Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Distinguish the risk factors for and clinical features of the female athlete triad and relative energy deficiency.
2. Describe changes in menstruation and bone health that occur with the female athlete triad and relative energy deficiency.
3. Propose management strategies for patients with the female athlete triad and relative energy deficiency.
In 1992, the American College of Sports Medicine coined the term "female athlete triad" (FAT), defining this condition as the constellation of disordered eating, amenorrhea, and osteoporosis.1 The triad is a syndrome characterized by metabolic injury due to an energy deficiency that cannot fully support all physiologic processes.2 It is most commonly observed in athletes who participate in activities emphasizing leanness, aesthetics, and endurance.3 In young women who exercise, the prevalence of any 1 triad component ranges from 16.0% to 60.0%, the prevalence of any 2 ranges from 2.7% to 27.0%, and the prevalence of all 3 ranges from 0% to 15.9%.4 However, despite this high prevalence, a 2006 survey demonstrated that only 17% of gynecologists were able to identify all 3 components of the triad.5 This lack of physician awareness can lead to delays in diagnosis and treatment for young women who may suffer sequelae. Patients and families themselves may also ignore or dismiss menstrual irregularity, assuming it is a normal consequence of exercise or generally common in the adolescent age group.
In 2007, the definition of the FAT was modified to the combination of low energy availability (LEA, with or without an eating disorder), menstrual dysfunction, and decreased bone mineral density.6,7 In this definition, all 3 components are not necessary for the diagnosis; therefore, patients may fall on a spectrum of varying severity. The terminology "relative energy deficiency in sport" (RED-S) was then introduced in 2014 by the International Olympic Committee to recognize that LEA can affect nonfemale athletes and has repercussions beyond the female reproductive system and skeleton. Sequelae may involve the cardiovascular, gastrointestinal, renal, and central nervous systems.8 Functionally, the FAT and RED-S encompass very similar conditions, although RED-S is more inclusive of subtler findings, which allows identification of more at-risk patients. For example, whereas a healthy athlete will have monthly menstrual cycles, optimal energy availability (EA), and healthy bones, a patient with RED-S will have reduced EA with or without disordered eating, irregular menstruation, and anovulation and lower bone mineral density compared with those of her age. If not addressed, the most severe situation reflects the most serious manifestation of the FAT: LEA (<30-kcal/kg fat-free mass/day) with or without disordered eating, oligomenorrhea, or functional hypothalamic amenorrhea (which may affect fertility) and osteoporosis or low bone mineral density, which then increases the risk of injury and fracture. This constellation of symptoms can be seen in a wide range of ages and type of athletic participation, from adolescents to elite athletes.9
Recognizing the risk factors for the FAT and RED-S has been addressed in this activity, along with current guidelines and recommendations for treatment to reestablish healthy eating and calorie intake, so that these patients can continue to compete in their sports without injury or longer-term effects on bone health. As menstrual irregularities often prompt referral to a specialist, the gynecologist may be the first to recognize the underlying issue.
What Happens?
EA is the net balance between energy consumption and expenditure. LEA represents a negative balance between caloric intake and output, and is achieved via restricted intake, or overexpenditure, or both. Notably, this imbalance does not necessarily occur intentionally.3 LEA is considered to be the driving force behind the FAT, as the energy deficiency causes the body to be unable to support functions that are not necessary for survival.8 In this way, LEA may lead to menstrual irregularity, low bone mineral density, and injury.10
The exact mechanism of how the hypothalamic-pituitary-ovarian axis is affected by a state of LEA is not completely clear. LEA is thought to disrupt gonadotropin-releasing hormone (GnRH) pulsatility at the hypothalamus, which in turn results in changes to luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release, and subsequently influences estrogen and progesterone.11 In 2003, Loucks and Therma12 demonstrated a lower LH pulse frequency but a higher amplitude in subjects with LEA. In this study, mean 24-hour LH and FSH concentrations remained unchanged and estrogen levels were reduced. However, in 2012, Ackerman et al13 documented no difference in 8-hour overnight LH pulse frequency, a lower LH pulse amplitude, and a lower total pulsatile secretion in amenorrheic athletes compared with controls. This variability in results may be attributable to differences in blood collection timing and frequency, phase of menstrual cycle, or data analysis methods.14 LH causes theca cells to make androstenedione, which is then converted to estradiol by the aromatase enzyme. Therefore, a reduced frequency and amplitude of LH pulsatility alters the ovary's ability to produce estradiol, which results in hypoestrogenism. Kisspeptin also influences LH pulsatility and, thus, has been studied as a potential therapy to treat hypothalamic amenorrhea.15
LEA can cause other physiologic changes including alteration of thyroid hormones, leptin levels, carbohydrate metabolism, and the growth hormone/insulin-like growth factor-1 axis.2,11 A patient may adopt a "sick euthyroid" profile, with lower levels of thyroid hormones to reduce energy consumption. However, this energy sequestration is maladaptive in the long term, especially for adolescents who are growing.14 Leptin, which is primarily secreted by adipocytes, is low in states of low energy. Low levels are correlated with hypogonadism.13 There are alterations of appetite-regulating hormones, including ghrelin, which is released from the stomach and has a role in appetite initiation. High levels of ghrelin are correlated with a low energy state.14 Administration of ghrelin leads to a decrease in gonadotropin pulsatility and may contribute to changes in GnRH and LH pulsatility, which alters menstrual cycles.13 Levels of insulin and insulin-like growth factor 1 are decreased, along with increased growth hormone resistance.
Cortisol levels have been shown to have a U-shaped relationship with body mass index (BMI) and adiposity. Cortisol increases with energy abundance, but also increases in the setting of starvation and prolonged exercise as is commonly the case in women with the FAT. Having chronically high levels of a stress-response hormone, such as cortisol, is not healthy.14 In summary, LEA is associated with a higher prevalence of endocrine abnormalities, hypoglycemia and hypercholesterolemia, anemia, anxiety and depression, fatigue, possible endothelial dysfunction, which is a risk factor for cardiac disease, hypotension and electrolyte imbalances with severe calorie restriction, injury and fracture risk, and gastrointestinal symptoms. Athletes with LEA also demonstrate a higher prevalence of performance effects, including decreased training response, impaired judgment, and decreased concentration.16
Causes of Low Energy Availability
LEA may be due to disordered eating. The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), defines eating disorders as a "persistent disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food and that significantly impairs physical health or psychosocial functioning."17 Disordered eating may be due to the low calorie intake related to anorexia nervosa, bulimia nervosa, binge eating disorder, or for other unspecified reasons. Notably, the criterion for eating disorders no longer includes menstrual disturbance.18
Pressures specific to sports may contribute to eating disorders, such as dieting to enhance performance, overtraining, recurrent and nonhealing injuries, inappropriate coaching behavior, or regulations in certain sports.8 Those sports that emphasize leanness, aesthetics, or endurance may exacerbate this effect. Critical comments from coaches, parents, or teammates regarding performance or body image can also greatly impact the behavior of young women.10
Conversely, patients may have what appears to be a healthy diet, but if they do not consume enough calories to cover their energy expenditure, RED-S will again result. Some patients may have a weight or BMI in the normal range19 and still suffer menstrual irregularity or amenorrhea, signaling that their calorie intake is too low. Athletic adolescents may be actively choosing low-energy-density foods and may feel "full" before adequate calorie intake is achieved. Taking a detailed history is crucial to determine these at-risk individuals.
Lastly, RED-S may be the result of calorie overexpenditure. In particular, athletes who participate in endurance sports, such as marathon running, tend to have large increases in energy expenditure.20 Athletes must be counseled that overtraining can lead to LEA and is associated with injury and declining athletic performance in the long term.2,16
Menstrual Dysfunction
The menstrual cycle is a vital sign in young women.21,22 When there is not enough energy available, the body adjusts to conserve for essential functions23,24 and less energy is then used for long-term processes such as reproduction.2 Williams et al,25 in a prospective trial of women age 18 to 30 years with controlled feeding and supervised laboratory-based exercise, demonstrated that the magnitude of energy deficit affects the frequency of menstrual dysfunction. However, a specific threshold of EA below which menstrual dysfunction occurred has not been documented.11,26 It is likely that individual variability exists in the energy deficit necessary to impact menstrual function.27 Although BMI can be used as an initial screening tool for the FAT and RED-S, not all patients with menstrual dysfunction are underweight.
Primary and secondary amenorrhea, and oligomenorrhea, can be seen in the FAT. Secondary amenorrhea is defined as the absence of menses for 90 days or more any time after menarche21 whereas oligomenorrhea is defined as menstrual cycles occurring at intervals greater than 35 days. Amenorrhea or oligomenorrhea for at least 6 months warrants further evaluation.10
Functional hypothalamic amenorrhea (FHA) is the term used to describe amenorrhea resulting from LEA. FHA exists along this continuum of menstrual dysfunction and occurs when low weight, excessive exercise, and/or stress leads to anovulation and the absence of menses. A state of LEA disrupts the hypothalamic-pituitary-ovarian axis, with the downstream effects of decreased GnRH, FSH, LH, and estrogen. FHA is a diagnosis of exclusion and is made when there are low levels of FSH, LH, and estradiol in the absence of another underlying cause.28
Low Bone Density
In addition to menstrual dysfunction, LEA contributes to low bone mineral density. LEA induces changes in insulin-like growth factor 1, leptin, and peptide YY, which in turn results in deficiencies in vitamin D and calcium. Both calcium and vitamin D are necessary for bone mineralization. Estrogen deficiency results in overactivity of osteoclasts, which produces increased bone degradation and weaker bones.10 The hormonal changes observed in women with amenorrhea or anorexia nervosa have consistently shown negative effects on bone mineral density, bone microarchitecture, and bone turnover.14 In addition, amenorrheic athletes have demonstrated lower bone mineral density, impaired microarchitecture, reduced estimates of bone strength, and higher rates of fracture when compared with eumenorrheic athletes and nonathlete controls.14
Emphasizing their risk of injury in sports may help adolescents understand how important it is to increase their calorie intake. As 90% of peak bone mass is attained by age 18, people with low bone mineral density as part of the FAT can have long-term effects on their bone health, including never achieving their optimal peak bone mass,10 which can in turn increase the lifetime risk of osteopenia, osteoporosis, and fractures.
Evaluation
When a clinician assesses a patient for the triad, some clues to look for include: a history of menstrual irregularity and/or amenorrhea; a history of stress fracture or recurrent injury; report of or witnessed critical comments about eating or weight from a parent, coach or peer; depression; a history of dieting or dietary changes; personality traits such as perfectionism and obsessiveness; pressure to lose weight and/or frequent weight changes; early start of sports-specific training or extra training; overtraining; and inappropriate coaching behavior.6
LEA can be assessed overtly by use of cutoffs for a BMI of less than 17.5 mg/m2 or body weight less than 85% of expected body weight, although keep in mind that these values may be higher for some individuals. Although EA is difficult to calculate precisely, clinicians can approximate EA through daily food and exercise logs or an accelerometer, which is a device worn to measure the user's level of physical activity.10 Some proposed biomarkers for energy deficiency include: triiodothyronine (T3), which may be low; a leptin level, which may be low; and cortisol, which may be high.29 A resting metabolic rate can also be checked using calorimetry, which can be performed by a nutritionist or registered dietician.
To assess for low bone density, a dual-energy absorptiometry (DXA) scan is recommended in patients with any of the following: oligomenorrhea or amenorrhea for at least 6 months, disordered eating for at least 6 months, stress fracture, or a fracture resulting from minimal trauma. In adolescents, DXA results are reported as a z score. The z score compares the bone density with that of an average person of the same age and sex; therefore, the control values are more accurate for younger patients than the standard T scores used for adults. Although the specific diagnoses of "osteopenia" and "osteoporosis" cannot be made for adolescents, if a patient has low bone mineral density, follow-up yearly DXA scans of the total hip and lumbar spine are recommended.
When assessing amenorrhea, pregnancy and outflow obstruction should be ruled out. Laboratory tests to consider include FSH, prolactin, thyroid-stimulating hormone (TSH), and free thyroxine (T4). A progestin "challenge"10 can be prescribed: after 5 to 10 days of oral progestin such as medroxyprogesterone acetate, if there is endometrial growth, a withdrawal bleeding will occur 2 to 14 days later. No bleeding indicates inadequate estrogenization of the endometrium.
Management
Initial and best management in patients with LEA starts with correcting the calorie deficit. The first step in this process should be explaining to patients and families that nutritional support is crucial, with the goal of increasing caloric intake and/or decreasing energy expenditure. Patients may benefit from nutritional support from professionals versed in RED-S to ensure that calorie intake is adequate for the patient's calorie expenditure, which is generally higher for an athlete as compared with a more sedentary individual. Changes in diet and exercise regimen should be individualized and updated regularly based on the patient's needs.11 In general, athletes are also recommended to get 1500 mg/day of calcium through diet, with supplementation if needed.8 The US Department of Agriculture recommends 600 to 800 IU of vitamin D daily, although greater levels may be required to reach the goal of 25-hydroxy vitamin D serum levels of more than 30 ng/mL.11
Pharmacologic therapy may also be considered. Hormonal therapy with transdermal estradiol and cyclic progestin is recommended for bone health by the Endocrine Society Clinical Practice Guideline on Functional Hypothalamic Amenorrhea for those patients who do not have return of menses after "a reasonable trial of nutritional, psychological, and/or modified exercise intervention."30 Transdermal estradiol has been shown to be more effective than oral hormone therapy, potentially because the transdermal formulation bypasses first-pass metabolism through the liver.16
The decision-making process for an athlete's return to play should be based on both the athlete's health and the requirements of the specific sports.8 The American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, and the Society for Adolescent Health and Medicine-all recommend against the use of oral contraceptive pills as first-line treatment for menstrual dysfunction in the setting of eating disorders.18 Although oral contraceptive pills may induce menstrual bleeding, and they can be prescribed as a contraceptive if necessary, they do not improve bone mineral density, although the exact mechanism is not completely clear.28,31 As the induced menses from oral contraceptive pills may mask LEA, further bone loss could occur.8 Neither transdermal nor oral estrogen will restore hypothalamic-pituitary function, which is the ultimate goal. Bisphosphonates are not recommended in adolescents and premenopausal women, as they are stored for a long time in bones and have been shown to be teratogenic.8
Patients may benefit from psychologic support, such as cognitive behavioral therapy (CBT). Patients with eating disorders are recommended to receive psychologic therapy29; however, patients without underlying eating disorders may also benefit from some type of therapy. A randomized controlled trial in 2013 showed that, compared with a control group treated with observation only, women with FHA who received CBT had a higher rate of ovarian function, amelioration of hypercortisolism, and improvement in neuroendocrine and metabolic concomitants of FHA, including leptin and thyroid levels.32
Summary
The FAT is classically defined as the combination of LEA, menstrual dysfunction, and low bone mineral density. RED-S exists along a similar spectrum, although is more inclusive of subtle findings, and applies to athletes of all sexes. LEA compels the body to conserve energy for essential processes and, in patients assigned female at birth, leads to disruption in the menstrual cycle and bone mineralization. Diagnosis and treatment must begin as early as possible to avoid short-term problems such as injury, and long-lasting effects, particularly impaired bone health. Management is primarily nutritional support. Additional psychosocial or pharmacologic treatment may be beneficial. Estrogen therapy can be used for bone support; the transdermal route is preferred. Progestin must be given concurrently with estrogen therapy for endometrial protection, and it should be noted that estrogen is not a substitute for nutritional support. The goal is to reestablish normal endogenous hormonal activity, as evidenced by a regular ovulatory menstrual cycle.
Practice Pearls
* Screening for RED-S in those with a BMI of 17.5 mg/m2 or less or body weight 85% or less of expected is recommended, with additional evaluation through daily food logs. Recall, however, that weight or BMI may be in the normal range in RED-S.
* For those with menstrual dysfunction, initial recommended laboratory tests for evaluation include FSH, prolactin, TSH, and T4. An oral progestin challenge can be considered to evaluate endometrial growth, as a clinical indicator for the estrogen level.
* A DXA scan with the z score is the recommended assessment tool for low bone density after 6 months of persistent amenorrhea, stress fracture (or fracture with minimal injury), and disordered eating for at least 6 months, with subsequent annual testing in adolescents with low bone density on initial screening.
* Nutritional support is most important. If management with nutritional support fails, psychologic and pharmacologic treatment can be considered as second-line therapies, with the goal of improving bone health and resumption of regular ovulatory menstrual cycles.
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