M. J. De Souza1 and R. J. Toombs
(1)
Women’s Health and Exercise Laboratory, Noll Laboratory, Department of Kinesiology, Penn State University, University Park, PA 16802, USA
M. J. De Souza
Email: mjd34@psu.edu
Abstarct
The Female Athlete Triad [1, 2] is a syndrome of interrelated conditions that involves disordered eating, low bone mass, and amenorrhea in physically active women and female athletes. This condition was first described by the American College of Sports Medicine in 1997 [1] and is associated with significant health risks. The condition is most common in women involved in sports that emphasize leanness, such as cross country running, gymnastics, and figure skating [2, 3]; however, this condition also impacts recreationally physically active women [4]. Inadequate nutrition precedes the clinical sequelae of amenorrhea and low bone mass. Nutritional deficits are typically associated with internal and external pressures on these women to maintain a low body weight, and most often present as disordered eating [5–7]. The etiology of amenorrhea in exercising women is secondary to inadequate caloric intake in the face of high exercise-related energy expenditure, resulting in a net energy deficit. The energy deficit, in turn, stimulates compensatory mechanisms such as weight loss and energy conservation that translate to hypothalamic suppression of ovarian function and amenorrhea [6, 8, 9].
Introduction
The Female Athlete Triad [1, 2] is a syndrome of interrelated conditions that involves disordered eating, low bone mass, and amenorrhea in physically active women and female athletes. This condition was first described by the American College of Sports Medicine in 1997 [1] and is associated with significant health risks. The condition is most common in women involved in sports that emphasize leanness, such as cross country running, gymnastics, and figure skating [2, 3]; however, this condition also impacts recreationally physically active women [4]. Inadequate nutrition precedes the clinical sequelae of amenorrhea and low bone mass. Nutritional deficits are typically associated with internal and external pressures on these women to maintain a low body weight, and most often present as disordered eating [5–7]. The etiology of amenorrhea in exercising women is secondary to inadequate caloric intake in the face of high exercise-related energy expenditure, resulting in a net energy deficit. The energy deficit, in turn, stimulates compensatory mechanisms such as weight loss and energy conservation that translate to hypothalamic suppression of ovarian function and amenorrhea [6, 8, 9].
In the past two decades, much has been learned about symptoms, risk factors, causes, and treatment strategies for the Female Athlete Triad, and particularly amenorrhea, although only limited clinical guidelines are available to date [2, 10]. The only clinical recommendation for the prevention and treatment of amenorrhea in physically active women and athletes is to increase caloric intake and/or reduce exercise energy expenditure [10]. No specific dietary guidelines exist to date, and the rationale for reducing training when caloric intake is already high is likely an excessively conservative approach, since exercise per se does not play a causal role in the etiology of athletic amenorrhea [8, 11]. This chapter describes the most recent scientific findings about the relationship between energy balance and menstrual regularity, and provides clinicians with a practical approach to the diagnosis and treatment of these problems commonly observed in physically active adolescent and adult women and female athletes.
A New Model
The Female Athlete Triad was first identified over 10 years ago by the American College of Sports Medicine [1]. Recently, the emergence of a new model for understanding the Female Athlete Triad has greatly advanced our understanding of the condition [2]. Originally, the three components of the Triad were presented as clinical endpoints that included disordered eating, low bone mass, and amenorrhea [1]. The components of the Female Athlete Triad are known to be interrelated since energy deficiency associated with disordered eating plays a causal role in the development of menstrual disturbances [9, 11, 12], and both energy deficiency and a low estrogen environment associated with amenorrhea play a causal role in initiating bone loss [13–15]. In the new Triad model [2] described in Fig. 7.1, these interrelationships are reaffirmed; however, each component of the Female Athlete Triad is represented as a continuum of severity from health to disease. At the “healthy” end of the continuum of each Triad component are optimal energy availability, the presence of normal ovulatory menstrual cycles, and optimal bone health [2]. At the “unhealthy” end of the continuum of each Triad component are the clinical outcomes associated with each, including energy deficiency, with or without disordered eating, abnormal menstrual cycles, functional hypothalamic amenorrhea, and bone loss [2].
Fig. 7.1
The continuum of the Female Athlete Triad beginning with healthy energy, menstrual, and bone health status at one end of the continuum and the unhealthy outcomes of the Triad at the other end of the Triad continuum, including disordered eating, amenorrhea, and osteoporosis. BMD bone mineral density; LPD luteal phase defect. Modified and reprinted with permission from Nattiv et al. [2]
Key points that are highlighted by the new model of the Female Athlete Triad are that many athletes may not present with more severe conditions at the extremes of the continuums, but rather may display intermediate, or “subclinical,” presentations of one or more of the conditions, and, most importantly, that progression along the three continuums can occur at different rates. For example, an athlete may show signs of restrictive eating but may not meet the clinical criteria for an eating disorder. She may also display subtle menstrual disturbances, such as a change in menstrual cycle length, anovulation, or luteal phase defects, but may not yet have developed amenorrhea. Likewise, she may be losing bone mass but may not yet have dropped below her age-matched normal range for bone mineral density (BMD). While the conditions represented by each continuum can present independent of the other two, it is more likely that, because of the clear associations among the three conditions, an athlete suffering from one element of the Female Athlete Triad is also suffering from the others even if only in a subclinical manner. Thus, it is important to understand that an athlete may present at different stages on each continuum and has the capacity to change stages on each continuum at varying rates. For example, changes can occur daily when considering energy status, monthly when considering the time course necessary for energetic changes to impact menstrual function, and annually when considering the time course necessary for energetic and menstrual changes to impact bone health [2].
The Prevalence of Athletic Amenorrhea
The prevalence of amenorrhea has been reported to range from 6 to 43% in runners [16–21], 1–21% in both high school [22] and collegiate athletes across a wide assortment of sports [3, 23], and as high as 69% in ballet dancers [24]. Of course, the prevalence of amenorrhea in athletes and physically active women grossly exceeds the 2–5% observed in the general population of sedentary college-aged women [25–27].
It is important to note that adolescent athletes are likely to experience a higher prevalence of menstrual cycle disturbances and amenorrhea; Baker et al. [28] demonstrated that adolescent runners experienced a significantly higher prevalence of amenorrhea than their adult counterparts (67% vs. 9%). Primary amenorrhea and delayed menarche have also been reported in many adolescent athletes, particularly gymnasts, ballet dancers, runners, divers, and cheerleaders [3, 29–31]. Primary amenorrhea and delayed menarche in adolescent athletes are often solely attributed to exercise training without appropriate regard for social self-selection factors known to influence the timing of pubertal maturation, particularly in sports like gymnastics and ballet [30, 32].
The Etiology of Athletic Amenorrhea
Primary amenorrhea has recently been defined as the failure to achieve menarche by age 15 in the presence of normal development of secondary sex characteristics [33]. The definition of secondary amenorrhea in the exercise literature has varied, but should be defined conservatively as no menses for 90 days or 3 months, or less than 5 menses in 12 months [6]. Oligomenorrhea is defined as the presence of irregular and inconsistent cycle intervals of 36–90 days [6], although care must be taken to exclude other causes of oligomenorrhea, particularly polycystic ovarian syndrome [34]. Indeed, it is certainly not surprising that many athletes bring their preexisting condition of polycystic ovarian syndrome to the athletic environment.
In athletes, the amenorrhea is hypothalamic in origin, characterized by decreased gonadotropin-releasing hormone (GnRH) pulsatility and, as a result, suppressed levels of circulating gonadotropins and ovarian steroids; however, the responsiveness of the pituitary gland to GnRH remains unaltered [35]. Amenorrhea is associated with an extreme deficiency in estrogen, while less severe perturbations of menstrual function, such as oligomenorrhea and anovulation, have less severe deficits in estrogen, as assessed by daily urinary measurements of ovarian steroids when calculated as an area under the curve [4, 36]. Figure 7.2 demonstrates the examples of the estrogen exposure associated with varying menstrual perturbations in exercising women, contrasted with ovulatory cycles in both sedentary and exercising women when assessed by the daily excretion of urinary estrone and pregnanediol glucuronides.
Fig. 7.2
Representative menstrual cycles of exercising women with varying menstrual disturbances and the corresponding estrogen exposure (c, d, e) contrasted to ovulatory cycles and the associated estrogen exposure of both a sedentary woman (a) and an exercising woman (b). Note the suppressed estrogen exposure associated with anovulatory and amenorrheic menstrual status. *E1G and PdG for SedOv cycle was adjusted based on creatinine excretion; E1G and PdG for all other cycles are corrected for hydration based on specific gravity. SedOv Sedentary Ovulatory; ExOv Exercising Ovulatory; ExLPDExercising Luteal Phase Deficient; ExAnov Exercising Anovulatory; ExAmen Exercising Amenorrheic; E1G estrone-1-glucoronide; PdG pregnanediol glucoronide; AUC area under the curve
Physiological Considerations
The significance of energy deficiency as a cause of Female Athlete Triad-related menstrual disturbances and bone loss is now more apparent than ever. Indeed, we have suggested that these menstrual disturbances should be referred to as energy-related menstrual disturbances [37]. Research has well established that one of the primary causes of Triad-related health problems is a chronic energy deficiency [6, 9, 11]. In other words, the amount of calories an athlete or physically active woman consumes is simply not adequate to meet the energetic demands of her daily exercise training energy expenditure, a concept often referred to as low energy availability [2]. When the volume of energy is inadequate to meet energetic demands, the body repartitions energy away from reproduction and growth and toward other more essential energy-consuming processes such as thermoregulation, cell maintenance, and locomotion [38]. The reliance of reproductive function on nutritional factors, such as food availability and energy balance, is also well established in nonwesternized subsistence communities who are impacted by seasonal food availability and high energy expenditures during harvests [39–41]. Energy deficiency in these cases occurs because there is a negative balance between food intake resulting from seasonal availability in food and energy expenditure associated with work in the fields, or travel from one remote location to another [39, 40]. Irrespective of the cause of the energy deficiency, a relative chronic energy drain persists, a concept first published by Michelle Warren in 1980 [42], that results in reproductive suppression. Energy deficiency is often associated with weight loss in a metabolic environment that favors energy conservation. An environment of energy conservation involves a decrease in resting energy expenditure (REE), suppression of total triiodothyronine (TT3), insulin-like growth factor-1 (IGF-1) and leptin concentrations, and elevated ghrelin and cortisol concentrations [36, 43–46] (see Fig. 7.3). Suppression of REE has been well documented in amenorrheic, exercising women concomitant with the abovementioned alterations in metabolic hormonal profiles consistent with nutritional restriction [13, 36, 47, 48]. Additional evidence for the relationship between energy deficiency and energy-related menstrual disturbances comes from the results of cross-sectional studies of metabolic hormones and substrates in exercising women with subtle menstrual disturbances such as luteal phase defects and anovulation that illustrate similar, but less severe, adaptive changes than those observed in amenorrheic, exercising women [36, 45, 49].
Fig. 7.3
The metabolic and hormonal alterations that are associated with a hypometabolic and amenorrheic environment in exercising women. Metabolic hormones and gut peptides are characteristically altered secondary to an energy deficient environment and gonadotropin and ovarian steroids are characteristically suppressed secondary to an estrogen-deficient environment. TT 3 total triiodothyronine; IGF-1 insulin-like growth factor-1; IGFB1 insulin-like growth factor binding protein-1; PYY peptide YY; LHluteinizing hormone; FSH follicle-stimulating hormone
It is noteworthy that a low body weight is not always a reliable indicator of chronic energy deficiency nor is a stable body weight a reliable indicator of energy balance [50]. The metabolic adaptations that act to conserve energy and reduce energy expenditure and body weight can also, in some cases, result in weight stability, albeit at a lower set point that may present as a restoration in energy balance with ongoing chronic alterations indicative of an energy-conserved metabolic and endocrine environment [50]. To forecast the presence of an energy deficiency in our laboratory [12, 13, 36], we have successfully utilized the ratio of REE (as measured in the laboratory) to the Harris–Benedict [51] predicted REE (measured REE/predicted REE). Since the majority of published reports [52–54] of REE in underweight women utilized the Harris–Benedict equation [51] to predict REE, we reasoned that this equation was likely to be useful for our purposes. We further observed that in clinical models of starvation, such as anorexia nervosa [52–54], a reduced ratio of measured REE to predicted REE by the Harris–Benedict equation [51] is often in the range of 60–80%. As such, we operationally defined energy deficiency in exercising women as a ratio of measured REE to predicted REE of less than 90% and energy replete as a ratio of measured REE to predicted REE of greater than 90% [12, 13, 36]. We have successfully utilized this strategy in several published papers to date, and it is consistently corroborated by metabolic hormone (TT3 and ghrelin concentrations) data, indicative of adaptations to an energy-deficient state [12, 13, 36].
Elegant short-term experiments by Loucks and colleagues [11, 55–57] manipulating both dietary intake and energy expenditure have consistently demonstrated a strong relationship between low energy availability, suppressed metabolic hormones and suppression of the GnRH pulse generator. The design of the Loucks et al. [11] experiments involved having subjects expend 15 kcal/kg lean body mass (LBM) per day during supervised exercise sessions for 5 days at 70% of aerobic capacity while consuming a standardized diet intended to set energy availability at a balanced level of 45 kcal/kg LBM/day or at mild, moderate, and severe levels of energy restriction of 30, 20, 10 kcal/kg LBM/day, respectively [11]. At all levels of restriction, metabolic hormones, including TT3, IGF-1, insulin, leptin, and cortisol, were altered in an incremental manner with these effects most dramatic at the severe level of energy restriction of 10 kcal/kg LBM/day [11]. Similarly, LH pulsatility was most dramatically impacted at the severe level of energy restriction, but suppression of LH pulsatility was also noted even at mild (30 kcal/kg LBM/day) and modest (20 kcal/kg LBM/day) levels of energy restriction [11].
Convincing evidence for a causal relationship between low energy availability and menstrual cyclicity was provided by the prospective training studies in monkeys elegantly executed by Williams et al. [8, 9]. Williams et al. [8, 9] demonstrated two key relationships, (1) that amenorrhea could be induced in exercising monkeys and that the onset of the amenorrhea was related to the volume of calories restricted during the exercise training, and (2) that the amenorrhea could be reversed by increasing food intake without any moderation of the daily exercise training. The authors point out that the resumption of ovulatory cycles in the amenorrheic monkeys had a dose-dependent relationship with the volume of energy available such that the monkeys that ate the most calories recovered ovulatory function in the shortest time period [9]. It is also noteworthy that in this study, a key marker of energy balance, TT3, was significantly related to both the induction and reversal of amenorrhea providing additional evidence to support the premise that suppression of reproductive function is linked with adaptive energy conservation when there is an imbalance created by inadequate caloric intake in the face of increased exercise energy expenditure [8, 9].
Psychological Considerations
As previously described, energy deficiency occurs when there is a negative balance between food intake and exercise energy expenditure. Because an athlete’s energy supply can be purposely manipulated, it warrants a special comment. It is clear that in many cases of the Female Athlete Triad, there is some form of disordered eating behavior that contributes to the energy deficiency [2, 7, 23, 58]. The disordered eating presents in a variety of ways, but most often as a high drive for thinness (DT) or as a purposeful dietary restriction of caloric intake [2, 7, 23]. The incidence of disordered eating behaviors in physically active women and athletes is reportedly as high as 62%, particularly in esthetic or lean build sports like gymnastics, ballet, and cross country running [59]; whereas, the prevalence of the more severe, clinical eating disorders (anorexia and bulimia) was reportedly ∼2–3% in a group of over 400 collegiate athletes [3]. These disordered eating behaviors, of course, can cause a chronic energy deficiency. Women with a high DT demonstrate a preoccupation with body weight and body shape, and a fear of gaining weight [58, 60, 61]. Numerous reports support a strong relationship between disordered eating, DT, and amenorrhea in exercising women [2, 7, 12, 16, 23, 58]. Indeed, in our previous work, we demonstrated that a high DT was associated with energy deficiency as indicated by significant relationships between REE and metabolic hormones such as TT3 and ghrelin [12]. Figure 7.4 demonstrates the aforementioned relationships. From a physiological standpoint, a high DT promotes the conscious restriction of food intake and/or the excessive participation in exercise; thus, this particular disordered eating attitude is likely associated with the development of an energy deficit as we have demonstrated in our work [12].
Fig. 7.4
The relationships between drive for thinness (DT) and metabolism in sedentary and exercising women grouped according to DT score on the Eating Disorder Inventory. (a) Resting energy expenditure (REE) adjusted for fat-free mass (FFM) among three groups of women categorized by exercise status and DT score to include (1) a sedentary group with a normal DT score, (2) an exercising group with a normal DT score, and (3) an exercising group with a high DT score. (b) The ratio of actual REE to predicted REE among the three groups. (c, d) The concentrations of total triidothyronine (TT3) and ghrelin among the three groups. Note the suppressed ratio of measured REE/predicted REE suggestive of an energy deficiency; these data are corroborated by suppressed TT3and elevated ghrelin concentrations. a p <0.05 ExHigh-DT vs. SedNormal-DT and ExNormal-DT. b p <0.05 ExNormal-DT vs. SedNormal-DT. SedNormal-DT Sedentary Normal-DT; ExNormal-DT Exercising Normal DT; ExHigh-DT Exercising High-DT. Reprinted with permission from De Souza et al. [12]
DT is also related to the conscious restriction of food intake, often referred to as cognitive dietary restraint [37]. Cognitive dietary restraint refers to the chronic effort to achieve or maintain a desired body weight by consciously restricting food intake [62]. It has also been associated with compromised reproductive function to include amenorrhea and decreased bone mass [37, 63, 64]. In our own laboratory, we have recently demonstrated that high cognitive dietary restraint scores are associated with reduced lumbar spine and total body BMD in physically active women such that the highest cognitive dietary restraint scores are related to the lowest BMD values and the most severe menstrual disturbances such as amenorrhea [37].
It is also noteworthy to remember that some athletes and physically active women can experience an energy deficiency in the absence of disordered eating; that is, even if they are not consciously restricting their food intake, these individuals may simply not eat enough food to fuel their exercise energy expenditure. A busy class schedule, travel, stress, and other factors can hinder female athletes from maintaining an adequate diet for training. Thus, some athletes who do not present with disordered eating symptoms or behaviors are often overlooked in discussions of the Female Athlete Triad. Likewise, it is important to remember that some athletes may present with a clinical eating disorder of anorexia or bulimia nervosa and warrant specialized intervention strategies with trained clinicians.
Bone Health Considerations
Suppression of reproductive function is associated with stress fractures, loss of BMD, the failure to achieve peak bone mass, and osteoporosis [13]. There are numerous reports of significantly lower BMD values on the order of 2–6% at the spine, hip, and total body among amenorrheic athletes when compared to their regularly menstruating counterparts [13, 16, 65–68]. In fact, Christo et al. [68] reported that 38 and 19% of amenorrheic athletes had lumbar and hip BMD Z-scores, respectively, at least one standard deviation below that of an age-matched sedentary population. It is important to note that BMD in exercising women should actually be higher than that observed in a reference population of sedentary women. The current recommendations for appropriate BMD criteria to diagnose low BMD or osteoporosis in athletes utilize the guideline published for premenopausal women by the International Society for Clinical Densitometry [69]. These criteria utilize a Z-score of −2.0 or lower to diagnose low BMD, and when a secondary risk factor is also present, such as hypogonadism or nutritional deficiency, a diagnosis of osteoporosis may be applied [69]. The prevalence of osteopenia in amenorrheic athletes is estimated to range from 1.4 to 50% [16, 65, 70–72]. The prevalence of osteoporosis is lower [16, 72]. Stress fractures are two to four times more common in athletes and physically active women with amenorrhea than their physically active counterparts who are menstruating [2, 73].
A closer look at the negative alterations that occur in the bones of female athletes via peripheral quantitative computed tomography reveals that trabecular BMD as well as cortical thickness are common targets of amenorrhea-associated bone loss in athletes. In a comparison of two samples of elite, retired gymnasts, Ducher et al. [74] observed that those athletes with a history of amenorrhea had significantly reduced trabecular density at the distal radius and tibia and significantly lower bone strength at the distal radius when compared to the eumenorrheic, retired gymnasts. Additionally, cortical thickness was significantly greater and medullary area significantly smaller at the proximal radius of the gymnasts without a history of amenorrhea, providing support for the role of estrogen in endocortical apposition [74]. Moreover, Misra et al. [75, 76] has reported that the low bone mass observed in energy-deficient amenorrheic women may be the consequence of light trabecular and thin cortical bones [75]. In a sample of 34 anorexic adolescents, Misra et al. [75] reported significantly decreased lumbar bone mineral content (BMC) adjusted for bone area (BA) when compared to controls but no significant differences were observed between anorexics and controls in lumbar BA adjusted for height, indicating that the significantly lower BMD of the lumbar spine, composed primarily of trabecular bone, was due to light and undermineralized rather than thin bones. In contrast, no significant differences were reported for whole body BMC adjusted for BA between anorexic women and controls; however, whole body BA adjusted for height was significantly decreased among the anorexic subjects, indicating that at sites of primarily cortical bone, hormonal and nutritional deficiencies lead to thin but poorly mineralized bone [75].
It has generally been accepted that chronic hypoestrogenism is the major cause of bone loss in exercising women. However, the effects of food restriction and energy deficiency on BMD represent an estrogen-independent mechanism for bone loss that involves some of the metabolic-related hormones altered with exercise-associated amenorrhea (see Fig. 7.5). These hormones, i.e., IGF-1 and leptin, play an important role in modulating bone turnover and BMD in these women. Evidence that these factors can impact bone in exercising women with exercise-associated amenorrhea includes several observations that oral contraceptive use in these women and other energy deficient models like anorexia does not unequivocally lead to appropriate recovery of BMD [14, 77, 78]. Therefore, additional factors other than simply estrogen deficiency must be taken into account.
Fig. 7.5
The mechanism for bone loss in exercising amenorrheic women. The combination of a high energy expenditure and a low energy intake suppresses circulating concentrations of certain ovarian steroids and metabolic markers, all of which have an impact on bone metabolism, leading to the uncoupling of bone turnover and subsequent bone loss. TT 3 triiodothyronine; IGF-1 insulin-like growth factor-1
Thus, the mechanism underlying the bone loss observed in amenorrheic athletes is twofold, including both hormonal and nutritional components (see Fig. 7.5) [13, 14]. Bone is an active tissue, undergoing cycles of resorption and formation. In the face of both an estrogen and energy deficiency, an uncoupling of bone turnover occurs, creating the unfavorable environment of increased bone resorption and decreased bone formation, ultimately resulting in bone loss [13]. As demonstrated by Ihle and Loucks [15], the decrease in estrogen that occurs with a reduction in energy availability coincides with an increase in markers of bone resorption, providing support for the role of estrogen in suppressing the bone-resorbing effects of osteoclasts. De Souza et al. [13] also demonstrated that in estrogen-deficient exercising women, urinary C-terminal telopeptide concentrations are elevated. Likewise, markers of bone formation appear to be sensitive to alterations in the nutritional and metabolic environment [13, 15]. Ihle and Loucks [15] observed that the decrease in metabolic indicators of nutritional status, namely, insulin, TT3, and IGF-1, coincided with decreases in bone formation markers. De Souza et al. [13] also reported a significant reduction in osteocalcin and type I procollagen carboxy-terminal propeptide, markers of bone formation, in an environment that was energy deficient but estrogen replete in exercising women.
Recently, the role of leptin, an adipocyte-derived hormone, in modulating the bone loss observed in amenorrheic women has been intensely studied [79]. Several investigators have reported reduced leptin levels in women with amenorrhea, associated with both anorexia and exercise [13, 80, 81], and the absence of the diurnal rhythm of leptin in amenorrheic athletes [82]. In our own laboratory [13], we have demonstrated that leptin was significantly related to markers of bone formation, i.e., osteocalcin and type I procollagen carboxy-terminal propeptide, in exercising women with an energy deficiency. Miller et al. [80] observed significantly reduced leptin in amenorrheic, anorexic women when compared to eumenorrheic, anorexic women, suggesting that leptin exerts a permissive influence on hypothalamic function. Additionally, through central and peripheral mechanisms, leptin exerts both antiosteogenic and osteogenic effects on bone mass [83]. Leptin receptors are present at the level of the hypothalamus; the binding of leptin to these receptors initiates the cascade that results in an increase in cortical bone but a decrease in cancellous bone [83]. Leptin also directly stimulates bone formation at the level of bone cells by stimulating osteoblastic differentiation via leptin receptors present on osteoblasts [83]. However, it has recently been suggested that leptin does not act via the hypothalamus, but rather leptin may regulate bone by inhibiting serotonin synthesis and release in the brainstem, which in turn acts on the hypothalamus via specific serotonin receptors [84].
Diagnosis and Treatment
The optimal occasion to screen for Triad-related disorders, including amenorrhea in athletes, is during the preparticipation physical exam. Recently, the Female Athlete Triad Coalition has published a strategy for the preparticipation exam, and this reference can be located at http://www.femaleathletetriad.org/for-professionals/information-for-physicians/.
Athletes and physically active women presenting with primary or secondary amenorrhea require evaluation, to first rule out pregnancy as well as other underlying endocrinopathies. Since amenorrhea in an athlete is secondary to hypothalamic suppression of the ovarian axis [85], no single blood test or evaluation can confirm such a diagnosis. Indeed the diagnosis of functional hypothalamic amenorrhea secondary to energy deficiency in athletes is a diagnosis of exclusion. An algorithm for the athlete presenting with secondary amenorrhea can be viewed in Fig. 7.6. Endocrinopathies that must be ruled out include (1) pregnancy, (2) pituitary causes such as prolactinomas, (3) adrenal causes such as adult-onset adrenal hyperplasia and Cushing’s disease, (4) thyroid disease, (5) ovarian tumors, (6) gonadotropin mutations, (7) hypothalamic causes, (8) premature ovarian failure, and (9) polycystic ovarian syndrome [86]. Other less common causes of amenorrhea exist in a small percentage of cases [86]. The most common causes of amenorrhea are usually identified following a thorough medical history, physical examination, and evaluation of follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and prolactin [86]. Readers are referred to the ASRM guidelines [86] for the appropriate algorithms for a more detailed differential diagnosis and interpretation of blood work. If the athlete demonstrates any physical evidence of androgen excess (i.e., hirsutism, acne, androgenic alopecia) or polycystic ovaries, additional laboratory testing that may be useful includes free testosterone and dihydroepiandrosterone sulfate (DHEA-S). A serum estradiol and a progesterone challenge test may be useful to assess the degree of hypoestrogenism [86].
Fig. 7.6
Algorithm for the diagnosis of functional hypothalamic amenorrhea (FHA) among athletes presenting with secondary amenorrhea. A thorough physical exam and evaluation of hormone concentrations are necessary to rule out underlying endocrinopathies. FSHfollicle-stimulating hormone; LH luteinizing hormone; TSH thyroid stimulating hormone; HCG human chorionic gonadotropin; DHEA-SO4 dihydroepiandrosterone sulfate; PCOS polycystic ovarian syndrome; AP anteroposterior
Other diagnostic tests that may be useful for an amenorrheic athlete include a BMD assessment of the anteroposterior spine (L1-L4) and of the total hip, since bone loss or the failure to achieve peak bone mass must be suspected in these women secondary to energy deficiency and hypoestrogenism [13, 14]. The diagnosis of low BMD in these women should be based on the lowest Z-score observed at these sites [69], and, when athletes are of adolescent age (less than age 20), the diagnosis should be determined from a BMD test of both the total body and the anteroposterior spine. It is most helpful to obtain age-matched controls, particularly in younger women.
Due to the multifaceted nature of exercise-associated amenorrhea, clinicians utilize various treatment strategies, each aimed at addressing an underlying cause or a consequence of the hypothalamic amenorrhea. Few treatment guidelines for amenorrheic athletes are published, but the overwhelming approach recommended is increased food intake and weight restoration, which are likely the best strategies for the resumption of menses and improved bone health [10, 87, 88]. Clinicians must be patient when using this strategy [89–91] and may find it beneficial to enlist the assistance of a registered dietician with demonstrated expertise in the determination of exercise energy expenditure needs. It is important to recall that in monkey studies conducted by Williams et al. [8, 9], the resumption of menses occurred the fastest in the monkeys that ate the most calories during the refeeding paradigm. The assessment of exercise energy expenditure is an essential component of an appropriate refeeding strategy in these exercising women and must be maintained until the goal of resumption of menses has been achieved. In our own laboratory, we are conducting an ongoing 12-month randomized controlled trial to determine the effectiveness of increased energy intake to reverse amenorrhea as well as improve energy and bone marker status in women with exercise-associated amenorrhea; this project is referred to as REFUEL. Preliminary data in five exercising women with amenorrhea demonstrate that an energy prescription of 20–40% above energy expenditure needs averaged 536 calories/day and resulted in the resumption of menses in 3/5 subjects within 4 months and 4/5 subjects within 6 months [92]. Interestingly, we also observed significant changes in metabolic markers that promoted a pro- bone health environment to include decreased ghrelin and increased concentrations of markers of bone formation [92]. Small studies [93–95] of the effects of weight gain on the resumption of menses are reported in the literature, and these results are displayed in Table 7.1. Athletes should also be required to meet the dietary guidelines of 1,000–1,500 mg calcium and 400–800 IU Vitamin D3 intake, either in their daily diet or with supplementation, particularly those athletes who reside at northern latitude and have limited exposure to sunlight.
Table 7.1
Effects of weight gain and resumption of menses on bone mineral density (BMD) among women with exercise-associated amenorrhea
|
Study |
Duration |
Weight gain |
Menses resumed (# of subjects) |
BMD % change |
|
|
Resumed |
Did not resume |
||||
|
Observational |
|||||
|
Drinkwater et al. [94] |
15.5 months |
↑1.9 kg |
7 of 9 |
6.3% (spine) |
−3.4% (spine) |
|
Keen and Drinkwater [93] |
8.1 years |
None |
8 of 11 |
No change |
|
|
Warren et al. [95] |
2 years |
Not reported |
7 of 19 |
17.5% (spine) |
4.0% (spine) |
|
Case |
|||||
|
Zanker et al. [97] |
12 years |
8.1 kg |
OC and hormone therapy |
16.9% (proximal femur) |
|
|
Fredericson and Kent, [98] |
8 years |
↑BMI 5.5 kg/m2 |
OC therapy |
25.5% ( spine) 19.5% (hip) |
|
In some cases, of course, athletes may be noncompliant, particularly those involved in sports which emphasize leanness and in competitive athletes; in these women, it may be necessary to decrease the duration or intensity of training. It may also be helpful, in some cases, to involve a clinical psychologist to help the athlete cope with body image issues or disordered eating behaviors when present. Indeed, cognitive behavioral therapy has been demonstrated to be more beneficial than nutritional counseling alone in some women with hypothalamic amenorrhea with disordered eating behaviors [96] and may likely benefit the athlete struggling with disordered eating behaviors, body image disturbances, and the prescription of increased energy intake.
Because the etiology of bone loss among amenorrheic women is founded upon both a nutritional and hormonal deficiency, weight gain and subsequent resumption of menses have provided hopeful results for the recovery of at least some bone mass. There are a few case studies [97, 98] and small sample size studies [93–95] examining the BMD outcome in amenorrheic athletes who have increased energy intake for the purpose of restoration of menses and improving BMD. In those reports [93–95, 97–101], BMD is positively impacted by ∼1–10%, but to date, reports have demonstrated only limited potential to normalize bone mass to that of eumenorrheic, physically active controls. Table 7.1 summarizes these data.
Similar studies have been performed in the anorexic population; among those studies that have included both weight gain and the resumption of menses, increases in BMD have been reported of similar magnitude (1–10%) in those who have recovered menses; whereas, continual decreases in BMD were observed in those who did not recover menses [75, 80, 102]. Weight gain independent of the resumption of menses has shown to have a positive effect on BMD as well as restore the coupling of bone formation and resorption [75, 103–106]. It appears that BMD can be increased if both mechanisms that underlie bone loss – hormonal and metabolic – are addressed. However, it is essential to understand that despite some recovery of bone, normalization of BMD is unlikely. It is very interesting to note the recent evidence that increased caloric intake leading to weight gain and the resumption of menses was associated with an increase in BMC adjusted for BA at the spine and, at the level of the whole body, an increase in BA adjusted for height was noted, indicating that both nutritional and hormonal recovery may improve the mineralization of trabecular bone and the growth of cortical bone [75].
For many clinicians, the administration of sex steroids has been a convenient alternative to the recommendation of changes in energy intake or expenditure, but the outcomes, particularly related to bone health, have been equivocal, at best, and are not recommended as the first line of therapeutic options (see Table 7.2). Clearly, an oral contraceptive strategy does nothing to restore fertility in these women. Due to estrogen’s role in preserving bone [107] and the hypoestrogenic nature of amenorrhea, oral contraceptive or estrogen therapy has, however, been perceived as a logical strategy to reverse amenorrheic-associated bone loss. The primary problem with this line of thinking is that the bone loss is primarily secondary to energy deficiency, that when exacerbated, results in hypoestrogenism [13]. Thus, oral contraceptive therapy fails to address the root cause of the problem; that is, energy deficiency. As displayed in Table 7.2, the results of several hormonal interventions in exercising amenorrheic women have been confounding [31, 77, 108–110], indicating that oral contraceptive or estrogen therapy may halt the progression of further bone loss and increase BMD slightly but may not completely restore bone mass to that observed in a young, healthy age-matched population [87]. Although significant increases of ∼1–9% in bone mass were observed in some studies [77, 109, 110], these improvements in BMD were often site-specific or minimal. Other investigators have reported nonsignificant improvements or no changes in BMD following the oral contraceptive therapy [31, 108]. Bolton et al. [106] have suggested that one reason for the failure of oral contraceptive therapy to yield more positive results to BMD may be because this therapeutic strategy tends to disproportionally suppress bone formation relative to resorption. Another explanation is that oral contraceptive therapy does nothing to reverse the energy deficient environment of suppressed bone formation and, given the data by Bolton et al. [106], may even exacerbate the problem.
Table 7.2
Effects of hormonal therapy on bone mineral density (BMD) among women with exercise-associated amenorrhea
|
Study |
Sample |
Treatment |
Duration |
BMD % change in Tx group |
|||
|
TB |
LS |
Hip |
FN |
||||
|
Hergenroeder et al. [77] |
n = 15 |
•Ethinyl estradiol (0.035 mg) •Norethindrone (0.5–1.0 mg) or Medroxyprogesterone (10 mg) |
12-month intervention |
2.7% |
9.4% |
19.0% |
|
|
Castelo-Branco et al. [99] |
n = 64 |
•Ethinyl estradiol (0.02–0.03 mg) •Desogestrel (0.15 mg) |
12-month intervention |
2.4–2.5% |
|||
|
Rickenlund et al. [109] |
n = 13 |
•Ethinyl estradiol (0.03 mg) •Levonorgestrel (0.15 mg) |
10-month intervention |
1.8% |
1.0% |
||
|
De Crée et al. [101] |
n = 7 |
•Ethinyl estradiol (0.05 mg) •Cyproterone acetate (2 mg) |
8-month cohort |
9.5% |
|||
|
Cumming [100] |
n = 8 |
•Conjugated estrogen (0.0625 mg) or •Transdermal estradiol (0.05 mg) |
24-month retrospective observational |
8.0% |
4.1% |
||
|
Gibson et al. [108] |
n = 34 |
•Estriol (1 mg) and Estradiol (2 mg) 12 days •Estriol (1 mg), Estradiol (2 mg), and Norethisterone acetate (1 mg) 10 days •Estriol (0.5 mg) and Estradiol (1 mg) 6 days |
9.3-month intervention |
No change |
No change |
No change |
|
|
Warren et al. [31] |
n = 55 |
•Premarin (0.625) •Provera (10 mg) |
24-month intervention |
5.6% |
|||
|
Warren et al. [110] |
n = 27 |
•Ethinyl estradiol (0.035 ng) •Norgestimate (0.180–0.250 mg) |
10-month intervention |
1.5% |
No change |
||
TB total body; LS lumbar spine; FN femoral neck
In view of the pivotal role of leptin in the regulation of both reproduction and bone turnover [111], recombinant leptin has been administered as a possible treatment for women with hypothalamic amenorrhea associated with exercise or nutritional deficiency [79]. Welt et al. [79] observed an increase in follicular size and the initiation of ovulatory cycles (three of eight subjects) as well as increased levels of luteinizing hormone, estradiol, IGF-1, and bone formation markers following 2–3 months of administration. Two key issues of concern with this therapeutic option is that these improvements were observed in the face of a commensurate loss of body weight and body fat as well as a reduction in hunger and food intake, findings clearly undesirable in an already underweight population of women.
The peptide IGF-1 is also an important link between nutritional status and growth; its presence at normal levels not only indicates nutritional stability, but also mediates anabolic effects on bone [112]. IGF-1 levels are often reduced in amenorrheic athletes [46, 113] and anorexic women [114–116]. Grinspoon et al. [114, 115] administered recombinant human IGF-1 (rhIGF-1) combined with either a placebo or an oral contraceptive to osteopenic, anorexic women. Based on the results of this study [114, 115], it was concluded that a combined treatment of both an anabolic agent such as rhIGF-1 and an antiresorptive agent such as oral contraceptives, but not either treatment alone, may promote an increase in BMD of ∼2% among women with anorexia-associated amenorrhea and perhaps also among women with exercise-associated amenorrhea, although not tested to date. As such, this strategy offers only limited potential and requires further investigation as a long-term therapeutic option.
Limited available data suggest that current clinician practices for the treatment of amenorrhea among athletes are changing. Based on a survey administered to 159 physicians of the American Medical Society for Sports Medicine in 1995 [117], 92% reported that they administered sex steroids to treat amenorrheic athletes. Interestingly, calcium supplementation closely followed sex steroid supplementation with up to 87% of the respondents indicating this therapy was also a recommended treatment strategy [117]. Only about 50% of the respondents utilized therapies targeted to the root of the problem, such as increased caloric intake (64%), decreased exercise (57%), and weight gain (43%). More recently, in 2007, Carlson et al. [118] administered a similar survey to 126 clinicians, reporting once again that calcium supplementation seemed to be the preferred method of treatment with 69% of respondents recommending this therapy to more than 75% of patients with athletic amenorrhea. In contrast, however, the administration of sex steroid therapy appeared to decline in use with only 14% of respondents primarily prescribing this therapy [118]. Instead, when compared to the percentage of clinicians in this study who preferentially prescribed sex steroids, a greater percentage of clinicians recommended increased caloric intake (48%), increased body weight (37%), or a reduction in exercise energy expenditure (28%) to greater than 75% of amenorrheic athletes [118]. Thus, this more recent report suggests that clinicians’ preferences for treatment have evolved to prefer strategies that involve increased caloric intake and weight gain rather than sacrificing some components of the athlete’s exercise training or masking the problem with hormone therapy. Physical therapists and athletic trainers often approach the problem from an educational perspective, offering information regarding changes in diet and training and, when necessary, providing referrals to physicians or dieticians [119].
Conclusions
The Female Athlete Triad is a serious medical condition that signals the presence of an energy deficiency that may be secondary to disordered eating, and is associated with menstrual disturbances and either premature bone loss or the failure to achieve peak bone mass. The etiology of menstrual disturbances associated with the Triad is causally linked to energy deficiency, and as such, there is no justification to fear that exercise itself is unhealthy for women. Indeed, physically active women and athletes have much to gain from physical activity and exercise but must be careful to meet their energetic requirements and include this issue in their training regime. As such, undernutrition plays a key role in triggering Triad-related problems; on the other hand, this means good nutrition is key to preventing the condition. While the conditions represented by each continuum can present independent of the other two conditions, it is more likely that, because of the clear associations among the three conditions, an athlete suffering from one element of the Female Athlete Triad is also suffering from the others, even if only in a subclinical manner. Thus, it is important to understand that an athlete may present at different stages on each continuum and has the capacity to change stages on each continuum at varying rates. For example, changes can occur daily when considering energy status, monthly when considering the time course necessary for energetic changes to impact menstrual function, and annually when considering the time course necessary for energetic and menstrual changes to impact bone health [2].
The nutritional etiology of the Triad warrants emphasis, and treatment strategies should be focused on improving nutritional status in these physically active women and athletes. The best approach recommended is increased food intake and weight restoration, which are likely the best strategies for the resumption of menses and improved bone health [10, 87, 88]. Clinicians must be patient when using this strategy [89–91] and may find it beneficial to enlist the assistance of a registered dietician with demonstrated expertise in the determination of exercise energy expenditure needs. For good reason then, as described in the text of this chapter, most educational efforts aimed at preventing Female Athlete Triad-related problems and amenorrhea in athletes should focus on nutrition and eating behaviors.
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