EA is the core component of the triad. It is defined as the amount of EI remaining for bodily functions after EEE: EA = (EI − EEE) / fat free mass (FFM). Normal energy balance in healthy women is found when EA is approximately 45 kcal·kg−1 FFM per day. In the setting of low EA, physiological mechanisms strive to restore energy balance and promote survival at the expense of energy utilization for cellular maintenance, thermoregulation, growth, and skeletal and reproductive health (65). Menstrual dysfunction is noted with EA less than 30 kcal·kg−1 FFM per day (37), and bone health may be affected at intermediate levels (31,36).
Low EA may be inadvertent or intentional and does not exclusively occur in the setting of disordered eating. Risk factors for low EA include a history of restrictive eating, prolonged exercise periods, vegetarian diets, early sport-specific training, participation in sports favoring lean physiques, sudden training intensity increase, and injury (41).
At the extreme, athletes with low EA may present with eating disorders, as defined by the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria (5). All eating disorders are serious clinical mental conditions with many potential adverse health outcomes including multisystem organ involvement and death. They are frequently associated with other psychiatric comorbidities including depression, anxiety, and substance abuse (68).
DSM-IV classifications include anorexia nervosa, bulimia nervosa, and eating disorder not otherwise specified (ED-NOS). Anorexia nervosa is defined as a body weight of less than 85% expected for height and age in conjunction with an intense fear of gaining weight, disturbed body image, and amenorrhea. In anorexia nervosa, mortality is increased sixfold, and 20% of deaths are a result of suicide (7,41). Less than half of patients with anorexia nervosa will recover fully, and 20% remain chronically affected by the disorder (55).
Bulimia nervosa encompasses recurrent episodes (at least twice weekly for three months) of binge eating in association with recurrent inappropriate compensatory behavior to prevent weight gain (i.e., self-induced vomiting, laxatives, fasting, and excessive exercise). Bulimia often occurs in the setting of normal range body weight, and self-evaluation is unduly influenced by body shape and weight. The ED-NOS classification applies to individuals who do not meet all of the criteria for anorexia nervosa or bulimia.
Proposed updated DSM criteria (DSM 5) include elimination of amenorrhea as a diagnostic criterion for anorexia nervosa, decreased required frequency of binge eating/compensatory behaviors for bulimia nervosa, and addition of a binge eating disorder classification. These changes may affect the prevalence of these conditions (33). Regardless of the diagnostic criteria, early recognition and prompt mental health treatment referrals are essential for the effective management of these conditions and the prevention of adverse outcomes.
The second component of the triad, menstrual function, occurs along a spectrum from eumenorrhea to functional hypothalamic amenorrhea. The spectrum includes primary amenorrhea, secondary amenorrhea, oligomenorrhea, anovulation, and luteal phase dysfunction. Understanding the spectrum of menstrual dysfunction is critical to recognition. Eumenorrhea is defined by cycles occurring at median adult intervals of 28 ± 7 d. Amenorrhea is the absence of menstrual cycles for more than 90 d. Primary amenorrhea is defined as the absence of menarche by the age of 15 years (46). Secondary amenorrhea occurs with the loss of three or more consecutive cycles after menarche. Oligomenorrhea is defined as menstrual cycles occurring at greater than 35-d intervals. Luteal suppression is noted by a luteal phase lasting less than 11 d or in the setting of low progesterone. Luteal dysfunction and anovulation may be clinically asymptomatic yet still have negative effects on reproductive and bone health (41).
In healthy women, pulsatile gonadotropin-releasing hormone (GnRH) release from the hypothalamus is critical for normal pituitary stimulation of pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release. These hormones promote normal menstruation through their action on the ovaries to produce estrogen and progesterone. Low EA induces a hypometabolic state that disrupts the GnRH pulse generator in the hypothalamus, leading to a cascade of effects manifesting in menstrual dysfunction.
Contrary to popular belief, strenuous exercise alone does not cause disruption of the hypothalamic-pituitary-ovarian axis. In actuality, insufficient dietary intake in the setting of sports participation (low EA) is the driving force behind menstrual dysfunction in female athletes. In young women, LH pulsatility was compromised after 5 d of low EA, but exercise in the setting of adequate EA did not affect LH pulsatility (37). In female monkeys, functional hypothalamic amenorrhea could be induced by increasing energy expenditure without increasing dietary intake. However normalization of EA through dietary modifications, without decreasing exercise levels, was effective for resumption of menses (66).
While the differential diagnosis of amenorrhea is broad (46), in the absence of pregnancy or anatomic defects, the majority of cases are related to four conditions: polycystic ovary syndrome (PCOS), hypothalamic amenorrhea, hyperprolactinemia, and ovarian failure. Functional hypothalamic amenorrhea is a diagnosis of exclusion, and alternative causes of menstrual dysfunction should be evaluated. The American Society for Reproductive Medicine (ASRM) endorses history, physical examination, and evaluation of FSH, thyroid-stimulating hormone (TSH), and prolactin levels for initial screening for most causes of amenorrhea (Fig. 1). In PCOS, the LH/FSH ratio may be greater than 2, but gonadotropin levels are not confirmatory. Differentiation of PCOS from hypothalamic amenorrhea requires clinical judgment, aided by the presence of androgenization. Additionally evaluation of LH and estradiol levels should be considered given the correlation between low EA and low LH pulsatility (37) as well as low estradiol’s relationship to endothelial dysfunction (28).
Bone Mineral Density
The third triad component, BMD, occurs along a continuum from optimal bone health to low BMD and osteoporosis. Bone strength is determined by BMD, as well as bone mineral content and quality (2), and is influenced heavily by genetics. Bone quality relates to microarchitecture, turnover, geometry, and size (1,10). Low EA affects bone strength directly through decreased bone formation. Additionally bone strength is affected indirectly through increased bone resorption that results from a low EA-induced hypoestrogenic state. Bone turnover markers are affected after only 5 d of low EA in otherwise healthy individuals (31), and BMD is correlated inversely with the length of menstrual dysfunction (17).
In general clinical practice, evaluation of low bone strength and osteoporosis is currently based upon dual-energy x-ray absorptiometry (DXA) results, which quantify only the BMD component of bone strength. The guidelines developed by the International Society for Clinical Densitometry for evaluation of bone density in premenopausal women may underestimate the prevalence of low bone density in female athletes. Healthy, young female athletes participating in weight-bearing sports typically have 5% to 15% higher BMD than their age-matched counterparts (41,45). Therefore ACSM recommends more stringent guidelines for the diagnosis of impaired bone health in this population. ACSM defines “low BMD” as a Z-score between −1.0 and −2.0 and osteoporosis as BMD Z-score ≤2.0, both in the setting of secondary risk factors for fracture (41). ACSM recommends BMD screening for individuals with a cumulative history of hypoestrogenism or disordered eating or eating disorder lasting 6 months or more and/or a history of stress fractures or minimal impact fractures. For those individuals in whom the triad components are persistent, serial DXAs are recommended at 12 months, using the same DXA machine for comparison.
In postmenopausal women, osteoporosis may be due to an increased rate of bone loss and/or failure to reach optimal peak bone mass in youth. This highlights the importance of early recognition and treatment of impaired bone health in childhood and adolescence for the prevention of negative outcomes in adulthood.
Coronary endothelial dysfunction predicts long-term atherosclerotic disease progression and cardiovascular events (23,52,57,58). However direct measurements of coronary endothelial function are invasive, expensive, and time consuming. Brachial artery flow-mediated vasodilation (FMD) measurement is considered the gold standard of noninvasive endothelial assessment as it is highly correlated with coronary endothelium-dependent dilation (6,34,35,42,60).
High-resolution ultrasound is used to measure brachial artery diameter before and after induction of forearm ischemia by suprasystolic blood pressure cuff inflation. After cuff deflation in normal subjects, resultant reactive hyperemia and shear stress stimulus induce nitric oxide release and vasodilation, with subsequent increases in brachial artery diameter. FMD is defined as the percentage increase in diameter of the brachial artery, which is typically ≥5% in athletes (60). Impaired dilatory responses are seen in the setting of endothelial dysfunction. While many clinical settings may not have the capability of measuring FMD directly, studies suggest that endothelial dysfunction in athletes may be correlated with amenorrhea, BMD Z-scores less than −1.0, and estradiol levels ≤40 pg·mL−1 (28,47).
Rehabilitation of the Female Athlete Triad: A Multidisciplinary Approach
Given the varied nutritional, metabolic, endocrine, and often psychological concerns related to the triad, effective treatment often demands a multidisciplinary treatment approach. Sports physicians should serve as the coordinator of the treatment team and be responsible for identifying other team members and monitoring their therapeutic contribution (61). Registered sports dieticians, mental health professionals, coaches, athletic trainers, family, friends, and teammates can all play instrumental roles in the treatment and recovery of athletes with the triad. All treatment team members must work together to develop strategies to effectively manage affected athletes, and all members must appreciate the importance of treatment timing on therapeutic outcomes (61).
The NCAA recommends that treatment of student-athletes with disordered eating focus on general health and nutrition, with a deemphasis on body weight. Performance enhancement through proper nutrition, adequate sleep, avoidance of substance use, and mental and emotional preparedness should be emphasized by sports personnel in lieu of weight management, especially in lean physique sports with a higher risk of disordered eating (53).
ACSM’s initial goal of treatment for all triad components is to increase EA. EA can be increased through increased energy intake and/or reduced energy expenditure (41). In the setting of inadvertent low EA, education, counseling, and monitoring by a registered sports dietician may be sufficient to increase EA through increased awareness of nutritional needs. Additionally the body may not possess sufficient physiological mechanisms to increase dietary intake in response to energy expenditure in the same way it responds to low EA secondary to decreased intake. Ad libitum dietary intake response to increased expenditure is blunted further by high-carbohydrate diets (36). Therefore nutritional counseling becomes vital to rectify low EA in athletes, in lieu of reliance on insufficient hunger and satiety cues. Athletes should be counseled to eat specific types and amounts of foods on a predetermined schedule. Periodization of training may require similar periodization of EA. In the setting of menstrual dysfunction, EA goals should be at least 30 kcal·kg−1 FFM per day (36,37) and nutritional monitoring should be continued until menses resume and are maintained in sport.
Attention should be paid to daily age-specific requirements for micronutrients essential to bone health, including calcium and vitamin D. Supplementation should be initiated when needs are not met through dietary adjustments or to address deficiencies (32) (Table 4).
In the case of disordered eating or clinically defined eating disorders, evaluation and management by a trained mental health professional becomes necessary. It is crucial that this clinician has expertise in the treatment of eating disorders in the athletic population and has an understanding of the physical and psychological demands of the individual’s sport. Treatment options include individual, group, or family therapy as well as pharmacotherapy and hospitalization. These treatments may be used alone or in combination as appropriate. Individual therapy provides insight into the psychological roots of the disorder and whether it predated sports participation, while allowing for individualization of coping and symptom management strategies.
Cognitive behavioral therapy (CBT) is considered one of the most effective psychotherapy treatments for eating disorders. Other treatment options include acceptance and commitment therapy and dialectical behavioral therapy (68). For anorexia nervosa, current treatment centers on psychotherapy and nutritional management, although access to mental health treatment may be limited by many insurance policies (50). For the treatment of bulimia nervosa, limited randomized controlled trials have investigated pharmacologic adjuncts to psychotherapy including selective serotonin reuptake inhibitors, other antidepressants, and mood stabilizers. For bulimia, pharmacotherapy and CBT are more effective when combined. However, to date, more limited benefits have been found for the pharmacologic treatment of anorexia nervosa (20).
For athletes with disordered eating or eating disorders, a written treatment contract is recommended by ACSM. Athletes must agree to comply with the treatment plan as outlined in the contract, place treatment requirements above competition goals, and adhere to activity modifications when necessary for health promotion. In breaches of contract or failure to gain weight, the athlete may be removed from training and competition, but medical management should continue (41). The NCAA recommends that an athlete be considered “injured” until a formal medical evaluation is completed, and withheld from training or competition for the following reasons: 1) a medical condition that precludes sports participation, 2) diagnosis of anorexia nervosa, or 3) when sports participation is integral to the athlete’s disordered eating (53). In the setting of eating disorders, electrocardiogram should be performed to evaluate for QT prolongation.
Alternatively, in situations where weight loss is an appropriate goal for health or sport performance, athletes should have sufficient access to nutritional counseling. EA should be between 30 and 45 kcal·kg−1 FFM per day, as determined by nutritional evaluation with attention to general health, weight loss, and performance goals (36). A multidisciplinary approach to weight management becomes vital to safely meeting weight and performance goals.
After improvement of EA, restoration of menses may take more than a year and is associated with body mass index (BMI) and weight increases (8). Oral contraceptive pills (OCPs) may regulate menstrual cycles but have not been shown to address the underlying metabolic changes that lead to menstrual dysfunction and impaired bone health in this population. Regulation of menstrual cycles using OCPs may mask underlying, persistent metabolic derangements and decrease the drive to address these conditions through EA restoration. However in the setting of persistent amenorrhea despite correction of low EA, reproductive medicine evaluation is warranted.
Increases in BMD have been associated with increases in body weight (41). Skeletal “catch-up” growth into the third decade has been noted in an amenorrheic runner after normalization of BMI (21). Weight training and impact activities should be combined for augmentation of BMD. The U.S. Centers for Disease Control and Prevention recommends approximately 30 min for adults and 60 min for children of daily physical activity. In children, muscle and bone building exercises such as gymnastics, running, jumping rope, jungle gym, and push-ups should be performed 3 d or more per week. In adults, weight training exercises should address all major muscle groups in 2 to 3 sets of 12 repetitions maximum at least twice weekly (13). Calcium and vitamin D intake should be optimized.
OCPs are not recommended as first-line therapy for low BMD. However ACSM recommends OCP initiation in athletes over age 16 years with persistent functional hypothalamic amenorrhea and declining BMD despite nutritional intervention, in hopes of preventing further BMD decline (41). Due to the lack of research and concerns for premature growth plate closure, OCPs are not recommended for athletes less than 16 years old. Bisphosphonates, a common treatment option for postmenopausal osteoporosis, are not suggested for the young athlete. Teratogenicity concerns persist years after cessation of this pharmacologic treatment, due to long-term bisphosphonate storage in bone (38). In the absence of other triad components, endocrinology referral for evaluation of alternative causes of abnormal bone health should be considered (30).
Data suggest that endothelial dysfunction improves with physiological restoration of menstrual function (24,67). Alternatively Rickenlund et al. (48) noted significant improvement in brachial artery FMD with a low-dose combined OCP (30-µg ethinyl estradiol and 150-µg levonorgestrel), which was attributed to estrogen’s proposed protective endothelial effect through increasing nitric oxide bioavailability. However postmenopausal studies by the Women’s Health Initiative noted increased cardiovascular events and breast cancer incidence or mortality in women treated with combined hormonal replacement (51). While safety has not been established in premenopausal women, nonhormonal treatments should be considered in this population.
Folic acid supplementation recently has gained support for the treatment of endothelial dysfunction. Folic acid is felt to assist in endothelial function through its critical role in tetrahydrobiopterin regeneration, an essential cofactor in nitric oxide (NO) production (Fig. 2). Daily supplementation may increase NO production as well as produce direct antioxidant effects. Supplementation has been shown to improve brachial artery FMD in populations with chronic disease including coronary artery disease and diabetes mellitus (62,63). Several recent small studies suggest efficacy in the athletic population. Supplementation of 10 mg·d−1 for 4 wk improved brachial artery FMD in amenorrheic runners and ballet dancers (25,29). Eumenorrheic runners with low-normal FMD improved their FMD with folic acid supplementation when compared to a placebo-controlled group (26).
Folic acid supplementation generally is well tolerated without documented adverse reactions at doses effective for endothelial function improvement in athletes and those with chronic disease (25,26,29,62,63). Adverse effects have been noted in higher doses (>15 mg·d−1) and include dyspepsia, sleep disturbances, and dermatologic conditions, and seizures have been reported in those using anticonvulsants. Caution is recommended when prescribing to athletes with malabsorption syndromes or vegan diets, as folic acid supplementation may mask or exacerbate a vitamin B12 deficiency (68). These promising results warrant future large-scale studies to address minimal effective dosing and treatment length for folic acid supplementation for the treatment of endothelial dysfunction.
Prevention: The Ultimate Treatment Strategy
Ideally educational initiatives will be the most effective tool in the prevention of the female athlete triad. Educational programs must be far reaching and include health professionals, coaching staff, athletic trainers, physical and health education instructors, school administrators, athletes, teammates, family, and friends. Education should be initiated in the elementary school years, with an emphasis on maintaining optimal EA throughout the life course. Children and adolescents should be aware of their age-appropriate nutritional requirements (32) (Table 4) and the importance of weight-bearing exercise for bone health. The myth that athletic amenorrhea is normal must be debunked, and athletes must understand the consequences of menstrual dysfunction on reproductive and skeletal health.
Several interventional programs have shown promise in improving knowledge of and decreasing risk factors for the triad. The Athletes Targeting Healthy Exercise and Nutrition Alternatives project was a peer-led, coach-facilitated program administered to middle and high school students that demonstrated short-term and 1-year follow-up decreases in eating disorder risk factors (18). The Female Athlete Body Project was a peer-led cognitive dissonance approach to prevent eating disorders in athletes with significant decreases in negative effect, eating pathology and body dissatisfaction at 6 wk of follow-up (56). Becker et al. (11) studied an athlete-modified dissonance prevention program and a healthy weight initiative program. Investigators noted significant improvements in certain eating disorder risk factors at 6 wk and 1 year of follow-up and an increase in the number of athlete participants seeking medical evaluation for the triad. Temme et al. (59) found limited knowledge of triad components amongst high school students, and short-term knowledge improved significantly after a peer-based mentoring program. Further research is needed to determine what programs will have the most far-reaching and long-term effects on triad prevention. The support of sport governing bodies will be essential for effective implementation of these programs.
ACSM recommends regular physical activity for all girls and women, as the benefits of physical activity outweigh the risks. However the female athlete triad and triad components pose a significant risk to the health of young, female athletes. Emphasis must be placed on prevention, recognition, and treatment of this complex interplay of metabolic and endocrine factors in order to promote healthy nutritional and physical activity profiles in these young athletes. Effective treatment often requires a multidisciplinary approach, and all treatment team members should play a vital role in the successful rehabilitation of athletes with the triad. Treatment should be centered on restoration of EA, as low EA is the driving force behind the other triad components.
Athletes with functional hypothalamic amenorrhea possess reproductive steroid hormonal profiles similar to postmenopausal women, and endothelial dysfunction has been demonstrated in both populations. Further research is needed to determine whether endothelial dysfunction in young athletes carries the same long-term cardiovascular risks well documented in older women. However it may be imperative to identify and treat those athletes at risk for endothelial dysfunction to prevent progression of atherosclerotic disease seen in postmenopausal women.
The ultimate goal of triad treatment should be prevention, and future research should identify what programs are most effective for triad knowledge acquisition and risk factor reduction. Programs must incorporate interventions that reach a diverse range of sports and activity levels, as the triad does not affect only athletes participating in lean physique sports. The ultimate goal of all interventions should be to facilitate a nutritionally sound and physically active lifestyle for girls and young women that can be maintained throughout their life course.
The authors declare no conflicts of interest and do not have any financial disclosures.
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