2005;90: Yoshida N, Ikeda H, Sugi K, et al. Impaired endothelium dependent and -independent vasodilation in young female athletes with exercise-associated amenorrhea. Arterioscler Thromb Vasc Biol. 2006;26: Soleimany G, Dadgostar H, Lot fi an S, et al. Bone mineral changes and cardiovascular effects among female athletes with chronic menstrual dysfunction. Asian J Sports Med. 2012;3(1): Hoch AZ, Lynch SL, Jurva JW, et al. Folic acid supplementation improves vascular function in amenorrheic runners. Clin J Sport Med. 2010;20: Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, et al. Oral contraceptives improve endothelial function in amenorrheic athletes. J Clin Endocrinol Metab. 2005;90: Bayliss DA, Millhorn DE. Central neural mechanisms of progesterone action: application to the respiratory system. J Appl Physiol. 1992;73(2):

30 310 Lebrun, Joyce, and Constantini 61. England SJ, Farhi LE. Fluctuations in alveolar CO 2 and in base excess during the menstrual cycle. Respir Physiol. 1976;26: Schoene RB, Robertson HT, Pierson DJ, et al. Respiratory drives and exercise in menstrual cycles of athletic and nonathletic women. J Appl Physiol. 1981;50: Dutton K, Blanksby BA, Morton AR. CO2 sensitivity changes during the menstrual cycle. J Appl Physiol. 1989;67: Sansores RH, Abboud RT, Kennell C, et al. The effect of menstruation on the pulmonary carbon monoxide diffusing capacity. Am J Respir Crit Care Med. 1995;152: Beck SA. Asthma in the female: hormonal effect and pregnancy. Allergy Asthma Proc. 2001;22: Pernoll ML, Metcalfe J, Kovach PA, et al. Ventilation during rest and exercise in pregnancy and postpartum. Respir Physiol. 1975;25(3): Forbes L. Do exogenous oestrogens and progesterone in fl uence asthma? Thorax. 1999;54: Nicklas BJ, Hackney AC, Sharp RL. The menstrual cycle and exercise: performance, muscle glycogen, and substrate responses. Int J Sports Med. 1989;10: Bunt JC. Metabolic actions of estradiol: signi fi cance for acute and chronic exercise responses. Med Sci Sports Exerc. 1990;22: Hackney AC, McCracken-Compton MA, Ainsworth B. Substrate responses to submaximal exercise in the midfollicular and midluteal phases of the menstrual cycle. Int J Sport Nutr. 1994;4: Hackney AC, Muoio D, Meyer WR. The effect of sex steroid hormones on substrate oxidation during prolonged submaximal exercise in women. Jpn J Physiol. 2000;50(5): Campbell SE, Febbraio MA. Effects of ovarian hormones on exercise metabolism. Curr Opin Clin Nutr Metab Care. 2001;4(6): D Eon T, Braun B. The roles of estrogen and progesterone in regulating carbohydrate and fat utilization at rest and during exercise. J Womens Health Gend Based Med. 2002;11(3): D Eon TM, Sharoff C, Chipkin SR, et al. Regulation of exercise carbohydrate metabolism by estrogen and progesterone in women. Am J Physiol Endocrinol Metab. 2002;283:E Ruby BC, Robergs RA. Gender differences in substrate utilisation during exercise. Sports Med. 1994;17: Tarnopolsky MA, Atkinson SA, Phillips SA, et al. Carbohydrate loading and metabolism during exercise in men and women. J Appl Physiol. 1995;78: James AP, Lorraine M, Cullen D, et al. Muscle glycogen supercompensation: absence of a genderrelated difference. Eur J Appl Physiol. 2001;85(6): Lavoie JM, Dionne N, Helie R, et al. Menstrual cycle phase dissociation of blood glucose homeostasis during exercise. J Appl Physiol. 1987;62: Hausswirth C, Le Meur Y. Physiological and nutritional aspects of post-exercise recovery: speci fi c recommendations for female athletes. Sports Med. 2011;41(10): Isacco L, Duche P, Boisseau N. In fl uence of hormonal status on substrate utilization at rest and during exercise in the female population. Sports Med. 2012;42(4): Diamond MP, Wentz AC, Cherrington AD. Alterations in carbohydrate metabolism as they apply to reproductive endocrinology. Fertil Steril. 1988;50: Godsland IF. The in fl uence of female sex steroids on glucose metabolism and insulin action. J Intern Med. 1996;240 Suppl 738: Goodman MP. Are all estrogens created equal? A review of oral vs. transdermal therapy. J Womens Health. 2012;212(2): Reinke U, Ansah B, Voigt KD. Effect of the menstrual cycle on carbohydrate and lipid metabolism in normal females. Acta Endocrinol (Copenh). 1972;69(4): Campbell SE, Angus DJ, Febbraio MA. Glucose kinetics and exercise performance during phases of the menstrual cycle: effect of glucose ingestion. Am J Physiol Endocrinol Metab. 2001;281(4):E Lopez LM, Grimes DA, Schulz KF. Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. Cochrane Database Syst Rev. 2009;7(4):CD doi: / cd pub Lopez LM, Grimes DA, Schulz KR. Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. Cochrane Database Syst Rev. 2012;18(4):CD doi: / cd pub4.

31 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance Sitruk-Ware R, Nath A. Metabolic effects of contraceptive steroids. Rev Endocr Metab Disord. 2011;12(2): Paternoster DM, Lazzarin L, Dalla PS. Contraception in diabetic women. Minerva Ginecol. 1997;49(12): Stachenfeld NS. Sex hormone effects on body fl uid regulation. Exerc Sport Sci Rev. 2008;36(3): Olson BR, Forman MR, Lanza E, et al. Relation between sodium balance and menstrual cycle symptoms in normal women. Ann Intern Med. 1996;125: White CP, Hitchcock CL, Vigna YM, et al. Fluid retention over the menstrual cycle: 1-year data from the prospective ovulation cohort. Obstet Gynecol Int. 2011;2011: Rickenlund A, Carlström K, Ekblom B, et al. Effects of oral contraceptives on body composition and physical performance in female athletes. J Clin Endocrinol Metab. 2004;89(9): Stanczyk FZ. All progestins are not created equal. Steroids. 2003;68(10 13): De Souza MJ, West SL, Jamal SA, et al. The presence of both an energy de fi ciency and estrogen de fi ciency exacerbate alterations of bone metabolism in exercising women. Bone. 2008;43: Williams NI, Reed JL, Leidy HJ, et al. Estrogen and progesterone exposure is reduced in response to energy de fi ciency in women aged years. Hum Reprod. 2010;25(9): Ackerman KE, Misra M. Bone health and the female athlete triad in adolescent athletes. Phys Sportsmed. 2011;39(1): Feldmann JM, Belsha JP, Eissa MA, et al. Female adolescent athletes awareness of the connection between menstrual status and bone health. J Pediatr Adolesc Gynecol. 2011;24(5): Kleerekoper M, Brienza RS, Schultz LR, et al. Oral contraceptive use may protect against low bone mass. Henry Ford Hospital Osteoporosis Cooperative Research Group. Arch Intern Med. 1991;151: Liu SL, Lebrun CM. Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review. Br J Sports Med. 2006;40(1): Scholes D, Ichikawa L, LaCroix AZ, et al. Oral contraceptive use and bone density in adolescent and young adult women. Contraception. 2010;81(1): Berenson AB, Breitkopf CR, Grady JJ, et al. Effects of hormonal contraception on bone mineral density after 24 months of use. Obstet Gynecol. 2004;103: Allali F, El Mansouri L, Abourazzuak FZ, et al. The effect of past use of oral contraceptive on bone mineral density, bone biochemical markers and muscle strength in healthy pre and post menopausal women. BMC Womens Health. 2009;9:31. doi: 10P1186/ Wanichsetakul P, Kamudhamas A, Watanaruangkovit P, et al. Bone mineral density at various anatomic bone sites in women receiving combined oral contraceptives and depot-medroxyprogesterone acetate for contraception. Contraception. 2002;65: Marshall J. Thermal changes in the normal menstrual cycle. BMJ. 1963;12: Horvath SM, Drinkwater BL. Thermoregulation and the menstrual cycle. Aviat Space Environ Med. 1982;53: Stephenson LA, Kolka MA. Thermoregulation in women. Exerc Sport Sci Rev. 1993;21: Kelly G. Body temperature variability (Part 1): a review of the history of body temperature and its variability due to site selection, biological rhythms, fi tness, and aging. Altern Med Rev. 2006;11(4): Nakayama T, Suzuki M, Ishizuka N. Action of progesterone on preoptic thermosensitive neurones. Nature. 1975;258(5530): White MD, Cabanac M. Exercise hyperpnea and hyperthermia in humans. J Appl Physiol. 1996;81(3): Hirata K, Nagasaka T, Hirai A, et al. Effects of human menstrual cycle on thermoregulatory vasodilation during exercise. Eur J Appl Physiol. 1986;54: Kolka MA, Stephenson LA. Effect of luteal phase elevation in core temperature on forearm blood fl ow during exercise. J Appl Physiol. 1997;82(4): Hessemer V, Bruck K. In fl uence of menstrual cycle on shivering, skin blood fl ow, and sweating responses measured at night. J Appl Physiol. 1985;59:

32 312 Lebrun, Joyce, and Constantini 114. Hessemer V, Bruck K. In fl uence of menstrual cycle on thermoregulatory, metabolic, and heart rate responses to exercise at night. J Appl Physiol. 1985;59: Frascarolo P, Schutz Y, Jequier E. Decreased thermal conductance during the luteal phase of the menstrual cycle in women. J Appl Physiol. 1990;69: Cunningham DJ, Cabanac M. Evidence from behavioral thermoregulatory responses of a shift in setpoint temperature related to the menstrual cycle. J Physiol Paris. 1971;63(3): Harvey OL, Crocket HE. Individual differences in temperature changes during the course of the menstrual cycle. Hum Biol. 1932;4: Stachenfeld NS, Silva C, Keefe DL. Estrogen modi fi es the temperature effects of progesterone. J Appl Physiol. 2000;88(5): Charkoudian N, Johnson JM. Female reproductive hormones and thermoregulatory control of skin blood fl ow. Exerc Sport Sci Rev. 2000;28(3): Halbreich U, Tworek H. Altered serotonergic activity in women with dysphoric premenstrual syndromes. Int J Psychiatry Med. 1993;23: Posthuma BW, Bass JJ, Bull SB, et al. Detecting changes in functional ability in women with premenstrual syndrome. Am J Obstet Gynecol. 1987;156: Hagemann G, Ugur T, Schleussner E, et al. Changes in brain size during the menstrual cycle. PLoS One. 2011;6(2):e Sherwin BB. Hormones, mood, and cognitive functioning in postmenopausal women. Obstet Gynecol. 1996;87:20S Zlotnik A, Grenbaum BF, Mohar B, et al. The effects of estrogen and progesterone on blood glutamate levels: evidence from changes of blood glutamate levels during the menstrual cycle in women. Biol Reprod. 2011;84(3): Joseph JE, Swearingen JE, Corbly CR, et al. In fl uence of estradiol on functional brain organization for working memory. Neuroimage. 2012;59(3): Pompili A, Arnone B, Gasbarri A. Estrogens and memory in physiological and neuropathological conditions. Psychoneuroendocrinology. 2012;37(9): Park EM, Cho S, Frys KA, et al. Inducible nitric oxide synthase contributes to gender differences in ischemic brain injury. J Cereb Blood Flow Metab. 2006;26: Mihalik JP, Ondrak KS, Buskiewieca KM, et al. The effects of menstrual cycle phase on clinical measure of concussion in healthy college-aged females. J Sci Med Sport. 2009;12: Singh M, Su C. Progesterone and neuroprotection. Horm Behav. 2012; 22. (In Press, Corrected Proof) 130. Mordecai KL, Rubin LH, Maki PM. Effects of menstrual cycle phase and oral contraceptive use on verbal memory. Horm Behav. 2008;54(2): Cicinelli E, De Tommaso M, Cianca A, et al. Oral contraceptive therapy modulates hemispheric asymmetry in spatial attention. Contraception. 2011;84(6): Griksienne R, Ruksenas O. Effects of hormonal contraceptives on mental rotation and verbal fl uency. Psychoneuroendocrinology. 2011;36(8): Kraemer RR, Francois M, Castracane VD. Estrogen mediation of hormone responses to exercise. Metabolism. 2012;61(10): Costa AM, Breitenfeld L, Siva AJ. Genetic inheritance effects on endurance and muscle strength: an update. Sports Med. 2012;42(6): Tucker R, Collins M. What makes champions? A review of the relative contribution of genes and training to sporting success. Br J Sports Med. 2012;46(8): Noakes TD. Time to move beyond a brainless exercise physiology: the evidence for complex regulation of human exercise performance. Appl Physiol Nutr Metab. 2011;36(1): Noakes TD. Fatigue is a brain-derived emotion that regulates the exercise behavior to ensure the protection of whole body homeostasis. Front Physiol. 2012;3(82): Fortney SM, Beckett WS, Carpenter AJ, et al. Changes in plasma volume during bed rest: effects of menstrual cycle and estrogen administration. J Appl Physiol. 1988;65(2): Jurkowski JEH, Jones NL, Toews CJ, et al. Effects of menstrual cycle on blood lactate, O 2 delivery, and performance during exercise. J Appl Physiol. 1981;51: Dombovy ML, Bonekat HW, Williams TH, et al. Exercise performance and ventilatory response in the menstrual cycle. Med Sci Sports Exerc. 1987;19:111 7.

33 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance Van Beek E, Houben AJHM, Van Es PN, et al. Peripheral haemodynamics and renal function in relation to the menstrual cycle. Clin Sci. 1997;91: Cherney DZI, Scholey JW, Cattran DC, et al. The effect of oral contraceptives on the nitric oxide system and renal function. Am J Physiol Renal Physiol. 2007;293:F Zengin K, Tokac M, Duzenli MA, et al. In fl uence of menstrual cycle on cardiac performance. Maturitas. 2007;58(1): Smekal F, von Duvillard SP, Frigo P, et al. Menstrual cycle: no effect on exercise cardiorespiratory variables or blood lactate concentration. Med Sci Sports Exerc. 2007;39(7): Moran VH, Leathard HL, Coley J. Cardiovascular functioning during the menstrual cycle. Clin Physiol. 2000;20(6): Adkisson EJ, Cassey DP, Beck DT, et al. Central, peripheral and resistance arterial reactivity: fl uctuates during the phases of the menstrual cycle. Exp Biol Med (Maywood). 2010;235(1): Carter JR, Lawrence JE, Klein JS. Menstrual cycle alters sympathetic neural responses to orthostatic stress in young, eumenorrheic women. Am J Physiol Endocrinol Metab. 2009;297(1):E Carter JR, Klein JC, Schwartz CE. Effects of oral contraceptives on sympathetic nerve activity during orthostatic stress in young, healthy women. Am J Physiol Regul Integr Comp Physiol. 2010;298(1):R Sita A, Miller SB. Estradiol, progesterone, and cardiovascular response to stress. Psychoneuroendocrinology. 1996;21: Rosano GMC, Leonardo F, Sarrel PM, et al. Cyclical variation in paroxysmal supraventricular tachycardia in women. Lancet. 1996;347: Mukamal KJ, Muller JE, Maclure M, et al. Variation in the risk of onset of acute myocardial infarction during the menstrual cycle. Am J Cardiol. 2002;90: Hamelin BA, Méthot J, Arsenault M, et al. In fl uence of the menstrual cycle on the timing of acute coronary events in premenopausal women. Am J Med. 2003;114: Rosano FMC, Sarrel PM, Poole-Wilson PA, et al. Bene fi cial effect of estrogen on exercise-induced myocardial ischemia in women with coronary artery disease. Lancet. 1993;342: Littler WA, Bojorges-Bueno R, Banks J. Cardiovascular dynamics in women during the menstrual cycle and oral contraceptive therapy. Thorax. 1974;29: Lehtovirta P, Kuikka J, Pyorala T. Hemodynamic effects of oral contraceptives during exercise. Int J Gynaecol Obstet. 1977;15: Birch K, Cable N, George K. Combined oral contraceptives do not in fl uence post-exercise hypotension in women. Exp Physiol. 2002;87(5): George KP, Birch KM, Jones B, et al. Estrogen variation and resting left ventricular structure and function in young healthy females. Med Sci Sports Exerc. 2000;32(2): Willekes C, Hoogland HJ, Keizer HA. Three months use of third-generation oral contraceptives does not affect artery wall properties. Ultrasound Med Biol. 1999;25(5): Berenson AB, Rahman M, Wilkinson G. Effect of injectable and oral contraceptives on serum lipids. Obstet Gynecol. 2009;114(4): Rott H. Thrombotic risks of oral contraceptives. Curr Opin Obstet Gynecol. 2012;24(4): Hannaford PC. Epidemiology of the contraceptive pill and venous thromboembolism. Thromb Res. 2011;127(3):S Manzoli L, De Vito C, Marzuillo C, et al. Oral contraceptives and venous thromboembolism: a systematic review and meta-analysis. Drug Saf. 2012;36(3): Beller JP, McCartney CR. Cardiovascular risk and combined oral contraceptives: clinical decisions in settings of uncertainty. Am J Obstet Gynecol. 2013;208(1): doi: /j.ajog Epub 2012 Feb Farha S, Asosingh J, Laskowski D, et al. Pulmonary gas transfer related to markers of angiogenesis during the menstrual cycle. J Appl Physiol. 2007;103: Bemben DA, Salm PC, Salm AJ. Ventilatory and blood lactate responses to maximal treadmill exercise during the menstrual cycle. J Sports Med Phys Fitness. 1995;35: MacNutt MJ, De Souza MJ, Tomczak SE, et al. Resting and exercise ventilatory chemosensitivity across the menstrual cycle. J Appl Physiol. 2012;112(5): Beidleman BA, Rock PB, Muza SR, et al. Exercise VE and physical performance at altitude are not affected by menstrual cycle phase. J Appl Physiol. 1999;86(5):

34 314 Lebrun, Joyce, and Constantini 168. Brutsaert TD, Spielvogel H, Caceres E, et al. Effect of menstrual cycle phase on exercise performance of high-altitude native women at 3600 m. J Exp Biol. 2002;205(Pt 2): Takase K, Nishiyasu T, Asano K. Modulating effects of the menstrual cycle on cardiorespiratory responses to exercise under acute hypobaric hypoxia. Jpn J Physiol. 2002;52(6): Vrieze A, Postma DS, Kerstjens HA. Perimenstrual asthma: a syndrome without known cause or cure. J Allergy Clin Immunol. 2003;112(2): Chhabra SK. Premenstrual asthma. Indian J Chest Dis Allied Sci. 2005;47: Chandler MH, Schuldheisz S, Phillips BA, et al. Premenstrual asthma: the effect of estrogen on symptoms, pulmonary function, and beta 2-receptors. Pharmacotherapy. 1997;17: Balzano F, Fuschill S, Melillo F, et al. Asthma and sex hormones. Allergy. 2001;56: Boschetto P, Miotto D, Mapp CE. Chapter 8: Women and asthma. Eur Respir Monit. 2003;25: Haggerty CL, Ness RB, Kelsey S, et al. The impact of estrogen and progesterone on asthma. Ann Allergy Asthma Immunol. 2003;90:284 91; quiz 291 3, Stanford KR, Mickleborough TD, Ray S, et al. In fl uence of menstrual cycle phase on pulmonary function in asthmatic athletes. Eur J Appl Physiol. 2006;96: Salam MT, Wenten M, Gilliland FD. Endogenous and exogenous sex steroid hormones and asthma and wheeze in young women. J Allergy Clin Immunol. 2006;117: Townsend EA, Meuchel LW, Thompson MA, et al. Estrogen increases nitric-oxide production in human bronchial epithelium. J Pharmacol Exp Ther. 2011;339(3): Oguzulgen IK, Turktas H, Erbas D. Airway in fl ammation in premenstrual asthma. J Asthma. 2002;39(6): Thornton JS, Lewis J, Lebrun CM, et al. Clinical characteristics of women with menstrual-linked asthma. Respir Med. 2012;106(9): doi: 10:1016/j.rmed Ensom MH. Gender-based differences and menstrual cycle-related changes in speci fi c diseases: implications for pharmacotherapy. Pharmacotherapy. 2000;20: Choi IS. Gender-specific asthma treatment. Allergy Asthma Immunol Res. 2011;3(2): Magadle R, Berar-Yanay N, Weiner P. Long-acting bronchodilators in premenstrual exacerbation of asthma. Respir Med. 2001;95(9): Pasaoglu F, Mungan D, Abadoglu O, et al. Leukotriene receptor antagonists: a good choice in the treatment of premenstrual asthma? J Asthma. 2008;45: Tan KS, McFarlane LC, Lipworth BJ. Modulation of airway reactivity and peak fl ow variability in asthmatics receiving the oral contraceptive pill. Am J Respir Crit Care Med. 1997;155: Derimanov GS, Oppenheimer J. Exacerbation of premenstrual asthma caused by an oral contraceptive. Ann Allergy Asthma Immunol. 1998;81: McNeill AW, Mozingo E. Changes in the metabolic cost of standardized work associated with the use of an oral contraceptive. J Sports Med Phys Fitness. 1981;21(3): Montes A, Lally D, Hale RW. The effects of oral contraceptives on respiration. Fertil Steril. 1983;39(4): Notelovitz M, Zauner C, McKenzie L, et al. The effect of low-dose oral contraceptives on cardiorespiratory function, coagulation, and lipids in exercising young women: a preliminary report. Am J Obstet Gynecol. 1987;156(3): Lebrun CM, Petit MA, McKenzie DC, et al. Decreased maximal aerobic capacity with use of a triphasic oral contraceptive in highly active women: a randomised controlled trial. Br J Sports Med. 2003;37(4): Packard KA, Lenz TL, Elder B, et al. Oral contraceptive use may attenuate menstrual cycle-induced ventilatory changes in endurance trained runners. Open Sports Med J. 2011;5: Hackney AC. Effects of the menstrual cycle on resting muscle glycogen content. Horm Metab Res. 1990;22: Lamont LS. Lack of in fl uence of the menstrual cycle on blood lactate. Phys Sportsmed. 1986;14: De Souza MJ, Maguire MS, Rubin KR, et al. Effects of menstrual phase and amenorrhea on exercise performance in runners. Med Sci Sports Exerc. 1990;22(5): Kanaley JA, Boileau RA, Bahr JA, et al. Substrate oxidation and GH responses to exercise are independent of menstrual phase and status. Med Sci Sports Exerc. 1992;24(8):

35 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance Eston RG, Burke EJ. Effects of the menstrual cycle on selected responses to short constant-load exercise. J Sports Sci. 1984;2: McCracken M, Ainsworth B, Hackney AC. Effects of menstrual cycle phase on the blood lactate responses to exercise. Eur J Appl Physiol. 1994;69: Paul DR, Mulroy SM, Horner JA, et al. Carbohydrate-loading during the follicular phase of the menstrual cycle: effects on muscle glycogen and exercise performance. Int J Sport Nutr Exerc Metab. 2001;11(4): Bailey SP, Zacher CM, Mittleman KD. Effect of menstrual cycle phase on carbohydrate supplementation during prolonged exercise to fatigue. J Appl Physiol. 2000;88(2): McLay RT, Thomson CD, Williams SM, et al. Carbohydrate loading and female endurance athlete: effect of menstrual cycle phase. Int J Sport Nutr Exerc Metab. 2007;17(2): Dean TM, Perreault L, Mazzeo RS, et al. No effect of menstrual cycle phase on lactate threshold. J Appl Physiol. 2003;95: Ruby BC, Robergs RA, Waters DL, et al. Effects of estradiol on substrate turnover during exercise in amenorrheic females. Med Sci Sports Exerc. 1997;29(9): Galliven EA, Singh A, Michelson D, et al. Hormonal and metabolic responses to exercise across time of day and menstrual cycle phase. J Appl Physiol. 1997;83(6): Forsyth JJ, Reilly T. The combined effect of time of day and menstrual cycle on lactate threshold. Med Sci Sports Exerc. 2005;37(12): Ashley CD, Kramer ML, Bishop P. Estrogen and substrate metabolism: a review of contradictory research. Sports Med. 2000;29(4): Bonen A, Haynes FW, Graham TE. Substrate and hormonal responses to exercise in women using oral contraceptives. J Appl Physiol. 1991;70(5): Zderic TW, Coggan AR, Ruby BC. Glucose kinetics and substrate oxidation during exercise in the follicular and luteal phases. J Appl Physiol. 2001;90(2): Casazza GA, Jacobs KA, Suh SH, et al. Menstrual cycle phase and oral contraceptive effects on triglyceride mobilization during exercise. J Appl Physiol. 2004;97(1): Devries MC, Hamadeh MJ, Phillips SM, et al. Menstrual cycle phase and sex in fl uence muscle glycogen utilization and glucose turnover during moderate-intensity endurance exercise. Am J Physiol Regul Integr Comp Physiol. 2006;291(4):R Horton TJ, Miller EK, Bourret K. No effect of menstrual cycle phase on glycerol or palmitate kinetics during 90 min of moderate exercise. J Appl Physiol. 2006;100: Suh SH, Casazza GA, Horning MA, et al. Effects of oral contraceptives on glucose fl ux and substrate oxidation rates during rest and exercise. J Appl Physiol. 2003;94(1): Jacobs KA, Casazza GA, Suh SH, et al. Fatty acid reesteri fi cation but not oxidation is increased by oral contraceptive use in women. J Appl Physiol. 2005;98(5): Wells CL, Horvath S. Heat stress responses related to the menstrual cycle. J Appl Physiol. 1973;35: Wells CL, Horvath SM. Responses to exercise in a hot environment as related to the menstrual cycle. J Appl Physiol. 1974;36: Stephenson LA, Kolka MA, Wilkerson JE. Metabolic and thermoregulatory responses to exercise during the human menstrual cycle. Med Sci Sports Exerc. 1982;14: Marsh SA, Jenkins DG. Physiological responses to the menstrual cycle. Implications for the development of heat illness in female athletes. Sports Med. 2002;32(10): Inoue Y, Tanaka Y, Omori K, et al. Sex- and menstrual cycle-related differences in sweating and cutaneous blood fl ow in response to passive heat exposure. Eur J Appl Physiol. 2005;94(3): Kuwahara T, Inoue Y, Taniguchi M, et al. Effects of physical training on heat loss responses of young women to passive heating in relation to menstrual cycle. Eur J Appl Physiol. 2005;94(4): Ichinose TK, Inoue Y, Hirata M, et al. Enhanced heat loss responses induced by short-term endurance training in exercising women. Exp Physiol. 2009;94(1): Walters TJ, Ryan KL, Tate LM, et al. Exercise in the heat is limited by a critical internal temperature. J Appl Physiol. 2000;89(2): Booth J, Marino F, Ward JJ. Improved running performance in hot humid conditions following whole body precooling. Med Sci Sports Exerc. 1997;29(7):943 9.

36 316 Lebrun, Joyce, and Constantini 222. Duf fi eld R, Green R, Castle P, et al. Precooling can prevent the reduction of self-paced exercise intensity in the heat. Med Sci Sports Exerc. 2010;42(3): Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982;14(5): Pivarnik JM, Marichal CJ, Spillman T, et al. Menstrual cycle phase affects temperature regulation during endurance exercise. J Appl Physiol. 1992;72: Gonzalez-Alonso J, Teller C, Andersen SL, et al. In fl uence of body temperature on the development of fatigue during prolonged exercise in the heat. J Appl Physiol. 1999;86(3): Carpenter AJ, Nunneley SA. Endogenous hormones subtly alter women s response to heat stress. J Appl Physiol. 1988;65(5): Davies CT. In fl uence of skin temperature on sweating and aerobic performance during severe work. J Appl Physiol. 1979;47(4): Galloway SDR, Maughan RJ. Effect of ambient temperature on the capacity to perform prolonged cycle exercise in man. Med Sci Sports Exerc. 1997;29(9): Grucza R, Pekkarinen H, Titov E, et al. In fl uence of the menstrual cycle and oral contraceptives on thermoregulatory responses to exercise in young women. Eur J Appl Physiol. 1993;67: Garcia AM, Lacerda MG, Fonseca IAT, et al. Luteal phase of the menstrual cycle increases sweating rate during exercise. Braz J Med Biol Res. 2006;39(9): Stephenson LA, Kolka MA. Plasma volume during heat stress and exercise in women. Eur J Appl Physiol Occup Physiol. 1988;57(4): Sunderland C, Nevill M. Effect of the menstrual cycle on performance of intermittent, high-intensity shuttle running in a hot environment. Eur J Appl Physiol. 2003;888(45): Martin JR, Buono MJ. Oral contraceptives elevate core temperature and heart rate during exercise in the heat. Clin Physiol. 1997;17: Rogers SM, Baker MA. Thermoregulation during exercise in women who are taking oral contraceptives. Eur J Appl Physiol. 1997;75: Tenaglia SA, McLellan TM, Klentrou PP. In fl uence of menstrual cycle and oral contraceptives on tolerance to uncompensable heat stress. Eur J Appl Physiol Occup Physiol. 1999;80(2): Robertson LA, Higgs LS. Menstrual cycle variations in physical work capacity, postexercise blood lactate, and perceived exertion (abstract). Can J Appl Sport Sci. 1983;8: Birch KM, Reilly T. The effect of eumenorrheic menstrual cycle phase on physiological responses to a repeated lifting task. Can J Appl Physiol. 1997;22: Birch KM, Reilly T. Manual handling performance: the effects of menstrual cycle phase. Ergonomics. 1999;42(20): Petrofsky JS, LeDonne DM, Rinehart JS, et al. Isometric strength and endurance during the menstrual cycle. Eur J Appl Physiol. 1976;35: Wirth JC, Lohman TG. The relationship of static muscle function to use of oral contraceptives. Med Sci Sports Exerc. 1982;14: Davies BN, Elford JCC, Jamieson KF. Variations in performance of simple muscle tests at different phases of the menstrual cycle. J Sports Med Phys Fitness. 1991;31: Higgs SL, Robertson LA. Cyclic variations in perceived exertion and physical work capacity in females. Can J Appl Sport Sci. 1981;6: Dibrezzo R, Fort IL, Brown B. Relationships among strength, endurance, weight, and body fat during three phases of the menstrual cycle. J Sports Med Phys Fitness. 1991;31: Janse de Jonge XA, Boot CR, Thom JM, et al. The in fl uence of menstrual cycle phase on skeletal muscle contractile characteristics in humans. J Physiol. 2001;530(Pt 1): Lebrun CM, McKenzie DC, Prior JC, et al. Effects of menstrual cycle phase on athletic performance. Med Sci Sports Exerc. 1995;27(3): Dieli-Conwright CM, Spektor TM, Rice JC, et al. In fl uence of hormone replacement therapy on eccentric exercise induced myogenic gene expression in postmenopausal women. J Appl Physiol. 2009;107: Greising SM, Baltgalvis KA, Lowe DA, et al. Hormone therapy and skeletal muscle strength: a metaanalysis. J Gerontol A Biol Sci Med Sci. 2009;64(10): Phillips SK, Sanderson AG, Birch K, et al. Changes in maximal voluntary force of human adductor pollicis muscle during the menstrual cycle. J Physiol. 1996;496:551 7.

37 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance Greeves JP, Cable NT, Luckas MJ, et al. Effects of acute changes in oestrogen on muscle function of the fi rst dorsal interosseus muscle in humans. J Physiol. 1997;500(Pt 1): Fridén C, Hirschberg AL, Saartok T. Muscle strength and endurance do not signi fi cantly vary across 3 phases of the menstrual cycle in moderately active premenopausal women. Clin J Sport Med. 2003;13(4): Sarwar R, Niclos BB, Rutherford OM. Changes in muscle strength, relaxation rate, and fatiguability during the human menstrual cycle. J Physiol. 1996;493: Bambaeichi E, Reilly T, Cable NT, et al. The isolated and combined effects of menstrual cycle phase and time-of-day on muscle strength of eumenorrheic females. Chronobiol Int. 2004;21(4 5): Dawson EA, Reilly T. Menstrual cycle, exercise and health. Biol Rhythm Res. 2009;40(1): Petrofsky J, Al Malty A, Suh HJ. Isometric endurance, body and skin temperature and limb and skin blood fl ow during the menstrual cycle. Med Sci Monit. 2007;13(3):CR Salomoni S, Soares FA, de Oliveira Nascimento FA, et al. Gender differences in muscle fatigue of the biceps brachii and in fl uences of female menstrual cycle in electromyography variables. Conf Proc IEEE Eng Med Biol Soc. 2008;2008: Soares FA, Salomoni SE, Veneziano WH, et al. On the behavior of surface electromyographic variables during the menstrual cycle. Physiol Meas. 2011;32(5): Kadi F. Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle. A basis for illegal performance enhancement. Br J Pharmacol. 2008;154(3): Alexander GM, Sherwin BB, Bancroft J, et al. Testosterone and sexual behavior in oral contraceptive users and nonusers: a prospective study. Horm Behav. 1990;24(3): Enea C, Boisseau N, Fargeas-Gluck MA, et al. Circulating androgens in women: exercise-induced changes. Sports Med. 2011;41(1): Brownlee KK, Hackney AC. Steroid hormone responses to intensive prolonged endurance exercise in women. Acta Kinesiol (University Tartu). 2007;12: Enea C, Boisseau N, Ottavy M, et al. Effects of menstrual cycle, oral contraception, and training on exercise-induced changes in circulating DHEA-sulphate and testosterone in young women. Eur J Appl Physiol. 2009;106(3): Nakamura Y, Aizawa K, Imai T, et al. Hormonal responses to resistance exercise during different menstrual cycle states. Med Sci Sports Exerc. 2011;43(6): Reis E, Frick U, Schmidtbleicher D. Frequency variations of strength training sessions triggered by the phases of the menstrual cycle. Int J Sports Med. 1995;16(8): Enns DB, Tiidus PM. The in fl uence of estrogen on skeletal muscle. Sex matters. Sports Med. 2010;40(1): Lowe DA, Baltgalvis KA, Greising SA. Mechanisms behind estrogen s bene fi cial effect on muscle strength in females. Exerc Sport Sci Rev. 2010;38(2): Elliott KJ, Cable NT, Reilly T, et al. Effect of menstrual cycle phase on the concentration of bioavailable 17-beta oestradiol and testosterone and muscle strength. Clin Sci. 2003;105: Elliott KJ, Cable NT, Reilly T. Does oral contraceptive use affect maximum force production in women? Br J Sports Med. 2005;39(1): Erratum in: Br J Sports Med. 2005;39(3): Bushman B, Masterson G, Nelsen J. Anaerobic power performance and the menstrual cycle: eumenorrheic and oral contraceptive users. J Sports Med Phys Fitness. 2006;46(1): Peters C, Burrows M. Androgenicity of the progestin in oral contraceptives does not affect maximal leg strength. Contraception. 2006;74(6): Nichols AW, Hetzler RK, Villanueva RJ, et al. Effects of combination oral contraceptives on strength development in women athletes. J Strength Cond Res. 2008;22(5): Bernardes RP, Radomski MW. Growth hormone responses to continuous and intermittent exercise in females under oral contraceptive therapy. Eur J Appl Physiol Occup Physiol. 1998;79(1): Hansen M, Langberg H, Holm L, et al. Effect of administration of oral contraceptives on the synthesis and breakdown of myo fi brillar proteins in young women. Scand J Med Sci Sports. 2011;21(1): Thompson HS, Hyatt JP, De Souza MJ, et al. The effects of oral contraceptives on delayed onset muscle soreness following exercise. Contraception. 1997;56: Kendall B, Eston R. Exercise-induced muscle damage and the potential protective role of estrogen. Sports Med. 2002;32(2):

38 318 Lebrun, Joyce, and Constantini 275. Redman LM, Scroop GS, Norman RJ. Impact of menstrual cycle phase on the exercise status of young sedentary women. Eur J Appl Physiol. 2003;90: Gamberale F, Strindberg L, Wahlberg I. Female work capacity during the menstrual cycle: physiological and psychological reactions. Scand J Work Environ Health. 1975;1(2): Girija B, Veeraiah S. Effect of different phases of menstrual cycle on physical working capacity in Indian population. Indian J Physiol Pharmacol. 2011;55(2): Nohara M, Momoeda M, Kubota T, et al. Menstrual cycle and menstrual pain problems and related risk factors among Japanese female workers. Ind Health. 2011;49(2): Daggett A, Davies V, Boobis L. Physiological and biochemical responses to exercise following oral contraceptive use (abstract). Med Sci Sports Exerc. 1983;15: Bryner RE, Tof fl e RC, Ullrich IH, et al. Effect of low dose oral contraceptives on exercise performance. Br J Sports Med. 1996;30: Rechichi C, Dawson B, Goodman C. Oral contraceptive phase has no effect on endurance test. Int J Sports Med. 2008;29(4): Lynch NJ, Nimmo MA. Effects of menstrual cycle phase and oral contraceptive use on intermittent exercise. Eur J Appl Physiol Occup Physiol. 1998;78(6): Giacomoni M, Falgairette G. Decreased submaximal oxygen uptake during short duration oral contraceptive use: a randomized cross-over trial in premenopausal women. Ergonomics. 2000;43(10): Casazza GA, Suh SH, Miller BF, et al. Effects of oral contraceptives on peak exercise capacity. J Appl Physiol. 2002;93(5): Redman LM, Scroop GC, Westlander G, et al. Effect of a synthetic progestin on the exercise status of sedentary young women. J Clin Endocrinol Metab. 2005;90: De Bruyn-Prevost R, Masset C, Sturbois X. Physiological response from years women to aerobic and anaerobic physical fi tness tests at different periods during the menstrual cycle. J Sports Med. 1984;24: Doolittle TL, Engbretsen J. Performance variations during the menstrual cycle. J Sports Med. 1972;12: Parish HC, Jakeman PM. The effects of menstruation upon repeated maximal sprint performance. J Sports Sci. 1987;1: Bale P, Nelson G. The effects of menstruation on performance of swimmers. Aust J Sci Med Sport. 1985;March: Miscek CM, Potteiger JA, Nau KL, et al. Do varying environment and menstrual cycle conditions affect anaerobic power output in female athletes? J Strength Cond Res. 1997;11: Masterson G. The impact of the menstrual phases on anaerobic power performance in collegiate women. J Strength Cond Res. 1999;13(4): Okudan N, Gokbel H, Ucok K, et al. Serum leptin concentration and anaerobic performance do not change during the menstrual cycle of young females. Neuroendocrinol Lett. 2005;26(4): Middleton LE, Wenger HA. Effects of menstrual phase on performance and recovery in intense intermittent activity. Eur J Appl Physiol. 2006;96(1): Tsampoukos A, Peckham EA, James R, et al. Effect of menstrual cycle phase on sprinting performance. Eur J Appl Physiol. 2010;109(4): Shaharudin S, Ghosh AK, Ismail AA. Anaerobic capacity of physically active eumenorrheic females at mid-luteal and mid-follicular phases of ovarian cycle. J Sports Med Phys Fitness. 2011;51(4): Redman LM, Weatherby RP. Measuring performance during the menstrual cycle: a model using oral contraceptives. Med Sci Sports Exerc. 2004;36(1): Giacomoni M, Bernard T, Gavarry O, et al. In fl uence of the menstrual cycle phase and menstrual symptoms on maximal anaerobic performance. Med Sci Sports Exerc. 2000;32(2): Sunderland D, Tunaley V, Homer F, et al. Menstrual cycle and oral contraceptives effects on growth hormone response to sprinting. Appl Physiol Nutr Metab. 2011;36(4): Lynch NJ, DeVito G, Nimmo MA. Low dosage monophasic oral contraceptive use and intermittent exercise performance and metabolism in humans. Eur J Appl Physiol. 2001;84: Rebelo AC, Zuttin RS, Verlengia R, et al. Effect of low-dose combined oral contraceptive on aerobic capacity and anaerobic threshold level in active and sedentary young women. Contraception. 2010;81(4):

39 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance Rougier G, Linquette Y. Menstruation and physical exercises. Presse Med. 1962;70: Erdelyi GJ. Gynecological survey of female athletes. J Sports Med Phys Fitness. 1962;2: Eston RG. The regular menstrual cycle and athletic performance. Sports Med. 1984;1(6): Fraccaroli F. Sports performance of women during the menstrual cycle. Minerva Med. 1980;71(48): Wilson CA, Abdenour TE, Keye WR. Menstrual disorders among intercollegiate athletes and non athletes. perceived impact on performance. Athl Train J NATA. 1991;26: Kishali NF, Imamoglu O, Katkat D, et al. Effects of menstrual cycle on sports performance. Int J Neurosci. 2006;116: Brooks-Gunn J, Gargiulo JM, Warren MP. The effect of cycle phase on the performance of adolescent swimmers. Phys Sportsmed. 1986;14: Fomin SK, Pivovarova VI, Voronova VI. Changes in the special working capacity and mental stability of well-trained woman skiers at various phases of the biological cycle. Sports Train Med Rehab. 1989;1: Oosthuyse T, Bosch AN, Jackson S. Cycling time trial performance during different phases of the menstrual cycle. Eur J Appl Physiol. 2005;94(3): Vaiksaar S, Jürimäe J, Mäestu J, et al. No effect of menstrual cycle phase on fuel oxidation during exercise in rowers. Eur J Appl Physiol. 2011;111(6): Vaiksaar S, Jürimäe J, Mäestu J, et al. No effect of menstrual cycle phase and oral contraceptive use on endurance performance in rowers. J Strength Cond Res. 2011;25(6): Burkman Jr RT. Noncontraceptive effects of hormonal contraceptives: bone mass, sexually transmitted disease and pelvic in fl ammatory disease, cardiovascular disease, menstrual function, and future fertility. Am J Obstet Gynecol. 1994;170(5 Pt 2): Möller-Nielsen J, Hammar M. Women s soccer injuries in relation to the menstrual cycle and oral contraceptive use. Med Sci Sports Exerc. 1989;21(2): Möller-Nielsen J, Hammar M. Sports injuries and oral contraceptive use. Is there a relationship? Sports Med. 1991;12(3): Sulak PJ, Cressman BE, Waldrop E, et al. Extending the duration of active oral contraceptive pills to manage hormone withdrawal symptoms. Obstet Gynecol. 1997;89(2):19 183; review Wright KP, Johnson JV. Evaluation of extended and continuous use oral contraceptives. Ther Clin Risk Manag. 2008;4(5): Shrader SP, Dickerson LM. Extended- and continuous-cycle oral contraceptives. Pharmacotherapy. 2008;28(8): Vaiksaar S, Jürimäe J, Mäestu J, et al. Phase of oral contraceptive cycle and endurance capacity of rowers. Percept Mot Skills. 2011;113(3): Rechichi C, Dawson V. Effect of oral contraceptive cycle phase on performance in team sport players. J Sci Med Sport. 2009;12(1): Rechichi C, Dawson R. Oral contraceptive phase does not affect 200-m swim time trial performance. J Strength Cond Res. 2012;26(1): Grif fi n LY, Agel J, Albohm MJ, et al. Noncontact anterior cruciate ligament injuries: risk factors and prevention strategies. J Am Acad Orthop Surg. 2000;8(3): Grif fi n LY, Albohm MJ, Arendt EA, et al. Understanding and preventing noncontact anterior cruciate ligament injuries: a review of the Hunt Valley II meeting, January Am J Sports Med. 2006;34(9): Shultz SJ, Schmitz RJ, Nguyen AD, et al. ACL Research Retreat V: an update on ACL injury risk and prevention. March 25 27, Greensboro, NC. J Athl Train. 2010;45: Renstrom P, Ljungqvist A, Arendt E, et al. Non-contact ACL injuries in female athletes: an International Olympic Committee current concepts statement. Br J Sports Med. 2008;42: Chandrashekar N, Mansouri H, Slauterbeck J, et al. Sex-based differences in the tensile properties of the human anterior cruciate ligament. J Biomech. 2006;39(16): Park SK, Stefanyshyn DJ, Ramage B, et al. Alterations in knee joint laxity during the menstrual cycle in healthy women leads to increases in joint loads during selected athletic movements. Am J Sports Med. 2009;37(6): Park SK, Stefanyshyn DJ, Ramage B, et al. Relationship between knee joint laxity and knee joint mechanics during the menstrual cycle. Br J Sports Med. 2009;43:174 9.

40 320 Lebrun, Joyce, and Constantini 328. Liu S, Al-Shaikh R, Panossian V, et al. Primary immunolocalization of estrogen and progesterone target cells in the human anterior cruciate ligament. J Orthop Res. 1996;14: Yu W, Liu S, Hatch J, et al. Effect of estrogen on cellular metabolism of the human anterior cruciate ligament. Clin Orthop. 1999;366: Yu W, Panossian V, Hatch J, et al. Combined effects of estrogen and progesterone on the anterior cruciate ligament. Clin Orthop. 2001;383: Dragoo JL, Lee RS, Benhaim P, et al. Relaxin receptors in the human female anterior cruciate ligament. Am J Sports Med. 2003;31: Faryniarz DA, Bhargave AM, Lajam C, et al. Quantitation of estrogen receptors and relaxin binding in human anterior cruciate ligament fi broblasts. In Vitro Cell Dev Biol Anim. 2006;42: Dragoo JL, Castillo TN, Braun HJ, et al. Prospective correlation between serum relaxin concentration and anterior cruciate ligament tears among elite collegiate female athletes. Am J Sports Med. 2011;39(10): Slauterbeck J, Clevenger C, Lundberg W, et al. Estrogen level alters the failure load of the rabbit anterior cruciate ligament. J Orthop Res. 1999;17: Slauterbeck JR, Fuzie SF, Smith MP, et al. The menstrual cycle, sex hormones, and anterior cruciate ligament injury. J Athl Train. 2002;37: Deie M, Sakamaki Y, Sumen Y, et al. Anterior knee laxity in young women varies with their menstrual cycle. Int Orthop. 2002;26: Hertel J, Williams NI, Olmsted-Kramer LC, et al. Neuromuscular performance and knee laxity do not change across the menstrual cycle in female athletes. Knee Surg Sports Traumatol Arthrosc. 2006;14: Zazulak BT, Paterno M, Myer GD, et al. The effects of the menstrual cycle on anterior knee laxity: a systematic review. Sports Med. 2006;36(10): Heitz N, Eisenhower P, Beck C, et al. Hormonal changes throughout the menstrual cycle and increased ACL laxity in females. J Athl Train. 1999;34: Romani W, Patrie J, Curl LA, et al. The correlations between estradiol, estrone, estriol, progesterone, and sex hormone-binding globulin and anterior cruciate ligament stiffness in healthy, active females. J Womens Health (Larchmt). 2003;12(3): Karageanes SJ, Blackburn K, Vangelos ZA. The association of the menstrual cycle with the laxity of the anterior cruciate ligament in adolescent female athletes. Clin J Sport Med. 2000;10: Wojtys EM, Huston LJ, Lindenfeld TN, et al. Association between the menstrual cycle and anterior cruciate ligament injuries in female athletes. Am J Sports Med. 1998;26: McShane JM, Balsbaugh T, Simpson Z, et al. Letters to the editor. Am J Sports Med. 2000;28(1): Wojtys EM, Huston LJ, Boynton MD, et al. The effect of the menstrual cycle on anterior cruciate ligament injuries in women as determined by hormone levels. Am J Sports Med. 2002;30(2): Myklebust G, Maehlum S, Holm I, et al. A prospective cohort study of anterior cruciate ligament injuries in elite Norwegian team handball. Scand J Med Sci Sports. 1998;8: Myklebust G, Engebretsen L, Braekken IH, et al. Prevention of anterior cruciate ligament injuries in female team handball players: a prospective intervention study over three seasons. Clin J Sport Med. 2003;13: Arendt EA, Agel J, Dick R. Anterior cruciate ligament injury patterns among collegiate men and women. J Athl Train. 1999;34(2): Arendt EA, Bershadsky B, Agel J. Periodicity of noncontact anterior cruciate ligament injuries during the menstrual cycle. J Gend Specif Med. 2002;5: Adachi N, Nawata K, Maeta M, et al. Relationship of the menstrual cycle phase to anterior cruciate ligament injuries in teenaged female athletes. Arch Orthop Trauma Surg. 2008;128: Beynnon BD, Johnson RJ, Braun S, et al. The relationship between menstrual cycle phase and anterior cruciate ligament injury: a case control study of recreational alpine skiers. Am J Sports Med. 2006;34(5): Ruedl G, Pooner P, Linortner I, et al. Are oral contraceptive use and menstrual cycle phase related to anterior cruciate ligament injury risk in female recreational skiers? Knee Surg Sports Traumatol Arthrosc. 2009;17:

41 Chapter 16 / Effects of Female Reproductive Hormones on Sports Performance Fischer GM. Comparison of collagen dynamics in different tissues under in fl uence of estradiol. Endocrinology. 1973;93: Eiling E, Bryant AL, Petersen A, et al. Effects of menstrual-cycle hormone fl uctuations on musculotendinous stiffness and knee joint laxity. Knee Surg Sports Traumatol Arthrosc. 2007;15: Park SK, Stefanyshyn DJ, Loitz-Ramage B, et al. Changing hormone levels during the menstrual cycle affect knee laxity and stiffness in healthy female subjects. Am J Sports Med. 2009;37(3): Burgess KE, Pearson SJ, Onambélé GL. Menstrual cycle variations in oestradiol and progesterone have no impact on in vivo medial gastrocnemius tendon mechanical properties. Clin Biomech. 2009;24: Burgess KE, Pearson SJ, Onambélé G. Patellar tendon properties with fl uctuating menstrual cycle hormones. J Strength Cond Res. 2010;24(8): Bryant AL, Clark RA, Bartold S, et al. Effects of estrogen on the mechanical behavior of the human Achilles tendon in vivo. J Appl Physiol. 2008;105: Kubo K, Miyamoto M, Tanaka S, et al. Muscle and tendon properties during menstrual cycle. Int J Sports Med. 2009;30(2): Shultz SJ, Schmitz RJ, Nguyen A-D, et al. Knee joint laxity and its cyclic variation in fl uence tibiofemoral motions during weight acceptance. Med Sci Sports Exerc. 2011;43(2): Bell DR, Myrick MP, Blackburn JT, et al. The effect of menstrual-cycle phase on hamstring extensibility and muscle stiffness. J Sport Rehabil. 2009;18(4): Bell DR, Blackburn JT, Ondrak KS, et al. The effects of oral contraceptive use on muscle stiffness across the menstrual cycle. Clin J Sport Med. 2011;21(6): Bell DR, Blackburn JT, Norcorss MF, et al. Estrogen and muscle stiffness have a negative relationship in females. Knee Surg Sports Traumatol Arthrosc. 2012;20(2): Huston LJ, Wojtys EM. Neuromuscular performance characteristics in elite female athletes. Am J Sports Med. 1996;24: Abt JP, Sell TC, Laudner KG, et al. Neuromuscular and biomechanical characteristics do not vary across the menstrual cycle. Knee Surg Sports Traumatol Arthrosc. 2007;15: Fridén C, Ramsey DK, Backstrom T, et al. Altered postural control during the luteal phase in women with premenstrual symptoms. Neuroendocrinology. 2005;81: Fridén C, Hirschberg AL, Saartok T, et al. Knee joint kinaesthesia and neuromuscular coordination during three phases of the menstrual cycle in moderately active women. Knee Surg Sports Traumatol Arthrosc. 2006;14: Fu Q, Okazaki K, Shibata S, et al. Menstrual cycle effects on sympathetic neural responses to upright tilt. J Physiol (Lond). 2009;587: Swanik CB, Lephart SM, Swanik KA, et al. Neuromuscular dynamic restraint in women with anterior cruciate ligament injuries. Clin Orthop Relat Res. 2004;425: Dedrick GS, Sizer PS, Merkle JN, et al. Effect of sex hormones on neuromuscular control patterns during landing. J Electromyogr Kinesiol. 2008;18: Fouladi R, Rahabi R, Naseri N, et al. Menstrual cycle and knee joint position sense in healthy female athletes. Knee Surg Sports Traumatol Arthrosc. 2012;20(8): Chaudhari AM, Lindenfeld TN, Andriacchi TP, et al. Knee and hip loading patterns at different phases in the menstrual cycle: implications for the gender difference in anterior cruciate ligament injury rates. Am J Sports Med. 2007;35(5): Shultz SJ, Schmitz RJ, Kong Y, et al. Cyclic variations in multiplanar knee laxity in fl uence landing biomechanics. Med Sci Sports Exerc. 2012;44(5): Hlavacova N, Wawruch M, Tisonova J, et al. Neuroendocrine activation during combined mental and physical stress in women depends on trait anxiety and the phase of the menstrual cycle. Ann N Y Acad Sci. 2008;1158: Hoffman M, Harter RA, Hayes BT, et al. The interrelationships among sex hormone concentrations, motoneuron excitability, and anterior tibial displacement in women and men. J Athl Train. 2008;43(4): Clark RA, Simon B, Bryant AL. Tibial acceleration variability during consecutive gait cycles is in fl uenced by the menstrual cycle. Clin Biomech. 2010;25:

42 322 Lebrun, Joyce, and Constantini 376. Myer GD, Ford KR, Brent JL, et al. An integrated approach to change the outcome Part I: neuromuscular screening methods to identify high ACL injury risk athletes. J Strength Cond Res. 2012;26(8): Hicks-Little CA, Thatcher JR, Hauth JM, et al. Menstrual cycle stage and oral contraceptive effects on anterior tibial displacement in collegiate female athletes. J Sports Med Phys Fitness. 2007;47(2): Hansen M, Miller BF, Holm L, et al. Effect of administration of oral contraceptives in vivo on collagen synthesis in tendon and muscle connective tissue in young women. J Appl Physiol. 2009;106: Agel J, Bershadsky B, Arendt EA. Hormonal therapy: ACL and ankle injury. Med Sci Sports Exerc. 2006;38(1): Cammarata ML, Dhaher YY. The differential effects of gender, anthropometry, and prior hormonal state on frontal plane knee joint stiffness. Clin Biomech (Bristol, Avon). 2008;23(7): Vescovi JD. The menstrual cycle and anterior cruciate ligament injury risk: implications of menstrual cycle variability. Sports Med. 2011;41(2): Shultz SJ, Kirk SE, Johnson ML, et al. Relationship between sex hormones and anterior knee laxity across the menstrual cycle. Med Sci Sports Exerc. 2004;36: Hewett TE. Neuromuscular and hormonal factors associated with knee injuries in female athletes. Sports Med. 2000;29(5): Shultz SJ, Sander TC, Kirk SE, et al. Sex differences in knee joint laxity change across the female menstrual cycle. J Sports Med Phys Fitness. 2005;45(4): Hewett TE, Zazulak BT, Myer GD. Effects of the menstrual cycle on anterior cruciate ligament injury risk a systematic review. Am J Sports Med. 2007;35: