Clinical Journal of Sport Medicine:
2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad: 1st International Conference Held in San Francisco, CA, May 2012, and 2nd International Conference Held in Indianapolis, IN, May 2013
De Souza, Mary Jane PhD*; Nattiv, Aurelia MD†; Joy, Elizabeth MD, MPH‡; Misra, Madhusmita MD§; Williams, Nancy I. ScD*; Mallinson, Rebecca J. PhD*; Gibbs, Jenna C. PhD¶; Olmsted, Marion PhD‖; Goolsby, Marci MD**; Matheson, Gordon MD, PhD††
*Penn State University, Department of Kinesiology, University Park, Pennsylvania;
†University of California Los Angeles, Los Angeles, California;
‡Intermountain Healthcare, Salt Lake City, Utah;
§Harvard Medical School, Boston, Massachusetts;
¶University of Waterloo, Waterloo, Ontario, Canada;
‖University of Toronto, Toronto, Ontario, Canada;
**Hospital for Special Surgery, New York, New York;
††Stanford University, Stanford, California.
Corresponding Author: Mary Jane De Souza, PhD, FACSM, Women's Health and Exercise Laboratory, 104 Noll Laboratory, Department of Kinesiology, Penn State University, University Park, PA 16802 (email@example.com).
Expert Panel: In addition to the authors above, the Expert Panel members were Michelle Barrack, PhD, RD, California State University Northridge, Northridge, California; Louise Burke, PhD, Australian Institute of Sport, Australia; Barbara Drinkwater, PhD, FACSM, Washington; Connie Lebrun, MD, University of Alberta, Edmonton, Alberta, Canada; Anne B. Loucks, PhD, Ohio University, Athens, Ohio; Margo Mountjoy, MD, McMaster University, Guelph, Ontario, Canada; Jeanne Nichols, PhD, San Diego State University, San Diego, California; Jorunn Sungot Borgen, PhD, Norwegian School of Sport Sciences, Oslo, Norway.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.cjsportmed.com).
The authors report no conflicts of interest.
Received December 09, 2013
Accepted December 31, 2013
Abstract: The Female Athlete Triad is a medical condition often observed in physically active girls and women, and involves 3 components: (1) low energy availability with or without disordered eating, (2) menstrual dysfunction, and (3) low bone mineral density. Female athletes often present with 1 or more of the 3 Triad components, and an early intervention is essential to prevent its progression to serious endpoints that include clinical eating disorders, amenorrhea, and osteoporosis. This consensus statement represents a set of recommendations developed following the first (San Francisco, California) and second (Indianapolis, Indianna) International Symposia on the Female Athlete Triad. It is intended to provide clinical guidelines for physicians, athletic trainers, and other health care providers for the screening, diagnosis, and treatment of the Female Athlete Triad and to provide clear recommendations for return to play. The 2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad Expert Panel has proposed a risk stratification point system that takes into account magnitude of risk to assist the physician in decision-making regarding sport participation, clearance, and return to play. Guidelines are offered for clearance categories, management by a multidisciplinary team, and implementation of treatment contracts. This consensus paper has been endorsed by The Female Athlete Triad Coalition, an International Consortium of leading Triad researchers, physicians, and other health care professionals, the American College of Sports Medicine, the American Medical Society for Sports Medicine, and the American Bone Health Alliance.
This consensus statement is the first of its kind and represents a set of recommendations developed following the first (San Francisco, California) and second (Indianapolis, Indiana) International Consensus Meetings on the Female Athlete Triad (Triad). It is intended to provide clinical guidelines for physicians, athletic trainers, and other health care providers for the treatment of the Triad and to provide clear recommendations for return to play. The Consensus recommendations herein were developed using a consensus-based approach similar to that utilized by the International Consensus Statement on Concussion.1 This consensus statement will serve as a supplement to the American College of Sports Medicine (ACSM) revised position stand on the Triad published in 2007. The 2007 position stand provided the scientific evidence documenting the existence and causes of the Triad.2 Practical information for athletes, coaches, and parents and a list of resources and helpful information on the Triad can be readily viewed on the Female Athlete Triad Coalition Web site at http://www.femaleathletetriad.org. This consensus paper has been endorsed by The Female Athlete Triad Coalition, an International Consortium of leading Triad researchers, physicians, and other healthcare professionals, the American College of Sports Medicine, the American Medical Society for Sports Medicine, and the American Bone Health Alliance.
While agreement exists concerning the primary guidelines and recommendations communicated in this document, the authors acknowledge that the underlying levels of scientific evidence regarding some elements of the Triad, particularly related to treatment strategies, are still evolving. The treatment guidelines and return-to-play recommendations proposed herein are based on published literature available to date, with consensus from the international team of experts convened at the 2 meetings. As such, management and return-to-play decisions should be based on informed clinical judgment keeping in mind individual risk factors and concerns as described herein.
DEFINITION OF THE FEMALE ATHLETE TRIAD MODEL
The Triad is a medical condition often observed in physically active girls and women, and involves any 1 of the 3 components: (1) low energy availability (EA) with or without disordered eating (DE), (2) menstrual dysfunction, and (3) low bone mineral density (BMD)2 (see Figure 1). Female athletes often present with 1 or more of the 3 Triad components, and an early intervention is essential to prevent its progression to serious endpoints that include clinical eating disorders (EDs), amenorrhea, and osteoporosis.2
In 1997, the Task Force on Women's Issues of ACSM published the first Triad position stand which described a syndrome of 3 distinct but interrelated conditions: DE, amenorrhea, and osteoporosis.3 Subsequent cross-sectional studies defined the Triad based on critical endpoints for each of the 3 Triad components to include ED, amenorrhea, and osteoporosis. The components of the Triad are known to be interrelated since energy deficiency associated with DE plays a causal role in the development of menstrual disturbances,4–6 and an energy deficiency and a hypoestrogenic environment associated with amenorrhea play a causal role in low BMD.7–10
In studies conducted after the publication of the 1997 Triad position stand, investigators identified negative health consequences of the Triad associated with subclinical/less severe conditions than the aforementioned clinical endpoints. Reports of a high prevalence of subclinical menstrual disturbances, including luteal phase defects and anovulatory cycles, were observed in athletes and recreationally active women.11,12 Investigators have documented mild-to-moderate low BMD among athletes with oligomenorrhea and subclinical menstrual disturbances (ie, anovulation and luteal phase defects).13,14 Other investigators have identified that a delay in menarche,15,16 a history of oligomenorrhea and amenorrhea,17–19 and/or low BMD (not just osteoporosis) were significant risk factors for stress fractures and bone stress injury in athletes17,18,20 and female military recruits.21,22 Findings from controlled laboratory studies indicated that low EA caused hormone disruptions characterized by suppressed metabolic and reproductive hormones, suppressed bone formation, and increased bone resorption.9,23–25 A causal relationship for the induction of menstrual disorders associated with low EA was carefully documented in the literature.5,26,27 The reversal of amenorrhea was also demonstrated to be related to EA.5,27 Therefore, to better reflect the most recent research, as well as to more comprehensively identify athletes at risk for developing negative health consequences, there was a clear need to revise the 1997 definition of the Triad.
In 2007, the Triad was redefined as a syndrome of low EA with or without DE, functional hypothalamic amenorrhea (FHA), and osteoporosis.2 Energy availability is defined conceptually and behaviorally as the amount of dietary energy remaining after exercise training for all other physiological functions each day.28 The new Triad model represented each component as the pathological endpoint of 1 of the 3 interrelated spectrums ranging from a healthy endpoint to subclinical and clinical conditions.2 At the “healthy” end of the continuum, each Triad component is optimized, that is, EA meets total energy expenditure, reproductive, and bone health needs; ovulatory menstrual cycles are maintained; and bone mass is normal.2 At the “unhealthy” end of the continuum, each Triad component presents the clinical endpoints of the syndrome, including low EA with or without DE, FHA, and osteoporosis.2
The goal in presenting Triad conditions along a spectrum was to highlight the importance of recognizing athletes who exhibit subclinical abnormalities and thus allow for early intervention. The Panel supports the notion that prevention and early intervention remains the key to avoid the more serious clinical endpoints of the Triad (ie, ED, amenorrhea, or osteoporosis). Furthermore, given the recent focus on subclinical menstrual disturbances and bone-related concerns, the Panel agreed that the 2007 presentation of the Triad model as a spectrum is most appropriate and most useful for designing treatment and return-to-play guidelines.
HEALTH CONSEQUENCES ASSOCIATED WITH THE TRIAD
Why is the Triad Harmful to an Athlete's Health?
Chronic low EA can have significant effects on health and physical performance, particularly when a clinical ED is present.29 Low EA plays a causal role in the induction of exercise-associated menstrual disturbances.5,30 Hypoestrogenemia associated with prolonged reproductive suppression can negatively impact musculoskeletal and cardiovascular health.7,31,32 Low EA can also have negative musculoskeletal effects independent of hypoestrogenism.7,8 Bone stress injuries, including the spectrum of stress reactions and stress fractures, are more common in female athletes with menstrual irregularities and/or low BMD,15–20 as well as female military recruits.21,22 Bone stress injuries also sideline female athletes and reduce competitive performance. Poorer sport performance has been documented in junior elite swimmers who exhibited ovarian suppression and evidence of energy deficiency when compared to their normally cycling counterparts.33 Other medical complications of Triad disorders can extend to the endocrine, gastrointestinal, renal, and neuropsychiatric systems.2,34–36 A complete discussion of the health consequences of the Triad is beyond the scope of this paper and can be found elsewhere.2,37
SCREENING, RISK STRATIFICATION, AND DIAGNOSIS OF THE TRIAD
What are the Best Tools to Screen for the Triad?
Early detection of athletes at risk is critical to prevent the Triad. Screening for the Triad should be undertaken as part of the Preparticipation Physical Evaluation (PPE).38–40 The PPE should include questions that address all aspects of the Triad spectrums. The current standard screening PPE form, endorsed jointly by 6 US medical societies,41 includes 9 questions related to the Triad. Likewise, the International Olympic Committee (IOC)-endorsed Periodic Health Examination (PHE)40 proposes 8 questions to screen girls and young women for the Triad.
Although there is limited evidence related to the efficacy of screening questions,42 the Consensus Panel recommended that female athletes undergo annual screening with the Triad-specific self-report questionnaire displayed in Table 1, followed by a more in-depth evaluation if the athlete has, or is at risk for, any Triad component. While such screening is most typically completed at the collegiate level, the Panel recommended screening for younger athletes (high school age) as well.43,44 A major point that the Panel emphasized is that existence of any one Triad component should prompt more thorough investigation for the others. Screening and early intervention in adolescent females for components of the Triad are especially important when one considers that 90% of peak bone mass is attained by 18 years of age,45 thereby providing a window of opportunity for optimizing bone health.
What are the Most Important Risk Factors to Screen for?
The Panel stated that the risk factors that should be assessed for the Triad include (1) history of menstrual irregularities and amenorrhea;2,46 (2) history of stress fractures;2,46 (3) history of critical comments about eating or weight from parent, coach, or teammate;47,48 (4) a history of depression;49–51 (5) a history of dieting;51,52 (6) personality factors (such as perfectionism, obsessiveness);53–55 (7) pressure to lose weight and/or frequent weight cycling;52 (8) early start of sport-specific training;52 (9) overtraining;52 (10) recurrent and nonhealing injuries;56 and (11) inappropriate coaching behavior.52,54 Physical examination signs such as low body mass index (BMI), weight loss, orthostatic hypotension, lanugo, hypercarotenemia, or other signs of an ED, such as parotid gland swelling or callus on the proximal interphalangeal joints (also known as Russell's Sign), should also prompt further evaluation. Obtaining an accurate menstrual history is important, starting from age of menarche to current and past menstrual patterns, noting months of consecutive missed menses and number of menses per year since menarche.41,57 Evaluation of secondary amenorrhea in girls can begin after 3 months or more of missed menses.57 A medication history should be obtained, including medications that may affect menstruation and/or BMD, such as oral contraceptive pills or other contraceptive agents, such as depot medroxyprogesterone acetate.58 A history of physician-diagnosed bone stress injuries and other fracture history should be noted,41 as well as a family history of ED, osteoporosis,59 and/or fractures.
DIAGNOSIS OF THE TRIAD
How are Triad Conditions Diagnosed?
Following screening, accurate diagnosis of any of the Triad disorders is dependent on a thorough evaluation of the athlete by the physician and other members of an experienced multidisciplinary health care team. Members of the multidisciplinary team should include a physician, a sports dietitian (a registered dietitian, who preferably is a board certified specialist in sports dietetics),60,61 and a mental health professional, if the athlete has DE or a clinical ED. Other members of the team may include an exercise physiologist, certified athletic trainer, and medical consultants.
The Consensus Panel agreed that essential to the process of screening, evaluation, diagnosis, and treatment is the athlete's honesty and willingness to participate in each of these steps. Each member of the multidisciplinary team must develop a therapeutic alliance with the athlete. The process of engagement and active participation in treatment is often ongoing, reflecting the challenges of restoring adequate EA. The Panel emphasized that written policies regarding screening, evaluation, and treatment of the Triad need to be reviewed with athletes and their parents, and supported by coaches and administrators.
How is Low EA Diagnosed?
The Panel emphasized that low EA cannot be diagnosed by estimating energy balance because athletes who have been in a state of negative energy balance may experience a suppression of physiological functions that restores energy balance and weight stability.2 Weight stability has been reported in amenorrheic athletes.62–65 Thus, an athlete could be in a state of energy balance but also in a state of low EA at the same time, and a stable body weight should not be used as an indicator of adequate EA.
As a first pass, overt signs of low EA can be indicated by low energy stores such as a BMI <17.5 kg/m2 or in adolescents <85% of expected body weight. In adolescents, absolute BMI cut-offs should not be used. The BMI percentile method for calculating estimated body weight examines an adolescent's weight in relation to the 50th BMI percentile (which is their expected body weight).66 Deviations for this point are used as an indicator of medical stability to set a target weight and to assess progress in adolescents with DE and ED.66 Body mass index percentiles adjusted for age and gender are recommended until age 20 by the Centers for Disease Control and Prevention (www.cdc.gov/growcharts). When body weight is not particularly low, more detailed information regarding food intake and energy expenditure is necessary to diagnose low EA. Other markers of low EA in the absence of DE and recent weight loss that should be explored include physiological signs of adaptation to chronic energy deficiency such as reduced resting metabolic rate (RMR),4,67 low triiodothyronine (low T3),4,67 and a ratio of measured RMR/predicted RMR less than 0.90.7,68–70
It is important to note that methods for assessing EA, dietary intake, and energy expenditure are improving but are imprecise. An experienced sports dietitian or an exercise physiologist can help provide expertise on completing these assessments. A particular index of daily EA is defined as energy intake (kcals) minus exercise energy expenditure (kcals) divided by kg of fat-free mass (FFM) or lean body mass.28 This index has been significantly associated with changes in reproductive6,24 and metabolic hormone concentrations and markers of bone formation and resorption9 that occur in controlled laboratory experiments where EA is manipulated using varying combinations of reductions in food intake and increases in exercise energy expenditure in women. From these short-term experiments, a threshold below which detrimental physiological changes in reproductive function, metabolism, and bone occur has been identified as 30 kcal/kg FFM/day.6 The Panel noted that outside the laboratory, determination of EA using this index is more difficult and is dependent on less precise measures of exercise energy expenditure, dietary energy intake, and body composition (weight and percent fat). Strategies to estimate dietary intake include 3-, 4- and 7-day dietary logs, 24-hour dietary recall, and food-frequency questionnaires.71 Regardless of the method chosen, accurate assessment of dietary intake can be challenging due to a number of factors such as underreporting of intake, modified intake during the period of reporting, and imprecise recording of portion sizes.71 Ideally, athletes thought to be at risk for nutritional deficiencies should undergo a comprehensive nutrition assessment by a registered sports dietitian.61 Actual estimates of energy expenditure can be accomplished using heart rate monitors and accelerometers,28 but practical estimates of exercise energy expenditure are also available, and are dependent on self-report. There are numerous Web-based calculators of exercise energy expenditure; however, the Panel recommends that the 2011 Compendium of Physical Activities be used to calculate exercise energy expenditure, whereby kilocalories of energy expenditure = metabolic equivalent of task (MET) × weight in kilograms × duration of activity in hours.72 All methods of estimating energy expenditure have an error associated with them, and any directional bias needs to be considered on an individual basis.73 The third component of the EA equation is kilograms of FFM, which is obtained from measurement of body weight in kilograms, and from an estimate of body fatness. Various methods can be used to estimate body fat. Dual-energy X-ray absorptiometry (DXA) is a precise method and widely available74; other clinically accessible methods commonly used among athletes include air-displacement plethysmography, skinfold measurements, and bioelectrical impedance.75 Having gathered the aforementioned data, one can access the Energy Availability Calculator provided on the Female Athlete Triad Coalition Web site (http://www.femaleathletetriad.org/calculators/) to estimate EA. Ideally, physically active women should aim for at least 45 kcal/kg FFM/day of energy intake to ensure adequate EA for all physiologic functions.2,28
How is Amenorrhea Diagnosed?
The Panel explained that athletes and physically active women presenting with primary or secondary amenorrhea require evaluation to rule out pregnancy and endocrinopathies since no single blood test can confirm a diagnosis. The diagnosis of FHA in athletes secondary to low EA is a diagnosis of exclusion. An algorithm, modified from the Jameson and De Groot textbook of endocrinology76 for the diagnosis of primary/secondary amenorrhea, can be viewed in Figure 2. Endocrinopathies that must be ruled out include (1) thyroid dysfunction, (2) hyperprolactinemia, (3) primary ovarian insufficiency, (4) hypothalamic and pituitary disorders (genetic or acquired), (5) hyperandrogenic conditions including polycystic ovary syndrome, virilizing ovarian tumors, adrenal tumors, nonclassic congenital adrenal hyperplasia, and Cushing's syndrome.77,78 Outflow tract obstruction is important to rule out in patients with primary amenorrhea. The most common causes of amenorrhea are usually identified following a thorough medical history, physical examination, and a pregnancy test, as well as evaluation of thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), and prolactin, to assess for thyroid disease, primary ovarian insufficiency, and hyperprolactinemia, respectively. A serum estradiol and/or a progesterone challenge test (medroxyprogesterone acetate 10 mg for 10 days) may be useful to assess the degree of hypoestrogenism. If there is physical evidence of androgen excess (ie, hirsutism, acne, androgenic alopecia), additional laboratory testing may include total and free testosterone, and dehydroepiandrosterone and its sulfate (DHEA/S). An early morning 17-hydroxyprogesterone may be obtained in those with hyperandrogenism to assess for nonclassic 21-hydroxylase deficiency (the most common cause of congenital adrenal hyperplasia) on initial or follow-up testing. A pelvic ultrasound may be obtained in those with clinical or biochemical hyperandrogenism to confirm polycystic ovaries or to rule out virilizing ovarian tumors.77,79 The primary care physician should refer to or consult with an endocrinologist for endocrine disorders they are not experienced in diagnosing or treating.
How is Low BMD Diagnosed?
The Panel has utilized the definitions published by the International Society of Clinical Densitometry (ISCD) for low BMD and osteoporosis in children and adolescents (see Table 2) and for premenopausal women (see Table 3),80 as well as ACSM-suggested criteria for female athletes involved in regular weight-bearing sports.2 Criteria are described below for who and what site should be considered for a DXA scan and how often DXA should be performed.
Who Should Get DXA Scans for BMD Testing?
The Panel agreed that indications for obtaining a DXA scan for BMD testing in an athlete should follow Triad risk stratification (see Clearance and Return to Play section) and include the following:
(1) ≥1 “High risk” Triad Risk Factors:
* History of a DSM-V-diagnosed eating disorder81
* BMI ≤ 17.5 kg/m2, <85% estimated weight, OR recent weight loss of ≥10% in 1 month
* Menarche ≥16 years of age
* Current or history of <6 menses over 12 months
* Two prior stress fractures, 1 high risk stress fracture (see Figure 4), or a low-energy nontraumatic fracture18,82,83
* Prior Z-score of <−2.0 (after at least 1 year from baseline DXA)
(2) ≥2 “Moderate risk” Triad Risk Factors:
* Current or history of DE for 6 months or greater
* BMI between 17.5 and 18.5, <90% estimated weight, OR recent weight loss of 5% to 10% in 1 month
* Menarche between 15 and 16 years of age
* Current or history of 6 to 8 menses over 12 months
* One prior stress reaction/fracture
* Prior Z-score between −1.0 and −2.0 (after at least 1-year interval from baseline DXA)
(3) In addition, an athlete with a history of ≥1 nonperipheral or ≥2 peripheral long bone traumatic fractures (nonstress), should be considered for DXA testing if there are 1 or more moderate- or high-risk Triad risk factors (see Figure 4). This will depend on the likelihood of fracture given the magnitude of the trauma (low or high impact) and age at which the fracture occurred. Athletes on medications for 6 months or greater that may impact bone (such as depot medroxyprogesterone acetate, oral prednisone, and others)84 should also be considered for DXA testing.
How Often Should Athletes Get DXA Testing?
The Panel agreed that the frequency of BMD assessment by DXA will depend on the initial BMD and ongoing clinical status of the athlete. We agree with the ISCD 2013 guidelines that repeat DXA screening should be obtained when the expected change in BMD Z-scores equals or exceeds the least significant change.85 Those with definitive indications for DXA testing may require BMD testing every 1 to 2 years to determine if there is ongoing bone loss, and to evaluate treatment.
Which Sites Should be Screened with a DXA Scan?
Bone mineral density Z-scores (and not T-scores) should be reported for all children, adolescents, and premenopausal women.
(1) Adult women ≥20 years
* Weight-bearing sites (posteroanterior spine, total hip, femoral neck)
* Non-weight-bearing sites, namely the radius (33%) if weight-bearing sites cannot be assessed for any reason.
(2) Children, adolescents, and young women <20 years
* Posteroanterior lumbar spine bone mineral content (BMC) and areal BMD
* Whole body less head if possible (otherwise whole body) BMC and areal BMD80
* Adjust for growth delay (with height or height age) or maturational delay (with bone age)
* Use pediatric reference data, and when possible, report height-adjusted Z-scores.86
NONPHARMACOLOGICAL TREATMENT GUIDELINES FOR THE CLINICAL SEQUELAE ASSOCIATED WITH THE TRIAD
What Evidence Exists in Support of Nonpharmacological Treatment Strategies?
Documentation of weight gain and restoration of menstrual function following amenorrhea has been provided by Kopp-Woodroffe et al87 and Dueck et al88 in case studies, in a retrospective analysis of female athletes following a clinical intervention,89 and in experiments in female cynomolgus monkeys.5 Studies in anorexic women demonstrate the efficacy of weight gain (and fat mass) for restoration of menses.90–93 In case studies of 5 amenorrheic athletes and recreationally active women in whom energy intake was increased via consumption of a sport nutrition beverage (approximately 360 kcal/d) and exercise training was reduced by 1 d/wk for 12 to 20 weeks, weight gain of 1 to 3 kg was observed and 3 of the 5 women resumed menses.87,88 In a 1-year prospective case study of 2 amenorrheic athletes undergoing controlled increased energy intake, recovery of menses coincided closely with increases in caloric intake and weight gain; body weight increased by 2.8 kg (5%) and 4.2 kg (8%) at 12 months in the 2 subjects.94 In a 5-year retrospective study of college athletes undergoing nonpharmacological therapy, Arends et al89 reported a significant increase in weight of 9% (mean weight gain, 5.3 ± 1.1 kg) in the 17.6% oligomenorrheic or amenorrheic athletes who resumed menstrual function (mean time to recovery, 15.6 ± 2.6 months) versus minimal weight gain (weight gain of 1.3 ± 1.1 kg) in those who did not resume menses. Causal evidence of the efficacy of increased energy intake to reverse menstrual disturbances was provided by Williams et al5 in female cynomolgus monkeys who demonstrated that restoration of menses was accompanied by an average weight gain of 5.7%.
Weight gain that leads to recovery of menstrual function is linked to improvement of other clinical outcomes characteristic of exercise-associated amenorrhea including low BMD90,95,96 and impaired endothelial function.97 More research is necessary to establish the time course of weight changes and the sensitivity, specificity, and success of nutritional and dietary interventions.
What are the Components of Nonpharmacological Treatment for Each Triad Condition?
Owing to the multifactorial etiology of the Triad, the Panel has established that an optimal treatment approach must address the underlying cause of the Triad, that is, low EA.2 Energy status must be normalized primarily through modifications of diet and exercise training, if necessary, with the goal of increasing EA.2,29 The consensus of our recommendations is focused on restoration or normalization of body weight as the best strategy for successful resumption of menses and improved bone health.2,89,90,96,98 The Panel noted that the development of any Triad treatment plan should include a consideration of the goals of the athlete, her unique diet and training practices, any coexisting conditions, and a system for monitoring changes.
Specific Nonpharmacologic Recommendations for Interventions in Athletes with Low EA
Specific treatment recommendations developed by the Panel depend on identifying how low EA developed in the athlete. There may be 4 unique pathways to low EA, and as such, 4 unique treatment recommendations.
1) If the cause of low EA is inadvertent undereating, then referral for nutritional education is sufficient. Nutrition education should ideally include a sports dietitian. An exercise physiologist can also complete an assessment of energy expenditure and EA.
2) If the cause for low EA is DE, the referral should be to a physician and for nutritional counseling with a sports dietitian.
3) If the cause for low EA is intentional weight loss without DE, then referral for nutritional education is sufficient.
4) If the cause for low EA involves clinical ED, treatment should include evaluation and management with a physician, nutritional counseling with a sports dietitian, and referral to a mental health practitioner for psychological treatment.2,99 In this case, the reversal of low EA will not be possible without psychological treatment.2,99–102
In general, the primary goal of treatment is to restore or normalize body weight, concomitant with an improvement in overall nutritional and energetic status.2,103,104 When DE is apparent, the Panel emphasized that the treatment plan in these athletes must focus on the modification of unhealthy attitudes, behaviors, and emotions related to food and body image that may perpetuate the DE.101,103,104 Weight gain is a primary concern for athletes with FHA who are underweight, and it is important to emphasize that the amount of weight gain that typically leads to resumption of menses is variable among individuals.87,88,94 In studies thus far, a range of approximately 5% to 10% of body weight or 1 to 4 kg of weight gain has been observed.87,88,94 This weight gain is often comprised of gains in fat mass in anorexic women,91–93 but in exercising women without clinical ED, gains in FFM have also been observed.87,94
Treatment Targets for Low EA
The Panel identified that targets of treatment are varied and depend on individual circumstances. Specific treatment targets may include 1 or more of the following:
* Reversal of recent weight loss105;
* Return to a body weight associated with normal menses90–94;
* Weight gain to achieve a BMI of ≥18.5 kg/m2 or ≥90% of predicted weight90,91,100,106,107;
* Energy intake should be set at a minimum of 2000 kcal/d, or more likely, a greater energy intake will be required, depending on exercise energy expenditure.94,108
Since the treatment goal is to restore or normalize body weight, the Panel recommended an increase in dietary energy intake, a decrease in exercise energy expenditure, or both. Recommendations should consider individual preferences and may depend on where the athlete is in the competitive season (reductions in training volume may not be feasible in season; acceptance of increased energy intake may be better received vs reduction in training volume). Prescribed changes in energy intake to achieve an increased BMI and/or body weight goal should be gradual, beginning with an approximately 20% to 30% increase in caloric intake over baseline energy needs, or the amount of energy required to gain approximately 0.5 kg every 7 to 10 days.87,88,94 For an athlete consuming 2000 kcal/d, this would represent a gradual increase of 200 to 600 kcal/d, accomplished over several months. If EA (intake kcals—exercise kcals)/kg FFM can be reliably estimated, the target should be at or greater than 45 kcal/kg FFM Specific strategies that have been successful in female athletes have been detailed in case study investigations.87,88,94
Steps in a Plan to Increase EA
Step 1): Perform an assessment of baseline energy needs that includes a thorough body weight history including questions about associated changes in menstrual status. Energy intake can be assessed using diet logs and dietary analysis programs. Energy expenditure can be estimated by measuring or estimating RMR and exercise energy expenditure. Resting metabolic rate can be estimated using one of several algorithms,109–111 and multiplying by an activity factor112,113 will account for exercise energy expenditure, thereby providing an estimate of total energy expenditure needs.
Step 2): Using the appropriate target for EA, meal plans should be developed that incorporate a variety of factors. Specifically, diet quality, diet variety, food preferences, and practical aspects of food availability should be considered. Goals would include achieving an adequate balance of macronutrients and appropriate intake of micronutrients, particularly calcium, vitamin D, iron, zinc, and vitamin K. Whenever possible, the recommendation should be to increase intake of real foods versus dietary or meal supplements. Dietary recommendations should include incorporation of energy and nutrient-dense foods such as fortified milk drinks and essential fatty acids in the form of fish, healthy oils, nuts, avocados, and dried fruit. If there is a possibility of gastrointestinal discomfort with high caloric loads, small and frequent meals should be consumed throughout the day, with timing dependent on practice and competition. Particular attention should be paid to identifying times across the day where dietary energy intake may be particularly low.114 Adjustments in dietary strategies for increasing EA should also take into account changes across the season in accordance with competition schedules.
A successful treatment plan requires standardized periodic monitoring of body weight. Athletes should be weighed on the same scale, wearing minimal clothing, such as shorts and a t-shirt, to reduce the likelihood of falsifying their weight.115 The frequency of weight monitoring depends on the degree to which weight determines health and eligibility to participate in sport. A reasonable frequency is weekly when initiating a treatment program.
Specific Recommendations that Target ED
The goals of treatment for exercising women with ED is to normalize pathological eating behaviors, reduce dieting attempts, and alter negative emotions and beliefs associated with food and body image.116 Cognitive behavioral therapy (CBT) has been demonstrated to be an effective treatment approach for exercising women with ED117–119 and may be more beneficial than nutritional counseling alone in some women with amenorrhea particularly if DE behavior is present.120 Cognitive behavioral therapy may assist women with DE behaviors and body image disturbances to comply with an increased energy intake prescription and associated weight gain.
Specific Recommendations that Target Low BMD
In exercising women with low BMD, the Panel recommendations include increasing EA and optimizing weight gain and resumption of menses.121 Calcium and vitamin D status should be addressed.
The etiology of bone loss among amenorrheic women includes energy deficiency-related factors and estrogen deficiency.7,9,122 Thus, weight gain and subsequent resumption of menses are key to prevent further loss of bone mass.90,95 It is estimated that amenorrheic women will lose approximately 2% to 3% of bone mass per year if the condition remains untreated.90,95,96 Data on recovery of bone mass in amenorrheic athletes secondary to increased energy intake are limited. However, significant improvements in bone health outcomes were observed in case studies of amenorrheic female athletes who gained weight.105,106 In studies of anorexic women, investigators provide evidence of increases in BMD (1%–10%) associated with weight gain and resumption of menses;90,95,123,124 whereas, continual decreases in BMD were observed in those who did not recover menses.90,95 Miller et al95 reported that resumption of menses occurred in 75 anorexic women who gained 4 kg of body mass, on average, and the combined effects of weight gain and resumption of menses contributed to significant improvements in lumbar spine (3.1%) and hip BMD (1.8%). Misra et al90 demonstrated that menstrual recovery and weight gain attenuated further decreases in BMD in 34 anorexic girls aged 12 to 18 years over a 12-month period of time. In other prospective studies, similar findings are reported.124,125
In a retrospective study by Arends et al,89 percent weight gain was identified as the strongest predictor of resumption of menses in female collegiate athletes, and may also be a predictor of gains in BMD. Findings from case reports105,106 and retrospective analyses89 published to date demonstrate that weight gain can lead to substantial increases in BMD in an energy replete environment. Prospective, randomized controlled trials (RCTs) are necessary in large samples of exercising women with amenorrhea and low BMD to confirm the beneficial effects of increased body weight accomplished by increased energy intake on BMD.
Furthermore, substantial evidence exists in support of the positive effect of weight gain alone on BMD. Weight gain independent of resumption of menses has been shown to have a positive effect on BMD and to restore the coupling of bone formation and resorption.90,124–127 However, in spite of some recovery of bone mass, normalization of BMD is unlikely to occur with weight gain alone. From a treatment standpoint, both energy- and estrogen-dependent mechanisms of bone loss must be addressed in order to promote optimal increases in BMD. In summary, both nutritional and hormonal recovery is recommended to improve mineralization of trabecular bone and the growth of cortical bone.90,95,128
Weight-bearing exercise is a primary nonpharmacological strategy for increasing and maintaining BMD and geometry across the lifespan.129 Bone tissue is highly responsive to dynamic and high-magnitude loading,130 high-impact loading,131–135 and resistance training.136,137 Experiments in animals provide evidence of the positive effect of mechanical loading for optimizing bone formation.138,139 In a recent meta-analysis (n = 521; 7 studies, randomized controlled exercise trials ≥24 weeks) of the effects of exercise on BMD in premenopausal women,140 significant improvements in femoral neck and lumbar spine BMD were observed following weight-bearing exercise training. This finding highlights the utility of exercise (aerobic, strength, and/or high impact) for improving BMD at weight-bearing sites in premenopausal women. Specifically, programs with a combination of high-impact loading and resistance training represent effective methods of optimizing bone in the premenopausal years.141 Notably, in studies of the effect of high-impact loading or resistance training alone on BMD, investigators demonstrate mixed results.141,142 The majority of weight-bearing exercise interventions involved 2 or 3 days of training per week.141 For a review of the effects of exercise and bone the reader is referred to the ACSM Position Stand on Bone Health and Exercise.143
To date, prospective studies are lacking wherein investigators explore the impact of resistance training and high-magnitude loading on the bone health of amenorrheic athletes. However, lean mass has been reported to be a strong predictor of hip BMD among anorexic adolescents144 and also adolescent athletes and nonathletes.145 In agreement with these results, a longitudinal study assessing skeletal recovery in anorexic women over the course of 6 to 69 months demonstrated that percent change in FFM was a significant positive predictor of the change in hip and lumbar spine BMD, and, furthermore, was a stronger predictor of BMD change than the change in fat mass or body weight.95 These results suggest that increases in lean mass may be an important component of weight recovery, and, as such, the lean mass gained through resistance training may be beneficial for BMD in amenorrheic athletes. Increases in lean mass may also be beneficial for increasing bone size,146 thus improving bone strength and decreasing the risk of fracture, and improving athletic performance.
The Panel expressed concerns that high-impact activity in females with low BMD (± fractures) may in fact result in fracture.147 Further studies are necessary to determine the impact of combined weight-bearing programs on BMD and fracture risk in athletes with low BMD. There is also the notion that estrogen may be permissive for the osteogenic effects of mechanical loading,148 as data have demonstrated poor osteogenic benefits of mechanical loading in chronically amenorrheic athletes.128,149,150
What is the Recommended Time Course of Nonpharmacological Treatment (Including Follow-Up)?
Treatment of Triad conditions by increasing EA will result in recovery of physiological systems at different rates. Notably, the time to resumption of menses may vary among exercising women and is dependent on the severity of the energy deficiency and duration of menstrual dysfunction.89,90,94 An increase in EA can positively alter metabolic hormone profiles within days to weeks, with concomitant changes in body weight occurring over weeks and months. Weight gain has been observed as a clinically positive outcome associated with resumption of menses and enhanced bone health in exercising women.87,90,95,105,106 The recovery of menstrual function with strategies to increase EA can occur within several months94 but may take longer than 1 year.89 Improvements in BMD will occur more slowly, often over several years. Whether or not BMD can be restored to levels appropriate for age and training status remains unclear.151–153 A schematic of the time course of recovery of Triad factors is displayed in Figure 3.
Summary Comments Regarding Nonpharmacological Treatment
Overall, successful treatment of athletes and exercising women is contingent on a multidisciplinary approach for recovery from the Triad,2,154 including a primary care and/or sports medicine physician, a sports dietitian, and mental health practitioner. Depending on the individual situation, consultation from an endocrinologist, orthopedic surgeon, psychiatrist, exercise physiologist, certified athletic trainer, family members, and/or team coach (if applicable) may be helpful. This treatment approach is based on trusting and respectful interactions between health care providers and affected individuals. Consideration of the effects of treatment goals on health status, athletic performance, and personal identity/lifestyle is necessary to ensure treatment compliance and posttreatment adherence by affected female athletes and exercising women.
PHARMACOLOGICAL TREATMENT STRATEGIES FOR THE CLINICAL SEQUELAE OF THE TRIAD
Nonpharmacological measures should constitute initial management in female athletes with the Triad. For treatment of osteoporosis and/or in those athletes with multiple fracture history, the Panel emphasized that pharmacological management is to be considered if there is lack of response to nonpharmacological therapy for at least 1 year and if new fractures occur during nonpharmacological management. Pharmacological management may also be necessary in the psychological treatment of ED and DE, especially if there are significant comorbid conditions.
Low Energy Availability, Disordered Eating, and Eating Disorders
The Panel emphasized that low EA indicates that there is a problem, but does not differentiate between transient energy imbalance, DE, and clinically significant ED. Individuals who have unintentional low EA or mild DE may respond well to nutrition education designed to eliminate low EA. Individuals with significant DE may benefit from counseling with a mental health practitioner, in addition to nutrition education. In contrast, individuals who have an ED require intensive interdisciplinary attention and treatment. The American Psychiatric Association (APA) Practice Guidelines for the Treatment of ED recommend a multidisciplinary team approach to treatment, including a physician, mental health provider, and sports dietitian.155 Results of small randomized trials involving treatment approaches that include mindfulness training, dialectical behavior therapy, and other therapeutic approaches are emerging.156,157 Antidepressant medications, particularly selective serotonin reuptake inhibitors, can be helpful in the treatment of bulimia nervosa.158 The APA Practice Guidelines describe limited evidence to use medications to restore weight, prevent relapse, or treat chronic anorexia nervosa. Other psychotropic medications can be beneficial in treating comorbid conditions such as anxiety, depression, and obsessive compulsive behavior.155
One of the challenges in addressing low EA is that it may be difficult to identify which individuals have an ED that requires more comprehensive treatment. This can be amplified by denial that there is a problem and minimization of the difficulty in changing behaviors, which are common themes for individuals with ED. The team physician should work closely with the multidisciplinary team to determine the best treatment approach for an individual athlete. Readers are referred to the most recent Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) criteria related to ED for full diagnostic criteria for ED.81
Pharmacological strategies that target menstrual dysfunction are mostly experimental, as are strategies to optimize bone accrual in the adolescent athlete and to optimize BMD in adult athletes and exercising women, defined as at least 20 years old.
When considering pharmacological strategies to address amenorrhea and hypoestrogenemia in athletes and exercising women, the Panel emphasized that it is essential to reiterate that combined oral or nonoral routes of contraceptive therapy do not restore spontaneous menses; indeed, contraceptive therapy simply creates an exogenous ovarian steroid environment that often provides a false sense of security when induced withdrawal bleeding occurs.159 Moreover, combined oral contraceptive (COC) therapy is not consistently associated with improved BMD in amenorrheic athletes160–162 and may in fact further compromise bone health given first-pass effects on hepatic production of insulin-like growth factor-1 (IGF-1), an important bone trophic hormone163–165 (details in “Replacement of Gonadal Steroids” section). Therefore, the Panel emphasizes that nonpharmacological treatment strategies should be prioritized, particularly focusing on achieving resumption of menses,95,106 given the importance of menses and normal estrogen status to bone health.8,29,128,145,166
Consequences of hypogonadism (FHA) in athletes for which pharmacological treatment should be considered include:
* symptoms of estrogen deficiency, such as vaginal dryness and dyspareunia
* impaired bone health (despite implementation of nonpharmacological therapy).
Based on the etiopathogenesis of the Triad and the specific consequence of associated hypogonadism that requires treatment, several possible pharmacological strategies may be considered if nonpharmacological management is unsuccessful. This paper will address pharmacological options more specific to the consequence of impaired bone health.
Replacement of Gonadal Steroids
The major gonadal steroids include estrogen, progesterone, and testosterone, all of which are low in the amenorrheic athlete.
Overall, investigators have shown that oral estrogen-progesterone combination pills are not an effective strategy to increase BMD in low-weight conditions such as anorexia nervosa (both in adults and in adolescents).167,168 Studies of COCs or hormone therapy in athletes with FHA are less definitive.169 Available studies in women with FHA include retrospective,170,171 prospective,172–174 and cohort studies;175,176 however, very few RCTs have been performed.160–162,177 Additionally, most of these studies in women with FHA did not specifically target exercising women with FHA.
Pharmacological treatment that aims to restore regular menstrual cycles with COC does not normalize metabolic factors impairing bone health and will therefore likely not result in reversal of low BMD in the athlete with Triad disorders.2,159,172 The lack of efficacy of oral estrogen in improving BMD in conditions of low-weight and possibly normal-weight exercise-induced amenorrhea has been attributed to the suppressive effects of oral estrogen on hepatic IGF-1 production.163,164,173 Insulin-like growth factor-1 is a bone trophic factor that is secreted by the liver in response to growth hormone and is also produced locally in an autocrine manner by target tissues such as bone.178 It is speculated that the first-pass effect of exogenous estrogen through the liver suppresses IGF-1 production and upregulates the synthesis of binding proteins, such as IGFBP-1, which bind to IGF-1, further reducing its bioavailability.163 Given the low endogenous concentration of IGF-1 in amenorrheic athletes,145 a further reduction in IGF-1 levels secondary to the administration of oral estrogen likely limits the beneficial antiresorptive effects of estrogen.179 In addition, the type and dose of estrogen have been implicated in the lack of efficacy of oral estrogen in increasing BMD in energy-deficient states.168 As is stated in the 2007 ACSM Female Athlete Triad Position Stand, however, for women with FHA, increases in BMD are more closely associated with increases in weight than with COC administration,2,161 so these treatments likely need to be implemented in combination with nonpharmacological treatment to optimize effectiveness.161
Transdermal estradiol administration, when given in replacement doses, does not suppress IGF-1164,180–182 and therefore warrants further investigation as an alternative to COC therapy in the amenorrheic female athlete with the Triad. In an RCT in adolescent girls with anorexia nervosa, transdermal estradiol administered at doses of 100 μg twice weekly, with cyclic progesterone (2.5 mg daily for 10 days of every month to prevent unopposed estrogen stimulation of the uterus), increased BMD in this population without a reduction in IGF-1 levels.180 Bone accrual rates in girls with anorexia nervosa who received transdermal estradiol approximated that in normal-weight controls after controlling for weight changes, and BMD Z-scores were maintained.180 However, bone accrual needs to exceed that in controls for “catch-up” to occur and for BMD Z-scores to normalize to >−1.0. Likely because other hormonal alterations persist, catch-up does not always occur, as was shown in the same study.180 Although there are no published data regarding use of transdermal estradiol in FHA, RCT studies are ongoing to address this possible treatment strategy, and further study is warranted.
Vaginal estradiol administration also circumvents hepatic first pass metabolism, and a vaginal estrogen-progesterone combination contraceptive ring is now available. However, data regarding the impact of this form of estrogen administration on BMD are conflicting with one study suggesting maintenance of BMD, and another suggesting that it may be deleterious to bone compared with no treatment in premenopausal women.183,184 Thus, further research on vaginally-applied estrogen is necessary.
Data are limited regarding the impact of pharmacological therapies on muscle perfusion, although one study reported an improvement in endothelial dysfunction with use of COC therapy.185
The other gonadal hormone that is low in conditions of low-weight and in amenorrheic athletes and exercising women is testosterone, which has antiresorptive effects (direct and estrogen mediated)186,187 and also bone anabolic effects.187,188 There are no data available on testosterone administration in amenorrheic athletes and exercising women. However, a recent study in adult women with anorexia nervosa demonstrated no improvement in BMD with low-dose testosterone administration, despite increases in lean mass and initial increases in surrogate markers of bone formation.189
Normalizing Gonadotropin Pulsatility and Secretion
As stated earlier, the Panel contends that increasing EA through nutritional intervention is the best strategy for normalizing gonadotropin pulsatility and secretion. From a pharmacological perspective, experimental strategies include administering hormones that are low in Triad conditions and that mechanistically can contribute to amenorrhea and to low BMD, such as leptin and IGF-1, or administering antagonists of hormones that are high in Triad conditions and can contribute mechanistically to amenorrhea and low BMD, such as ghrelin, peptide YY (PYY), and adiponectin.
Few studies have examined the impact of administering metreleptin to women with FHA.190–192 Although metreleptin improved ovulatory status and increased bone mineral content in women with FHA, the women sustained significant weight loss and reductions in fat mass, even when doses of the drug were carefully titrated.190–192 These data are concerning and suggest that leptin administration is not good therapeutic strategy to normalize gonadotropin secretion and increase BMD in energy-deficient states, as in amenorrheic athletes and exercising women.
Insulin-like Growth Factor-1 Replacement
An important contributor to low BMD in amenorrheic athletes and exercising women is low IGF-1, particularly in those who are low weight. In both adolescents and adults with anorexia nervosa, administering recombinant human IGF-1 (rhIGF-1) increases levels of surrogate bone formation markers,193,194 and in one RCT in adult women with anorexia nervosa, giving rhIGF-1 (a bone anabolic hormone) with oral estrogen (antiresorptive) led to a 2.8% significant increase in BMD when compared with the group that received neither.194 Data are lacking regarding the efficacy of rhIGF-1 administered alone or with estrogen in improving bone health in exercise-induced amenorrhea.
Although in vitro studies and studies in rodents have demonstrated that high ghrelin, PYY, and adiponectin inhibit gonadotropin secretion,195–197 and high PYY and adiponectin are deleterious to bone,197–200 there are no data in animals or humans examining the impact of antagonists to these hormones on gonadotropin secretion and bone metabolism. In addition, a ghrelin antagonist runs the risk of eliminating the adaptive increase of an orexigenic stimulus, namely ghrelin, in this energy-deficient state.
Bone Mineral Density
Data are lacking regarding the efficacy of pharmacotherapy in treating low BMD with or without a fracture history in the female athlete. While pharmacologic therapy is recommended in postmenopausal women and men ≥age 50 years201 with osteoporosis, the threshold for pharmacological treatment in the young female athlete with low BMD, stress fractures, and/or impaired bone accrual is less clear.
It should be noted that the bones of amenorrheic and eumenorrheic athletes are subject to greater stress and strain secondary to specific athletic activities than that experienced by bones in nonathletes.202 Indeed, weight-bearing athletes should have higher BMD and other proxy indicators of bone strength secondary to chronic mechanical loading when compared to nonathletes.128,130,203 The 2007 ACSM Position Stand on the Triad thus suggested that BMD Z-scores of <−1.0 in athletes involved in repetitive or high-impact stress may be low enough to increase fracture risk, especially in those with additional risk factors for the Triad.2 Additionally, athletes with Triad risk factors who sustain bone stress injuries may have a delay in return to sport.18 However, it is still not clear whether pharmacotherapy is beneficial in athletes with low BMD in the absence of a fracture history, and, more importantly, whether or not treatment in this population prevents fractures and/or improves healing time and recovery in those who have sustained bone stress injuries.
Furthermore, some girls and women may have a genetically determined low peak bone mass or may have had previous insults to the skeleton (such as poor nutrition and FHA) that have since resolved. In these cases, BMD may have stabilized, in contrast to a female athlete with ongoing low EA and amenorrhea, who may have continued decreases in BMD, which could increase vulnerability to bone stress injury and fracture. Serial DXA measurements may be helpful in making this determination. There are currently no guidelines regarding the timing of initiation of pharmacological treatment in the young female athlete with established osteoporosis or for DXA assessment and follow-up (Tables 2 and 3).
The Panel has concluded that the decision to treat or not treat with pharmacological therapies does not depend on BMD Z-scores alone, but also on additional risk factors such as fracture history, genetics,204 cumulative Triad risk factors which have been associated with an increased risk for low BMD and bone stress injury, and rate of bone loss with nonpharmacological management.17,46 The Panel suggests that the nature of athletic activity, response to nonpharmacological management as demonstrated by return of menses and/or as noted on serial DXA assessments,2 severity of the medical situation, fracture history, and genetic predisposition, should all play a role in the decision to treat with pharmacological therapy.
The Panel emphasized that caution must be used when considering Food and Drug Administration (FDA)-approved postmenopausal treatment strategies for use in premenopausal women and children including Triad athletes and exercising women. Bisphosphonates have a very long half-life and should be used with extreme caution in women of child-bearing age for concerns of teratogenicity,205,206 although data to date are reassuring. The decision to initiate treatment with bisphosphonates in any premenopausal woman should be made on a case-by-case basis. Consideration should include individual fracture risk and potential medication-related adverse effects. There is concern regarding long-term use of bisphosphonates and the association with atypical femur fractures207,208 and osteonecrosis of the jaw.209 In addition, there are no published studies of bisphosphonate use in exercising and athletic women with Triad disorders. In one study in adult women with anorexia nervosa, bisphosphonate therapy (specifically risedronate) increased lumbar spine BMD compared to placebo189; however, a study in adolescent women with anorexia nervosa demonstrated no increase in spine BMD with alendronate given for a year.210 Bisphosphonates act by inhibiting bone resorption, and the differential effect of bisphosphonates in adults versus adolescents may relate to increased bone resorption in adults compared with a reduction in bone resorption in adolescents.211 There are few special considerations for using bisphosphonates in the younger population, such as glucocorticoid-induced osteoporosis and osteogenesis imperfecta.212–214 The Panel emphasized that any use of bisphosphonate therapy in young women with the Triad should only be executed by or in consultation with a board-certified endocrinologist or specialist in metabolic bone diseases. It must be emphasized that the aforementioned pharmacological therapies are not currently approved by the FDA for increasing BMD or for fracture reduction in young or adult athletes.189,215
To date, there are no published studies of denosumab or teriparatide use in girls and women with Triad disorders. A preliminary report in older women with anorexia nervosa demonstrated that treatment with teriparatide for 6 months increased bone formation (158%) and lumbar spine BMD (anteroposterior spine 6.0% and lateral spine 10.5%) compared to placebo.216 There is also a case study that suggests that 4 weeks of teriparatide was associated with bone healing, reduced pain, and resumption of normal activities in 2 premenopausal women with stress fractures.217
Pharmacological Treatment Considerations
Which Athletes and Exercising Women Should be Targeted for Pharmacological Therapy?
The Panel emphasized that nonpharmacological therapy is the mainstay of treatment for all athletes with 1 or more components of the Triad.
The Panel concluded that there is no evidence at this time to unequivocally recommend pharmacological therapy in athletes with the Female Athlete Triad disorders due to lack of evidenced-based research in this population. The Panel discussed that lack of response to nonpharmacological management (see definition below) may present a situation in which pharmacological therapy would be considered in an athlete with low BMD and a clinically significant fracture history. Pharmacological medications other than estrogen and progesterone are not recommended in the absence of a fracture history.
Pharmacological therapy may be considered in an athlete with:
* BMD Z-scores ≤−2.0 with a clinically significant fracture history (Tables 2 and 3; Figure 4) and lack of response to at least 1 year of nonpharmacological therapy (mainstay of treatment).
* BMD Z-scores between −1.0 and −2.0 with a clinically significant fracture history (Tables 2 and 3) and ≥2 additional Triad risk factors17,46 (Figure 4) AND lack of response to at least 1 year of nonpharmacological therapy.
Transdermal estradiol replacement with cyclic progesterone may be considered in young athletes ≥16 years and <21 years of age with FHA to prevent further bone loss during this critical window of optimal bone accrual if they have:
* BMD Z-scores ≤−2.0 without a clinically significant fracture history (Tables 2 and 3; Figure 4) and at least 1 additional Triad risk factor17,45 (in addition to FHA) (Figure 4) AND lack of response to at least 1 year of nonpharmacological therapy.
Lack of response to therapy has been defined as
* A clinically significant reduction in BMD Z-scores after at least 1 year of nonpharmacological therapy, or
* Occurrence of new clinically significant fractures during nonpharmacological treatment over the course of 1 year.
Further research is warranted to assess the outcomes of pharmacological management and potential risks in this population. Although stress fractures are generally believed to be less concerning than nonstress fractures, they are a common and frequent cause of morbidity, time away from training and competition in athletes, and loss of school and work days. In certain instances, these stress fractures can progress to devastating complete fractures at high-risk sites, such as the femoral neck,218,219 with consequences that can result in surgery and negatively affect exercise activity and quality of life. Of note, prolonged nonpharmacological management despite lack of response is of concern in younger athletes who are in the process of accruing peak bone mass, because the adolescent and young adult years are a critical window in time during which to optimize bone accrual,149,220 and deficits incurred at this time may be irreversible.152
As stated, there are no current treatments approved by the FDA for this specific population.215 Further research on pharmacological treatment alternatives is needed in this higher risk group of athletes with low BMD and a fracture history, as well as those with low BMD without a fracture history.
What Therapy can We Offer?
Increasing energy availability and optimizing energy status
* The Panel unanimously agreed that all athletes and exercising women, particularly those who are considered candidates for pharmacological therapy, should be counseled regarding lifestyle and behavioral changes to increase EA and optimize energy status.
* Nonpharmacological management should continue, even if pharmacological therapy is prescribed.
Calcium and vitamin D
* Calcium-rich foods should be recommended with optimal calcium intake between 1000 and 1300 mg/d.221
* Vitamin D status should be optimized. Daily intake of 600 IU of vitamin D is recommended by the Institute of Medicine for adolescents and adults up to age 70.221 Higher doses may be needed if deficient or insufficient in vitamin D. The Panel recommended that vitamin D levels be maintained between 32 and 50 ng/mL.222
Estrogen administration in female athletes with FHA or prolonged oligomenorrhea who have failed nonpharmacological management
* In athletes and exercising women with FHA and prolonged amenorrhea of hypothalamic origin who meet criteria for pharmacological therapy, a reasonable option is estrogen administration with cyclic progesterone after ruling out other causes of amenorrhea. It is also essential to consider contraceptive needs of the athlete. Before starting therapy, a thorough history and examination should be conducted to rule out contraindications for estrogen therapy.
* Combined oral contraceptive therapy containing 20 to 35 μg of ethinyl estradiol may maintain BMD in those with very low BMD measures, although data are not definitive.168,172 Most studies in adolescents and adults with anorexia nervosa and in amenorrheic athletes suggest that COC therapies are not effective in increasing BMD161,162,167,168 or in reducing stress fractures,161 although they are effective for contraceptive needs when used in recommended doses.
* Transdermal estradiol (100 μg of 17β estradiol) with cyclic progesterone maintains BMD Z-scores in adolescents with anorexia nervosa180 and is a consideration for low-weight, amenorrheic athletes who meet criteria for pharmacological intervention. Athletes who are symptomatic with this dose for estrogen-related side effects such as nausea, bloating, and breast tenderness may be started on a lower dose of the transdermal patch (50 μg) and the dose increased to 100 μg after 1 month.
* Cyclic progesterone is necessary in those on transdermal estradiol to avoid deleterious effects of unopposed estrogen on the uterine lining, and we recommend 200 mg of micronized progesterone or 5 to 10 mg of medroxy progesterone acetate for 12 days of every month.223,224
* Of importance, the combination of transdermal estradiol and cyclic oral progesterone in the described doses has unproven contraceptive efficacy, and other contraceptive methods are necessary if contraception is desired.
* If estrogen replacement is considered in an athlete with a known or family history of thrombophilic disorders, we recommend consulting with a hematologist to assess whether tailoring the estrogen dose, route, and regimen to minimize risk is an option, with full written informed consent of the patient.225 If estrogen replacement is instituted, management should include ongoing follow-up with a hematologist.
* Testosterone, DHEA, leptin, or rhIGF-1 replacement is not recommended at this time in athletes who meet criteria for pharmacological therapy, due to lack of studies in the female athlete population and potential adverse effects.
When Should Pharmacological Options Other than Estrogen be Considered as Options for Treatment?
Pharmacological options other than estrogen replacement/COC
* In rare instances, pharmacological management other than estrogen replacement/COC therapy can be considered when athletes meet criteria for osteoporosis and have failed nonpharmacological therapy (with recurrent fractures), and meet 1 of the following criteria:
- Contraindications to estrogen;
- Lack of response to estrogen replacement after ≥18 to 24 months in a compliant patient;
- Eumenorrheic athletes/exercisers (not hypoestrogenic) who meet criteria for therapy;
- Athletes with multiple debilitating fractures and significant morbidity.
* For the last 2 indications, patients should undergo a complete metabolic work-up, and genetic testing may be considered depending on the history of the patient and her family history.
* Other pharmacological options include bisphosphonates and teriparatide, which are effective strategies for treating postmenopausal osteoporosis226,227 and osteoporosis in special populations,212,213 but for whom data are limited in younger women, including the female athlete. If such options are considered, the athlete/exerciser should be referred to an endocrinologist or an expert in metabolic bone diseases for further management, and treatment should be implemented only in conjunction with the endocrinologist or expert in metabolic bone disorders.
* Teriparatide is administered once daily as a subcutaneous injection and is bone anabolic. While this is a promising agent in adult athletes and studies are ongoing, data regarding its efficacy in a younger population are lacking at this time. Of note, this drug is contraindicated in pregnancy, and there is a black box warning for those at increased baseline risk for osteosarcoma, namely children with open epiphyses, individuals with unexplained elevations of alkaline phosphatase, those with Paget's disease, and individuals with a prior history of external beam radiation therapy or implant radiotherapy of the skeleton (Product Information: FORTEO(R) subcutaneous solution, teriparatide subcutaneous solution. Eli Lilly and Company, Indianapolis, Indiana, 2004).
* Bisphosphonates are effective in increasing BMD in adult women with anorexia nervosa,189 but should be considered in athletes who meet criteria for pharmacological intervention with options other than estrogen replacement only when no other strategy is effective or when other strategies are contraindicated. Reproductive-age women taking bisphosphonates should be prescribed birth control measures and counseled at length regarding the very long half-life of these medications and potential teratogenic effects on the fetus should pregnancy occur. If bisphosphonate therapy is prescribed, a time limit for these ongoing treatments, as in adults, should be considered due to potential risks of prolonged therapy.205,206
* There are no known studies using denosomab for osteoporosis treatment in premenopausal women or children, and thus this pharmacologic alternative is not recommended and remains experimental in this group.
CLEARANCE AND RETURN TO PLAY
Despite widespread awareness and educational efforts on the Female Athlete Triad,2,3,228 there have been no standardized guidelines for clearance and return to play. As a result, many female athletes with the Triad are being cleared at their preparticipation physical examination without being adequately assessed, managed, or treated, and often return to play without structured follow-up.
How can Risk Stratification be Used to Evaluate Health and Participation Risk?
More recent studies assessing health outcomes of single and combined risk factors for the Triad have demonstrated that there is increased cumulative risk for the outcomes of both low BMD,46 stress fracture, and bone stress injury16,17 resulting in a dose-response relationship that is related to magnitude of risk of Triad disorders and subsequent impact on bone health and susceptibility to fracture. These findings are of significance with regard to management of the Triad, clearance, and return to play, and emphasize the important role that risk stratification may have in optimizing the athlete's health and minimizing risk for injury and illness.
Prospective return-to-play data has demonstrated that female collegiate runners with menstrual dysfunction had more severe bone stress injuries on magnetic resonance imaging (MRI) compared with eumenorrheic runners.18 Low BMD and higher MRI grade bone stress injuries, were independent predictors of delay in return to play. In addition, athletes with bone stress injuries in skeletal sites of predominantly trabecular bone structure (femoral neck, sacrum, and pelvis) had a delay in return to play compared to those athletes with bone stress injuries at cortical bone sites.18 Marx et al83 found that female athletes with stress fractures in regions of mostly trabecular bone had lower BMD than those at cortical sites. These studies18,83 highlight the importance of Triad risk factors on bone stress injury outcomes, and the value of risk stratification. Future research is needed to assess the impact of Triad risk factors on return to play.
What is the Role of the Team Physician in the Return-To-Play Decision for Triad Athletes?
According to the 2012 Consensus Statement on “The Team Physician and the Return to Play Decision,”229 the physician's duty is “to return an injured or ill athlete to practice or competition without putting the individual at undue risk for injury or illness.” In addition, the team physician's role is to establish a return-to-play process, evaluate the athlete with medical conditions, treat and rehabilitate the athlete, and return the athlete to play after it is determined to be safe to do so.
In summary, with increasing evidence that the athlete's risk for unfavorable outcomes of low BMD and/or bone stress injuries is greater with cumulative risk factors for the Triad,16,17,46 evidence that Triad risk factors may contribute to more severe bone stress injuries and a delay in return to play,18 and due to the lack of standard of care guidelines for the Triad, the Panel recommends the following risk stratification protocol be implemented (Figures 4 and 5). This risk stratification protocol has been translated into a worksheet for the physician (Figure 4) that incorporates evidence-based risk factors for the Triad,16,17,46 and takes into account the magnitude (or severity) of risk, assigning a point value for risk factors in each Triad spectrum based on risk severity (low, moderate, and high risk). This cumulative risk stratification protocol is then translated into clearance and return-to-play guidelines for the Triad based on the athlete's cumulative risk score (Figure 5). Future research is needed to assess if implementation of a risk stratification model results in improved outcomes for female athletes with Triad disorders.
Risk Stratification and the Multidisciplinary Team
Who are the Members of the Multidisciplinary Team?
The Panel emphasized that the primary goal of the risk stratification protocol is to optimize health and reduce risk for injury and illness associated with the Female Athlete Triad. Best practice for outpatient management of the Triad can be accomplished with a multidisciplinary team consisting of the team physician, sports dietitian, and often a mental health practitioner.102 Other team members may include the athlete's coach, athletic trainer, family members, and other professionals, depending on the athlete's unique situation.
What are the Recommendations for Clearance and Return to Play Based on Risk Stratification?
Athletes at low risk, by risk stratification for the Triad, can be fully cleared (assuming otherwise healthy). Referral to the multidisciplinary team for the low-risk athlete is not required, and can be individualized. Athletes at moderate risk for the Triad can be cleared provisionally or receive limited clearance. Provisional clearance would include clearance for full training/competition, with the understanding that the athlete will be compliant with the recommendations outlined by the multidisciplinary team. With limited clearance, the athlete is cleared, but there are limitations specified with the athlete's training and competition, based on the athlete's health status. The athlete may be able to participate in progressively more training/competition as health status improves, as specified and outlined by the multidisciplinary team. It is recommended that athletes at moderate or high risk for the Triad be referred by the team physician to the appropriate multidisciplinary team member(s) and that a follow-up be scheduled to assess progress and review results of any tests ordered.
Those athletes determined to be at high risk are restricted from training and competition. In this category, the athlete's status can be provisional or the athlete may be disqualified. If the health care team determines that the athlete may be able to reach the stated health goals, the status is provisional, and a plan is outlined by the multidisciplinary team for a given period of time, and reevaluated as the athlete's health status improves, if appropriate. If severity of risk is determined to be too high for athletic participation at the time of the preparticipation examination, and prognosis determined to be poor, the athlete is disqualified and clearance/return to play reevaluated with clinical progress, if appropriate. In such instances, the athlete may require more intensive outpatient treatment, inpatient hospitalization, or residential care prior to reassessment for clearance and return to play.
Similar to the FRAX algorithm developed by the World Health Organization230,231 that uses clinical risk factors with or without BMD to assist with clinical decision making in postmenopausal women and men to reduce fracture risk, it is hoped that this risk stratification developed for the Triad will assist health care providers working with female athletes to minimize risk associated with the Triad disorders. With ongoing research, updates to the risk stratification can be implemented in hopes of guiding treatment and decision making for clearance and return to play.
How Does the Team Physician Utilize Contracts?
Athletes in the moderate-risk and high-risk categories should receive a written contract that is reviewed and presented to them by the team physician after their initial evaluation. Although a verbal contract may be sufficient, the Panel recommends a written contract. The goal of the written contract is to specify the criteria necessary for ongoing or future clearance and return to play for the female athlete with the multidisciplinary team members, and to ensure a shared understanding of how the clinical status of the athlete will be followed with each member of the multidisciplinary team.
The team physician coordinates the treatment goals with each multidisciplinary team member, and includes the specific recommendations in the contract, in addition to the requested frequency of visits and expectations for each team member. The team physician then reviews the recommendations with the athlete, and answers any questions. In the case of the written contract, both athlete and team physician sign the contract after it is discussed. (See Appendix, Supplemental Digital Content 1, http://links.lww.com/JSM/A42, for an example of a written contract for the Female Athlete Triad, which can be modified based on the athlete's clearance status).
Decision-Based Model for Return to Play
What Other Factors Play a Role in Clearance and the Return-To-Play Decision?
In addition to risk stratification, the team physician must take into account the athlete's unique situation in making the final decision for clearance and return to play.232 The decision-based return-to-play model developed by Creighton et al233 points out the complexities in return-to-play decision-making. There are medical factors and severity of risk considerations that need to be considered in the return-to-play decision. In addition, the return-to-play decision also involves consideration of sport risk modifiers (such as type of sport and competitive level), and willingness of the athlete to participate in her treatment. Athletes participating in leanness sports, for example, have been found to be at higher risk for Triad disorders.234 Although low BMI and/or low body weight are included as risk factors in the Triad risk stratification table (Figure 4), it is important to recognize that low body fat is not independently associated with menstrual dysfunction, low BMD, and stress fracture.19,235 It is not the recommendation of the Expert Panel convened to systematically address body fat in female athletes, but to consider low body fat as a consequence of inadequate dietary intake and/or excessive exercise, and address those issues in the continuing effort to optimize EA, restore normal reproductive function, and promote bone health. A decision-based model for the Triad, modified with permission from Creighton et al,233 illustrates some of the complex issues that need to be considered prior to the decision for clearance and return to play of the female athlete (Figure 6).
In the evaluation of health risk and participation risk, an important consideration is also the age of the athlete. The preadolescent and adolescent athlete has more vulnerability to physeal and other skeletal injuries, especially during periods of rapid growth. Adolescence is a period of rapid bone mineral acquisition.45,149,220 Inadequate EA and menstrual dysfunction may result in a delay of bone mineralization that lags behind bone linear growth.236 The mechanical stresses from repetitive loading in this population may increase susceptibility to fracture147 in an already vulnerable area of bone, which may have potentially catastrophic consequences. Case reports of devastating displaced femoral neck stress fractures in female adolescent athletes with Triad disorders are concerning and suggest that better screening and management of the Triad is imperative to minimize future fracture risk and potential for life-long disability.219,237,238 Furthermore, prospective studies are needed to identify thresholds of physical activity and sport beyond which may be detrimental to bone health.
Similar scrutiny should be directed toward athletes meeting DSM-V criteria for an ED.81 While the presence of an ED is considered a high-risk attribute in the Cumulative Risk Factor Assessment (Figure 4), it should be noted that patients with EDs have a higher risk of premature mortality when compared to individuals with other psychiatric diagnoses, and that is especially true for those with anorexia nervosa.239 Risk factors associated with a higher premature mortality rate among individuals with anorexia nervosa include (1) longer duration of illness (>10 years); (2) lower BMI (<16 kg/m2); (3) concurrent alcohol abuse; and (4) poor social adjustment.239–241 It is the recommendation of the Consensus Panel that athletes diagnosed with anorexia nervosa who have a BMI <16 kg/m2 or with moderate-to-severe bulimia nervosa (purging >4 times per week)81 should be categorically restricted from training and competition. Future participation is dependent on treatment of their ED, including ascertainment of BMI >18.5 kg/m2, cessation of bingeing and purging, and close interval follow-up with the multidisciplinary team.241
In some cases, participation in sport becomes fully integrated with an ED and isolation and treatment of the ED, such that resuming participation in the sport is not a realistic goal for the short or moderate term. It is important that EDs be recognized as a serious mental illness and that their impact and potentially long and pernicious course not be underestimated.
Finally, it is of paramount importance that the team physician has the ultimate say in the decision-making process for clearance and return to play.229,232,242 Although the team physician has this authority to make the final decision, the decision is often the product of consultation with the multidisciplinary team, and other concerned parties. The physician must always have the athlete's health and safety as the first priority in the decision-making process, which should supersede all other pressures or circumstances that may arise.
Young girls and women with the Female Athlete Triad have significant health risks. Historically, many of these athletes have been cleared for sport participation without appropriate evaluation, management, and treatment. Similarly, after medical illness or injury, athletes with the Triad often return to play prematurely, and without adequate treatment and follow-up. It is the team physician's responsibility to ensure that each and every athlete that is cleared for participation in sport or returning to play after an injury or illness return only when it is determined safe to do so. The 2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad Expert Panel has proposed an evidenced-based risk stratification point system that takes into account magnitude of risk to assist the physician in decision-making regarding sport participation, clearance, and return to play. Guidelines are offered for clearance categories, management by a multidisciplinary team, and implementation of treatment contracts. Future research is needed to study whether risk stratification, clearance, and return-to-play guidelines are an effective means to optimize health and reduce risk for injury and illness for the Triad.
The authors and expert panel would like to acknowledge the contributions of Jim Whitehead, Executive Vice President and CEO, American College of Sports Medicine; Mimi Johnson, MD; and Tyler Wadsworth, MD. Their encouragement, expertise and support contributed to the successful development of this document. All authors have contributed substantially to the manuscript and have been involved in designing and drafting the manuscript. MJD, AN, EJ, and MM planned, constructed, and drafted the paper and were also involved in revising the manuscript. NW, MO, MG, and GM were involved in drafting, reviewing, and editing the manuscript. RM and JG were involved in writing and revising the manuscript and creating tables and figures. Members of the invited Expert Panel participated in Consensus Conference meetings held in June 2012 and June 2013, as well as provided the authors with guidance and feedback on the consensus process and manuscript.
1. McCrory P, Meeuwisse W, Aubry M, et al.. Consensus statement on concussion in sport—the 4th International Conference on Concussion in Sport, held in Zurich, November 2012. Clin J Sport Med. 2013;23:89–117.
2. Nattiv A, Loucks AB, Manore MM, et al.. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc. 2007;39:1867–1882.
3. Otis CL, Drinkwater B, Johnson M, et al.. American college of sports medicine position stand. The female athlete triad. Med Sci Sports Exerc. 1997;29:i–ix.
4. De Souza MJ, Lee DK, VanHeest JL, et al.. Severity of energy-related menstrual disturbances increases in proportion to indices of energy conservation in exercising women. Fertil Steril. 2007;88:971–975.
5. Williams NI, Helmreich DL, Parfitt DB, et al.. Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training. J Clin Endocrinol Metab. 2001;86:5184–5193.
6. Loucks AB, Thuma JR. Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women. J Clin Endocrinol Metab. 2003;88:297–311.
7. De Souza MJ, West SL, Jamal SA, et al.. The presence of both an energy deficiency and estrogen deficiency exacerbate alterations of bone metabolism in exercising women. Bone. 2008;43:140–148.
8. De Souza MJ, Williams NI. Beyond hypoestrogenism in amenorrheic athletes: energy deficiency as a contributing factor for bone loss. Curr Sports Med Rep. 2005;4:38–44.
9. Ihle R, Loucks AB. Dose-response relationships between energy availability and bone turnover in young exercising women. J Bone Miner Res. 2004;19:1231–1240.
10. Mallinson RJ, Williams NI, Hill BR, et al.. Body composition and reproductive function exert unique influences on indices of bone health in exercising women. Bone. 2013;56:91–100.
11. De Souza MJ, Miller BE, Loucks AB, et al.. High frequency of luteal phase deficiency and anovulation in recreational women runners: blunted elevation in follicle-stimulating hormone observed during luteal-follicular transition. J Clin Endocrinol Metab. 1998;83:4220–4232.
12. De Souza MJ, Toombs RJ, Scheid JL, et al.. High prevalence of subtle and severe menstrual disturbances in exercising women: confirmation using daily hormone measures. Hum Reprod. 2010;25:491–503.
13. Tomten SE, Falch JA, Birkeland KI, et al.. Bone mineral density and menstrual irregularities. A comparative study on cortical and trabecular bone structures in runners with alleged normal eating behavior. Int J Sports Med. 1998;19:92–97.
14. Sowers M, Randolph JF Jr, Crutchfield M, et al.. Urinary ovarian and gonadotropin hormone levels in premenopausal women with low bone mass. J Bone Miner Res. 1998;13:1191–1202.
15. Field AE, Gordon CM, Pierce LM, et al.. Prospective study of physical activity and risk of developing a stress fracture among preadolescent and adolescent girls. Arch Pediatr Adolesc Med. 2011;165:723–728.
16. Tenforde AS, Sayres LC, McCurdy ML, et al.. Identifying sex-specific risk factors for stress fractures in adolescent runners. Med Sci Sports Exerc. 2013;45:1843–1851.
17. Barrack MT, Gibbs JC, De Souza MJ, et al.. Higher incidence of bone stress injury with increasing female athlete triad risk factors: a prospective multisite study of exercising girls and women. Am J Sports Med. In press.
18. Nattiv A, Kennedy G, Barrack MT, et al.. Correlation of MRI grading of bone stress injuries with clinical risk factors and return to play: a 5-year prospective study in collegiate track and field athletes. Am J Sports Med. 2013;41:1930–1941.
19. Duckham RL, Peirce N, Meyer C, et al.. Risk factors for stress fracture in female endurance athletes: a cross-sectional study. BMJ Open. 2012;2:e001920. doi:10.1136/bmjopen-2012-001920.
20. Kelsey JL, Bachrach LK, Procter-Gray E, et al.. Risk factors for stress fracture among young female cross-country runners. Med Sci Sports Exerc. 2007;39:1457–1463.
21. Lauder TD, Dixit S, Pezzin LE, et al.. The relation between stress fractures and bone mineral density: evidence from active-duty Army women. Arch Phys Med Rehabil. 2000;81:73–79.
22. Rauh MJ, Macera CA, Trone DW, et al.. Epidemiology of stress fracture and lower-extremity overuse injury in female recruits. Med Sci Sports Exerc. 2006;38:1571–1577.
23. Loucks AB, Heath EM. Induction of low-T3 syndrome in exercising women occurs at a threshold of energy availability. Am J Physiol. 1994;266(3 pt 2):R817–R823.
24. Loucks AB, Verdun M, Heath EM. Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. J Appl Physiol. 1998;84:37–46.
25. Hilton LK, Loucks AB. Low energy availability, not exercise stress, suppresses the diurnal rhythm of leptin in healthy young women. Am J Physiol Endocrinol Metab. 2000;278:E43–E49.
26. Williams NI, Bullen BA, McArthur JW, et al.. Effects of short-term strenuous endurance exercise upon corpus luteum function. Med Sci Sports Exerc. 1999;31:949–958.
27. Williams NI, Caston-Balderrama AL, Helmreich DL, et al.. Longitudinal changes in reproductive hormones and menstrual cyclicity in cynomolgus monkeys during strenuous exercise training: abrupt transition to exercise-induced amenorrhea. Endocrinology. 2001;142:2381–2389.
28. Loucks AB. Low energy availability in the marathon and other endurance sports. Sports Med. 2007;37:348–352.
29. De Souza MJ, Williams NI. Physiological aspects and clinical sequelae of energy deficiency and hypoestrogenism in exercising women. Hum Reprod Update. 2004;10:433–448.
30. Bullen BA, Skrinar GS, Beitins IZ, et al.. Induction of menstrual disorders by strenuous exercise in untrained women. N Engl J Med. 1985;312:1349–1353.
31. O'Donnell E, Harvey PJ, Goodman JM, et al.. Long-term estrogen deficiency lowers regional blood flow, resting systolic blood pressure, and heart rate in exercising premenopausal women. Am J Physiol Endocrinol Metab. 2007;292:E1401–E1409.
32. Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, et al.. Amenorrhea in female athletes is associated with endothelial dysfunction and unfavorable lipid profile. J Clin Endocrinol Metab. 2005;90:1354–1359.
33. Vanheest JL, Rodgers CD, Mahoney CE, et al.. Ovarian suppression impairs sport performance in junior elite female swimmers. Med Sci Sports Exerc. 2014;46:156–166.
34. Becker AE, Grinspoon SK, Klibanski A, et al.. Eating disorders. N Engl J Med. 1999;340:1092–1098.
35. Golden NH, Katzman DK, Kreipe RE, et al.. Eating disorders in adolescents: position paper of the Society for Adolescent Medicine. J Adolesc Health. 2003;33:496–503.
36. Rome ES, Ammerman S, Rosen DS, et al.. Children and adolescents with eating disorders: the state of the art. Pediatrics. 2003;111:e98–e108.
37. Barrack MT, Ackerman KE, Gibbs JC. Update on the female athlete triad. Curr Rev Musculoskelet Med. 2013;6:195–204.
38. Rumball JS, Lebrun CM. Preparticipation physical examination: selected issues for the female athlete. Clin J Sport Med. 2004;14:153–160.
39. Rumball JS, Lebrun CM. Use of the preparticipation physical examination form to screen for the female athlete triad in Canadian interuniversity sport universities. Clin J Sport Med. 2005;15:320–325.
40. Ljungqvist A, Jenoure P, Engebretsen L, et al.. The International Olympic Committee (IOC) consensus statement on periodic health evaluation of elite athletes March 2009. Br J Sports Med. 2009;43:631–643.
41. American Academy of Family Physicians, American Academy of Pediatrics, American College of Sports Medicine, American Medical Society for Sports Medicine, American Orthopaedic Society for Sports Medicine, American Osteopathic Academy of Sports Medicine. Preparticipation Physical Evaluation. 4th ed. In: Bernhardt DT, Roberts WO, eds. Elk Grove, IL: American Academy of Pediatrics; 2010.
42. Mencias T, Noon M, Hoch AZ. Female athlete triad screening in National Collegiate Athletic Association Division I athletes: is the preparticipation evaluation form effective? Clin J Sport Med. 2012;22:122–125.
43. Rauh MJ, Nichols JF, Barrack MT. Relationships among injury and disordered eating, menstrual dysfunction, and low bone mineral density in high school athletes: a prospective study. J Athl Train. 2010;45:243–252.
44. Thein-Nissenbaum JM, Rauh MJ, Carr KE, et al.. Menstrual irregularity and musculoskeletal injury in female high school athletes. J Athl Train. 2012;47:74–82.
45. Matkovic V, Jelic T, Wardlaw GM, et al.. Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. Inference from a cross-sectional model. J Clin Invest. 1994;93:799–808.
46. Gibbs JC, Nattiv A, Barrack MT, et al.. Low bone density risk is higher in exercising women with multiple Triad risk factors. Med Sci Sports Exerc. 2014;46:167–176.
47. Francisco R, Narciso I, Alarcao M. Individual and relational risk factors for the development of eating disorders in adolescent aesthetic athletes and general adolescents. Eat Weight Disord. 2013;18:403–411.
48. Gomes AR, Martins C, Silva L. Eating disordered behaviours in Portuguese athletes: the influence of personal, sport, and psychological variables. Eur Eat Disord Rev. 2011;19:190–200.
49. Jacobi C, Fittig E, Bryson SW, et al.. Who is really at risk? Identifying risk factors for subthreshold and full syndrome eating disorders in a high-risk sample. Psychol Med. 2011;41:1939–1949.
50. Rosen LW, Hough DO. Pathogenic weight-control behaviors of female college gymnasts. Phy Sportsmed. 1988;16:140–144.
51. Liechty JM, Lee MJ. Longitudinal predictors of dieting and disordered eating among young adults in the US. Int J Eat Disord. 2013;46:790–800.
52. Sundgot-Borgen J. Risk and trigger factors for the development of eating disorders in female elite athletes. Med Sci Sports Exerc. 1994;26:414–419.
53. Thompson RA, Sherman RT. “Good athlete” traits and characteristics of anorexia nervosa: are they similar? Eat Disord. 1999;7:181–190.
54. Sundgot-Borgen J, Torstveit MK. Aspects of disordered eating continuum in elite high-intensity sports. Scand J Med Sci Sports. 2010;20(suppl 2):112–121.
55. Leon GR. Eating disorders in female athletes. Sports Med. 1991;12:219–227.
56. Thein-Nissenbaum JM, Rauh MJ, Carr KE, et al.. Associations between disordered eating, menstrual dysfunction, and musculoskeletal injury among high school athletes. J Orthop Sports Phys Ther. 2011;41:60–69.
57. Diaz A, Laufer MR, Breech LL. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics. 2006;118:2245–2250.
58. Scholes D, LaCroix AZ, Ichikawa LE, et al.. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med. 2005;159:139–144.
59. Loud KJ, Micheli LJ, Bristol S, et al.. Family history predicts stress fracture in active female adolescents. Pediatrics. 2007;120:E364–E372.
60. Selected issues for nutrition and the athlete: a team physician consensus statement. Med Sci Sports Exerc. 2013;45:2378–2386.
61. Rodriguez NR, Di Marco NM, Langley S. American College of Sports Medicine position stand. Nutrition and athletic performance. Med Sci Sports Exerc. 2009;41:709–731.
62. Deuster PA, Kyle SB, Moser PB, et al.. Nutritional intakes and status of highly trained amenorrheic and eumenorrheic women runners. Fertil Steril. 1986;46:636–643.
63. Kaiserauer S, Snyder AC, Sleeper M, et al.. Nutritional, physiological, and menstrual status of distance runners. Med Sci Sports Exerc. 1989;21:120–125.
64. Myerson M, Gutin B, Warren MP, et al.. Resting metabolic rate and energy balance in amenorrheic and eumenorrheic runners. Med Sci Sports Exerc. 1991;23:15–22.
65. Marcus R, Cann C, Madvig P, et al.. Menstrual function and bone mass in elite women distance runners. Endocrine and metabolic features. Ann Intern Med. 1985;102:158–163.
66. Le Grange D, Doyle PM, Swanson SA, et al.. Calculation of expected body weight in adolescents with eating disorders. Pediatrics. 2012;129:e438–e446.
67. O'Donnell E, Harvey PJ, De Souza MJ. Relationships between vascular resistance and energy deficiency, nutritional status and oxidative stress in oestrogen deficient physically active women. Clin Endocrinol (Oxf). 2009;70:294–302.
68. Gibbs JC, Williams NI, Scheid JL, et al.. The association of a high drive for thinness with energy deficiency and severe menstrual disturbances: confirmation in a large population of exercising women. Int J Sport Nutr Exerc Metab. 2011;21:280–290.
69. Scheid JL, Williams NI, West SL, et al.. Elevated PYY is associated with energy deficiency and indices of subclinical disordered eating in exercising women with hypothalamic amenorrhea. Appetite. 2009;52:184–192.
70. De Souza MJ, Hontscharuk R, Olmsted M, et al.. Drive for thinness score is a proxy indicator of energy deficiency in exercising women. Appetite. 2007;48:359–367.
71. Heaney S, O'Connor H, Gifford J, et al.. Comparison of strategies for assessing nutritional adequacy in elite female athletes' dietary intake. Int J Sport Nutr Exerc Metab. 2010;20:245–256.
72. Ainsworth BE, Haskell WL, Herrmann SD, et al.. 2011 Compendium of Physical Activities: a second update of codes and MET values. Med Sci Sports Exerc. 2011;43:1575–1581.
73. Koehler K, Braun H, De Marees M, et al.. Parallel assessment of nutrition and activity in athletes: validation against doubly labelled water, 24-h urea excretion, and indirect calorimetry. J Sports Sci. 2010;28:1435–1449.
74. Toombs RJ, Ducher G, Shepherd JA, et al.. The impact of recent technological advances on the trueness and precision of DXA to assess body composition. Obesity (Silver Spring). 2012;20:30–39.
75. Meyer NL, Sundgot-Borgen J, Lohman TG, et al.. Body composition for health and performance: a survey of body composition assessment practice carried out by the Ad Hoc Research Working Group on Body Composition, Health and Performance under the auspices of the IOC Medical Commission. Br J Sports Med. 2013;47:1044–1053.
76. Illingworth P. Amenorrhea, Anovulation, and Dysfunctional Uterine Bleeding. In: Jameson JL, De Groot LJ, eds. Endocrinology Adult and Pediatric. 6th ed. St. Louis, MO: Saunders, an affiliate of Elsevier, Inc; 2010:2341–2355.
77. Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2004;82(suppl 1):S33–S39.
78. De Souza MJ, Toombs RJ. Amenorrhea associated with the female athlete triad: etiology, diagnosis and treatment. In: Santoro NF, Neal-Perry G, eds. Amenorrhea: A Case-Based, Clinical Guide: Springer Science+Business Media; 2010.
79. Legro RS, Arslanian SA, Ehrmann DA, et al.. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4565–4592.
80. Lewiecki EM, Gordon CM, Baim S, et al.. International Society for Clinical Densitometry 2007 adult and pediatric official positions. Bone. 2008;43:1115–1121.
81. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
82. Boden BP, Osbahr DC. High-risk stress fractures: evaluation and treatment. J Am Acad Orthop Surg. 2000;8:344–353.
83. Marx RG, Saint-Phard D, Callahan LR, et al.. Stress fracture sites related to underlying bone health in athletic females. Clin J Sport Med. 2001;11:73–76.
84. Tannirandorn P, Epstein S. Drug-induced bone loss. Osteoporos Int. 2000;11:637–759.
85. Malabanan AO, Rosen HN, Vokes TJ, et al.. Indications of DXA in women younger than 65 years and men younger than 70 years: the 2013 official positions. J Clin Densitom. 2013;16:467–471.
86. Gordon CM, Baim S, Bianchi ML, et al.. Special report on the 2007 Pediatric Position Development Conference of the International Society for Clinical Densitometry. South Med J. 2008;101:740–743.
87. Kopp-Woodroffe SA, Manore MM, Dueck CA, et al.. Energy and nutrient status of amenorrheic athletes participating in a diet and exercise training intervention program. Int J Sport Nutr. 1999;9:70–88.
88. Dueck CA, Matt KS, Manore MM, et al.. Treatment of athletic amenorrhea with a diet and training intervention program. Int J Sport Nutr. 1996;6:24–40.
89. Arends JC, Cheung MY, Barrack MT, et al.. Restoration of menses with nonpharmacologic therapy in college athletes with menstrual disturbances: a 5-year retrospective study. Int J Sport Nutr Exerc Metab. 2012;22:98–108.
90. Misra M, Prabhakaran R, Miller KK, et al.. Weight gain and restoration of menses as predictors of bone mineral density change in adolescent girls with anorexia nervosa-1. J Clin Endocrinol Metab. 2008;93:1231–1237.
91. Golden NH, Jacobson MS, Schebendach J, et al.. Resumption of menses in anorexia nervosa. Arch Pediatr Adolesc Med. 1997;151:16–21.
92. Misra M, Prabhakaran R, Miller KK, et al.. Role of cortisol in menstrual recovery in adolescent girls with anorexia nervosa. Pediatr Res. 2006;59(4 pt 1):598–603.
93. Misra M, Soyka LA, Miller KK, et al.. Regional body composition in adolescents with anorexia nervosa and changes with weight recovery. Am J Clin Nutr. 2003;77:1361–1367.
94. Mallinson RJ, Williams NI, Olmsted MP, et al.. A case report of recovery of menstrual function following a nutritional intervention in two exercising women with amenorrhea of varying duration. J Int Soc Sports Nutr. 2013;10:34.
95. Miller KK, Lee EE, Lawson EA, et al.. Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab. 2006;91:2931–2937.
96. Audi L, Vargas DM, Gussinye M, et al.. Clinical and biochemical determinants of bone metabolism and bone mass in adolescent female patients with anorexia nervosa. Pediatr Res. 2002;51:497–504.
97. Hoch AZ, Jurva JW, Staton MA, et al.. Athletic amenorrhea and endothelial dysfunction. WMJ. 2007;106:301–306.
98. American Academy of Pediatrics. Medical concerns in the female athlete. Pediatrics. 2000;106:610–613.
99. Temme KE, Hoch AZ. Recognition and rehabilitation of the female athlete triad/tetrad: a multidisciplinary approach. Curr Sports Med Rep. 2013;12:190–199.
100. Sherman RT, Thompson RA. Practical use of the International Olympic Committee Medical Commission position stand on the female athlete triad: a case example. Int J Eat Disord. 2006;39:193–201.
101. Beals KA. Disordered Eating Among Athletes: A Comprehensive Guide for Health Professionals. Champaign, IL: Human Kinetics; 2004.
102. Joy EA, Wilson C, Varechok S. The multidisciplinary team approach to the outpatient treatment of disordered eating. Curr Sports Med Rep. 2003;2:331–336.
103. Sundgot-Borgen J. Weight and eating disorders in elite athletes. Scand J Med Sci Sports. 2002;12:259–260.
104. Bratland-Sanda S, Sundgot-Borgen J. Eating disorders in athletes: overview of prevalence, risk factors and recommendations for prevention and treatment. Eur J Sport Sci. 2013;13:499–508.
105. Zanker CL, Cooke CB, Truscott JG, et al.. Annual changes of bone density over 12 years in an amenorrheic athlete. Med Sci Sports Exerc. 2004;36:137–142.
106. Fredericson M, Kent K. Normalization of bone density in a previously amenorrheic runner with osteoporosis. Med Sci Sports Exerc. 2005;37:1481–1486.
107. Dominguez J, Goodman L, Sen Gupta S, et al.. Treatment of anorexia nervosa is associated with increases in bone mineral density, and recovery is a biphasic process involving both nutrition and return of menses. Am J Clin Nutr. 2007;86:92–99.
108. Joy E. Is the pill the answer for patients with the female athlete triad? Curr Sports Med Rep. 2012;11:54–55.
109. Harris JA, Benedict FG. A Biometric Study of the Basal Metabolism in Man. WA, DC: Carnegie Institution of Washington; 1919:370–373. DC (Pub No 279).
110. Cunningham JJ. Body composition as a determinant of energy expenditure: a synthetic review and a proposed general prediction equation. Am J Clin Nutr. 1991;54:963–969.
111. Frankenfield D, Roth-Yousey L, Compher C. Comparison of predictive equations for resting metabolic rate in healthy nonobese and obese adults: a systematic review. J Am Diet Assoc. 2005;105:775–789.
112. Black AE, Coward WA, Cole TJ, et al.. Human energy expenditure in affluent societies: an analysis of 574 doubly-labelled water measurements. Eur J Clin Nutr. 1996;50:72–92.
113. Food and Agricultural Organization of the United Nations, World Health Organization, United Nations University. FAO/WHO/UNU Expert Consultation. Energy and Protein Requirements. WHO Technical Report Series. 724: 1–206. Geneva: World Health Organization; 1985.
114. Reed JL, De Souza MJ, Williams NI. Changes in energy availability across the season in Division I female soccer players. J Sports Sci. 2013;31:314–324.
115. Jaffa T, Davies S, Sardesai A. What patients with anorexia nervosa should wear when they are being weighed: report of two pilot surveys. Eur Eat Disord Rev. 2011;19:368–370.
116. Zach KN, Smith Machin AL, Hoch AZ. Advances in management of the female athlete triad and eating disorders. Clin Sports Med. 2011;30:551–573.
117. Brownley KA, Berkman ND, Sedway JA, et al.. Binge eating disorder treatment: a systematic review of randomized controlled trials. Int J Eat Disord. 2007;40:337–348.
118. Shapiro JR, Berkman ND, Brownley KA, et al.. Bulimia nervosa treatment: a systematic review of randomized controlled trials. Int J Eat Disord. 2007;40:321–336.
119. Wilfley DE, Bishop ME, Wilson GT, et al.. Classification of eating disorders: toward DSM-V. Int J Eat Disord. 2007;40(suppl):S123–S129.
120. Berga SL, Marcus MD, Loucks TL, et al.. Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy. Fertil Steril. 2003;80:976–981.
121. Winters-Stone KM, Snow CM. Musculoskeletal response to exercise is greatest in women with low initial values. Med Sci Sports Exerc. 2003;35:1691–1696.
122. Misra M, Klibanski A. Bone health in anorexia nervosa. Curr Opin Endocrinol Diabetes Obes. 2011;18:376–382.
123. Viapiana O, Gatti D, Dalle Grave R, et al.. Marked increases in bone mineral density and biochemical markers of bone turnover in patients with anorexia nervosa gaining weight. Bone. 2007;40:1073–1077.
124. Bolton JG, Patel S, Lacey JH, et al.. A prospective study of changes in bone turnover and bone density associated with regaining weight in women with anorexia nervosa. Osteoporos Int. 2005;16:1955–1962.
125. Compston JE, McConachie C, Stott C, et al.. Changes in bone mineral density, body composition and biochemical markers of bone turnover during weight gain in adolescents with severe anorexia nervosa: a 1-year prospective study. Osteoporos Int. 2006;17:77–84.
126. Heer M, Mika C, Grzella I, et al.. Bone turnover during inpatient nutritional therapy and outpatient follow-up in patients with anorexia nervosa compared with that in healthy control subjects. Am J Clin Nutr. 2004;80:774–781.
127. Hotta M, Shibasaki T, Sato K, et al.. The importance of body weight history in the occurrence and recovery of osteoporosis in patients with anorexia nervosa: evaluation by dual x-ray absorptiometry and bone metabolic markers. Eur J Endocrinol. 1998;139:276–283.
128. Ackerman KE, Nazem T, Chapko D, et al.. Bone microarchitecture is impaired in adolescent amenorrheic athletes compared with eumenorrheic athletes and nonathletic controls. J Clin Endocrinol Metab. 2011;96:3123–3133.
129. Bailey CA, Brooke-Wavell K. Exercise for optimising peak bone mass in women. Proc Nutr Soc. 2008;67:9–18.
130. Nikander R, Sievanen H, Heinonen A, et al.. Femoral neck structure in adult female athletes subjected to different loading modalities. J Bone Miner Res. 2005;20:520–528.
131. Ramsdale SJ, Bassey EJ. Changes in bone mineral density associated with dietary-induced loss of body mass in young women. Clin Sci (Lond). 1994;87:343–348.
132. Bassey EJ, Rothwell MC, Littlewood JJ, et al.. Pre- and postmenopausal women have different bone mineral density responses to the same high-impact exercise. J Bone Miner Res. 1998;13:1805–1813.
133. Vainionpaa A, Korpelainen R, Leppaluoto J, et al.. Effects of high-impact exercise on bone mineral density: a randomized controlled trial in premenopausal women. Osteoporos Int. 2005;16:191–197.
134. Winters-Stone KM, Snow CM. Site-specific response of bone to exercise in premenopausal women. Bone. 2006;39:1203–1209.
135. Kato T, Terashima T, Yamashita T, et al.. Effect of low-repetition jump training on bone mineral density in young women. J Appl Physiol. 2006;100:839–843.
136. Martyn-St James M, Carroll S. Progressive high-intensity resistance training and bone mineral density changes among premenopausal women: evidence of discordant site-specific skeletal effects. Sports Med. 2006;36:683–704.
137. Wallace BA, Cumming RG. Systematic review of randomized trials of the effect of exercise on bone mass in pre- and postmenopausal women. Calcif Tissue Int. 2000;67:10–18.
138. Lanyon LE. Functional strain in bone tissue as an objective, and controlling stimulus for adaptive bone remodelling. J Biomech. 1987;20:1083–1093.
139. Rubin CT, Lanyon LE. Regulation of bone mass by mechanical strain magnitude. Calcif Tissue Int. 1985;37:411–417.
140. Kelley GA, Kelley KS, Kohrt WM. Exercise and bone mineral density in premenopausal women: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2013;2013:741639.
141. Martyn-St James M, Carroll S. Effects of different impact exercise modalities on bone mineral density in premenopausal women: a meta-analysis. J Bone Miner Metab. 2010;28:251–267.
142. Kelley GA, Kelley KS. Efficacy of resistance exercise on lumbar spine and femoral neck bone mineral density in premenopausal women: a meta-analysis of individual patient data. J Womens Health (Larchmt). 2004;13:293–300.
143. Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, et al.. American College of Sports Medicine position stand. Exercise and physical activity for older adults. Med Sci Sports Exerc. 2009;41:1510–1530.
144. Misra M, Miller KK, Cord J, et al.. Relationships between serum adipokines, insulin levels, and bone density in girls with anorexia nervosa. J Clin Endocrinol Metab. 2007;92:2046–2052.
145. Christo K, Prabhakaran R, Lamparello B, et al.. Bone metabolism in adolescent athletes with amenorrhea, athletes with eumenorrhea, and control subjects. Pediatrics. 2008;121:1127–1136.
146. Petit MA, Beck TJ, Lin HM, et al.. Femoral bone structural geometry adapts to mechanical loading and is influenced by sex steroids: the Penn State Young Women's Health Study. Bone. 2004;35:750–759.
147. Loud KJ, Gordon CM, Micheli LJ, et al.. Correlates of stress fractures among preadolescent and adolescent girls. Pediatrics. 2005;115:e399–e406.
148. Saxon LK, Turner CH. Estrogen receptor beta: the antimechanostat? Bone. 2005;36:185–192.
149. Ducher G, Bass SL, Saxon L, et al.. Effects of repetitive loading on the growth-induced changes in bone mass and cortical bone geometry: a 12-month study in pre/peri- and postmenarcheal tennis players. J Bone Miner Res. 2011;26:1321–1329.
150. Ackerman KE, Putman M, Guereca G, et al.. Cortical microstructure and estimated bone strength in young amenorrheic athletes, eumenorrheic athletes and non-athletes. Bone. 2012;51:680–687.
151. Drinkwater BL, Nilson K, Ott S, et al.. Bone mineral density after resumption of menses in amenorrheic athletes. JAMA. 1986;256:380–382.
152. Jonnavithula S, Warren MP, Fox RP, et al.. Bone density is compromised in amenorrheic women despite return of menses: a 2-year study. Obstet Gynecol. 1993;81(5 pt 1):669–674.
153. Keen AD, Drinkwater BL. Irreversible bone loss in former amenorrheic athletes. Osteoporos Int. 1997;7:311–315.
154. Nazem TG, Ackerman KE. The female athlete triad. Sports Health. 2012;4:302–311.
156. Wanden-Berghe RG, Sanz-Valero J, Wanden-Berghe C. The application of mindfulness to eating disorders treatment: a systematic review. Eat Disord. 2011;19:34–48.
158. Aigner M, Treasure J, Kaye W, et al.. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of eating disorders. World J Biol Psychiatry. 2011;12:400–443.
159. Bergstrom I, Crisby M, Engstrom AM, et al.. Women with anorexia nervosa should not be treated with estrogen or birth control pills in a bone-sparing effect. Acta Obstet Gynecol Scand. 2013;92:877–880.
160. Warren MP, Brooks-Gunn J, Fox RP, et al.. Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: a longitudinal study. Fertil Steril. 2003;80:398–404.
161. Cobb KL, Bachrach LK, Sowers M, et al.. The effect of oral contraceptives on bone mass and stress fractures in female runners. Med Sci Sports Exerc. 2007;39:1464–1473.
162. Gibson JH, Mitchell A, Reeve J, et al.. Treatment of reduced bone mineral density in athletic amenorrhea: a pilot study. Osteoporos Int. 1999;10:284–289.
163. Leung KC, Johannsson G, Leong GM, et al.. Estrogen regulation of growth hormone action. Endocr Rev. 2004;25:693–721.
164. Weissberger AJ, Ho KK, Lazarus L. Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab. 1991;72:374–381.
165. 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;106:1435–1443.
166. Cobb KL, Bachrach LK, Greendale G, et al.. Disordered eating, menstrual irregularity, and bone mineral density in female runners. Med Sci Sports Exerc. 2003;35:711–719.
167. Strokosch GR, Friedman AJ, Wu SC, et al.. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study. J Adolesc Health. 2006;39:819–827.
168. Klibanski A, Biller BM, Schoenfeld DA, et al.. The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metab. 1995;80:898–904.
169. Vescovi JD, Jamal SA, De Souza MJ. Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature. Osteoporos Int. 2008;19:465–478.
170. Hartard M, Kleinmond C, Kirchbichler A, et al.. Age at first oral contraceptive use as a major determinant of vertebral bone mass in female endurance athletes. Bone. 2004;35:836–841.
171. Cumming DC. Exercise-associated amenorrhea, low bone density, and estrogen replacement therapy. Arch Intern Med. 1996;156:2193–2195.
172. Rickenlund A, Carlstrom K, Ekblom B, et al.. Effects of oral contraceptives on body composition and physical performance in female athletes. J Clin Endocrinol Metab. 2004;89:4364–4370.
173. Rickenlund A, Thoren M, Nybacka A, et al.. Effects of oral contraceptives on diurnal profiles of insulin, insulin-like growth factor binding protein-1, growth hormone and cortisol in endurance athletes with menstrual disturbance. Hum Reprod. 2010;25:85–93.
174. Warren MP, Miller KK, Olson WH, et al.. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study. Contraception. 2005;72:206–211.
175. De Cree C, Lewin R, Ostyn M. Suitability of cyproterone acetate in the treatment of osteoporosis associated with athletic amenorrhea. Int J Sports Med. 1988;9:187–192.
176. Gremion G, Rizzoli R, Slosman D, et al.. Oligo-amenorrheic long-distance runners may lose more bone in spine than in femur. Med Sci Sports Exerc. 2001;33:15–21.
177. Hergenroeder AC, Smith EO, Shypailo R, et al.. Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months. Am J Obstet Gynecol. 1997;176:1017–1025.
178. Ohlsson C, Bengtsson BA, Isaksson OG, et al.. Growth hormone and bone. Endocr Rev. 1998;19:55–79.
179. Lebow J, Sim L. The influence of estrogen therapies on bone mineral density in premenopausal women with anorexia nervosa and amenorrhea. Vitam Horm. 2013;92:243–257.
180. Misra M, Katzman D, Miller KK, et al.. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res. 2011;26:2430–2438.
181. Kam K, Park Y, Cheon M, et al.. Effects of immobilization stress on estrogen-induced surges of luteinizing hormone and prolactin in ovariectomized rats. Endocrine. 2000;12:279–287.
182. Cardim HJ, Lopes CM, Giannella-Neto D, et al.. The insulin-like growth factor-I system and hormone replacement therapy. Fertil Steril. 2001;75:282–287.
183. Massaro M, Di Carlo C, Gargano V, et al.. Effects of the contraceptive patch and the vaginal ring on bone metabolism and bone mineral density: a prospective, controlled, randomized study. Contraception. 2010;81:209–214.
184. Massai R, Makarainen L, Kuukankorpi A, et al.. The combined contraceptive vaginal ring and bone mineral density in healthy pre-menopausal women. Hum Reprod. 2005;20:2764–2768.
185. Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, et al.. Oral contraceptives improve endothelial function in amenorrheic athletes. J Clin Endocrinol Metab. 2005;90:3162–3167.
186. Wiren KM, Zhang XW, Olson DA, et al.. Androgen prevents hypogonadal bone loss via inhibition of resorption mediated by mature osteoblasts/osteocytes. Bone. 2012;51:835–846.
187. Riggs BL, Khosla S, Melton LJ 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23:279–302.
188. Abu EO, Horner A, Kusec V, et al.. The localization of androgen receptors in human bone. J Clin Endocrinol Metab. 1997;82:3493–3497.
189. Miller KK, Meenaghan E, Lawson EA, et al.. Effects of risedronate and low-dose transdermal testosterone on bone mineral density in women with anorexia nervosa: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2011;96:2081–2088.
190. Welt CK, Chan JL, Bullen J, et al.. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351:987–997.
191. Sienkiewicz E, Magkos F, Aronis KN, et al.. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism. 2011;60:1211–1221.
192. Chou SH, Chamberland JP, Liu X, et al.. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci USA. 2011;108:6585–6590.
193. Misra M, McGrane J, Miller KK, et al.. Effects of rhIGF-1 administration on surrogate markers of bone turnover in adolescents with anorexia nervosa. Bone. 2009;45:493–498.
194. Grinspoon S, Thomas L, Miller K, et al.. Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. J Clin Endocrinol Metab. 2002;87:2883–2891.
195. Kluge M, Schussler P, Uhr M, et al.. Ghrelin suppresses secretion of luteinizing hormone in humans. J Clin Endocrinol Metab. 2007;92:3202–3205.
196. Lu M, Tang Q, Olefsky JM, et al.. Adiponectin activates adenosine monophosphate-activated protein kinase and decreases luteinizing hormone secretion in LbetaT2 gonadotropes. Mol Endocrinol. 2008;22:760–771.
197. Wen JP, Lv WS, Yang J, et al.. Globular adiponectin inhibits GnRH secretion from GT1-7 hypothalamic GnRH neurons by induction of hyperpolarization of membrane potential. Biochem Biophys Res Commun. 2008;371:756–761.
198. Wong IP, Driessler F, Khor EC, et al.. Peptide YY regulates bone remodeling in mice: a link between gut and skeletal biology. PLoS One. 2012;7:e40038.
199. Luo XH, Guo LJ, Xie H, et al.. Adiponectin stimulates RANKL and inhibits OPG expression in human osteoblasts through the MAPK signaling pathway. J Bone Miner Res. 2006;21:1648–1656.
200. Vulliemoz NR, Xiao E, Xia-Zhang L, et al.. Decrease in luteinizing hormone pulse frequency during a five-hour peripheral ghrelin infusion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab. 2004;89:5718–5723.
201. Watts NB, Lewiecki EM, Miller PD, et al.. National Osteoporosis Foundation 2008 Clinician's Guide to Prevention and Treatment of Osteoporosis and the World Health Organization Fracture Risk Assessment Tool (FRAX): what they mean to the bone densitometrist and bone technologist. J Clin Densitom. 2008;11:473–477.
202. Forwood MR, Burr DB. Physical activity and bone mass: exercises in futility? Bone Miner. 1993;21:89–112.
203. Nikander R, Sievanen H, Uusi-Rasi K, et al.. Loading modalities and bone structures at nonweight-bearing upper extremity and weight-bearing lower extremity: a pQCT study of adult female athletes. Bone. 2006;39:886–894.
204. Estrada K, Styrkarsdottir U, Evangelou E, et al.. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012;44:491–501.
205. Marini JC. Do bisphosphonates make children's bones better or brittle? N Engl J Med. 2003;349:423–426.
206. Papapoulos SE, Cremers SC. Prolonged bisphosphonate release after treatment in children. N Engl J Med. 2007;356:1075–1076.
207. Desai PA, Vyas PA, Lane JM. Atypical femoral fractures: a review of the literature. Curr Osteoporos Rep. 2013;11:179–187.
208. Shane E, Burr D, Abrahamsen B, et al.. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29:1–23.
209. Khosla S, Burr D, Cauley J, et al.. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479–1491.
210. Golden NH, Iglesias EA, Jacobson MS, et al.. Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2005;90:3179–3185.
211. Hoshino H, Takahashi M, Kushida K, et al.. The relationships between the degree of beta-isomerization of type I collagen degradation products in the urine and aging, menopause and osteoporosis with fractures. Osteoporos Int. 1999;9:405–409.
212. Bishop N, Adami S, Ahmed SF, et al.. Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382:1424–1432.
213. Rizzoli R, Adachi JD, Cooper C, et al.. Management of glucocorticoid-induced osteoporosis. Calcif Tissue Int. 2012;91:225–243.
214. Bachrach LK, Ward LM. Clinical review 1: bisphosphonate use in childhood osteoporosis. J Clin Endocrinol Metab. 2009;94:400–409.
215. Bachrach LK, Sills IN. Clinical report-bone densitometry in children and adolescents. Pediatrics. 2011;127:189–194.
216. Fazeli P, Wang I, Miller K, et al.. Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa. Abstract LB-SA33 presented at: American Society of Bone and Mineral Research Annual Meeting 2013, Baltimore, MD.
217. Raghavan P, Christofides E. Role of teriparatide in accelerating metatarsal stress fracture healing: a case series and review of literature. Clin Med Insights Endocrinol Diabetes. 2012;5:39–45.
218. Goolsby MA, Nattiv AN, Casper J. Predictors for stress fracture and stress fracture rate in male and female collegiate track athletes: a prospective analysis. Paper presented at: The 17th Annual American Medical Society for Sports Medicine Annual Meeting, The Canadian Academy of Sport Medicine, 2008 Annual Meeting, In Collaboration With: American Osteopathic Academy of Sports Medicine, Australasian College of Sports Physicians, March 25-29, 2008, Las Vegas, NV. Clin J Sport Med. 2008;18:188.
219. Okamoto S, Arai Y, Hara K, et al.. A displaced stress fracture of the femoral neck in an adolescent female distance runner with female athlete triad: a case report. Sports Med Arthrosc Rehabil Ther Technol. 2010;2:6.
220. Whiting SJ, Vatanparast H, Baxter-Jones A, et al.. Factors that affect bone mineral accrual in the adolescent growth spurt. J Nutr. 2004;134:696S–700S.
222. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al.. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–1930.
225. MacLennan AH. HRT in difficult circumstances: are there any absolute contraindications? Climacteric. 2011;14:409–417.
226. Oswald AJ, Berg J, Milne G, et al.. Teriparatide treatment of severe osteoporosis reduces the risk of vertebral fractures compared with standard care in routine clinical practice. Calcif Tissue Int. 2014;94:176–182.
227. Eriksen EF, Halse J, Moen MH. New developments in the treatment of osteoporosis. Acta Obstet Gynecol Scand. 2013;92:620–636.
228. Yeager KK, Agostini R, Nattiv A, et al.. The female athlete triad: disordered eating, amenorrhea, osteoporosis. Med Sci Sports Exerc. 1993;25:775–777.
229. Herring SA, Kibler WB, Putukian M. The team physician and the return-to-play decision: a consensus statement-2012 update. Med Sci Sports Exerc. 2012;44:2446–2448.
230. Kanis JA, Johnell O, Oden A, et al.. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385–397.
231. McCloskey E, Kanis JA. FRAX updates 2012. Curr Opin Rheumatol. 2012;24:554–560.
232. Herring SA, Kibler WB, Putukian M. Team physician consensus statement: 2013 update. Med Sci Sports Exerc. 2013;45:1618–1622.
233. Creighton DW, Shrier I, Shultz R, et al.. Return-to-play in sport: a decision-based model. Clin J Sport Med. 2010;20:379–385.
234. Torstveit MK, Sundgot-Borgen J. Participation in leanness sports but not training volume is associated with menstrual dysfunction: a national survey of 1276 elite athletes and controls. Br J Sports Med. 2005;39:141–147.
235. Kasa-Vubu JZ, Rosenthal A, Murdock EG, et al.. Impact of fatness, fitness, and ethnicity on the relationship of nocturnal ghrelin to 24-hour luteinizing hormone concentrations in adolescent girls. J Clin Endocrinol Metab. 2007;92:3246–3252.
236. Caine D, DiFiori J, Maffulli N. Physeal injuries in children's and youth sports: reasons for concern? Br J Sports Med. 2006;40:749–760.
237. Goolsby MA, Barrack MT, Nattiv A. A displaced femoral neck stress fracture in an amenorrheic adolescent female runner. Sports Health. 2012;4:352–356.
238. Haddad FS, Bann S, Hill RA, et al.. Displaced stress fracture of the femoral neck in an active amenorrhoeic adolescent. Br J Sports Med. 1997;31:70–72.
239. Smink FR, van Hoeken D, Hoek HW. Epidemiology of eating disorders: incidence, prevalence and mortality rates. Curr Psychiatry Rep. 2012;14:406–414.
240. Zipfel S, Lowe B, Reas DL, et al.. Long-term prognosis in anorexia nervosa: lessons from a 21-year follow-up study. Lancet. 2000;355:721–722.
241. Franko DL, Keshaviah A, Eddy KT, et al.. A longitudinal investigation of mortality in anorexia nervosa and bulimia nervosa. Am J Psychiatry. 2013;170:917–925.
242. Matheson GO, Shultz R, Bido J, et al.. Return-to-play decisions: are they the team physician's responsibility? Clin J Sport Med. 2011;21:25–30.
female athlete triad; energy availability; amenorrhea; menstrual disturbances; disordered eating; low bone mass; bone health; female athletes; nonpharmacological treatment; pharmacological treatment; return to play
Supplemental Digital Content
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Highlight selected keywords in the article text.