Female athlete triad: past, present, and future directions
Review Article

Female athlete triad: past, present, and future directions

William A. Ranson, Diana C. Patterson, Alexis C. Colvin

Department of Orthopaedic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: DC Patterson, AC Colvin; (III) Provision of study materials or patients: WA Ranson; (IV) Collection and assembly of data: WA Ranson; (V) Data analysis and interpretation: WA Ranson; (VI) Manuscript writing: All authors (VII) Final approval of manuscript: All authors. .

Correspondence to: William A. Ranson. 50 E 98th St #9H-1, New York, NY 10029, USA. Email: will.ranson@icahn.mssm.edu.

Abstract: Since the passage of Title IX in 1972, female participation in athletics has increased significantly. More girls and young women have been able to experience the psychosocial and physical health-related benefits of organized sports. Hand-in-hand with increased participation, however, has been a dramatic increase in a dangerous yet widely underdiagnosed sports-related condition—the female athlete triad. The triad was originally defined as the presence of disordered eating (DE), amenorrhea, and osteoporosis. Further research revealed these diagnostic criteria to be too narrow in scope however, and today’s definition has evolved into that of a dynamic interrelationship between decreased energy availability (EA), menstrual dysfunction, and low bone mineral density (BMD). If left untreated, long-term consequences include irreversible decreases in BMD and a predisposition to potentially debilitating musculoskeletal injuries. First line therapy is generally non-pharmacological with treatments aimed at altering eating and exercise behavior. In behavior modification refractory cases, certain pharmacological treatments may be utilized but this practice remains controversial. While no pharmacological approach to treatment is yet recommended, a recent clinical trial provides compelling evidence and its implications warrant further investigation.

Keywords: Female athlete triad; triad; amenorrhea; bone health; energy availability (EA)


Received: 30 November 2017; Accepted: 18 December 2017; Published: 11 January 2018.

doi: 10.21037/aoj.2017.12.09


Background

From the passage of Title IX federal legislation in 1972 to modern day, female participation in organized sports at all levels has increased dramatically. The stated intention of the law was to eliminate sex-based discrimination in all educational activities receiving federal financial support, including school sanctioned sports teams (1). In 1971, the year prior to enactment of Title IX, there were approximately 310,000 female athletes in the US, just 0.29% of the female population (2,3). By 2012, female participation in sports had climbed to 3,373,000, with 2.15% of the female population in the US participating in some level of organized athletics (4). Perhaps unsurprisingly, with increased female participation, a parallel increase in sports-related injury and disease has been observed.

Throughout the 1970’s, increases in self-reporting and physician observation of altered menarche in female athletes caught the attention of researchers. In 1977, Malina and Spirduso reported delayed menarche in high school-, college-, and Olympic-level athletes in comparison to non-athletes (5). Throughout the 1980’s, published literature investigated a connection between altered menarche, disordered eating (DE), and reduced bone mass in young female athletes (6-8). With increasing concern backed by a growing body of literature, the American College of Sports Medicine (ACSM) convened a panel in 1992 to lay the groundwork for a coordinated approach to prevention and treatment (9). During this meeting, the term the female athlete triad was first defined as a syndrome consisting of, but not limited to, DE, amenorrhea, and osteoporosis found in physically active girls and women.

Almost immediately following publication of the ACSM definition of the triad in 1992, the literature began to reveal growing dissatisfaction with its limits. Of particular concern was that athletes with less severe manifestations of these symptoms were being overlooked, as the diagnostic definition at the time included only clinical endpoints of each component (10). De Souza and Williams addressed this in 2004 by proposing an expansion of the definition to include subclinical presentations of DE, amenorrhea, and osteoporosis (11). This proposal was successfully integrated into the 2007 ACSM Position Stand and the triad’s diagnostic criteria underwent several important alterations. First, the Position Stand established a sliding model in which an athlete can fall anywhere on a continuum, from the disease state to optimal health, for each of the three interrelated components at any given point in time. Additionally, the definition was broadened, replacing DE with low energy availability (EA), amenorrhea with menstrual dysfunction, and osteoporosis with low bone mineral density (BMD) (12). In 2014, a comprehensive consensus statement was published by the Female Athlete Triad Coalition (FATC), and subsequently endorsed by the ACSM, that reaffirmed the diagnostic definition of the triad established in the 2007 ACSM Position Stand and emphasized the importance of early intervention in avoiding long-term damage (13).


Definition

According to the ACSM, the female athlete triad is a spectrum of abnormalities in EA, menstrual function, and BMD (12). The three abnormalities have been shown to be intimately connected and for each of the three a patient may present anywhere from good health to the disease state at any given time. Importantly, as one of the components may have a subclinical presentation yet still pose serious long-term danger if not addressed, an athlete need present with only one of the three components to be diagnosed under the umbrella of female athlete triad syndrome (13).

Decreased EA

Originally termed “disordered eating”, this component of the triad was refined in 2007 to refer to a spectrum of “energy availability”, defined as dietary energy intake minus exercise energy expenditure. Low EA may result from insufficient dietary intake, excessive energy expenditure, or a combination of the two. Importantly, patients may still be defined as experiencing low EA even if they have not been diagnosed with a specific eating disorder (ED) or DE (12). Overt signs of low EA include BMI ≤17.5 kg/m2 or <85% of expected weight for adolescents (12). Quantitatively, low EA is defined as energy intake (kcals) less energy expenditure due to exercise (kcals) divided by kilograms of fat free body mass (FFM), with low EA for female athletes considered to be less than 45 kcal kg-1 fat-free body mass per day (12,14). Additionally, reduced resting metabolic rate (RMR) and low triiodothyronine (T3) are physiologic adaptations to chronic energy deficits and should be considered diagnostic indicators of low EA (15,16).

Menstrual dysfunction

Menstrual dysfunction is a spectrum of symptoms ranging from luteal phase defects to amenorrhea (both primary and secondary) (17). Primary amenorrhea is defined as the failure to reach menarche. The American College of Obstetricians and Gynecologists (ACOG) states that an absence of menarche by 15 years of age or lack of menarche greater than three years after thelarche (Tanner stage II breast development) warrants further investigation (18). Secondary amenorrhea is defined by the achievement of menarche and establishment of a normal menstrual cycle for some period of time before an absence of menses in three consecutive months (19). Oligomenorrhea is similar to secondary amenorrhea in that it occurs following menarche, but rather than a complete halt of the menstrual cycle, menstruation occurs less frequently than every 35 days (20). Anovulation and luteal phase deficiency are additional findings that qualify an individual as having menstrual dysfunction. However, unlike amenorrhea and oligomenorrhea, they are asymptomatic and thus difficult to diagnose on clinical history alone (17).

Low BMD

Low BMD, the third defining characteristic of the triad, is thought to be a downstream effect of amenorrhea and associated disturbances in physiologic hormone cycling. The gold standard for BMD assessment is dual energy X-ray absorptiometry (DEXA) measurements of skeletal elements. From these scans, a Z-score is calculated to compare the patient’s BMD to that of a sample of the general population matched for both sex and age. The International Society for Clinical Densitometry (ISCD) definition of low BMD is utilized in establishing the diagnosis in children, adolescents and pre-menopausal women (21). For both children and adults, a Z-score <−1.0 is considered abnormal and a Z-score <−2.0 is diagnostic of low BMD (22). Low BMD can manifest clinically as stress fractures of the vertebra or long bones in female athletes.


Epidemiology

Over the past several decades, a plethora of research has been conducted on the prevalence of the three triad characteristics in populations ranging from sedentary high school students to elite female endurance athletes (23-41). Prevalence rates in these studies, however, vary substantially for nearly all symptoms and combinations due to differing study methodology and changing diagnostic criteria. The 2007 change in ACSM position stand, replacing DE with low EA, for example, has made determination of prevalence more difficult. To date no studies have been conducted to determine the prevalence of low EA in female athletes (24).

With the current consensus that the underlying etiology of the triad is low EA, it is not surprising that “lean sport athletes”, i.e., participants in sports that place an emphasis on endurance training, low body weight, lean physique, and aestheticism, tend to be affected in greater proportions than their non-lean sport counterparts (23,25). The three studies to date investigating rates of all three triad conditions simultaneously in young female athletes found a prevalence of 1.5–6.7% in lean sport athletes while non-lean sport athletes had a prevalence of 0.0–2.0% (25-27). Additionally, in a study of 186 elite female athletes under the age of 40, 35.6% lean sport athletes displayed DE and menstrual dysfunction while only 13.5% of non-lean sport athletes displayed such symptoms (25). Similar trends in DE and menstrual dysfunction between lean and non-lean sport athletes have been echoed by multiple other investigators (26,28,29).

The reported prevalence of any single triad characteristic varies greatly between studies. The prevalence of DE, for example, ranges from 7.1% in a study of 84 collegiate athletes to 89.2% in a study of 67 elite female Malaysian athletes. Despite this, most studies place the prevalence of DE among female athletes between 15% and 30% (30-36). Similarly, reported prevalence of menstrual dysfunction among studies utilizing self-reported menstrual history or menstrual history surveys ranges from 6% to 79% (25,27,28,32,42). In an attempt to improve both accuracy and precision, several studies have utilized hormone level measurements to diagnose menstrual dysfunction. The studies utilizing this approach found the prevalence of menstrual dysfunction to be between 41% and 50% for female athletes (37-39).

Despite extensive historical use of the World Health Organization T-score, recent practice has shifted towards the utilization of the ISCD Z-score for the diagnosis of low BMD. Unlike the T-score, which controls only for gender (43), the Z-score controls for both age and gender and is thought to be a better measure of low BMD in younger populations (44). Studies utilizing the Z-score have shown the prevalence of low BMD, defined as a Z-score <−1.0, in young female athletes to be between 10% and 25% (24,27,28,35) while that of endurance athletes tends to be greater, between 30% and 40% (40,41).


Diagnosis

Low EA

Screening for low EA always begins with a thorough history of diet, exercise, and eating habits. Determination of an individual’s EA can be accomplished through 3- or 7-day dietary logs, a 24-hour food recall log, or food-frequency questionnaire (13). While relatively simple to administer and complete, this method relies on self-reporting and can be inaccurate (45). When self-reporting is suspicious or unreliable, physical indicators become more important. These include recent weight loss or signs of DE or ED such as bradycardia, lanugo, poor dentition, orthostatic hypotension, parotitis, and Russell’s sign, calluses on the knuckles or back of the hand due to repeated self-induced vomiting of long periods of time (12,13,46,47). Importantly, absence of recent weight loss does not rule out the presence of low EA, as studies have demonstrated the body’s preferential disruption of physiological function in favor of stabilizing mass under certain conditions (8,12,48-50).

Studies have shown certain metabolic abnormalities to be associated with triad symptoms. Elevated concentrations of serum growth hormone (GH) (51), ghrelin (52,53), peptide YY (PYY) (53), and urinary 24 hour cortisol (39) as well as decreased levels of insulin (54), plasma glucose (54), serum triiodothyronine (TT3) (15,52) and insulin-like growth factor-1 (IGF-1) (55) have been linked with this population. While these findings are not pathognomonic, blood testing for these species may be used to aid in diagnosis when history and physical examination alone prove insufficient (13).

Menstrual dysregulation

The diagnosis of menstrual dysfunction secondary to low EA is one of exclusion (13). When a patient presents with complaints that arouse clinical suspicion of menstrual dysfunction, the 2014 FATC Consensus Statement suggests using an algorithm modified from the Jameson et al. textbook of endocrinology (56). First, history and physical examination should be performed to rule out uterine pathology, outflow tract obstruction, and disorders of sexual differentiation as causes of primary amenorrhea. Pregnancy must be ruled out with a urine test. Primary ovarian insufficiency, one of the most common causes of amenorrhea, can be ruled out by testing follicle stimulating hormone (FSH) levels. Hyperprolactinemia and thyroid dysfunction can be ruled out via prolactin and thyroid stimulating hormone (TSH) tests, respectively. The presence of hypothalamic and pituitary disorders can be assessed with a serum estradiol or progesterone challenge test to quantify the degree of hypoestrogenism. Finally, hyperandrogenic conditions including polycystic ovary syndrome, virilizing ovarian tumors, adrenal tumors, nonclassic congenital adrenal hyperplasia, and Cushing’s syndrome (13,57,58) may be ruled out by measuring testosterone (total and free) and dehydroepiandrosterone and its sulfate (DHEA/S) (13) paired with an early morning 17-hydroxyprogesterone test (to assess for non-classic 21-hydroxylase deficiency), and a pelvic ultrasound.

Low BMD

The third component of the triad, low BMD, is analyzed using DXA measurements. For children and adolescents <20 years of age, a posterior-anterior (PA) radiographic view of the spine and a total body less head (TBLH) image should be utilized (59). In adults aged ≥20 years, a PA view of the lumbar spine and an image of the hip should be used (60). From these scans, a Z-score can be calculated. For both children and adults, a Z-score <−1.0 is considered abnormal and a Z-score <−2.0 is diagnostic of low BMD (22). In both cases, prior history of fracture and associated trauma should be investigated in depth.


Etiologies and consequences

A deficit in EA is the cornerstone of the triad and precipitates a trickle-down effect, altering menstrual function, BMD, and cardiovascular health (11). When EA drops below a certain threshold, approximately 30 kcal/kg FFM/day, a physiologic shift occurs in which metabolic fuels are redirected from costly reproductive functions toward processes essential for sustaining life (61). As a result, release of gonadotropin releasing hormone (GnRH) from the hypothalamus is reduced, producing a stark decline in circulating estrogen levels. Lending to the importance of early recognition and treatment, studies have shown that decreases in EA below 30 kcal/kg FFM/day can lead to menstrual disturbances within 5 days (50,62-67).

Musculoskeletal health is of particular concern in female athletes with menstrual dysregulation as high levels of estrogen are needed to reverse bone resorption (68,69). In amenorrheic athletes, BMD declines consistently for as long as estrogen levels are depressed (70,71) resulting in constantly increasing risk of musculoskeletal injury (72-75). Even more troubling is that by 18 years of age, females have typically accumulated 90–95% of their peak BMD and will work to maintain this bone mass throughout adulthood (76-78). Failure to achieve peak bone mass during this period predisposes these individuals to clinically low BMD throughout adulthood, leading to increased incidence of painful and potentially debilitating stress fractures throughout their adult life (79,80). Emphasizing the importance of early detection and intervention, it has been shown that accumulated loss of BMD due to low EA and menstrual dysfunction may not be reversible in all cases (70,81,82).

Although it is not one of the three defining symptoms, recent literature has proposed that deleterious changes in cardiovascular health may also be associated with the triad (11). It is hypothesized that disruption of the HPG (hypothalamic-pituitary-gonadal) axis may decrease endothelial function and predispose female athletes to early heart disease. Estrogen is necessary to promote nitric oxide (NO) production and vascular endothelial release (83). Endothelial-derived NO and its vasodilatory properties promote anti-atherosclerotic effects while suppressed NO release in amenorrheic athletes has been associated with decreased flow mediated dilation (FMD) of vessels, increased total cholesterol and LDL, and decreased overall cardiovascular health (84-86). Additional long-term, prospective studies are necessary.


Interventions

Non-pharmacological treatment

Nutritional intervention is the first line therapy for female athletes with symptoms as it most directly targets the underlying etiology (87). Through either modification of diet, exercise frequency and intensity, or both, the energy status of the athlete must first be normalized. In the return to play (RTP) guidelines published by the FATC in 2014, a gradual increase in body mass is advised with patients ideally increasing their energy intake to 20–30% above baseline needs for a weight gain goal of approximately 0.5 kg every 7 to 10 days (13). Additional studies have suggested that gain of between 1–4 kg of body mass is associated with the resumption of menses, however this number varies between individuals. A target EA of 45 kcal kg-1 FFM d-1 is a better goal than absolute weight gain (47,87-89).

While increasing EA is a mainstay of treatment in every athlete, specific recommendations vary to match the manner in which the individual came to develop low EA. For cases in which the cause of low EA is undereating in the absence of DE, referral to a sports dietitian for nutritional education is sufficient. If the cause of low EA is DE, the athlete should be directed to a physician for assessment and management, a mental health professional for psychological treatment, and a dietitian (12,90).

The goal for treatment of low EA via non-pharmacological methods is to reverse the patient’s energy deficit, allowing normalization of the HPG axis and bone metabolism. In the first few days following the initiation of treatment, likely before weight gain is even noticeable, metabolic hormone profiles will improve and bone formation will be upregulated (13,64). Weight gain to a target EA of 45 kcal kg-1 FFM d-1 will take months, but may be shorter depending on the severity of symptoms at presentation (13). Weight gain has been associated with the resumption of menses in exercising women (89,91-93). However, in several cases menstruation didn’t occur for more than a year following treatment initiation and weight gain (47,92,94). Improvements in BMD, secondary to the effects of improved metabolic hormone profiles, increased weight bearing upon weight gain, and restored LH pulsatility, are thought to be the final physiological change to occur. However, existing literature is in disagreement as to whether BMD levels appropriate for age and build can be fully restored (81,95,96).

Pharmacological treatment

Pharmacological treatment of the triad remains controversial, with the most recent FATC Consensus Statement stating that, due to a lack of evidence-based research, pharmacological therapy cannot be recommended unequivocally (13). Despite this guideline, concerned physicians often prescribe pharmacological treatment regimens when more conservative non-pharmacological management has proven ineffective. In such scenarios, worsening BMD with recurrent long bone fractures, prolonged amenorrhea, or development of ED despite 12 months of conservative treatment is generally considered sufficient to warrant pharmacological intervention (13,87).

Young females presenting with ED require an interdisciplinary approach to treatment, particularly the inclusion of a mental health professional. While treatment in these cases may initially utilize non-pharmacological approaches such as positive psychology and behavioral therapy (97), prescription of certain medications may be highly beneficial. In particular, utilization of selective serotonin reuptake inhibitors (SSRI) has been shown to be helpful in the treatment of bulimia nervosa (98) while a growing body of evidence has found olanzapine useful in weight-related outcomes of anorexia nervosa (AN) treatment (99-101).

The majority of pharmacological therapies utilized both currently and in recent years to treat low BMD in young females have revolved around the replacement of gonadal steroids (13). Following recognition of low estrogen levels and their effects in the amenorrheic athlete, treatment with combined oral contraceptives (COC) became a primary interest. In theory, COC therapy would artificially elevate estrogen levels, decrease osteoclastic bone resorption activity and ultimately increase BMD (87). Further studies showed, however, that while COC does indeed increase estrogen levels, this treatment has not yielded consistent improvements in BMD in amenorrheic athletes (102-106). It is thought that the first pass metabolism of COC drugs in the liver decreases the hepatic production of IGF-1 (107-109). Overall, COC therapy does slow osteoclastic bone resorption, but its negative effect on bone trophic hormone levels predominates (103,105).

In a recent RCT assessing adolescent girls with AN by Misra et al., a transdermal estradiol (100 mg 17-B-estradiol) patch coupled with cyclic oral progestin (2.5 mg d-1 medroxyprogesterone, 10 d mo-1) (110) was administered. In the 18-month trial, increases in lumbar spine BMD were reported at each of the three measurement time points included in the study. Additionally, the change in IGF-1 across the 18 month intervention showed no significant difference between the group receiving transdermal estradiol and placebo (110). It is thought that non-oral administration of estradiol bypasses first-pass metabolism, avoiding a decrease of hepatic IGF-1 secretion and ultimately producing the desirable effect of increased BMD (109-112).

In addition, some medications typically used in the treatment of low BMD in older and postmenopausal women have been utilized in young female athletes (113,114). Bisphosphonates, compounds that impair osteoclast function and slow bone resorption, have been considered (115). However, they have a very long half-life and substantial teratogenicity (116,117). Due to this side effect, it is generally recommended that bisphosphonates only be used with extreme caution as a last line of treatment (13,118). Recombinant parathyroid hormone (rPTH) is being investigated for use in young amenorrheic athletes, but no public studies regarding its safety and efficacy exist yet (114,118,119).


RTP

Despite continued research into risk factors, diagnosis, and treatment, there were no standardized guidelines for athlete clearance and RTP until recently. In hopes of solving this issue, the 2014 FATC consensus statement outlined a score-based cumulative risk assessment calculation and corresponding RTP risk stratification rubric for ease of physician use and standardization of patient management (13). The cumulative risk assessment worksheet grades the clinical presentation of six risk factors on a scale of increasing severity. Upon summation of the score, the patient falls into one of three categories: full clearance, provisional/limited clearance, or restricted from training and competition. To date, no studies have been conducted to assess the efficacy of the proposed RTP protocols.

When making the RTP decision, input from the multidisciplinary team of healthcare professionals treating the patient is advisable and input from other concerned parties such as parents and coaches can be valuable. Ultimately, however, it is of the utmost importance that the athlete’s physician make the ultimate decision on RTP (120-122). Because of a current lack of evidence to validate the proposed RTP assessment and guidelines as well as the unique circumstances of each individual athlete, the RTP decision is seen as more of an art than a science. The physician must consider input from involved parties in conjunction with the patient’s past medical history, lab tests, sport played, and any conflicts of interest that may be present (123). In making such a difficult decision the patient’s current and future health must, in all cases, supersede external pressures and circumstances.


Acknowledgements

None.


Footnote

Conflicts of Interest: AC Colvin is Committee Member of AAOS and Editorial Board of Annals of Joint. The other authors have no conflicts of interest to declare.


References

  1. Title IX, Education Amendments of 1972. Cited 2017 Feb 2. Available online: https://www.dol.gov/oasam/regs/statutes/titleix.htm
  2. Barra A. Before and After Title IX: Women in Sports - Interactive Feature - NYTimes.com. New York Times. 2012. Cited 2017 Feb 2. Available online: http://www.nytimes.com/interactive/2012/06/17/opinion/sunday/sundayreview-titleix-timeline.html?_r=1&#/#time12_264
  3. Centers for Disease Control and Prevention. Population by age groups, race, and sex for 1960-97. 1998. Cited 2017 Feb 2. Available online: https://www.cdc.gov/nchs/data/statab/pop6097.pdf
  4. United States Census Bureau. Annual Estimates of the Resident Population by Sex, Race, and Hispanic Origin for the United States, States, and Counties: April 1, 2010 to July 1, 2014. 2014. Cited 2017 Dec 5. Available online: https://factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml?src=bkmk
  5. Malina RM, Spirduso WW, Tate C, et al. Age at menarche and selected menstrual characteristics in athletes at different competitive levels and in different sports. Med Sci Sports 1978;10:218-22. [PubMed]
  6. Warren MP, Brooks-Gunn J, Hamilton LH, et al. Scoliosis and fractures in young ballet dancers. Relation to delayed menarche and secondary amenorrhea. N Engl J Med 1986;314:1348-53. [Crossref] [PubMed]
  7. Howat PM, Carbo ML, Mills GQ, et al. The influence of diet, body fat, menstrual cycling, and activity upon the bone density of females. J Am Diet Assoc 1989;89:1305-7. [PubMed]
  8. Marcus R, Cann C, Madvig P, et al. Menstrual function and bone mass in elite women distance runners. Ann Intern Med 1985;102:158-63. [Crossref] [PubMed]
  9. Yeager KK, Agostini R, Nattiv A, et al. The female athlete triad: disordered eating, amenorrhea, osteoporosis. Med Sci Sports Exerc 1993;25:775-7. [Crossref] [PubMed]
  10. Slater J, Brown R, McLay-Cooke R, et al. Low Energy Availability in Exercising Women: Historical Perspectives and Future Directions. Sports Med 2017;47:207-20. [Crossref] [PubMed]
  11. De Souza MJ, Williams NI. Physiological aspects and clinical sequelae of energy deficiency and hypoestrogenism in exercising women. Hum Reprod Update 2004;10:433-48. [Crossref] [PubMed]
  12. Nattiv A, Loucks AB, Manore MM, et al. The female athlete triad. Med Sci Sports Exerc 2007;39:1867-82. [Crossref] [PubMed]
  13. Joy E, De Souza MJ, Nattiv A, et al. 2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad. Curr Sports Med Rep 2014;13:219-32. [PubMed]
  14. Loucks AB. Low energy availability in the marathon and other endurance sports. Sports Med 2007;37:348-52. [Crossref] [PubMed]
  15. 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;88:971-5. [Crossref] [PubMed]
  16. 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. [Crossref] [PubMed]
  17. Weiss Kelly AK, Hecht S. COUNCIL ON SPORTS MEDICINE AND FITNESS. The Female Athlete Triad. Pediatrics 2016;138:e20160922. [Crossref] [PubMed]
  18. ACOG Committee on Adolescent Health Care. ACOG Committee Opinion No. 349, November 2006: Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstet Gynecol 2006;108:1323-8. [Crossref] [PubMed]
  19. Braverman PK, Sondheimer SJ. Menstrual disorders. Pediatr Rev 1997;18:17-25. [Crossref] [PubMed]
  20. Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol 2014;124:193-7. [Crossref] [PubMed]
  21. Lewiecki EM, Gordon CM, Baim S, et al. International Society for Clinical Densitometry 2007 Adult and Pediatric Official Positions. Bone 2008;43:1115-21. [Crossref] [PubMed]
  22. Baim S, Leonard MB, Bianchi ML, et al. Official Positions of the International Society for Clinical Densitometry and Executive Summary of the 2007 ISCD Pediatric Position Development Conference. J Clin Densitom 2008;11:6-21. [Crossref] [PubMed]
  23. Gibbs JC, Williams NI, De Souza MJ, et al. Prevalence of Individual and Combined Components of the Female Athlete Triad. Med Sci Sports Exerc 2013;45:985-96. [Crossref] [PubMed]
  24. Hoch AZ, Pajewski NM, Moraski L, et al. Prevalence of the female athlete triad in high school athletes and sedentary students. Clin J Sport Med 2009;19:421-8. [Crossref] [PubMed]
  25. Torstveit MK, Sundgot-Borgen J. The female athlete triad exists in both elite athletes and controls. Med Sci Sports Exerc 2005;37:1449-59. [Crossref] [PubMed]
  26. Quah YV, Poh BK, Ng LO, et al. The female athlete triad among elite Malaysian athletes: prevalence and associated factors. Asia Pac J Clin Nutr 2009;18:200-8. [PubMed]
  27. Beals KA, Hill AK. The prevalence of disordered eating, menstrual dysfunction, and low bone mineral density among US collegiate athletes. Int J Sport Nutr Exerc Metab 2006;16:1-23. [Crossref] [PubMed]
  28. Nichols JF, Rauh MJ, Lawson MJ, et al. Prevalence of the female athlete triad syndrome among high school athletes. Arch Pediatr Adolesc Med 2006;160:137-42. [Crossref] [PubMed]
  29. Thein-Nissenbaum JM, Carr KE. Female athlete triad syndrome in the high school athlete. Phys Ther Sport 2011;12:108-16. [Crossref] [PubMed]
  30. Beals KA, Manore MM. Disorders of the female athlete triad among collegiate athletes. Int J Sport Nutr Exerc Metab 2002;12:281-93. [Crossref] [PubMed]
  31. Burrows M, Shepherd H, Bird S, et al. The components of the female athlete triad do not identify all physically active females at risk. J Sports Sci 2007;25:1289-97. [Crossref] [PubMed]
  32. Cobb KL, Bachrach LK, Greendale G, et al. Disordered Eating, Menstrual Irregularity, and Bone Mineral Density in Female Runners. Med Sci Sports Exerc 2003;35:711-9. [Crossref] [PubMed]
  33. Holderness CC, Brooks-Gunn J, Warren MP. Eating disorders and substance use: a dancing vs a nondancing population. Med Sci Sports Exerc 1994;26:297-302. [Crossref] [PubMed]
  34. Nichols JF, Rauh MJ, Barrack MT, et al. Disordered eating and menstrual irregularity in high school athletes in lean-build and nonlean-build sports. Int J Sport Nutr Exerc Metab 2007;17:364-77. [Crossref] [PubMed]
  35. 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;45:243-52. [Crossref] [PubMed]
  36. Vardar SA, Vardar E, Altun GD, et al. Prevalence of the female athlete triad in edirne, Turkey. J Sports Sci Med 2005;4:550-5. [PubMed]
  37. Broocks A, Pirke KM, Schweiger U, et al. Cyclic ovarian function in recreational athletes. J Appl Physiol 1985;1990:2083-6. [PubMed]
  38. 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. [Crossref] [PubMed]
  39. 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;83:4220-32. [PubMed]
  40. Barrack MT, Rauh MJ, Nichols JF. Prevalence of and traits associated with low BMD among female adolescent runners. Med Sci Sports Exerc 2008;40:2015-21. [Crossref] [PubMed]
  41. Pollock N, Grogan C, Perry M, et al. Bone-mineral density and other features of the female athlete triad in elite endurance runners: a longitudinal and cross-sectional observational study. Int J Sport Nutr Exerc Metab 2010;20:418-26. [Crossref] [PubMed]
  42. 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. [Crossref] [PubMed]
  43. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994;843:1-129. [PubMed]
  44. Writing Group for the ISCD Position Development Conference. Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom 2004;7:17-26. [Crossref] [PubMed]
  45. 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;20:245-56. [Crossref] [PubMed]
  46. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Arlington, 2013. Available online: http://encore.llu.edu/iii/encore/record/C__Rb1280248__SDSM-V__P0,2__Orightresult__X3;jsessionid=ABB7428ECBC4BA66625EDD0E0C5AAFA5?lang=eng&suite=cobalt%5Cnhttp://books.google.com/books?id=EIbMlwEACAAJ&pgis=1
  47. 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. [Crossref] [PubMed]
  48. Deuster PA, Kyle SB, Moser PB, et al. Nutritional intakes and status of highly trained amenorrheic and eumenorrheic women runners. Fertil Steril 1986;46:636-43. [Crossref] [PubMed]
  49. Kaiserauer S, Snyder AC, Sleeper M, et al. Nutritional, physiological and menstrual status of distance runners. Med Sci Sports Exerc 1989;21:120-5. [Crossref] [PubMed]
  50. 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. [Crossref] [PubMed]
  51. Waters DL, Qualls CR, Dorin R, et al. Increased pulsatility, process irregularity, and nocturnal trough concentrations of growth hormone in amenorrheic compared to eumenorrheic athletes. J Clin Endocrinol Metab 2001;86:1013-9. [PubMed]
  52. De Souza MJ, Leidy HJ, O’Donnell E, et al. Fasting ghrelin levels in physically active women: Relationship with menstrual disturbances and metabolic hormones. J Clin Endocrinol Metab 2004;89:3536-42. [Crossref] [PubMed]
  53. 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;52:184-92. [Crossref] [PubMed]
  54. Laughlin GA, Yen SS. Nutritional and endocrine-metabolic aberrations in amenorrheic athletes. J Clin Endocrinol Metab 1996;81:4301-9. [PubMed]
  55. Laughlin GA, Yen SS. Hypoleptinemia in women athletes: Absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab 1997;82:318-21. [Crossref] [PubMed]
  56. Jameson JL, DeGroot LJ, de Kretser DM. Endocrinology: Adult and pediatric. Philadelphia: Saunders/Elsevier, 2010.
  57. The Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. 2008 Compend Pract Comm Reports. 2008;90:S219-25. Available online: http://www.sciencedirect.com/science/article/pii/S0015028208035279
  58. De Souza MJ, Toombs RJ. Amenorrhea Associated With the Female Athlete Triad: Etiology, Diagnosis, and Treatment. In: Santoro NF, Neal-Perry G. editors. Amenorrhea: A Case-Based, Clinical Guide. Springer Science+Business Media; 2010. New York: Springer Science+Business Media, 2010:101-25.
  59. Gordon CM, Leonard MB, Zemel BS. 2013 Pediatric Position Development Conference: executive summary and reflections. J Clin Densitom 2014;17:219-24. [Crossref] [PubMed]
  60. Kendler DL, Borges JL, Fielding RA, et al. The Official Positions of the International Society for Clinical Densitometry: Indications of Use and Reporting of DXA for Body Composition. J Clin Densitom 2013;16:496-507. [Crossref] [PubMed]
  61. Wade GN, Schneider JE, Li HY. Control of fertility by metabolic cues. Am J Physiol 1996;270:E1-19. [PubMed]
  62. 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. [Crossref] [PubMed]
  63. 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. [Crossref] [PubMed]
  64. Ihle R, Loucks AB. Dose-response relationships between energy availability and bone turnover in young exercising women. J Bone Miner Res 2004;19:1231-40. [Crossref] [PubMed]
  65. Beidleman BA, Puhl JL, De Souza MJ. Energy balance in female distance runners. Am J Clin Nutr 1995;61:303-11. [Crossref] [PubMed]
  66. Fogelholm GM, Kukkonen-Harjula TK, Taipale SA, et al. Resting metabolic rate and energy intake in female gymnasts, figure-skaters and soccer players. Int J Sports Med 1995;16:551-6. [Crossref] [PubMed]
  67. Mulligan K, Butterfield GE. Discrepancies between energy intake and expenditure in physically active women. Br J Nutr 1990;64:23-36. [Crossref] [PubMed]
  68. Järvinen TLN, Kannus P, Sievänen H. Estrogen and bone--a reproductive and locomotive perspective. J Bone Miner Res 2003;18:1921-31. [Crossref] [PubMed]
  69. Riggs BL, Khosla S, Melton LJ. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998;13:763-73. [Crossref] [PubMed]
  70. Drinkwater BL, Bruemner B, Chesnut C. Menstrual history as a determinant of current bone density in young athletes. JAMA 1990;263:545-8. [Crossref] [PubMed]
  71. Lloyd T, Myers C, Buchanan JR, et al. Collegiate women athletes with irregular menses during adolescence have decreased bone density. Obstet Gynecol 1988;72:639-42. [PubMed]
  72. Bennell K, Matheson G, Meeuwisse W, et al. Risk factors for stress fractures. Sports Med 1999;28:91-122. [Crossref] [PubMed]
  73. Bennell KL, Malcolm SA, Thomas SA, et al. Risk Factors for Stress Fractures in Track and Field Athletes. Am J Sports Med 1996;24:810-8. [Crossref] [PubMed]
  74. 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;39:1457-63. [Crossref] [PubMed]
  75. Barrow GW, Saha S. Menstrual irregularity and stress fractures in collegiate female distance runners. Am J Sports Med 1988;16:209-16. [Crossref] [PubMed]
  76. Weaver CM, Gordon CM, Janz KF, et al. The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. Osteoporos Int 2016;27:1281-386. [Crossref] [PubMed]
  77. Baxter-Jones AD, Faulkner RA, Forwood MR, et al. Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J Bone Miner Res 2011;26:1729-39. [Crossref] [PubMed]
  78. 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. [Crossref] [PubMed]
  79. Clarke BL, Khosla S. Physiology of Bone Loss. Radiol Clin North Am 2010;48:483-95. [Crossref] [PubMed]
  80. Johnell O, Kanis JA, Oden A, et al. Predictive Value of BMD for Hip and Other Fractures. J Bone Miner Res 2005;20:1185-94. [Crossref] [PubMed]
  81. Keen AD, Drinkwater BL. Irreversible bone loss in former amenorrheic athletes. Osteoporos Int 1997;7:311-5. [Crossref] [PubMed]
  82. 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. [Crossref] [PubMed]
  83. Sobrino A, Vallejo S, Novella S, et al. Mas receptor is involved in the estrogen-receptor induced nitric oxide-dependent vasorelaxation. Biochem Pharmacol 2017;129:67-72. [Crossref] [PubMed]
  84. 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;90:1354-9. [Crossref] [PubMed]
  85. Zeni Hoch A, Dempsey RL, Carrera GF, et al. Is there an association between athletic amenorrhea and endothelial cell dysfunction? Med Sci Sports Exerc 2003;35:377-83. [Crossref] [PubMed]
  86. Yoshida N, Ikeda H, Sugi K, et al. Impaired endothelium-dependent and -independent vasodilation in young female athletes with exercise-associated amenorrhea. Arterioscler Thromb Vasc Biol 2006;26:231-2. [Crossref] [PubMed]
  87. Southmayd EA, Hellmers AC, De Souza MJ. Food Versus Pharmacy: Assessment of Nutritional and Pharmacological Strategies to Improve Bone Health in Energy-Deficient Exercising Women. Curr Osteoporos Rep 2017;15:459-72. [Crossref] [PubMed]
  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. [Crossref] [PubMed]
  89. 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. [Crossref] [PubMed]
  90. Temme KE, Hoch AZ. Recognition and rehabilitation of the female athlete triad/tetrad: a multidisciplinary approach. Curr Sports Med Rep 2013;12:190-9. [Crossref] [PubMed]
  91. Fredericson M, Kent K. Normalization of bone density in a previously amenorrheic runner with osteoporosis. Med Sci Sports Exerc 2005;37:1481-6. [Crossref] [PubMed]
  92. 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;93:1231-7. [Crossref] [PubMed]
  93. 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;36:137-42. [Crossref] [PubMed]
  94. 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. [Crossref] [PubMed]
  95. Drinkwater BL, Nilson K, Ott S, et al. Bone mineral density after resumption of menses in amenorrheic athletes. JAMA 1986;256:380-2. [Crossref] [PubMed]
  96. 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;81:669-74. [PubMed]
  97. 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. [Crossref] [PubMed]
  98. 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;12:400-43. [Crossref] [PubMed]
  99. Bissada H, Tasca GA, Barber AM, et al. Olanzapine in the treatment of low body weight and obsessive thinking in women with anorexia nervosa: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2008;165:1281-8. [Crossref] [PubMed]
  100. Brambilla F, Garcia CS, Fassino S, et al. Olanzapine therapy in anorexia nervosa: psychobiological effects. Int Clin Psychopharmacol 2007;22:197-204. [Crossref] [PubMed]
  101. Attia E, Kaplan AS, Walsh BT, et al. Olanzapine versus placebo for out-patients with anorexia nervosa. Psychol Med 2011;41:2177-82. [Crossref] [PubMed]
  102. 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;176:1017-25. [Crossref] [PubMed]
  103. 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;72:206-11. [Crossref] [PubMed]
  104. Rickenlund A, Carlström K, Ekblom B, et al. Effects of Oral Contraceptives on Body Composition and Physical Performance in Female Athletes. J Clin Endocrinol Metab 2004;89:4364-70. [Crossref] [PubMed]
  105. Grinspoon SK, Friedman AJ, Miller KK, et al. Effects of a triphasic combination oral contraceptive containing norgestimate/ethinyl estradiol on biochemical markers of bone metabolism in young women with osteopenia secondary to hypothalamic amenorrhea. J Clin Endocrinol Metab 2003;88:3651-6. [Crossref] [PubMed]
  106. 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;39:1464-73. [Crossref] [PubMed]
  107. Lebow J, Sim L. The influence of estrogen therapies on bone mineral density in premenopausal women with anorexia nervosa and amenorrhea. Vitam Horm 2013;92:243-57. [Crossref] [PubMed]
  108. Leung KC, Johannsson G, Leong GM, et al. Estrogen Regulation of Growth Hormone Action. Endocr Rev 2004;25:693-721. [Crossref] [PubMed]
  109. 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;72:374-81. [Crossref] [PubMed]
  110. 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;26:2430-8. [Crossref] [PubMed]
  111. Kam GY, Leung KC, Baxter RC, et al. Estrogens exert route- and dose-dependent effects on insulin-like growth factor (IGF)-binding protein-3 and the acid-labile subunit of the IGF ternary complex. J Clin Endocrinol Metab 2000;85:1918-22. [PubMed]
  112. Cardim HJ, Lopes CM, Giannella-Neto D, et al. The insulin-like growth factor-I system and hormone replacement therapy. Fertil Steril 2001;75:282-7. [Crossref] [PubMed]
  113. Cohen A, Fleischer J, Freeby MJ, et al. Clinical Characteristics and Medication Use among Premenopausal Women with Osteoporosis and Low BMD: The Experience of an Osteoporosis Referral Center. J Womens Health (Larchmt) 2009;18:79-84. [Crossref] [PubMed]
  114. Raghavan P, Christofides E. Elena Christofides. 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. [Crossref] [PubMed]
  115. Marini JC. Do Bisphosphonates Make Children’s Bones Better or Brittle? N Engl J Med 2003;349:423-6. [Crossref] [PubMed]
  116. Papapoulos SE, Cremers SC. Prolonged bisphosphonate release after treatment in children. N Engl J Med 2007;356:1075-6. [Crossref] [PubMed]
  117. Misra M, Klibanski A. Anorexia nervosa and bone. J Endocrinol 2014;221:R163-76. [Crossref] [PubMed]
  118. Gordon CM, Ackerman KE, Berga SL, et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2017;102:1413-39. [Crossref] [PubMed]
  119. Fazeli PK, Wang IS, Miller KK, et al. Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa. J Clin Endocrinol Metab 2014;99:1322-9. [Crossref] [PubMed]
  120. 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;44:2446-8. [Crossref] [PubMed]
  121. Herring SA, Kibler WB, Putukian M. Team Physician Consensus Statement: 2013 update. Med Sci Sports Exerc 2013;45:1618-22. [Crossref] [PubMed]
  122. 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. [Crossref] [PubMed]
  123. Creighton DW, Shrier I, Shultz R, et al. Return-to-Play in Sport: A Decision-based Model. Clin J Sport Med 2010;20:379-85. [Crossref] [PubMed]
doi: 10.21037/aoj.2017.12.09
Cite this article as: Ranson WA, Patterson DC, Colvin AC. Female athlete triad: past, present, and future directions. Ann Joint 2018;3:4.