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The Female Athlete Triad/Relative Energy Deficiency in Sports (RED-S)

A tríade da atleta feminina/déficit energético relativo no esporte (RED-S)

Abstract

In a healthy athlete, the caloric intake is sufficient for sports energy needs and body physiological functions, allowing a balance between energy availability, bone metabolism, andmenstrual cycle.Onthe other hand, an imbalance causedby low energy availability dueto a restrictive diet, eating disorders or long periods of energy expenditure leads to multisystemic deregulation favoring the essential functions of the body. This phenomenon, described as the female athlete triad, occurs in a considerable percentage of high-performance athletes, with harmful consequences for their future. The present review was carried out based on a critical analysis of themost recent publications available and aims to provide a global perception of the topic relative energy deficit in sport (RED-S). The objective is to promote theacquisition ofmore consolidated knowledgeon an undervaluedtheme, enabling the acquisition of preventive strategies, early diagnosis and/or appropriate treatment.

Keywords:
female athlete; low energy availability; amenorrhea; bone health; menstrual dysfunction

Resumo

Emumaatleta saudável, oaporte calórico é suficientepara anecessidade energética esportiva e para as funções fisiológicas corporais, permitindo um equilíbrio entre disponibilidade energética (DE), metabolismo ósseo e função menstrual. Por outro lado, um desequilíbrio devido à baixa disponibilidade energética (BDE) por dieta restritiva, perturbações alimentares ou grandes períodos de gasto energético conduz a uma desregulação multissistêmica priorizando as funções essenciais do corpo. Este fenômeno, descrito inicialmente como tríade da mulher atleta e, atualmente, comodéfice energético relativo no esporte (RED-S, nasigla eminglês) tem como pilares a BDE, disfunção menstrual e alterações na densidade mineral óssea (DMO), estando presente em uma percentagem considerável de atletas de alta competição, com consequências nefastas para o seu futuro a curto, médio e longo prazo. A presente revisão foi realizada a partir da análise crítica das publicações mais recentes disponíveis e pretende proporcionar uma percepção global do tema RED-S. O objetivo é promover a aquisição de um conhecimento mais consolidado sobre uma temática subvalorizada, possibilitando a aquisição de estratégias preventivas, diagnóstico precoce e/ou tratamento adequado.

Palavras-chave:
atleta feminina; baixa disponibilidade energética; amenorreia; saúde óssea; disfunção menstrual

Definition: Female Athlete Triad versus Relative Energy Deficiency in Sport

The female athlete triad, initially described in 1993 and conceptually defined in 1997 by the American College of Sports Medicine (ACSM), was based on the presence of eating disorders, amenorrhea and osteoporosis. In 2007, 3 new components were defined: low energy availability (LEA), menstrual dysfunction, and changes in bone mineral density.11 Yeager KK, Agostini R, Nattiv A, Drinkwater B. The female athlete triad: disordered eating, amenorrhea, osteoporosis. Med Sci Sports Exerc. 1993;25(07):775-777. Doi: 10.1249/00005768-199307000-00003
https://doi.org/10.1249/00005768-1993070...
22 Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MPAmerican College of Sports Medicine. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc. 2007;39(10):1867-1882. Doi: 10.1249/mss.0b013e318149f111
https://doi.org/10.1249/mss.0b013e318149...
33 De Souza MJ, Nattiv A, Joy E, Misra M, Williams NI, Mallinson RJ, et al; Expert Panel. 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, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013. Br J Sports Med. 2014;48(04): 289. Doi: 10.1136/bjsports-2013-093218
https://doi.org/10.1136/bjsports-2013-09...
Afterwards, it was concluded that the existence of all elements for its diagnosis was not essential, since there is a very high variety in incidence for each one and that it is dependent on the type of sport, which can lead to underdiagnoses. Therefore, since 2014, after meeting the International Olympic Committee (IOC), it was changed for relative energy deficiency in sport (RED-S,) meeting the need for a holistic approach.44 Mountjoy M, Sundgot-Borgen JK, Burke LM, Ackerman KE, Blauet C, Constantini N, et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update. Br J Sports Med. 2018; 52(11):687-697. Doi: 10.1136/bjsports-2018-099193
https://doi.org/10.1136/bjsports-2018-09...
55 Mountjoy M, Sundgot-Borgen J, Burke L, Carter S, Constantini N, Lebrun C, et al. The IOC consensus statement: beyond the Female Athlete Triad-Relative Energy Deficiency in Sport (RED-S). Br J Sports Med. 2014;48(07):491-497. Doi: 10.1136/bjsports-2014-093502
https://doi.org/10.1136/bjsports-2014-09...

This new concept allows the identification of energy deficiency as a key to the disruption of several physiological functions of different areas, such as reproduction, bone, endocrine, metabolic, hematological, growth and development, physiological, cardiovascular, gastrointestinal, and immunological, with consequences for the performance and health of the athlete in general.44 Mountjoy M, Sundgot-Borgen JK, Burke LM, Ackerman KE, Blauet C, Constantini N, et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update. Br J Sports Med. 2018; 52(11):687-697. Doi: 10.1136/bjsports-2018-099193
https://doi.org/10.1136/bjsports-2018-09...
66 Lages AS, Rebelo-Marques AR, Carrilho F. Défice Energético Relativo no Desporto (RED-S). Rev Med Desportiva Inf. 2018;9(05): 14-16. Doi: 10.23911/Defice_Energetico_Relativo_no_Desporto
https://doi.org/10.23911/Defice_Energeti...

Low Energy Availability

Low energy availability, due to food scarcity or excessive energy expenditure, causes physiological adaptations to ensure life maintenance.77 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(01):297-311. Doi: 10.1210/jc.2002-020369
https://doi.org/10.1210/jc.2002-020369...
Therefore, there are different mechanisms favoring essential processes88 Pauli SA, Berga SL. Athletic amenorrhea: energy deficit or psychogenic challenge? Ann N Y Acad Sci. 2010;1205:33-38. Doi: 10.1111/j.1749-6632.2010.05663.x
https://doi.org/10.1111/j.1749-6632.2010...
instead of secondary functions such as growth, development, and reproduction.99 Dufour DL, Sauther ML. Comparative and evolutionary dimensions of the energetics of human pregnancy and lactation. Am J Hum Biol. 2002;14(05):584-602. Doi: 10.1002/ajhb.10071
https://doi.org/10.1002/ajhb.10071...
Energy availability (EA) is calculated by subtracting the energy consumed (kcal) from the energy ingested (kcal) and dividing this value by the free fat mass (kg).1010 Loucks AB. Low energy availability in the marathon and other endurance sports. Sports Med. 2007;37(4-5):348-352. Doi: 10.2165/00007256-200737040-00019
https://doi.org/10.2165/00007256-2007370...
It consists of a theoretical concept, difficult to use on a routine basis. However, its knowledge and interpretation are important for a better evaluation of the athletes. The ideal EA should support the basic functions that allow a healthy state and adequate performance,44 Mountjoy M, Sundgot-Borgen JK, Burke LM, Ackerman KE, Blauet C, Constantini N, et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update. Br J Sports Med. 2018; 52(11):687-697. Doi: 10.1136/bjsports-2018-099193
https://doi.org/10.1136/bjsports-2018-09...
which is believed to be > 45kcal/kg of free fat mass/day.77 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(01):297-311. Doi: 10.1210/jc.2002-020369
https://doi.org/10.1210/jc.2002-020369...
Several authors have attempted to define the threshold beyond which LEA leads to metabolic changes. However, due to the high interpersonal variability, it is only possible to predict that < 30kcal/kg of free fat mass/day, there is a high probability of physiological adaptation favoring vital systems.44 Mountjoy M, Sundgot-Borgen JK, Burke LM, Ackerman KE, Blauet C, Constantini N, et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update. Br J Sports Med. 2018; 52(11):687-697. Doi: 10.1136/bjsports-2018-099193
https://doi.org/10.1136/bjsports-2018-09...
77 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(01):297-311. Doi: 10.1210/jc.2002-020369
https://doi.org/10.1210/jc.2002-020369...

Pathophysiology

The new LEA concept highlights the complexity of this theme, which involves several hormonal pathways. There has been extensive research in this area in an attempt to identify the trigger of pathophysiological changes. However, these appear to result from multiple changes with different influences on different organs and systems.

Adaptation to Energy Restriction

Low energy availability leads to a decrease in body fat mass with adaptation of normal adipose tissue activity and activation of different pathways after recognition as an internal stress state (namely activation of the hypothalamic-pituitary-adrenal [HPA] axis and the autonomic nervous system). These changes lead to neuroendocrine adaptations with energy redistribution in favor of vital systems preservation.1111 Rodriguez-Pacheco F, Martinez-Fuentes AJ, Tovar S, Pinilla L, Tena-Sempere M, Dieguez C, et al. Regulation of pituitary cell function by adiponectin. Endocrinology. 2007;148(01):401-410. Doi: 10.1210/en.2006-1019
https://doi.org/10.1210/en.2006-1019...
1212 Mitchell M, Armstrong DT, Robker RL, Norman RJ. Adipokines: implications for female fertility and obesity. Reproduction. 2005; 130(05):583-597. Doi: 10.1530/rep.1.00521
https://doi.org/10.1530/rep.1.00521...
We can, therefore, identify:

  • - - Decrease leptin1313 Ackerman KE, Slusarz K, Guereca G, Pierce L, Slattery M, Mendes N, et al. Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls. Am J Physiol Endocrinol Metab. 2012;302(07):E800-E806. Doi: 10.1152/ajpendo.00598.2011
    https://doi.org/10.1152/ajpendo.00598.20...
    1414 Franks PW, Farooqi IS, Luan J, Wong M-Y, Halsall I, O'Rahilly S, et al. Does physical activity energy expenditure explain the between-individual variation in plasma leptin concentrations after adjusting for differences in body composition? J Clin Endocrinol Metab. 2003;88(07):3258-3263. Doi: 10.1210/jc.2002-021426
    https://doi.org/10.1210/jc.2002-021426...
    : anorexigenic hormone secreted by adipocytes and regulated by energy state. Negative impact on gonadotropin-releasing hormone (GnRH) secretion.1515 Donato J Jr, Cravo RM, Frazão R, Gautron L, Scott MM, Lachey J, et al. Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest. 2011;121(01):355-368. Doi: 10.1172/JCI45106
    https://doi.org/10.1172/JCI45106...

  • - - Increased ghrelin1313 Ackerman KE, Slusarz K, Guereca G, Pierce L, Slattery M, Mendes N, et al. Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls. Am J Physiol Endocrinol Metab. 2012;302(07):E800-E806. Doi: 10.1152/ajpendo.00598.2011
    https://doi.org/10.1152/ajpendo.00598.20...
    1616 Misra M, Miller KK, Kuo K, Griffin K, Stewart V, Hunter E, et al. Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents. Am J Physiol Endocrinol Metab. 2005;289(02):E347-E356. Doi: 10.1152/ajpendo.00615.2004
    https://doi.org/10.1152/ajpendo.00615.20...
    1717 Christo K, Cord J, Mendes N, Miller KK, GoldsteinMA, Klibanski A, et al. Acylated ghrelin and leptin in adolescent athletes with amenorrhea, eumenorrheic athletes and controls: a cross-sectional study. Clin Endocrinol (Oxf). 2008;69(04):628-633. Doi: 10.1111/j.1365-2265.2008.03237.x
    https://doi.org/10.1111/j.1365-2265.2008...
    : orexigenic hormone secreted by gastric oxyntic cells. Levels inversely related to fat mass. It has an effect on the hypothalamus and on the pituitary gland, negatively affecting the secretion of GnRH, of adrenocorticotrophic hormone (ACTH), of growth hormone (GH), of follicle stimulating hormone (FSH), and of luteinizing hormone (LH).

  • - - Increased peptide YY: increased resistance to ghrelin. Associated with decreased release of GnRH and gonadotropins.1818 Scheid JL, De Souza MJ. Menstrual irregularities and energy deficiency in physically active women: the role of ghrelin, PYY and adipocytokines. Med Sport Sci. 2010;55:82-102. Doi: 10.1159/000321974
    https://doi.org/10.1159/000321974...

  • - - Decreased oxytocin1919 Lawson EA, Ackerman KE, Estella NM, Estella NM, Guereca G, Pierce L, et al. Nocturnal oxytocin secretion is lower in amenorrheic athletes than nonathletes and associated with bone microarchitecture and finite element analysis parameters. Eur J Endocrinol. 2013;168(03):457-464. Doi: 10.1530/EJE-12-0869
    https://doi.org/10.1530/EJE-12-0869...
    : apparently suppressive role in activity of the HPA axis and modifies the glucoregulatory response to caloric consumption.2020 Lawson EA. The effects of oxytocin on eating behaviour and metabolism in humans. Nat Rev Endocrinol. 2017;13(12): 700-709. Doi: 10.1038/nrendo.2017.115
    https://doi.org/10.1038/nrendo.2017.115...
    It has antidepressant and anxiolytic effects.2121 Afinogenova Y, Schmelkin C, Plessow F, Thomas JJ, Pulumo R, Micali N, et al. Low fasting oxytocin levels are associated with psychopathology in anorexia nervosa in partial recovery. J Clin Psychiatry. 2016;77(11):e1483-e1490. Doi: 10.4088/JCP.15m10217
    https://doi.org/10.4088/JCP.15m10217...

  • - - Decreased insulin with increased sensitivity.2222 Rickenlund A, Thorén M, Carlström K, von Schoultz B, Hirschberg AL. Diurnal profiles of testosterone and pituitary hormones suggest different mechanisms for menstrual disturbances in endurance athletes. J Clin Endocrinol Metab. 2004;89(02): 702-707. Doi: 10.1210/jc.2003-030306
    https://doi.org/10.1210/jc.2003-030306...
    its decrease has an negative influence on GnRH signaling.

  • - - Decreased insulin-like growth factor 1 (IGF-I): stimulates osteoblast function and bone formation. It mediates several actions by GH and may be responsible for increasing resistance to it.2323 Misra M, Klibanski A. Endocrine consequences of anorexia nervosa. Lancet Diabetes Endocrinol. 2014;2(07):581-592. Doi: 10.1016/S2213-8587(13)70180-3
    https://doi.org/10.1016/S2213-8587(13)70...
    2424 Laughlin GA, Yen SS. Nutritional and endocrine-metabolic aberrations in amenorrheic athletes. J Clin Endocrinol Metab. 1996;81 (12):4301-4309. Doi: 10.1210/jcem.81.12.8954031
    https://doi.org/10.1210/jcem.81.12.89540...
    2525 Gordon CM, Goodman E, Emans SJ, Grace E, Becker KA, Rosen CJ, et al. Physiologic regulators of bone turnover in young women with anorexia nervosa. J Pediatr. 2002;141(01):64-70. Doi: 10.1067/mpd.2002.125003
    https://doi.org/10.1067/mpd.2002.125003...
    2626 Trombetti A, Richert L, Herrmann FR, Chevalley T, Graf JD, Rizzoli R. Selective determinants of low bone mineral mass in adult women with anorexia nervosa. Int J Endocrinol. 2013; 2013:897193. Doi: 10.1155/2013/897193
    https://doi.org/10.1155/2013/897193...
    2727 Misra M, Miller KK, Bjornson J, Hackman A, Aggarwal A, Chung J, et al. Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab. 2003;88(12):5615-5623. Doi: 10.1210/jc.2003-030532
    https://doi.org/10.1210/jc.2003-030532...

  • - - Resistance to GH, despite its increase2323 Misra M, Klibanski A. Endocrine consequences of anorexia nervosa. Lancet Diabetes Endocrinol. 2014;2(07):581-592. Doi: 10.1016/S2213-8587(13)70180-3
    https://doi.org/10.1016/S2213-8587(13)70...
    2424 Laughlin GA, Yen SS. Nutritional and endocrine-metabolic aberrations in amenorrheic athletes. J Clin Endocrinol Metab. 1996;81 (12):4301-4309. Doi: 10.1210/jcem.81.12.8954031
    https://doi.org/10.1210/jcem.81.12.89540...
    : pituitary peptide, necessary for muscle and bone anabolism and metabolism of carbohydrates, proteins, and lipids.

  • - - Thyroid function: adaptation due to decreased energy expenditure with a decrease in T3 and thyrotropin-releasing hormone (TRH). Thyroxine and thyroid-stimulating hormone (TSH) without changes/lower limit of normal.88 Pauli SA, Berga SL. Athletic amenorrhea: energy deficit or psychogenic challenge? Ann N Y Acad Sci. 2010;1205:33-38. Doi: 10.1111/j.1749-6632.2010.05663.x
    https://doi.org/10.1111/j.1749-6632.2010...
    2828 Estour B, Germain N, Diconne E, Frere D, Cottet-Emard J-M, Carrot G, et al. Hormonal profile heterogeneity and short-term physical risk in restrictive anorexia nervosa. J Clin Endocrinol Metab. 2010;95(05):2203-2210. Doi: 10.1210/jc.2009-2608
    https://doi.org/10.1210/jc.2009-2608...
    2929 Gordon CM. Clinical practice. Functional hypothalamic amenorrhea. N Engl J Med. 2010;363(04):365-371. Doi: 10.1056/NEJMcp0912024
    https://doi.org/10.1056/NEJMcp0912024...
    3030 Berga SL, Mortola JF, Girton L, Suh B, Laughlin G, Pham P, et al. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 1989;68(02): 301-308. Doi: 10.1210/jcem-68-2-301
    https://doi.org/10.1210/jcem-68-2-301...
    3131 Michopoulos V, Mancini F, Loucks TL, Berga SL. Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized, controlled trial. Fertil Steril. 2013;99(07):2084-91.e1. Doi: 10.1016/j.fertnstert. 2013.02.036
    https://doi.org/10.1016/j.fertnstert...

  • - - Activation of HPA axis: An increase in basal cortisol leads to an increase in its nocturnal pulse amplitude, half-life, and area below the curve in amenorrhea athletes.3232 Schorr M, Lawson EA, Dichtel LE, Klibanski A, Miller KK. Cortisol measures across the weight spectrum. J Clin Endocrinol Metab. 2015;100(09):3313-3321. Doi: 10.1210/JC.2015-2078
    https://doi.org/10.1210/JC.2015-2078...
    3333 Ackerman KE, Patel KT, Guereca G, Pierce L, Herzog DB, Misra M. Cortisol secretory parameters in young exercisers in relation to LH secretion and bone parameters. Clin Endocrinol (Oxf). 2013;78 (01):114-119. Doi: 10.1111/j.1365-2265.2012.04458.x
    https://doi.org/10.1111/j.1365-2265.2012...
    Increase in beta-hydroxybutyrate (ketone synthesized in the liver: carrier of energy to peripheral tissues, activity as an energetic metabolite, cellular signaling functions). Cellular function, regardless of sports practice.66 Lages AS, Rebelo-Marques AR, Carrilho F. Défice Energético Relativo no Desporto (RED-S). Rev Med Desportiva Inf. 2018;9(05): 14-16. Doi: 10.23911/Defice_Energetico_Relativo_no_Desporto
    https://doi.org/10.23911/Defice_Energeti...

Hypothalamic Amenorrhea

As previously explained, exercise by its own has no suppressive effect on reproductive function. However, it can be the cause of menstrual disruptions by influencing energy availability. According to different studies, it is believed that functional hypothalamic amenorrhea occurs by the combination of different pathways in response to LEA, with a negative influence on GnRH: increased cortisol3434 Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(05):1413-1439. Doi: 10.1210/jc.2017-00131
https://doi.org/10.1210/jc.2017-00131...
and corticotropin-releasing hormone (CRH)3535 Martin B, Golden E, Carlson OD, Egan JM, Mattson MP, Maudsley S. Caloric restriction: impact upon pituitary function and reproduction. Ageing Res Rev. 2008;7(03):209-224. Doi: 10.1016/j. arr.2008.01.002
https://doi.org/10.1016/j...
in response to stress and decreased leptin, with impact directly GnRH (Fig. 1). Therefore, there is a decrease in the GnRH drive with reduction in frequency of FSH and LH pulsatility,2222 Rickenlund A, Thorén M, Carlström K, von Schoultz B, Hirschberg AL. Diurnal profiles of testosterone and pituitary hormones suggest different mechanisms for menstrual disturbances in endurance athletes. J Clin Endocrinol Metab. 2004;89(02): 702-707. Doi: 10.1210/jc.2003-030306
https://doi.org/10.1210/jc.2003-030306...
3030 Berga SL, Mortola JF, Girton L, Suh B, Laughlin G, Pham P, et al. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 1989;68(02): 301-308. Doi: 10.1210/jcem-68-2-301
https://doi.org/10.1210/jcem-68-2-301...
3636 Elliott-Sale KJ, Tenforde AS, Parziale AL, Holtzman B, Ackerman KE. Endocrine effects of relative energy deficiency in sport. Int J Sport Nutr Exerc Metab. 2018;28(04):335-349. Doi: 10.1123/ijsnem.2018-0127
https://doi.org/10.1123/ijsnem.2018-0127...
leading to changes in folliculogenesis and ovulatory function, resulting in lower estradiol and progesterone levels (Fig. 2).3737 Weiss Kelly AK, Hecht SCOUNCIL ON SPORTS MEDICINE AND FITNESS. The female athlete triad. Pediatrics. 2016;138(02): e20160922. Doi: 10.1542/peds.2016-0922
https://doi.org/10.1542/peds.2016-0922...

Figs. 1 and 2.
Influence of low energy availability on the menstrual cycle.

It is important to emphasize that there is a wide spectrum of possible menstrual patterns, namely ovulatory eumenorrhea, subclinical menstrual dysfunctions, and amenorrhea.3434 Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(05):1413-1439. Doi: 10.1210/jc.2017-00131
https://doi.org/10.1210/jc.2017-00131...
A higher rate of amenorrhea occurs in sports whose lean phenotype is imposed (gymnastics, running, among others). The prevalence of hypothalamic amenorrhea can be as high as 69%, compared with 2 to 5% in the general population.3737 Weiss Kelly AK, Hecht SCOUNCIL ON SPORTS MEDICINE AND FITNESS. The female athlete triad. Pediatrics. 2016;138(02): e20160922. Doi: 10.1542/peds.2016-0922
https://doi.org/10.1542/peds.2016-0922...
3838 Nichols JF, Rauh MJ, Barrack MT, Barkai HS, Pernick Y. Disordered eating and menstrual irregularity in high school athletes in leanbuild and nonlean-build sports. Int J Sport Nutr Exerc Metab. 2007;17(04):364-377. Doi: 10.1123/ijsnem.17.4.364
https://doi.org/10.1123/ijsnem.17.4.364...
3939 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(01):1-23. Doi: 10.1123/ijsnem.16.1.1
https://doi.org/10.1123/ijsnem.16.1.1...

Bone Metabolism

Bone development is negatively affected by LEA, with a decrease of different elements such as estrogens (inhibition of osteoclasts and growth of osteoblasts), IGF-1 (stimulation of osteoblastogenesis and promotion of bone formation), leptin (proliferation of osteoblasts) and T3 (proliferation of osteoblasts and promoting bone formation). Decrease in bone formation and bone turnover are the main consequences of changes in bone metabolism. This combination leads to loss of normal repair mechanisms for minor and major lesions, resulting in a higher risk of fracture.4040 Hotta M, Fukuda I, Sato K, Hizuka N, Shibasaki T, Takano K. The relationship between bone turnover and body weight, serum insulin-like growth factor (IGF) I, and serum IGF-binding protein levels in patients with anorexia nervosa. J Clin Endocrinol Metab. 2000;85(01):200-206. Doi: 10.1210/jcem.85.1.6321
https://doi.org/10.1210/jcem.85.1.6321...
4141 Dominguez J, Goodman L, Sen Gupta S, Mayer L, Etu SF,Walsh BT, 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(01):92-99. Doi: 10.1093/ajcn/86.1.92
https://doi.org/10.1093/ajcn/86.1.92...
4242 Viapiana O, Gatti D, Dalle Grave R, Todesco T, Rossini M, Braga V, et al. Marked increases in bone mineral density and biochemical markers of bone turnover in patients with anorexia nervosa gaining weight. Bone. 2007;40(04):1073-1077. Doi: 10.1016/j. bone.2006.11.015
https://doi.org/10.1016/j...
4343 Ihle R, Loucks AB. Dose-response relationships between energy availability and bone turnover in young exercising women. J Bone Miner Res. 2004;19(08):1231-1240. Doi: 10.1359/JBMR.040410
https://doi.org/10.1359/JBMR.040410...
In amenorrhea athletes, there is a decrease in bone mineral density (BMD), volumetric bone density, and strength associated with abnormal bone microarchitecture.4444 Ackerman KE, Nazem T, Chapko D, RussellM,Mendes N, Taylor AP, et al. Bone microarchitecture is impaired in adolescent amenorrheic athletes compared with eumenorrheic athletes and nonathletic controls. J Clin Endocrinol Metab. 2011;96(10):3123-3133. Doi: 10.1210/jc.2011-1614
https://doi.org/10.1210/jc.2011-1614...
4545 Mitchell DM, Tuck P, Ackerman KE, Sokoloff NC, Woolley R, Slattery M, et al. Altered trabecular bone morphology in adolescent and young adult athletes with menstrual dysfunction. Bone. 2015;81:24-30. Doi: 10.1016/j.bone.2015.06.021
https://doi.org/10.1016/j.bone.2015.06.0...
4646 Ackerman KE, Putman M, Guereca G, Taylor AP, Pierce L, Herzog D, et al. Cortical microstructure and estimated bone strength in young amenorrheic athletes, eumenorrheic athletes and non-athletes. Bone. 2012;51(04):680-687. Doi: 10.1016/j. bone.2012.07.019
https://doi.org/10.1016/j...
4747 Ackerman KE, Cano Sokoloff N, DE NardoMaffazioli G, Clarke HM, Lee H,Misra M. Fractures in relation tomenstrual status and bone parameters in young athletes. Med Sci Sports Exerc. 2015;47(08): 1577-1586. Doi: 10.1249/MSS.0000000000000574
https://doi.org/10.1249/MSS.000000000000...
Even in weight-bearing exercises with theoretical benefit in BMD, changes are described mainly when associated with restrictive eating habits and low weight.4848 Young N, Formica C, Szmukler G, Seeman E. Bone density at weight-bearing and nonweight-bearing sites in ballet dancers: the effects of exercise, hypogonadism, and body weight. J Clin Endocrinol Metab. 1994;78(02):449-454. Doi: 10.1210/jcem.78.2.8106634
https://doi.org/10.1210/jcem.78.2.810663...
4949 Robinson TL, Snow-Harter C, Taaffe DR, Gillis D, Shaw J, Marcus R. Gymnasts exhibit higher bone mass than runners despite similar prevalence of amenorrhea and oligomenorrhea. J Bone Miner Res. 1995;10(01):26-35. Doi: 10.1002/jbmr.5650100107
https://doi.org/10.1002/jbmr.5650100107...

Other Consequences

Cardiovascular: increase in total cholesterol, triglycerides, LDL and HDL.5050 Friday KE, Drinkwater BL, Bruemmer B, Chesnut C III, Chait A. Elevated plasma low-density lipoprotein and high-density lipoprotein cholesterol levels in amenorrheic athletes: effects of endogenous hormone status and nutrient intake. J Clin Endocrinol Metab. 1993;77(06):1605-1609. Doi: 10.1210/jcem.77.6.8263148
https://doi.org/10.1210/jcem.77.6.826314...
Impairment of endothelial function and increased vascular resistance5151 O'Donnell E, De Souza MJ. The cardiovascular effects of chronic hypoestrogenism in amenorrhoeic athletes: a critical review. Sports Med. 2004;34(09):601-627. Doi: 10.2165/00007256-200434090-00004
https://doi.org/10.2165/00007256-2004340...
5252 O'Donnell E, Harvey PJ, Goodman JM, De Souza MJ. 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(05):E1401--E1409. Doi: 10.1152/ajpendo.00547.2006
https://doi.org/10.1152/ajpendo.00547.20...
5353 Hoch AZ, Papanek P, Szabo A, Widlansky ME, Schimke JE, Gutterman DD. Association between the female athlete triad and endothelial dysfunction in dancers. Clin J Sport Med. 2011;21 (02):119-125. Doi: 10.1097/JSM.0b013e3182042a9a
https://doi.org/10.1097/JSM.0b013e318204...
associated with increased central fat.5454 Puder JJ, Monaco SE, Sen Gupta S, Wang J, Ferin M, Warren MP. Estrogen and exercise may be related to body fat distribution and leptin in young women. Fertil Steril. 2006;86(03):694-699. Doi: 10.1016/j.fertnstert.2006.02.085
https://doi.org/10.1016/j.fertnstert.200...
Amenorrheic athletes can have lower heart rates and systolic blood pressure, due to disruptions of the normal renin-angiotensin-aldosterone response.44 Mountjoy M, Sundgot-Borgen JK, Burke LM, Ackerman KE, Blauet C, Constantini N, et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update. Br J Sports Med. 2018; 52(11):687-697. Doi: 10.1136/bjsports-2018-099193
https://doi.org/10.1136/bjsports-2018-09...
In more severe LEA states, severe bradycardia, hypotension, valve abnormalities, pericardial effusion, and arrhythmias can occur.44 Mountjoy M, Sundgot-Borgen JK, Burke LM, Ackerman KE, Blauet C, Constantini N, et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update. Br J Sports Med. 2018; 52(11):687-697. Doi: 10.1136/bjsports-2018-099193
https://doi.org/10.1136/bjsports-2018-09...

Sports performance: impaired recovery with change in muscle mass and function5555 Fogelholm M. Effects of bodyweight reduction on sports performance. Sports Med. 1994;18(04):249-267. Doi: 10.2165/00007256-199418040-00004
https://doi.org/10.2165/00007256-1994180...
; interference in the glycogen reserve and protein synthesis.5656 Areta JL, Burke LM, Camera DM,West DW, Crawshaw S, Moore DR, et al. Reduced resting skeletalmuscle protein synthesis is rescued by resistance exercise and protein ingestion following short-term energy deficit. Am J Physiol Endocrinol Metab. 2014;306(08): E989-E997. Doi: 10.1152/ajpendo.00590.2013
https://doi.org/10.1152/ajpendo.00590.20...
The literature in this area is scarce, with only one study confirming a 10% decrease in the swimming speed of 400 m in athletes with amenorrhea versus eumenorrhea.5757 Vanheest JL, Rodgers CD, Mahoney CE, De Souza MJ. Ovarian suppression impairs sport performance in junior elite female swimmers. Med Sci Sports Exerc. 2014;46(01):156-166. Doi: 10.1249/MSS.0b013e3182a32b72
https://doi.org/10.1249/MSS.0b013e3182a3...

Bone metabolism: Because it occurs mostly in adolescence, there is a proven risk of loss of bone mass with potential inability to reach the bone peak, which in 90% of individuals is reached by age of 18.66 Lages AS, Rebelo-Marques AR, Carrilho F. Défice Energético Relativo no Desporto (RED-S). Rev Med Desportiva Inf. 2018;9(05): 14-16. Doi: 10.23911/Defice_Energetico_Relativo_no_Desporto
https://doi.org/10.23911/Defice_Energeti...

Diagnosis

The diagnosis of RED-S does not imply the existence of concrete clinical or laboratory changes. It consists of an active search for athletes at risk due to insufficient energy availability, either due to low input or excessive expenditure.

The diagnosis requires a low threshold of suspicion and an approach based on a detailed medical history that should include questions about diet, dietary changes, weight fluctuations, exercise, training hours, sleep changes, stress, mood, cycle menstruation, fractures, and substance abuse. It is also important to address psychosocial issues such as the need for social approval, the claim to perfectionism, ambitions and expectations, which are more marked in athletes with amenorrhea. Family history of eating and reproductive disorders should also be explored.3434 Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(05):1413-1439. Doi: 10.1210/jc.2017-00131
https://doi.org/10.1210/jc.2017-00131...
In order to standardize screening and follow-up, the IOC created the RED-S clinical assessment tool (CAT), which should be part of the annual health assessment of the athlete and/or whenever there is evidence of eating disorder, menstrual dysfunction (secondary amenorrhea >  6 months or primary amenorrhea > 16 years), history of stress fracture, significant weight loss, change in height in relation to the target family height in adolescents, deficient performance, or evident mood change.66 Lages AS, Rebelo-Marques AR, Carrilho F. Défice Energético Relativo no Desporto (RED-S). Rev Med Desportiva Inf. 2018;9(05): 14-16. Doi: 10.23911/Defice_Energetico_Relativo_no_Desporto
https://doi.org/10.23911/Defice_Energeti...
5858 Melin A, Tornberg AB, Skouby S, Faber J, Ritz C, Sjödin A, et al. The LEAF questionnaire: a screening tool for the identification of female athletes at risk for the female athlete triad. Br J Sports Med. 2014;48(07):540-545. Doi: 10.1136/bjsports-2013-093240
https://doi.org/10.1136/bjsports-2013-09...

Frequently, the first manifestation results in dysregulation of the menstrual cycle or in amenorrhea, and a functional etiology must be considered in the presence of oligomenorrhea and/or in the presence of amenorrhea for > 3 months.66 Lages AS, Rebelo-Marques AR, Carrilho F. Défice Energético Relativo no Desporto (RED-S). Rev Med Desportiva Inf. 2018;9(05): 14-16. Doi: 10.23911/Defice_Energetico_Relativo_no_Desporto
https://doi.org/10.23911/Defice_Energeti...
3434 Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(05):1413-1439. Doi: 10.1210/jc.2017-00131
https://doi.org/10.1210/jc.2017-00131...

Functional hypothalamic amenorrhea is characterized by the absence of menstrual cycles or by irregular cycles associated with estrogen deficiency due to insufficient stimulation or suppression of the hypothalamic-pituitary-ovary (HPO) axis in the absence of anatomical or organic pathology.3434 Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(05):1413-1439. Doi: 10.1210/jc.2017-00131
https://doi.org/10.1210/jc.2017-00131...

As it is an exclusion diagnosis, it is crucial to consider the main causes of amenorrhea, such as drugs, intracranial prolactinoma/tumor, Kallmann Syndrome (anosmia and hyposmia), thyroid pathology, chronic pathology, and congenital pathology (i.e., imperforate hymen, Mullerian abnormalities/androgen insensitivity syndrome [AIS]).5959 Perkins RB, Hall JE, Martin KA. Neuroendocrine abnormalities in hypothalamic amenorrhea: spectrum, stability, and response to neurotransmitter modulation. J Clin Endocrinol Metab. 1999;84 (06):1905-1911. Doi: 10.1210/jcem.84.6.5823
https://doi.org/10.1210/jcem.84.6.5823...
6060 Thangavelu K, Geetanjali S. Menstrual disturbance and galactorrhea in people taking conventional antipsychotic medications. Exp Clin Psychopharmacol. 2006;14(04):459-460. Doi: 10.1037/1064-1297.14.4.459
https://doi.org/10.1037/1064-1297.14.4.4...
6161 Illingworth P. Amenorrhea, anovulation, and dysfunctional uterine bleeding. In: Jameson JL, De Groot LJ, eds. Endocrinology: adult and pediatric. Philadelphia: Saunders/Elsevier; 2010: 2341-556262 Rebar R. Evaluation of amenorrhea, anovulation, and abnormal bleeding. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, et al., eds. Endotext. South Dartmouth: MDText.com, Inc.; 20006363 Bulun SE. Physiology and pathology of the female reproductive axis. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams textbook of endocrinology. 13th ed. Philadelphia: Elsevier; 2016:590-664 To complement this study, a complete physical examination with search for excess androgens signs is essential, and the need for gynecological evaluation and imaging studies should be considered.2929 Gordon CM. Clinical practice. Functional hypothalamic amenorrhea. N Engl J Med. 2010;363(04):365-371. Doi: 10.1056/NEJMcp0912024
https://doi.org/10.1056/NEJMcp0912024...
6464 Golden NH, Carlson JL. The pathophysiology of amenorrhea in the adolescent. Ann N Y Acad Sci. 2008;1135:163-178. Doi: 10.1196/annals.1429.014
https://doi.org/10.1196/annals.1429.014...
6565 Frumar AM, Meldrum DR, Judd HL. Hypercarotenemia in hypothalamic amenorrhea. Fertil Steril. 1979;32(03):261-2646666 Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106(01):6-15. Doi: 10.1016/j.fertnstert. 2016.05.003
https://doi.org/10.1016/j.fertnstert...

In hypothalamic functional amenorrhea, bradycardia, orthostatic hypotension, BMI < 18.5 kg / m2, parotid hypertrophy and/or signs of tissue hypoperfusion6565 Frumar AM, Meldrum DR, Judd HL. Hypercarotenemia in hypothalamic amenorrhea. Fertil Steril. 1979;32(03):261-264 are frequently accompanied by signs of hypoestrogenism, namely delayed puberty, breast atrophy, and vaginal atrophy.66 Lages AS, Rebelo-Marques AR, Carrilho F. Défice Energético Relativo no Desporto (RED-S). Rev Med Desportiva Inf. 2018;9(05): 14-16. Doi: 10.23911/Defice_Energetico_Relativo_no_Desporto
https://doi.org/10.23911/Defice_Energeti...

Complementary Diagnostic Tests

The initial study of amenorrhea includes the evaluation of hCG levels (to exclude pregnancy), FSH, prolactin and TSH. Some authors also recommend in the initial assessment the search of Free T4 (FT4), LH, estradiol and anti-Müllerian hormone (AMH).3434 Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(05):1413-1439. Doi: 10.1210/jc.2017-00131
https://doi.org/10.1210/jc.2017-00131...

Additional studies depend on clinical suspicion. In chronic disease or eating disorder: blood count, liver and kidney function, electrolyte Panel, calcium, magnesium, phosphorus, glycemia, erythrocyte sedimentation rate, and C-reactive protein should be requested3434 Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(05):1413-1439. Doi: 10.1210/jc.2017-00131
https://doi.org/10.1210/jc.2017-00131...
; in the presence of signs of hyperandrogenism, total testosterone, DHEA-S, and 17OH-progesterone should be considered.6767 Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007;92(02):405-413. Doi: 10.1210/jc.2006-1864
https://doi.org/10.1210/jc.2006-1864...
6868 Pinola P, Piltonen TT, Puurunen J, Vanky E, Sundström-Poromaa I, Stener-Victorin E, et al. Androgen profile through life in women with polycystic ovary syndrome: a Nordic multicenter collaboration study. J Clin Endocrinol Metab. 2015;100(09):3400-3407. Doi: 10.1210/jc.2015-2123
https://doi.org/10.1210/jc.2015-2123...

Expected results in functional amenorrhea are decreased LH or low normal, normal FSH (usually higher than LH) and E2 < 50pg/ml. The acute response after GnRH stimulation is preserved. Thyroid stimulating hormone, FT4, and testosterone are usually at the lower limit of normal.3030 Berga SL, Mortola JF, Girton L, Suh B, Laughlin G, Pham P, et al. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 1989;68(02): 301-308. Doi: 10.1210/jcem-68-2-301
https://doi.org/10.1210/jcem-68-2-301...
3131 Michopoulos V, Mancini F, Loucks TL, Berga SL. Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized, controlled trial. Fertil Steril. 2013;99(07):2084-91.e1. Doi: 10.1016/j.fertnstert. 2013.02.036
https://doi.org/10.1016/j.fertnstert...
3434 Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(05):1413-1439. Doi: 10.1210/jc.2017-00131
https://doi.org/10.1210/jc.2017-00131...
6969 Warren MP, Holderness CC, Lesobre V, Tzen R, Vossoughian F, Brooks-Gunn J. Hypothalamic amenorrhea and hidden nutritional insults. J Soc Gynecol Investig. 1994;1(01):84-88. Doi: 10.1177/107155769400100117
https://doi.org/10.1177/1071557694001001...
Anti-Müllerian hormone does not change, and there seems to be no interference in the ovarian reserve.7070 La Marca A, Pati M, Orvieto R, Stabile G, Carducci Artenisio A, Volpe A. Serum anti-müllerian hormone levels in women with secondary amenorrhea. Fertil Steril. 2006;85(05):1547--1549. Doi: 10.1016/j.fertnstert.2005.10.057
https://doi.org/10.1016/j.fertnstert.200...

Bone mineral density assessment should be considered when menstrual dysfunction (6–12 months of amenorrhea/oligomenorrhea, primary amenorrhea), low BMI (< 17.5 kg/m2) or significant weight loss (> 5–10% of body mass within 1 month), in the presence of minor stress/post-trauma fracture, or in the event of an eating disorder. It is advisable to use the Z-Score scale in preference to T-Score, as the first is adapted to age and gender. Any location in the skeleton can be assessed; however, the spine is the most consensual in adolescents and young women with amenorrhea.66 Lages AS, Rebelo-Marques AR, Carrilho F. Défice Energético Relativo no Desporto (RED-S). Rev Med Desportiva Inf. 2018;9(05): 14-16. Doi: 10.23911/Defice_Energetico_Relativo_no_Desporto
https://doi.org/10.23911/Defice_Energeti...
4444 Ackerman KE, Nazem T, Chapko D, RussellM,Mendes N, Taylor AP, et al. Bone microarchitecture is impaired in adolescent amenorrheic athletes compared with eumenorrheic athletes and nonathletic controls. J Clin Endocrinol Metab. 2011;96(10):3123-3133. Doi: 10.1210/jc.2011-1614
https://doi.org/10.1210/jc.2011-1614...
4545 Mitchell DM, Tuck P, Ackerman KE, Sokoloff NC, Woolley R, Slattery M, et al. Altered trabecular bone morphology in adolescent and young adult athletes with menstrual dysfunction. Bone. 2015;81:24-30. Doi: 10.1016/j.bone.2015.06.021
https://doi.org/10.1016/j.bone.2015.06.0...
7171 Crabtree NJ, Arabi A, Bachrach LK, Fewtrell M, Fulheihan GE-H, Kescskemethy HH, et al; International Society for Clinical Densitometry. Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: the revised 2013 ISCD Pediatric Official Positions. J Clin Densitom. 2014;17(02): 225-242. Doi: 10.1016/j.jocd.2014.01.003
https://doi.org/10.1016/j.jocd.2014.01.0...
7272 Bachrach LK, Guido D, Katzman D, Litt IF, Marcus R. Decreased bone density in adolescent girls with anorexia nervosa. Pediatrics. 1990;86(03):440-4477373 Soyka LA, Misra M, Frenchman A, Miller KK, Grinspoon S, Schoenfeld DA, et al. Abnormal bone mineral accrual in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab. 2002;87 (09):4177-4185. Doi: 10.1210/jc.2001-011889
https://doi.org/10.1210/jc.2001-011889...
7474 Grinspoon S, Thomas E, Pitts S, Gross E, Mickley D, Miller K, et al. Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa. Ann Intern Med. 2000;133(10): 790-794. Doi: 10.7326/0003-4819-133-10-200011210-00011
https://doi.org/10.7326/0003-4819-133-10...

The interpretation of densitometry in athletes must follow specific criteria, with BMD being considered lower than expected when Z-score> -1; low BMD if Z-score between -1 and -1.9 with risk factors (nutritional deficiencies, hypoestrogenism or stress fractures), and osteoporosis when Z-score < -2 with risk factors.22 Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MPAmerican College of Sports Medicine. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc. 2007;39(10):1867-1882. Doi: 10.1249/mss.0b013e318149f111
https://doi.org/10.1249/mss.0b013e318149...
33 De Souza MJ, Nattiv A, Joy E, Misra M, Williams NI, Mallinson RJ, et al; Expert Panel. 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, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013. Br J Sports Med. 2014;48(04): 289. Doi: 10.1136/bjsports-2013-093218
https://doi.org/10.1136/bjsports-2013-09...
4949 Robinson TL, Snow-Harter C, Taaffe DR, Gillis D, Shaw J, Marcus R. Gymnasts exhibit higher bone mass than runners despite similar prevalence of amenorrhea and oligomenorrhea. J Bone Miner Res. 1995;10(01):26-35. Doi: 10.1002/jbmr.5650100107
https://doi.org/10.1002/jbmr.5650100107...

Treatment

Due to the multifactorial etiology of female athlete triad - stress, weight loss, excessive exercise, and poor nutrition - a multidisciplinary team is essential for its approach.22 Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MPAmerican College of Sports Medicine. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc. 2007;39(10):1867-1882. Doi: 10.1249/mss.0b013e318149f111
https://doi.org/10.1249/mss.0b013e318149...
33 De Souza MJ, Nattiv A, Joy E, Misra M, Williams NI, Mallinson RJ, et al; Expert Panel. 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, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013. Br J Sports Med. 2014;48(04): 289. Doi: 10.1136/bjsports-2013-093218
https://doi.org/10.1136/bjsports-2013-09...

Nonpharmacological

Nonpharmacological treatment is always the first line of treatment, allowing resolution of most cases. As it is based on LEA, the aim is to restore normal balance with an individualized and dynamic nutritional, psychological, and sports plan that will allow the reestablishment of the hypothalamic-pituitary-ovary axis.44 Mountjoy M, Sundgot-Borgen JK, Burke LM, Ackerman KE, Blauet C, Constantini N, et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update. Br J Sports Med. 2018; 52(11):687-697. Doi: 10.1136/bjsports-2018-099193
https://doi.org/10.1136/bjsports-2018-09...
The increase of 5 to 10% of body weight or of 1 to 4 kg of weight with appropriate nutritional supply – 300 to 600 kcal caloric increase – distributed throughout the day and with protein and carbohydrate consumption preference.66 Lages AS, Rebelo-Marques AR, Carrilho F. Défice Energético Relativo no Desporto (RED-S). Rev Med Desportiva Inf. 2018;9(05): 14-16. Doi: 10.23911/Defice_Energetico_Relativo_no_Desporto
https://doi.org/10.23911/Defice_Energeti...

Vitamin Supplementation

Calcium and vitamin D have shown important benefits in decreasing the risk of stress fractures, as well as in their recovery, with supplementation recommended.7575 Moreira CA, Bilezikian JP. Stress fractures: concepts and therapeutics. J Clin Endocrinol Metab. 2017;102(02):525-534. Doi: 10.1210/jc.2016-2720
https://doi.org/10.1210/jc.2016-2720...
7676 Kim BY, Kraus E, Fredericson M, et al. Serum vitamin D levels are inversely associated with time lost to bone stress injury in a cohort of NCAA division I distance runners. Clin J Sport Med. 2016;26(02):e61 A daily dose of 1,300 mg of calcium (up to ,1500 mg/day) and of 800-1,000 IU of vitamin D (to achieve blood 25[OH]D concentration > 75-100 nmol/L)22 Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MPAmerican College of Sports Medicine. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc. 2007;39(10):1867-1882. Doi: 10.1249/mss.0b013e318149f111
https://doi.org/10.1249/mss.0b013e318149...
7777 NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA.2001;285(06):785-795. Doi: 10.1001/jama.285.6.785
https://doi.org/10.1001/jama.285.6.785...
7878 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(01):38-44. Doi: 10.1007/s11932-005-0029-1
https://doi.org/10.1007/s11932-005-0029-...
is recommended. The use of bisphosphonates should still be avoided, especially in young athlete women, considering its long half-life and its potential teratogenic effect in future pregnancies.

Pharmacological

Pharmacological treatment has a crucial role in selected cases. However, it should only be considered after failure in reestablishing menstruation after between 6 and 12 months of nonpharmacological therapy associated with a proven decrease in BMD. In presence of a young athlete with amenorrhea or oligomenorrhea, combined oral contraception is often used as an adjunct to normalize menstrual cycles. Despite the success in most cases, its use for this purpose is not recommended, as it may cover a possible physiological normalization and give false confidence to the athlete.44 Mountjoy M, Sundgot-Borgen JK, Burke LM, Ackerman KE, Blauet C, Constantini N, et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update. Br J Sports Med. 2018; 52(11):687-697. Doi: 10.1136/bjsports-2018-099193
https://doi.org/10.1136/bjsports-2018-09...
Corroborating the nonindication for its prescription, several studies report the lack of efficacy of oral estrogens in the recovery of BMD/bone protective effect.7979 Warren MP, Brooks-Gunn J, Fox RP, Holderness CC, Hyle EP, Hamilton WG, et al. Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: a longitudinal study. Fertil Steril. 2003;80(02):398-404. Doi: 10.1016/s0015-0282(03)00660-5
https://doi.org/10.1016/s0015-0282(03)00...
8080 Cobb KL, Bachrach LK, SowersM, Nieves J, Greendale GA, Kent KK, et al. The effect of oral contraceptives on bone mass and stress fractures in female runners. Med Sci Sports Exerc. 2007;39(09): 1464-1473. Doi: 10.1249/mss.0b013e318074e532
https://doi.org/10.1249/mss.0b013e318074...
This is justified by their hepatic “first-pass effect,” with potential suppression of liver production of IGF-1 impairing its bone trophic effect.66 Lages AS, Rebelo-Marques AR, Carrilho F. Défice Energético Relativo no Desporto (RED-S). Rev Med Desportiva Inf. 2018;9(05): 14-16. Doi: 10.23911/Defice_Energetico_Relativo_no_Desporto
https://doi.org/10.23911/Defice_Energeti...
8181 Southmayd EA, De Souza MJ. A summary of the influence of exogenous estrogen administration across the lifespan on the GH/IGF-1 axis and implications for bone health. Growth HormIGF Res. 2017;32:2-13. Doi: 10.1016/j.ghir.2016.09.001
https://doi.org/10.1016/j.ghir.2016.09.0...
Currently, when it is necessary to initiate hormone replacement, the most accepted approach consists of transdermal estradiol therapy (E2) (which does not affect IGF-I secretion) associated with a cyclic oral progestative for a short period.3434 Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(05):1413-1439. Doi: 10.1210/jc.2017-00131
https://doi.org/10.1210/jc.2017-00131...
Nevertheless, it is always important to remind athletes that this has no contraceptive effect.8282 Ackerman KE, Singhal V, Baskaran C, et al. Transdermal 17-betaestradiol has a beneficial effect on bone parameters assessed using HRpQCT compared to oral ethinyl estradiol-progesterone combination pills in oligoamenorrheic athletes: a randomized controlled trial. J Bone Miner Res. 2017;32(Suppl 1):S41 For contraceptive purposes, there is no contraindication for any method, although if there is a preference for combined contraceptive, we can offer the vaginal or transdermal route to avoid hepatic “first-pass effect”. The only method that allows the perception of normal recovery are nonhormonal methods, such as nonhormonal intrauterine devices.

Investigational Therapy

Recombinant parathyroid hormone: can be weighted for short periods of time when BMD is very low or in cases of delayed fracture healing.3434 Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(05):1413-1439. Doi: 10.1210/jc.2017-00131
https://doi.org/10.1210/jc.2017-00131...
It is contraindicated in adolescents or young adults with open growth plates. It has shown improvement in BMD and faster recovery.8383 Fazeli PK, Wang IS, Miller KK, Herzog DB, Misra M, Lee H, et al. Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa. J Clin Endocrinol Metab. 2014;99(04):1322-1329. Doi: 10.1210/jc.2013-4105
https://doi.org/10.1210/jc.2013-4105...
8484 Zhang D, Potty A, Vyas P, Lane J. The role of recombinant PTH in human fracture healing: a systematic review. J Orthop Trauma. 2014;28(01):57-62. Doi: 10.1097/BOT.0b013e31828e13fe
https://doi.org/10.1097/BOT.0b013e31828e...

Recombinant leptin: a promising therapy showing increased frequency and levels of LH pulse, improved follicular development, ovarian volume, E2 levels, increased T4, FT4, IGF-I, IGF-binding protein 3, bone alkaline phosphatase, and osteocalcin. However, decreased appetite and significant weight loss have been reported.8585 Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351(10):987-997. Doi: 10.1056/NEJMoa040388
https://doi.org/10.1056/NEJMoa040388...
Similar results can be achieved with metreleptin regarding weight loss and fat mass.8686 Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A. 2011;108(16):6585-6590. Doi: 10.1073/pnas.1015674108
https://doi.org/10.1073/pnas.1015674108...

Recovery after Treatment

Nonpharmacological therapy can restore menstrual cycles to normal in months. However, some athletes may maintain folliculogenesis and altered follicular dynamics for years, with decreased gonadotropins and sex steroid hormones. In these cases, a luteal phase defect may occur with long menstrual periods associated with premenstrual spotting or short cycles due to decreased progesterone secretion.8787 Santoro N. Update in hyper- and hypogonadotropic amenorrhea. J Clin Endocrinol Metab. 2011;96(11):3281-3288. Doi: 10.1210/jc.2011-1419
https://doi.org/10.1210/jc.2011-1419...
8888 Loucks AB, Verdun M, Heath EM. Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. J Appl Physiol (1985). 1998;84(01):37-46. Doi: 10.1152/jappl.1998. 84.1.37
https://doi.org/10.1152/jappl.1998...
Regarding bone metabolism, results can take several years to appear. Regardless of the positive correlation between increasing BMD and menstrual reestablishment, in many cases a full recovery is not achieved.8989 Cialdella-KamL, Guebels CP,Maddalozzo GF, Manore MM. Dietary intervention restored menses in female athletes with exerciseassociated menstrual dysfunction with limited impact on bone and muscle health. Nutrients. 2014;6(08):3018-3039. Doi: 10.3390/nu6083018
https://doi.org/10.3390/nu6083018...

Conclusion

Relative energy deficiency in sport consists of a low energy availability status mainly affecting young athletes, with potentially harmful and irreversible consequences on their health. Its prevalence is underestimated due to lack of and late diagnosis due to deficient knowledge of signs and symptoms. It is crucial and urgent to promote dissemination among different professionals, extending to athletes and their families, in order to increase alertness to this condition, allowing its prevention, early diagnosis, and adequate treatment.

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Publication Dates

  • Publication in this collection
    30 July 2021
  • Date of issue
    May 2021

History

  • Received
    15 June 2020
  • Accepted
    18 Feb 2021
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