Endocrine Reviews, 2024, 00, 1–33

https://doi.org/10.1210/endrev/bnae011
Advance access publication 15 March 2024
Review

Relative Energy Deficiency in Sport (REDs): Endocrine

Manifestations, Pathophysiology and Treatments
Angeliki M. Angelidi,1,2,* Konstantinos Stefanakis,1,2,3,4,* Sharon H. Chou,5

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Laura Valenzuela-Vallejo,1,2 Konstantina Dipla,6 Chrysoula Boutari,7 Konstantinos Ntoskas,4
Panagiotis Tokmakidis,3,4 Alexander Kokkinos,3 Dimitrios G. Goulis,8 Helen A. Papadaki,9
and Christos S. Mantzoros1,2,5
1
Department of Medicine, Boston VA Healthcare System, Boston, MA 02115, USA
2
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
3
First Propaedeutic Department of Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens,
Athens 11527, Greece
4
Department of Internal Medicine, 251 Air Force General Hospital, Athens 11525, Greece
5
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, MA 02115,
USA
6
Exercise Physiology and Biochemistry Laboratory, Department of Sports Science at Serres, Aristotle University of Thessaloniki, Serres 62100,
Greece
7
Second Propaedeutic Department of Internal Medicine, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki,
Thessaloniki 54642, Greece
8
Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki,
Thessaloniki 54124, Greece
9
Department of Hematology, University Hospital of Heraklion, School of Medicine, University of Crete, Heraklion 71500, Greece
Correspondence: Christos S. Mantzoros, MD, DSc, Beth Israel Deaconess Medical Center, 330 Brookline Ave, East Campus, ASN-249, Boston, MA 02215, USA.
Email: cmantzor@bidmc.harvard.edu.
*These authors have contributed equally to this work and share co-first authorship.

Abstract
Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy
Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the
underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and
long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological
systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a
broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and
hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs
and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on nonpharmacological,
behavioral, and lifestyle modifications that target its underlying cause-energy deficit. We also discuss treatment approaches aimed at
managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the
underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in
the pathophysiology and management of REDs.
In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or
lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures,
and improving performance.

Received: 17 November 2023. Editorial Decision: 12 March 2024. Corrected and Typeset: 16 April 2024
Published by Oxford University Press on behalf of the Endocrine Society 2024.
This work is written by (a) US Government employee(s) and is in the public domain in the US.
2 Endocrine Reviews, 2024, Vol. 00, No. 0

Graphical Abstract

Graphical Abstract
Underlying etiologies
Elite athletic and military cohorts
Strict diet regimens

Demanding Persistently
training regimens increased energy Peer-related and trainer pressure
expenditure

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Energy imbalance Persistently low energy intake

Physiological mediators Glucose, Insulin,

BCAA surge

Sustained shift from carbohydrate

Glycogen utilization depletion
to fatty acid metabolism
Low energy availability
Adipose tissue depletion
Leptin levels
Impaired energy homeostasis
Bodily adaptations both
as a result of and in response to
Endocrine manifestations low energy availability

Activin A GH pulse LH, FSH BMD Immunological

Follistatin GH sensitivity Sex steroids and hematological
F F IGFs, IGFBPs consequences
F A F
A F Functional HA Osteoporosis
A
A F Male infertility Stress fractures

Thyroid Catecholamines (?) Gastrointestinal Increased cardiovascular Performance

hormones ACTH Cortisol disturbances risk (limited evidence) Endurance
(long-term) Strength
Negative mental
health and sleep
consequences
Neuroendocrine axes Organ systems Performance
© 2024 Endocrine Society

Key Words: relative energy deficiency in sport, female athlete triad, low energy availability, pathophysiology, endocrinological disorders, therapeutic
approaches
Abbreviations: AFI, activin-follistatin-inhibin; AT, adipose tissue; BAT, brown adipose tissue; BM, bone marrow; BMAT, bone marrow adipose tissue; BMC,
bone mineral content; BMD, bone mineral density; BMI, body mass index; CLD, congenital leptin deficiency; DE, disordered eating; EA, energy availability;
EB, energy balance; EEE, exercise energy expenditure; EI, energy intake; FFM, fat-free mass; FHA, functional hypothalamic amenorrhea; FSTL3, follistatin
and follistatin-like 3; HA, hypothalamic amenorrhea; HPA, hypothalamic-pituitary-adrenal; HPG, hypothalamic-pituitary-gonadal; HRV, heart rate variability;
IOC, International Olympic Committee; JAK, Janus kinase; LEA, low energy availability; OPG, osteoprotegerin; P1NP, pro-peptide of type 1 collagen;
r-metHuLeptin, recombinant methionyl human leptin; RANKL, receptor-activator of nuclear factor κΒ ligand; REDs, Relative Energy Deficiency in Sport;
RMR, resting metabolic rate; SF, stress fracture; STAT, signal transducer and activator of transcription; TEE, total energy expenditure; WAT, white adipose
tissue.

• Basic, translational, and clinical research during en­

ESSENTIAL POINTS
ergy deprivation indicates the adipokine leptin as a
• Relative Energy Deficiency in Sport (REDs) refers to promising regulator of neuroendocrine function
a frequently overlooked constellation of disorders downregulated during LEA, which might be associ­
stemming from low energy availability (LEA) in di­ ated with several REDs-related disorders.
verse exercising populations of either biological • Currently, the front-line treatment approach targeting
sex. the underlying causes of LEA entails the incorporation
• REDs encompasses neuroendocrine abnormalities in of nutritional, behavioral, and lifestyle alterations.
central hypothalamic-pituitary axes, mainly the re­ • Leptin replacement therapy is currently not recom­
productive, thyroid, adrenal, and somatotropic axes mended by consensus guidelines for individuals with
as well as bone, hematological, immunological, hypothalamic amenorrhea or during low energy avail­
gastrointestinal, cardiovascular, neuromuscular, ability because its safety and effectiveness, including
and psychological abnormalities. potential benefits like improved neuroendocrine
Endocrine Reviews, 2024, Vol. 00, No. 0
function, menstrual and reproductive health, growth
factors, and bone health, require further investigation
for confirmation.
• The ACTH-cortisol and activin-follistatin-inhibin axes
have also been shown to be implicated as potential reg­
ulators of a variety of biological processes, including
development, reproduction, body composition, and en­
ergy metabolism, independently of leptin; however, the
full spectrum of diagnostic and therapeutic relevance of
the activin-follistatin-inhibin signaling pathways in
REDs is under investigation.
• Because more studies describing the diagnosis, clinic­
al relevance, and potential treatments of REDs are
being published, compounds in development, target­
ing the physiological pathways involved, could help
improve therapeutic outcomes in energy-deficient
populations suffering from REDs.
Over the past 3 decades, the fundamental role of energy avail­
ability (EA) in athletes’ health and overall well-being has at­
tracted increasing attention from the medical community,
international sports committees and federations, as well as
sports professionals and scientists in general (1).
In sports science and nutrition, EA is defined as the differ­
ence between total daily energy intake (EI) and exercise energy
expenditure (EEE) divided by the fat-free mass (FFM) (ie, EA
= (EI – EEE)/FFM, expressed in kcal/kg of FFM per day) (2-6).
EA represents the total energy at the body’s disposal to sup­
port fundamental physiological functions (such as thermo­
regulation, growth, maintenance of cellular homeostasis,
immune system functions, and reproduction) that underpin
optimal performance, adaptation to training, and ultimately
health (3, 4, 7). It should be emphasized that EA indicates
the total available energy after deducting the energy expended
during exercise, thereby highlighting the possibility that
excessive energy expenditure during exercise can divert energy
away from other critical physiological functions (8).
Moreover, energy balance (EB) is the difference between EI
and total energy expenditure (TEE) (ie, EB = EI – TEE). In a
broader sense, EB is the amount of energy remaining from
EI after subtracting total energy used by the body, including
the energy consumed for the function of all physiological sys­
tems (and is thus either positive or negative) (4). Therefore, it
is essential to acknowledge that EA and EB are not inter­
changeable but reflect 2 different parameters and should be
clearly differentiated to identify athletes at risk of or athletes
in a pathophysiologically abnormal state.
Both research evidence and clinical experience show that
athletes may adapt to situations of energy deficiency, particu­
larly during prolonged periods of severely low energy avail­
ability (LEA). This adaptation occurs by suppressing
energetically costly physiological processes (such as neuroen­
docrine function, and growth), reducing the athlete’s overall
energy requirements, and altering physiological functions
such as reproductive and bone health or insulin resistance sta­
tus and lipolysis. These changes aim to promote survival in en­
vironments of limited energy resources (4, 7, 9).
Considerable research, commencing several decades ago,
has been performed to elucidate the underlying causes of men­
strual dysfunction and low bone mineral density (BMD) lead­
ing to poor bone health (eg, osteoporosis and stress fractures
3
[SF]) observed mainly in high-performance female athletes
with or without a disordered eating (DE) behavior (9). Low
energy availability has been acknowledged as the cornerstone
for these unfavorable health outcomes recognized as the
Female Athlete Triad (10-13). Since its inception in 1992
(10) and reevaluation by the American College of Sports
Medicine in 1997 (12), the term “Female Athlete Triad” in­
volves any 1 of the following 3 interrelated components: (1)
LEA with or without DE, (2) menstrual dysfunction, and (3)
low BMD (9, 12, 14).
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Furthermore, over the past several decades, animal experi­
ments and clinical research (mainly observational studies
and survey data) have revealed that some male athletes and
soldiers may also experience similar LEA-induced physio­
logical abnormalities and health disruptions indicative of
those identified in the Female Athlete Triad (15-21). Thus, a
similar model was defined as the “Male Athlete Triad,” and
it consists of 3 interrelated conditions, namely the LEA (as
the key etiologic factor) and perturbation of bone and repro­
ductive health (alterations of the hypothalamic-pituitary-
gonadal [HPG] axis) (22, 23). However, he available evidence
in males is still more limited, chiefly focused in military popu­
lations and based mainly on epidemiological information, but
contradictory data still exist (17, 21, 24, 25). Therefore, fur­
ther research efforts focusing on the underlying physiological
mechanisms and long-term effects of the Male Athlete Triad
on health and performance are required.
In 2014, the International Olympic Committee (IOC) ex­
pert working group introduced a broader term, coined
Relative Energy Deficiency in Sport (REDs) syndrome (26), re­
ferring but not limited to the LEA-related abnormalities (in­
cluding also endocrine, hematological, immunological,
cardiovascular, cardiovascular, and psychological health dis­
orders) affecting athletic performance, physiological function,
and health status in physically active men and women (21, 26-
31). As awareness of REDs increases, regulatory organiza­
tions in the field of sports have begun outlining the clinical
evaluation, diagnostic workup, and basic treatment of the
syndrome (26, 30). There has also been extensive research
on DE as well as debate on the definition of REDs as a distinct
clinical entity, juxtaposed against overlapping features of the
Overtraining Syndrome (32) and, importantly, the Female
Athlete Triad (33). Thus, a “pathway for progress” has been
suggested to facilitate cooperation between the Female
Athlete Triad and REDs investigators, calling for quality stud­
ies with clinically relevant outcomes and aiming to establish
causality and address previous research gaps (34). In recent
years, significant scientific progress has advanced our under­
standing of the underlying physiology and psychology related
to REDs, culminating in the publication of the IOC consensus
statement on REDs in 2023 (6). Therefore, according to the
revised 2023 definition, REDs is identified as a syndrome re­
sulting from prolonged and/or severe LEA (problematic),
which affects athletes of both sexes, leading to impaired
physiological and/or psychological functioning, including det­
rimental health issues, compromised well-being, performance
challenges, and elevated injury risks (6).
The management of REDs should be multidisciplinary and
carried out by a team of sports and exercise professionals.
Current practice guidelines and consensus statements (14,
19, 35) highlight nutritional, behavioral, and lifestyle changes
as the recommended primary treatment strategies for both the
Female and Male Athlete Triad, as well as for REDs. To date,
4 Endocrine Reviews, 2024, Vol. 00, No. 0
there is a lack of effective pharmacological remedies to coun­
ter the negative consequences of REDs. The adipokine leptin,
the circulating levels of which reflect primarily the size of en­
ergy stores in adipose tissue and secondarily acute energy de­
privation, may be considered a potential contributory factor
to the pathophysiology of the syndrome because of its involve­
ment in regulating neuroendocrine function and energy
homeostasis. Leptin orchestrates an intricate response system
to conserve energy by suppressing nonessential functions vs
deficits, aiming to ensure the survival of the organism through
limiting procreation and preserving energy during LEA (36-
41) by influencing several neurohormonal axes affected in
REDs. Administration of recombinant methionyl human lep­
tin (r-metHuLeptin) to lean individuals with hypoleptinemia
in replacement doses to normalize the falling levels in response
to energy deprivation, confers neuroendocrine benefits (42-
44), including reversing the clinical manifestations of hypo­
thalamic amenorrhea (HA) (45-47). Furthermore, leptin
may help protect against LEA-induced low BMD and SF in
the long term (48-52). However, leptin replacement therapy
is not currently recommended pending further research on
its effectiveness and potential risks in addressing the syn­
drome’s pathophysiology. The activin-follistatin-inhibin
(AFI) axis is an additional hormonal system known for regu­
lating reproductive function and has secondary roles in main­
taining muscle mass, altering bone mass, and influencing
insulin sensitivity and thus lipolysis and glycemia (ie, provi­
sion of energy) (43, 53, 54). The role of the AFI axis in
REDs is starting to emerge and may also pinpoint to novel
therapeutic strategies, as is the stress hormone axis of
ACTH-cortisol, which is affected by both the leptin and the
AFI axis. Consequently, our recent and evolving understand­
ing of the underlying and mediating pathophysiological mech­
anisms is anticipated to change the way we approach,
diagnose, and treat this significant condition.
Military training may negatively affect well-being and
sports performance, especially among personnel who experi­
ence energy deficits during training and field exercises, which
can be linked to the Triad and REDs because of the high en­
ergy expenditures and reduced energy intake (21).
Therefore, this review summarizes available research on the
definition and recognition of LEA/REDs in athletic and mili­
tary cohorts. It further explores the characteristics of REDs
and discusses the pathophysiology of endocrine conduits be­
hind REDs, including leptin and the AFI axis. Additionally,
current and potential treatments for REDs, the Female
Athlete Triad, and related disorders are discussed.
LEA and the Manifestations of REDs
Definition of LEA
As mentioned, EA is calculated by subtracting the EEE from EI
and dividing it by the FFM (6). Severe and/or extended LEA
has been associated with several detrimental effects, with im­
paired reproductive function and bone health being the most
widely described. However, a consensus threshold for the
minimum EA required to sustain all the physiological func­
tions necessary for optimal health and sports performance
has not been achieved. Therefore, a precise threshold of
LEA remains undetermined, with ongoing debates in the sci­
entific community. This uncertainty in defining a clear-cut
threshold could also be attributed to the length of LEA expos­
ure, type of exercise, body size and composition, differences
between males and females and interpersonal variability, diet­
ary macronutrient composition, the lack of previous models
to consider jointly acute energy changes and chronic energy
availability and the fact that the type of methods for EA assess­
ment vary across studies and are not universally standardized
(eg, self-reported questionnaires) (2, 4, 5, 55).
In more detail, based on findings from early randomized
clinical trials investigating gonadotropin pulsatility in regu­
larly menstruating, habitually sedentary, young females of
normal body composition, LH pulse frequency and ampli­
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tude were considered not disrupted when EA levels were
set at 45 kcal/kg FFM/day (56). Moreover, it was found
that LH pulsatility did not follow a linearly proportional to
EA, whereas females with shorter luteal phases were more
susceptible to disruption of LH pulsatility by restricted EA
(56). Therefore, an EA of at least 45 kcal/kg FFM/day is typ­
ically recommended as the optimal EA to ensure sufficient
energy for healthy physiological function (4, 30). Likewise,
EA <30 kcal/kg of FFM/day, even for a short period, has
been associated with substantial perturbation of various
body systems (mainly including alterations in circulating thy­
roid hormones, disruptions in LH pulse frequency, and
increases in bone resorption) (56-58). Furthermore, our
comprehension of the LEA threshold or the range within
which males manifest REDs-related symptoms remains rela­
tively limited. Nonetheless, current evidence suggests that
this threshold is likely lower in males compared with females
(59). Furthermore, it is crucial to recognize that the manifes­
tations of REDs in males and the thresholds for LEA are less
understood and appear to differ from those in females, indi­
cating a need for gender-specific research in this area.
Therefore, an EA threshold lower than 30 kcal/kg FFM per
day has been considered a potential LEA threshold, mainly
based on short-term controlled clinical trials in females.
However, because of limited epidemiological information on
free-living individuals, paucity of long-term studies, and diver­
gent findings among research studies, fail to establish a stand­
ardized and robust threshold for LEA, which continues to be a
topic of active discussion (2, 5, 17, 24, 25, 30, 60, 61).
Our previous research highlights the importance of not only
considering the acute daily energy intake but also longer term
caloric reserves, specifically the amount of energy stored in
adipose tissue. We have found that the hormone leptin acts
as a “thermostat” by reflecting both acute changes in energy
intake (ie, leptin levels drop by approximately 50% of base­
line in response to acute and absolute caloric deprivation
and by only ∼10% of baseline after 3 days of acute and abso­
lute caloric deprivation even before any changes in total fat
mass and body weight occur) (62). The decreased leptin levels
inform the brain of these changes and activate molecular path­
ways that lead to the physiological changes depicted in the
graphical abstract. Nevertheless, it is important to note that
reductions in circulating leptin in relation to LEA have been
reported in earlier studies (63).
No consensus has been developed to date concerning a
targeted LEA threshold between optimal and impaired
physiological mechanisms, highlighting the complexity of ac­
curately identifying individuals at risk, and this needs to be a
priority for research in the future. Therefore, the currently
used EA cutoff points (ie, 30 kcal/kg FFM/day) serve as a pre­
liminary guide and should not be used diagnostically because
of the complex interplay of factors affecting LEA and REDs.
However, EA thresholds might be helpful to direct systematic
Endocrine Reviews, 2024, Vol. 00, No. 0
research on the mechanistic underpinnings of LEA and pro­
vide a gross tool to identify athletes at risk of LEA and subse­
quent performance decline and REDs development.
In conclusion, because of individual variability, including
gender differences as previously described, and the outlined
limitations, a precise threshold of LEA remains undetermined.
Thus, it is imperative to acknowledge the ongoing debates and
contradictions, which highlight the complexities and inherent
challenges in the evidence-based classification and precise def­
inition of both LEA and REDs. This underscores the need for
further research to refine our understanding and methods,
which is essential for advancing both scientific knowledge
and clinical applications related to this condition.
LEA: Causative Factor of REDs
It is crucial to acknowledge that LEA is the primary etiological
key factor of the REDs, which expands the concept of the
Female and Male Athlete Triad to encompass a wide range of
potentially LEA-related severe health consequences beyond
those included in the aforementioned Triad models (26, 56,
57, 64-66) and negatively affect the sport performance and well-
being of individuals at risk (67, 68). The underlying conditions
underpinning the development of LEA are multifactorial and
complex, including, but not limited to, an intentional or unin­
tentional reduction in caloric intake (eg, cultural eating habits,
restriction, binging, fasting, anorexia nervosa, other eating dis­
order/DE disorders) (69), an increase in daily exercise energy ex­
penditure (eg, prolonged acute exercise, intense and extended
duration training demands), and a poor awareness or miscon­
ceptions about the syndrome resulting in an inappropriate
matching of intake energy to the exercise energy demands (9,
26, 30, 70-72). Interestingly, psychological impairments can ei­
ther contribute to LEA and precede REDs (as an exposure vari­
able) or result from REDs (as an outcome) (26, 67).
However, it should be noted that LEA may not always dis­
rupt physiological processes and result in the clinical conse­
quences described in the REDs, a fact that is more apparent,
especially in males (30, 55, 72). Consequently, LEA may be
considered adaptable, particularly in the short term and in
the context of transient and reversible conditions, in which
LEA might be associated with a necessary and valuable activity
in sport (eg, body composition management and intensified
training) (6). On the contrary, LEA could be considered prob­
lematic when it persists over an extended duration or exhibits
specific characteristics indicative of a maladaptive response
(6). LEA exposure, in conjunction with other moderating
factors, may lead to impaired physiological processes.
Consequently, normal physiology can transition into patho­
physiology by disrupting physiological systems, ultimately re­
sulting in poor performance and health issues from
inadequate energy to support optimal functions (8). The char­
acteristics of problematic LEA and the potential moderating
factors may differ among individuals and body systems (eg,
sex, genetic characteristics, preexisting medical conditions,
and most importantly, energy reserves such as overall fat
mass at baseline, type of sport, exercise training duration and
characteristics). Moreover, emerging evidence suggests that be­
sides the amount of caloric consumption, the dietary patterns
followed (eg, low carbohydrate consumption) may exert a
negative impact on athletes’ health, but this remains to be stud­
ied further and in conjunction with underlying neuroendocrine
pathways activated or inactivated (73, 74).
5
However, additional research is warranted in this area.
More rigorous study designs are essential to improve the over­
all quality of evidence regarding the LEA definition and the
Female Athlete Triad and REDs-related outcomes (75).
Therefore, more prospective long-term studies considering
the impact of potential moderating and confounding factors
are needed to elucidate further the causality and timing of
the effects of energy deficiency on the Female Athlete Triad
and REDs development. It is also crucial to consider all of
the aforementioned factors jointly rather than independently
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of each other.
Key Abnormalities of REDs
The physiological consequences of REDs stem from problem­
atic LEA (graphical abstract) and encompass most neuroendo­
crine systems in the human body (Table 1). However, several
short- and long-term outcomes and related signs and symp­
toms are not REDs-specific, and these consequences can be
observed in the absence of LEA under the prism of different
health disorders. Therefore, the differential diagnosis should
always be considered and carefully conducted based on a com­
prehensive assessment and thorough evaluation of the patient’s
clinical presentation, imaging findings, and laboratory exami­
nations, as appropriate.
Substrate Metabolism and Food Intake
The biochemical fingerprint of short-term LEA can be ob­
served in the context of acute nutrient deprivation, which is
well known to trigger a classical physiological cascade.
Fasting- and energy-deficiency induced hypoglycemia (172,
173) can be partially prevented, owing to reduced insulin pro­
duction and elevated glucagon, epinephrine, and cortisol se­
cretion secondary to starvation (174, 175). However,
carbohydrate and glycogen stores are soon depleted, and glu­
coneogenesis takes over using amino acids and glycerol for 24
to 48 hours, followed by ketogenesis (174). After a few days, a
branched-chain amino acid surge triggers the shift to lipid me­
tabolism and ketogenesis, as attested by elevated cortisol, free
fatty acids, β-hydroxybutyrate, and ketone body concentra­
tions (173, 176, 177). Once adipose tissue (AT) reserves are
depleted, the lipolytic metabolic shift is followed by protein
catabolism. Caloric deprivation importantly produces
changes in circulating adipokines, the prime sensors of energy
deficiency and appetite and energy intake controlling hor­
mones and, thus, calibrators of adipose tissue energy reserves
and function. Acute energy deficits have a major effect on
body composition, energy balance, and hormone concentra­
tions, including leptin (42, 85, 178) but exerts little effect on
adiponectin (179). A sustained energy deficit leading to dimin­
ished AT reserves decreases leptin production and alters rest­
ing metabolic rate (RMR) and neuroendocrine profile to
prolong survival (180). In the long term, LEA can dysregulate
the secretion of orexigenic peptides (ie, ghrelin and PYY), with
studies reporting both increases and decreases in circulating
levels (181, 182).
Neuroendocrine Effects
Hypothalamic-pituitary-gonadal axis
Suppression of the HPG axis is a major adaptive mechanism in
states of energy deprivation. This adaptation occurs because
procreation may not be prioritized when the survival of the
6 Endocrine Reviews, 2024, Vol. 00, No. 0

Table 1. Most commonly reported clinical and biochemical manifestations reported in milieus of REDs

Physiological axis Manifestation Most common study type

Endocrine Hypothalamic-pituitary-gonadal Functional HA (12, 36, 61, 65, 68, 76-79) Systematic review
Society guidelines
Consensus statements
Prospective cohort
Cross-sectional
Diminished gonadotropin (LH, FSH) Open-label clinical trial
concentrations and pulses (56, 80-84) Prospective cohort
Decreased testosterone concentrations (81-83, Prospective cohort

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85-91) Cross-sectional
Decreased motile sperm count (86, 92) Cross-sectional
Abnormal sperm morphology (93)
Hypothalamic-pituitary-thyroid Reduced thyroid hormone concentrations (42, 57, Case-control
85, 94-97) Prospective cohort
Cross-sectional
Blunted TSH pulse and response to TRH (42, 96) Cross-sectional
Prospective (short-term)
Hypothalamic-pituitary-somatotropic Accentuated GH pulse peaks (short-term) (98, 99) Prospective cohort
Decreased IGF-1 levels (56, 85, 99-103) Prospective cohort
Increased IGFBP-1 levels (104) Clinical trial
Decreased IGFBP-4, IGFBP-6, GHBP levels (104) Clinical trial
Hypothalamic-pituitary-adrenal Elevated cortisol concentrations (105-109) Review
Prospective cohort
Blunted diurnal salivary cortisol pulse (42, 110, 111) Prospective cohort
Leptin, insulin, and ghrelin Reduced insulin levels (112) Prospective (short-term)
Elevated ghrelin levels (113) Cross-sectional
Reduced leptin levels (42, 45, 46, 104, 112, Clinical trial
114-116)
Bone Loss of BMD and premenopausal osteoporosis (17, 24, 25, 58, 70, 117, 118) Randomized controlled trials
Reviews, Society guidelines,
consensus statements
↑ NTX, CTX, bone resorption markers (58, 70, 119) Randomized and nonrandomized
trials
Cross-sectional
Stress fractures (120-136) Systematic review
Epidemiological
Prospective cohort
Case-control
Immunological Diminished lymphocyte and increased neutrophil counts (137-139) Review
Randomized controlled trial
Prospective cohort
Increased white blood cell counts (73) Prospective cohort
Increased IL-6 levels (140-142) Prospective cohort
Decreased monocytes and T-cell subpopulation (143) Prospective cohort
T-cell hyporesponsiveness (144) Clinical trial
Neutrophil hyporesponsiveness and decreased phagocytic activity (145, 146) Prospective cohort
Decreased IgA levels (64, 147) Prospective cohort
Cross-sectional
Increased likelihood of infections and illnesses (64, 147-151) Cross-sectional
Muscle and Decreased muscle mass and strength, increased risk of injuries (152-154) Randomized controlled trial
performance Cross-sectional
Prospective
Decreased explosive power (155) Prospective
Dysregulation of myokines (156, 157) Review
Reduced muscle glycogen content (158) Crossover randomized controlled trial
Decreased muscle protein synthesis (159) Clinical trial
Diminished activin and increased follistatin concentrations (43, 53, 111, 160, 161) Clinical trial
Prospective
Impaired sports performance (162) Review
Hematological Iron deficiency anemia (163, 164) Cross-sectional
Abnormal levels of ferritin and transferrin, elevated levels of hepcidin (73, 142, 165-167) Cross-sectional
Prospective
Case-control
Cardiovascular Endothelial dysfunction concurrent with HA—association with increased cardiovascular risk Cross-sectional
(168)
Gastrointestinal Nausea, regurgitation, upper abdominal bloating, diarrhoea, delayed gastric emptying and Systematic review
constipation (169, 170)
Increased intestinal permeability (170, 171) Systematic review

Abbreviations: BMD, bone mineral density; CTX, collagen type 1 C-telopeptide; GHBP, GH-binding protein; HA, hypothalamic amenorrhea; IGFBP, IGF binding
protein; NTX, N-terminal telopeptide.
Endocrine Reviews, 2024, Vol. 00, No. 0
organism is at risk because of LEA, which may not provide
sufficient energy to support the creation and development of
a new organism. LEA is associated with suppression of
GnRH signaling and pulsatility, reduced pituitary gonadotro­
pins, primarily LH levels (56, 80), and gonadal steroid hor­
mones, including decreased estrone-1-glucuronide (principal
metabolite of estradiol) and pregnanediol glucuronide (pri­
mary metabolite of progesterone), resulting in menstrual dis­
turbances (60) and functional hypothalamic amenorrhea
(FHA). Past studies have indicated that up to 50% of exercis­
ing women experience menstrual irregularities (76), whereas
FHA in itself constitutes 1 of the most common manifestations
of REDs (36, 77, 78). The presence of FHA depends on the
duration and severity of LEA (30) and was recently reviewed
(79). The highest prevalence for primary amenorrhea was re­
ported in rhythmic gymnastics at 25%, for secondary amenor­
rhea in cycling at 56%, and for oligomenorrhea in boxing at
55% (79). However, study and group heterogeneity, as well
as menstruation reporting, should be taken under careful con­
sideration (77, 183).
There are conflicting results from studies investigating the
occurrence of hypogonadism in male athletes, with some inves­
tigations underlining differences from female manifestations
and varying forms of gonadal disruption in duration, quality,
and reversibility, encompassing a vast array of hypogonadism
forms that occur in elite male athletes (184). Likewise, albeit
studied to a lesser extent, elite male endurance athletes may
display notable downregulation of gonadotropin concentra­
tions, blunted gonadotropin pulses, suppressed testosterone
levels, and impaired spermatogenesis (30, 81-83, 86). In mili­
tary milieus, a series of surveys on male Norwegian cadets
under a 5-day arduous training course has demonstrated
downregulated gonadotropin and sex steroid hormone levels
(87-89). Numerous other studies in energy-deprived male sol­
diers have proven similar changes in testosterone and sex ster­
oid hormones (185-188), even reaching “castrate levels”
following prolonged ranger training courses (85).
Hypothalamic-pituitary-thyroid axis
The hypothalamic-pituitary-thyroid axis also adapts to energy
deprivation (31) by implementing mechanisms that promote
and prolong survival through energy conservation (78).
Short-term energy deprivation exercise studies, including pre­
viously untrained regularly menstruating females, showed
that LEA induces a nonlinear reduction of T3 and free T3 lev­
els, which is associated with decreased metabolism and energy
expenditure in states of reduced energy availability, and an in­
crease of reverse T3 levels (ie, the inactive form of thyroid hor­
mone) (57, 94). Downregulation of T3 has also been
consistently observed in female athletes with LEA and FHA
compared with eumenorrheic individuals (95-97).
More complex findings regarding T4 and free T4 changes
have been observed. An increase of T4 has been described
(94), suggesting a potential mechanism related to decreased
conversion of T4 to T3, which is the active thyroid hormone.
Other studies either identified a decrease in T4 levels (96) or
did not detect a difference (57). Similar findings have been
noted in soldiers, wherein marked downregulations of T3,
T4, and TSH have been noted through longitudinal evalua­
tions of training male cadets and conscripts (85, 90, 186,
188). Supporting literature on male athletes is limited, and
in contrast to females, either a decrease or a neutral effect
7
on T3 levels has been observed, emphasizing the role of base­
line energy stores and sex (as indicated by varying leptin levels
in males and females) (112, 189).
LEA association with thyroid hormone alterations is likely
to be subject to several parameters, including participant’s
characteristics (within and between participant variability,
sex, menstrual status), the underlying causes of LEA (dietary
restriction, increased exercise energy expenditure), and the
type, duration, and volume of athletic training. Therefore,
the full consequences of LEA on thyroid-binding proteins
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and other components of the axis remain to be fully investi­
gated. This research should be conducted in the context of
the effects of those factors on both acute and chronic energy
availability (ie, acute changes in energy balance in relation
to the baseline energy stored in adipose tissue).
Hypothalamic-pituitary-somatotropic axis
In the anterior pituitary gland, GH is released by somatotroph
cells and binds to GH receptors in multiple tissues, including
the liver, which is the main organ responsible for IGF-1 secre­
tion. GH may stimulate the production of IGF-1 via binding to
GH receptor, activating Janus kinase 2 (JAK2) and subse­
quently the phosphorylation of signal transducer and activa­
tor of transcription 5 (STAT5), which plays an essential role
in IGF-1 gene expression (190, 191).
LEA accelerates GH pulse frequency and accentuates GH
peaks (98, 99), whereas it reduces IGF-1 production, poten­
tially reflecting peripheral resistance or reduced sensitivity to
growth signals through diminished liver production of IGFs
and downregulated hepatic and peripheral somatogenic re­
ceptor expression (56, 99-102).
LEA in the form of energy deprivation culminating in hypo­
thalamic amenorrhea, leads to increased levels of IGF binding
protein 1 (IGFBP-1) and diminished levels of IGFBP-4,
IGFBP-6, and growth hormone-binding globulin compared
with healthy individuals (104), potentially indicating a con­
sistent downregulation of hepatic GH receptors and reduced
bioactivity of growth factors, hampering overall circulating
GH activity. Moreover, resistance exercise, a potent anabolic
stimulus, increased GH response and decreased IGF-1 levels in
female and male participants during a short-term, calorie-
restricted LEA state while on a postexercise protein or carbo­
hydrate supplementation (103). Significant and consistent ef­
fects have been observed in male soldiers, wherein increased
energy expenditure leads to an upregulation of IGFBP-1 and
an intermediate downregulation of IGFBP-3 (186, 192,
193). These results suggest that a catabolic state may also limit
the effectiveness and/or the potential benefits of resistance ex­
ercise during the calorie-restricted state.
Finally, GH may exert effects on carbohydrate and lipid
metabolism and help to maintain euglycemia via the mobil­
ization of fat stores in an IGF-1-independent way (194,
195). Therefore, GH resistance could be considered an
adaptive response to LEA. The decreased IGF-1 levels may
help to conserve energy, and through a decreased negative
feedback at the pituitary, the subsequent increased circulat­
ing GH levels may help to maintain euglycemia under LEA
conditions (190).
Hypothalamic-pituitary-adrenal axis
Increased serum and cerebrospinal fluid cortisol concentra­
tion (105-107), reduced cortisol response to intense exercise
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Figure 1. Acute and chronic exercise-induced stress responses of neuroendocrine axes. Acute and chronic exercise, particularly in excess, constitute
important stress effectors. Acutely, this response activates the locus coeruleus-norepinephrine system and induces the secretion of catecholamines
(sympathetic response), while also boosting glucocorticoid production, which are known to acutely produce a spike in GH. Chronic stress, on the other
hand, also produces sustained increases in glucocorticoids through activation of the hypothalamic-pituitary-adrenal axis. The parent hormone, CRH, is
known to suppress GnRH through β-endorphins, as well as TRH, and increase somatostatin, which in turn inhibits GH and TRH. Meanwhile, increased
glucocorticoid production suppresses the concentrations of thyroid hormones, GH, and GnRH. These effects, when compounded and persistently
accentuated in chronic stress, which entails excessive exercise, may lead to lower muscle mass and BMD, as well as to increased visceral adiposity risk.
Abbreviations: BMD, bone mineral density; CRH, corticotropin-releasing hormone; GnRH, gonadotropin releasing hormone; IGFBP, IGF binding protein;
LC/NE, locus coeruleus-norepinephrine; SNS, sympathetic nervous system; TRH, thyroid releasing hormone.

(106), as well as accentuated cortisol pulse amplitude com­ Immunological Effects

pared with eumenorrheic exercisers (108) have all been estab­
lished in women with HA. The diurnal pulsatility of salivary
cortisol appears to be abolished in elite gymnasts, which
may indicate an adaptation to prolonged periods of LEA
(196). In the long term, however, cortisol levels may be in­
creased, reflecting an increasingly stressful situation from pro­
longed energy deprivation. Malnutrition and anorexia, on the
extreme spectrum of energy deficiency, as well as chronic ex­
cessive exercise, directly related to REDs, have been well-
established as effectuators of acute and chronic stress and
activate the hypothalamic-pituitary-adrenal (HPA) axis
(109, 197). In turn, this effect entails alterations in almost
all hypothalamic-pituitary axes and may lead to reductions
in muscle mass and BMD (Fig. 1). This increase in cortisol lev­
els is a mechanistically multifactorial process, which depends
not only on decreasing leptin levels, as all the previously de­
scribed neuroendocrine changes, but also on alterations in
the AFI axis and other proinflammatory molecules in the per­
iphery, as well as changes in neuropeptide levels centrally
(Figs. 1-3). The elucidation of energy deficiency-induced
changes in the HPA axis is further evident in studies of both
male and female soldiers, consistently reporting an upregula­
tion of cortisol (187, 188, 198, 199), which has been shown to
be more pronounced in females (200).
As attested by experiments in mice, mainly because of falling
leptin levels in response to energy deprivation, an abnormal
Th1/Th2 balance, upregulated production of proinflamma­
tory cytokines (ie, IL-6 and TNF-α), and cortisol is observed
with LEA and may increase the risk of specific infections
(201). In the 2018 and 2023 consensus statements (30,
202), the IOC noted that LEA might impair the immune sys­
tem, highlighting the increased rates of upper respiratory
and gastrointestinal tract infections based on observational
data from amenorrheic elite female distance runners (64)
and Olympic athletes assessed as being at risk for LEA (using
the low energy availability in females questionnaire) (148,
149). Findings of various studies have suggested adverse ef­
fects of energy restriction and weight loss on immunological
parameters, such as impaired humoral and cell-mediated im­
mune function and subsequent increased risk of potential in­
fections in athletes. In particular, 2 observational studies
exploring the effects of intensive training and rapid weight
loss on immunological markers revealed suppressed mucosal
immunity indicated by the reduced levels of salivary Ig A
and an increased upper respiratory tract infection incidence
in male and female elite taekwondo athletes (147, 150).
Decreased salivary Ig A levels and increased upper respiratory
tract infection symptoms were also observed in amenorrheic
Endocrine Reviews, 2024, Vol. 00, No. 0 9

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Figure 2. Endocrine effects underlying REDs-associated states across tissues and systems, highlighting the independent functions of leptin and the AFI
axis. Arrows with plus signs indicate positive relationships or feedback in states of hypoleptinemia; arrows with minus signs indicate negative feedback;
up and down arrows represent changes (increase or decrease, respectively) occurring under energy deprivation. Leptin is a central regulator of the HPG
axis and can simultaneously influence bone health both directly and indirectly through modulations in the reproductive system. In states of LEA, leptin
levels are decreased, thus leading to downregulation of the reproductive system and its hormones, bringing about long-term directly or indirectly bone
loss; these changes can be reversed through leptin supplementation. However, the AFI axis functions independently of leptin. LEA upregulates folli­
statins and decreases activins. Follistatins thus render the reproductive system inactive, help preserve precious muscle tissue, which is achieved through
follistatins blunting the catabolic functions of activins and myostatin. In the liver, follistatin concentrations are inversely correlated with insulin sensitivity
and improved glucose metabolism, thus leading to de novo lipogenesis and glycemia. Emerging evidence demonstrates that lower activins/follistatin
ratios are also linked to osteopenia and osteoporosis. Abbreviations: ACTRII, activin receptor type 2; AMH, anti-müllerian hormone; BMD, bone mineral
density; fT3, free triiodothyronine; FSTL3, follistatin-like 3; HPA, hypothalamic-pituitary-adrenal; HPG, hypothalamic-pituitary-gonadal; HPT, hypothal­
amic-pituitary-thyroid; IGF-1, insulin-like growth factor; IGFBP, IGF binding protein; TG, triglyceride.

elite female distance runners compared with the eumenorrheic
runners (203). Furthermore, weight loss (reduced energy in­
take) was associated with impaired cell-mediated immune
function (ie, decreased counts of specific monocytes and
T-cell subpopulations) and high susceptibility to upper re­
spiratory tract infection symptoms in an observational study
of judo athletes (143). In addition, weight reduction resulted
in decreased cytokine production (ie, interferon-g), prolifer­
ation of T cells (144), and neutrophil phagocytic activity
(145, 146) in case-control studies in amateur wrestlers and
judo athletes. However, in a randomized control trial, calorie
restriction during high-intensity exercise was associated with
an increase in IL-6 and TNF-a levels and a significant variation
in lymphocyte, leukocyte, and neutrophil counts (204). Of
note, a large cross-sectional evaluation of 2247 elite athletes
has shown markedly downregulated white blood cell and neu­
trophil counts in athletes trained for aerobic vs skill-based
sports, indicating a negative immune adaptive response which
is distinct for individuals at risk for LEA (205). On the other
hand, male soldiers also display reportedly increased circulat­
ing levels of IL-6 and TNF-a (140-142) as well as hepcidin,
also outlined in the hematological effects section that follows
and can display downregulated in vitro T-lymphocyte re­
sponses and increases in infection rates (151, 206). Further re­
search is needed to more precisely identify the relationship
between LEA, immunological parameters, immune functions,
and susceptibility to infectious diseases. However, these
changes should be seen in the broader context of energy de­
privation leading to immune dysfunction in a direct but also
in a potentially indirect way through alterations in leptin,
AFI, and cortisol levels. Pathophysiologically, similar but
more pronounced changes occur in other states of more severe
energy deprivation, such as in starving populations in devel­
oping countries.
Hematological Effects
Lower hemoglobin concentrations and iron deficiency have
been observed in both male and female professional athletes
(163, 164, 207). LEA has been associated with iron deficiency
and impaired ferritin levels, which may result in iron defi­
ciency anemia commonly seen in young female athletes
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Figure 3. Neuroendocrine regulation of reproduction, bone health, growth, thyroid, and adrenal function by leptin. Leptin concentrations are directly
proportional to AT energy reserves, yet obese patients demonstrate significant resistance to its hormonal effects. In the brain, leptin can act directly on
dopaminergic neurons or bind to its receptor in the hypothalamus, leading to upregulation of proopiomelanocortin and the downregulation of the ore­
xigenic NPY and agouti-related protein (AgRP) neurons, thus exerting a holistic control over appetite and food intake. Leptin directly influences the SNS in
animals but not in humans. The hypothalamic effects of leptin influence the pituitary downstream, affecting several vital endocrine axes in both animal
models and human cohorts. Through kisspeptin-1 and other neurons, GnRH secretion triggers LH and FSH production in a pulsatile manner directly
influenced by leptin’s circadian variations. Thyroid and corticoid hormone adaptations, driven by perturbations in TRH, TSH, and CRH, respectively, are
also influenced by leptin, especially in animal models but also in humans in lesser degrees. Leptin also exerts control over the growth factor IGF axis, with
administration in humans effectuating increases in IGF-1 and IGFBP-1. Last, leptin constitutes a key conduit of bone health, either directly or indirectly by
influencing estrogen and other trophic hormone concentrations. Abbreviations: AgRP, agouti-related protein; CNS, central nervous system; CRH, cor­
ticotropin-releasing hormone; E2, estradiol; IGF, insulin-like growth factor; Kiss1, kisspeptin-1; NPY, neuropeptide-Y; POMC, proopiomelanocortin; SNS,
sympathetic nervous system; TRH, thyrotropin-releasing hormone.

(208, 209). Iron deficiency has been suggested as a hemato­
logical concern of interest in the context of REDs, according
to the updated 2018 IOC consensus statement, and a potential
driver for other REDs-related health complications (30). The
prevalence of iron deficiency has also been frequently reported
in both male and female soldiers, both throughout and follow­
ing training (210-214), alongside elevated hepcidin and fer­
ritin concentrations (141, 142).
LEA may impact the iron balance in both direct and
indirect ways. Innately, an impaired reproductive axis in fe­
males results in menstrual dysfunction and amenorrhea.
Therefore, LEA may improve iron status by reducing iron
losses from menstrual bleeding. However, elevated acute
phase reactants and proinflammatory molecules, including
hepcidin concentrations (a known iron-regulating protein
associated with reduced dietary iron absorption and im­
paired iron metabolism) and abnormal ferritin levels, and
low-grade inflammation-induced iron deficiency have been
observed in athletes with a high-intensity workload (165).
Moreover, LEA accompanied by conditions with high en­
ergy expenditure may also trigger an immune response and
increase hepcidin levels, which may induce potential de­
clines in iron status (142, 166). However, the duration and
type of exercise might also have different effects on iron con­
centrations (167). In addition, an indirect effect of LEA on
iron levels may be secondary to undernutrition or decreased
macronutrient (ie, low carbohydrate availability) and
micronutrient intake combined with increased iron de­
mands and a substantial reduction in bioavailable iron in
athletes (215).
On the other hand, iron deficiency may also interact with
multiple physiological systems, resulting in exacerbated en­
ergy deficiency, impaired reproductive functions, and poor
bone health (the 3 pillars of the known Female Athlete
Triad), which are REDs-related health consequences (30,
216). In more detail, iron deficiency may be associated with re­
productive endocrine dysfunction, hyperprolactinemia, infertil­
ity issues, reduced metabolic efficiency, and worsened energy
status via impaired thyroid function (209). In addition, iron de­
ficiency may induce neuroendocrine abnormalities by impair­
ing the levels and function of dopamine, serotonin, and
norepinephrine neurotransmitters (217). These neuropeptide
Endocrine Reviews, 2024, Vol. 00, No. 0
alterations might contribute to traits associated with
anxiety-related disorder symptoms and disturbed appetitive
and eating behaviors (218, 219). In addition, iron deficiency
per se may induce negative feelings of anxiety, depression,
and low perceived quality of life (220). Therefore, it has
been proposed that iron deficiency may also affect the risk
for DE by increasing anxiety-related behaviors and disrupt­
ing eating behaviors via neuroendocrine aberrations (209).
Iron deficiency may also compromise bone health through
imbalances in growth factors (eg, GH and IGF-1 suppres­
sion), hypoxia-induced bone resorption, and thyroid dysre­
gulation (209).
The available research is limited. Future investigation is re­
quired to elucidate further the relationships between iron de­
ficiency and LEA and its components and explore the
potential effects of dietary interventions, supplementation,
neuroendocrine regulation, and restoration of menstrual func­
tion on iron metabolism and REDs outcomes.
Bone marrow fat actively contributes to various metabolic
processes such as energy storage, endocrine function, and
bone metabolism. The most abundant type of cells in the
bone marrow cavity and hematopoietic microenvironment
are bone marrow adipocytes. These cells play a crucial role
in maintaining the balance between the proliferation and dif­
ferentiation of hematopoietic stem cells, thereby supporting
normal blood cell formation (221). Bone marrow (BM) adi­
pose tissue (BMAT) is regulated in a distinct manner that re­
flects visceral fat stores in obesity and does not shrink under
caloric deprivation (221). BMAT possesses both metabolic-,
bone-, and immune-related properties and is considered the
third-largest fat storage after subcutaneous and visceral fat,
accounting for up to 70% of BM volume and ∼10% of total
adipose mass. It derives from marrow adipogenic lineage pre­
cursors, which are cells that possess adipocyte markers but do
not contain lipid droplets and function by preserving marrow
vasculature and preventing the differentiation of mesenchy­
mal progenitor cells into osteoblasts (222).
BMAT, a metabolically active, insulin-sensitive tissue, cor­
relates with the amount of visceral fat in obesity, whereas
obesity and aging induce ectopic adipocyte accumulation in
the BM (223, 224). BMAT accumulates in individuals with
chronic caloric restriction, such as in anorexia nervosa and
possibly REDs, or during skeletal growth periods, localized
principally within the tibia or femur (225). Studies in mice
have shown how BMAT fails to mobilize its lipid reserve dur­
ing moderate starvation (226) and is resistant to β-adrenergic
lipolysis stimulation.
Cardiovascular Effects
In young endurance athletes, a link between amenorrhea and
endothelial dysfunction has been suggested (168). Low estro­
gen levels have also been associated with unfavorable lipid
profiles and increased cardiovascular risk as well as compro­
mised orthostatic and cardiac sympathetic responses (168,
227).
Heart rate variability (HRV), reflecting autonomic nervous
system function, is a metric of fitness and performance in
sports and the military (228). Elite endurance athletes who
participated in a 4-year longitudinal study were classified as
experiencing fatigue or not based on their scoring on a specific
questionnaire designed and validated by the consensus group
on overtraining of the French Society of Sports Medicine
11
(229). Athletes classified in the “fatigue state” (score exceeded
20 negative items of 54) experienced a lower and more vari­
able HRV than their counterparts not classified in the fatigue
state (229). However, direct evidence regarding cardiovascu­
lar health and HRV in REDs in athletic populations and the
military is still limited; more research is warranted (33).
Gastrointestinal Effects
The redistribution of blood and nutrients toward metabolical­
ly active tissues during exercise can lead to gastrointestinal
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disturbances, alterations in the gut microbiome, and changes
in markers of gut health, damage, and permeability in healthy
exercising athletes (171, 230, 231). REDs has been associated
with gastrointestinal symptoms in athletes, such as gut dam­
age, increased intestinal permeability, delayed gastric empty­
ing, constipation, and worsened sphincter control (30, 171).
Several gastrointestinal disturbances (increased intestinal per­
meability, diarrhea, irritable bowel, chronic pain, and consti­
pation) (140, 232, 233) and even relevant clinical entities (eg,
Gulf War syndrome) (234) have been reported in soldiers, yet
these have not been adequately delineated in the context of
REDs.
Muscle and Performance Effects
The beneficial effects of exercise include reductions in body fat
and inflammation and improvements in strength and endur­
ance (235, 236). Moreover, adequate carbohydrate and pro­
tein intake are essential to maintain blood glucose levels,
replenish muscle glycogen, repair and synthesize muscle
tissue, promote muscle protein synthesis (237) and muscle
adaptation to training (238, 239), and maximize training out­
comes. In addition, it has been suggested that resistance exer­
cise combined with increased postexercise protein availability
may promote muscle protein synthesis in a dose-dependent
way during a short-term energy deficiency state and ultimately
preserve lean (muscle) mass in the long term (159).
Therefore, energy deficits, often accompanied by inad­
equate carbohydrate or protein intake (240), may lead to
lower muscle glycogen stores (56, 158), which may result
in unfavorable health outcomes (240) and sports perform­
ance (74). In addition, incomplete recovery and increased fa­
tigue further impede athletic or military goals (21, 30).
Importantly, as shown by a recent investigation in elite
male endurance athletes, reduced performance and explosive
power as a result of reduced energy availability may precede
hormonal changes (ie, reductions in IGF-1 levels) (155),
whereas previous studies on Norwegian soldiers have dem­
onstrated a progressive deterioration of muscle damage,
soreness, and blunted performance (241), and a marked
and persistent drop in performance even 1 week after hormo­
nal imbalances were normalized following refeeding (185).
Bone Health and Stress Fractures
Along with decreased muscle mass and reduced performance,
LEA may result in compromised bone health linked to in­
creased risk of SF in athletes and military personnel as well
as long-term consequences (ie, osteoporosis) (21, 118, 242).
Moreover, a negative dose-response association between EA
and bone turnover was found in a randomized control trial
in which the energy availability (ie, 10, 20, or 30 kcal/kg
FFM/day) was controlled in 29 young, regularly menstruating
12
exercising women (58). Potential sex differences have been de­
scribed, with females displaying increased bone resorption
and decreased bone formation (70). In male athletes, loss of
BMD is often characterized as a direct or indirect effect of
LEA, particularly in weight-restrictive, lean endurance sports
(eg, cycling, rowing, distance running), leading to prolonged
periods of LEA (71).
Both short-term diet-induced LEA and exercise-induced
LEA have been associated with reduced bone formation in
eumenorrheic women. Further evidence suggests that the
type of diet may also play a role in bone formation. In par­
ticular, a low-carbohydrate diet has been found to be associ­
ated with a more profound reduced bone formation, whereas
sufficient energy, including adequate carbohydrate support,
may mitigate the exercise-induced unfavorable bone turn­
over responses (74). Inadequate nutrition, regarding both
macronutrients (eg, carbohydrates, protein) and vitamins
and micronutrients (eg, vitamin D and calcium, iron), as
well as hormonal disturbances (eg, sex steroid deficiency,
GH resistance, hypercortisolism, mainly from hypoleptine­
mia and disturbances in other adipokines and the AFI axis)
may all directly and indirectly contribute to increased bone
resorption and low BMD. Additional SF risk factors among
athletes and military personnel include pronounced mechan­
ical stress without sufficient recovery (120).
Early case reports in athletes indicate that the most common
injuries are localized in the tibia (49.1%), tarsals (25.3%), and
metatarsals (8.8%), as well as the femur, fibula, and pelvis
(243). Furthermore, low weight and BMD have been associ­
ated with a higher risk of bone stress injuries in trabecular-rich
compared with cortical-rich locations (121). Military person­
nel is also heavily burdened by SF reaching a cumulative
incidence of 5.69 per 1000 person-years in large-scale epi­
demiological studies (122). These numbers differ between
men and women (reportedly 2.05 vs 7.47 per 1000 person-
years in male and female soldiers, respectively, representing
>5.2 million person-years of risk (123); other reports delin­
eate an incidence of 19.3 vs 79.9/1000 recruits respectively
in general SF (124) and a prevalence of 2.76 vs 5.78 per
1000 person-years respectively for ankle-foot complex SFs)
(125). Apart from epidemiology, soldiers are known to dis­
play elevated levels of bone turnover markers and parathor­
mone, which are, however, higher in male soldiers (119)
who similarly display a lower total bone mineral content
(BMC) compared with female counterparts (126). SFs impose
an estimated cost of $100 million annually to the US military,
not including lost duty (244).
More prolonged (58) studies with larger sample sizes are
needed to refine the dose-response relationships between
chronic restrictions of EA and bone turnover and the under­
lying mechanisms and determine the optimal nutritional inter­
ventions to restore bone health (117).
Pathophysiology and Mechanistic Pathways
Underlying REDs-associated Disorders
In states of LEA, the body strives to preserve the function of sys­
tems necessary for immediate survival, diverting energy from
nonessential systems (eg, reproduction). From an endocrine
point of view, exercise and inflammation both induce and are
influenced by various hormonal changes, particularly in adipo­
kines, which constitute the main cellular and metabolic signals
of AT and are prime regulators of energy balance (245).
Endocrine Reviews, 2024, Vol. 00, No. 0
Adipose Tissue
White AT (WAT) stores energy, brown AT (BAT) is consid­
ered a key mediator of thermogenesis. A third type of AT
termed “beige” or “brite” (brown-in-white) fat comprises re­
cruitable thermogenic brown adipocytes within WAT depots,
as demonstrated through in vitro and preclinical experiments
(246). BAT was first investigated as a key thermogenetic tissue
in small mammals (247). In humans, less than half of BAT de­
posits are activated under cold exposure, and BAT appears
less activated in obese individuals compared with lean coun­
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terparts (248). Exercise can induce “browning” of WAT,
causing AT to switch from storing white adipocytes to beige
adipocytes, and has been hypothesized to be an adaptive pro­
cess (249). Interestingly, BAT thermogenic activity may be
lower in male endurance athletes and chronically exercising
women compared with nonexercising controls (250, 251).
BAT activity is negatively correlated with amenorrhea dur­
ation (251), potentially indicating compromised metabolic ac­
tivity of BAT in REDs to preserve energy, but these data
remain to be confirmed, especially given that BAT is extremely
low to start with in normal adults. BMAT has also been impli­
cated in energy regulation, bone health, and hematopoiesis,
and its role as a mediator in REDs-related disorders is
emerging.
Leptin
Leptin physiology
Leptin is a hormone secreted by adipose tissue. It is an adipo­
kine that plays a crucial role in regulating energy metabolism
and adipose tissue. Leptin helps maintain the overall physio­
logical balance of the body and regulates important functions
related to metabolism (252). The circulating levels of leptin
display sexual dimorphism, being higher in women than in
men, and reflect mainly acute changes in energy intake (with
a precipitous drop in acute energy deprivation) as well as long-
term energy stores (with decreasing levels reflecting LEA).
Leptin binds and activates its receptors not only in the brain
but also in peripheral organs, thus mediating the effects of dys­
regulated energy homeostasis in most REDs-related hormonal
subsystems (Fig. 3) (1, 27, 37, 253). Therefore, leptin is a re­
liable indicator of energy availability and, by extension, en­
ergy deprivation in animals and humans (47, 62, 253).
In humans, the leptin gene is expressed primarily in WAT and
in much lower concentrations in other tissues such as the stom­
ach, placenta, mammary gland, and the immune system (254).
Leptin displays a pulsatile pattern of secretion, which is notably
accentuated in women and produces elevated basal leptin con­
centrations in the female sex (255). On a molecular level, leptin
can cross the blood-brain barrier through a facilitated system
and directly (256) binds in the brain but also in other organs
to its receptor LEPR, which belongs to the JAK-STAT family
of transcription factors, primarily in the hypothalamus and
more specifically in areas such as the arcuate nucleus of the
hypothalamus (256-258). In the context of neuroendocrine
regulation, falling leptin levels in the context of energy depriv­
ation activate orexigenic NPY/agouti-related protein neurons
(258) and inhibit anorexigenic proopiomelanocortin activity
in the brain, thus constituting the afferent signal of an
AT-mediated negative feedback loop regulating energy avail­
ability by influencing food intake and altering physiology (37,
259). Leptin regulates the hypothalamic-pituitary-peripheral
Endocrine Reviews, 2024, Vol. 00, No. 0
hormonal axes, as mentioned previously, and has secondary ac­
tions in peripheral tissues, including the immune system, bones,
muscle, and adipose tissue, all aiming at maintaining energy
homeostasis under normal physiological conditions but leading
to pathophysiological abnormalities and diseases such as SF
when the physiologically adaptive processes last longer than
they should.
Mice with deleted leptin genes, now identified as the ob/ob
phenotype, as well as humans with similar genetic defects, are
innately obese and display impaired thermogenesis, dimin­
ished energy expenditure, and endocrine and metabolic ab­
normalities (246, 260). Leptin replacement in these mice
and humans reduces fat mass without affecting lean body
mass and improves neuroendocrine function and metabolism
(261). In addition, females tend to have increased leptin pro­
duction and pulse amplitude, potentially indicating an innate
relative leptin resistance (255, 262). However, in LEA, short-
term fasting induces a profound and rapid decrease in serum
leptin concentrations, potentially through increased leptin
clearance (263), which precede and are disproportionate to
changes in fat mass (42, 44, 264). Moreover, the weight loss
attained during fasting with concomitant leptin administra­
tion in physiologic, supraphysiologic, or pharmacologic doses
is independent of dose or circulating leptin levels achieved
(263). Long-term energy deprivation through caloric restric­
tion likewise results in markedly downregulated leptin con­
centrations (265). Women with DE and amenorrhea are also
known to have reduced circulating leptin levels and blunted
pulses (107, 266, 267). In this energy-deficient milieu of low
basal leptin, human studies show notable neuroendocrine
benefits in response to both physiological and supraphysiolog­
ical doses of r-metHuLeptin (42, 45-47, 114) (Fig. 2).
Neuroendocrine effects of leptin
The pivotal role of leptin as key regulator of neuroendocrine
axes, whose dysfunctions constitute components of REDs, is
physiologically distinct between animals and humans.
Hypothalamic-pituitary-gonadal axis
Leptin stimulates GnRH release from incubated neuronal cells
and accentuates GnRH pulsatility, but not amplitude, in
hypothalamic neurons (268). Low leptin concentrations, com­
mon in LEA, downregulate GnRH secretion from the hypo­
thalamus, through either direct action or indirect changes in
neuropeptide systems, such as neurokinin or kisspeptin-
mediated pathways (269).
Ob/ob mice, which are sterile, regain reproductive capacity
following leptin administration (270). In calorically deprived
mice with low leptin levels, leptin administration has also been
shown to reverse the LEA-induced reductions in LH and tes­
tosterone (271). Likewise, r-metHuLeptin replacement stimu­
lated gonadotropin pulsatility, culminating in normal LH and
FSH secretion in a seminal study on a child with congenital
leptin deficiency (CLD) (272) and another case report of leptin
replacement in a female child with CLD for 24 months ob­
served restoration of LH pulsatility and pubertal develop­
ment, including menarche (273). In a case series of 3 adults
with CLD, leptin replacement increased LH and testosterone
levels, associated with the development of secondary sex char­
acteristics, in a male patient and induced ovulation in 2 female
patients (274).
13
Disruptions in circulating leptin and reproductive hormone
profiles are evident in LEA and have been observed in healthy
individuals after short-term starvation (88, 275). In 8 healthy
males, 72 hours of fasting altered LH pulsatility and markedly
decreased testosterone. Concomitant r-metHuLeptin admin­
istration maintained normal LH pulsatility and testosterone
levels (42). In a pilot study of 14 adult females with hypo­
thalamic amenorrhea resulting from vigorous exercise or
low weight, the administration of recombinant leptin
(r-metHuLeptin) appeared to improve reproductive func­
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tion. In particular, women who received r-metHuLeptin
demonstrated increases in LH pulsatility, estradiol concen­
trations, ovarian activity, and the number and size of follicles
(46). Another randomized placebo-controlled trial in women
with HA, 11 of whom were assigned to r-metHuLeptin and 9
to placebo, reported elevated estradiol and progesterone lev­
els in the leptin-treated women, in addition to improvements
in other neuroendocrine abnormalities after 36 weeks (45).
Treatment with r-metHuLeptin resulted in the resumption
of menses in a significant proportion of adhering participants
(114). During the entire study period, the r-metHuLeptin
dose was reduced in 5 of 11 metreleptin-treated participants
who lost more than 5% of their baseline body weight, where­
as 2 of the participants withdrew from the study because of
weight loss when circulating leptin levels exceeded the
physiologically normal range. Besides local injection site re­
actions developed by 1 participant, no other clinically signifi­
cant drug-related adverse events were documented (114).
Thus, leptin administration at replacement doses, sufficient
to maintain circulating leptin levels within the normal range,
normalizes neuroendocrine axes impairments from energy
deprivation. However, when leptin is administered in supra­
physiological doses, the side effect of further suppression of
fat mass and weight loss is observed (apparently as part of a
feedback loop to limit the endogenous contributions to circu­
lating leptin when the exogenously administered leptin is too
high).
Hypothalamic-pituitary-thyroid axis
Leptin stimulates thyrotropin-releasing hormone production
in hypothalamic cells of fasted rodents (276) and prevents
the fasting-induced downregulation of TSH pulsatility and
T4 secretion, albeit partially (271). In humans, LEPR muta­
tions result in low T4 levels but normal basal TSH levels
and sustained TSH responses to thyrotropin-releasing hor­
mone (277). In leptin-deficient children, leptin replacement in­
creased free T3 and free T4 concentrations (273).
In lean healthy men, r-metHuLeptin administration in re­
placement doses prevented the energy derivation-induced sup­
pression of TSH pulsatility and increased the concentrations of
free T4 but did not affect T3 and reverse T3 (42). However, in
7 women following a similar protocol, r-metHuLeptin did not
prevent fasting-induced fluctuations in thyroid hormones (44).
Women with HA receiving high-dose r-metHuLeptin for 3
months had increased TSH pulse frequency and amplitude
and transiently increased free T3 and free T4 levels (46),
whereas treatment over 36 weeks resulted in increased free
T3 but not free T4 or TSH levels, compared with placebo
(45). Thus, although the precise effects of leptin on the thyroid
axis remain to be fully elucidated, findings to date are consist­
ent with the hypothesis that fasting-induced thyroid hormone
changes are mediated through falling leptin levels due to
14
energy deprivation. It is however established that among over­
weight or obese individuals, who are leptin resistant, long-term
leptin replacement therapy to push circulating leptin levels to
even higher supraphysiologic levels does not produce any
changes in circulating TSH or any of the active thyroid hor­
mones, both total and free, indicating a neuroendocrine milieu
of leptin resistance (278).
Hypothalamic-pituitary-somatotropic axis
Incubation of human pituitary cells in leptin increases GH secre­
tion (279). and in mice, leptin prevents the fasting-induced sup­
pression of GH and IGF-1 and partially corrects GHRH mRNA
expression (280). In adults with CLD, r-metHuLeptin, in
physiological replacement doses, elevated IGFBP-1 and 2, but
not IGF-1 (274).
When administered in healthy men (42) or women (44)
undergoing a 72-hour complete energy deprivation, leptin
in replacement doses does not markedly influence GH pulsa­
tility or IGFBP levels but blunts the starvation-induced de­
crease (104) of total, but not free, IGF-1 secretion. In
contrast, in a 3-month pilot study of women with HA treated
with r-metHuLeptin, IGF-1 increased in the first month and
returned to baseline levels, whereas IGFBP-3 was markedly in­
creased during months 2 and 3 (46). A longer study of female
athletes with HA also found that r-metHuLeptin treatment for
36 weeks significantly increased total IGF-1 and tended to ele­
vate free IGF-1 and IGFBP-3 levels compared with controls
(104). These changes in women with HA are evident with
up to 2 years of r-metHuLeptin treatment (114). Overall, lep­
tin administration seems to have beneficial effects on the
GH-IGF1 axis in states of long-term energy deficiency rather
than short-term starvation.
Hypothalamic-pituitary-adrenal axis
LEA increases ACTH and corticosterone in mice, and leptin
administration inhibits corticotropin-releasing hormone
from hypothalamic cells and reverses the LEA-induced activa­
tion of the HPA axis (281). However, humans with LEPR mu­
tations do not present with HPA abnormalities (277),
indicating a key interspecies difference.
Short-term pharmacological leptin administration in
healthy fasted lean men (42) and women (44) does not affect
fasting-induced changes in plasma or urine cortisol concentra­
tions, cortisol pulsatility, or the HPA axis overall. Three
months of r-metHuLeptin treatment in women with HA failed
to induce changes in cortisol or ACTH levels (46); however,
long-term administration of replacement-dose leptin of 36
weeks to 2 years in women with HA results in marked declines
in cortisol levels (42, 45, 46, 114). Overall, leptin administra­
tion seems to have beneficial effects on the ACTH-cortisol axis
in states of long-term energy deficiency rather than short-term
starvation.
Sympathetic nervous system
Leptin also differentially affects components of the sympa­
thetic nervous system (heart rate, blood pressure, catechol­
amines) in animals and humans. In mice, leptin increases
BAT sympathetic tone in the dorsomedial hypothalamus
and activates sympathetic nerves (282-284). However, leptin
administration in short-term studies in healthy lean men and
women and long-term studies in women with HA do not dem­
onstrate any significant changes in resting metabolic rate,
Endocrine Reviews, 2024, Vol. 00, No. 0
body temperature, resting heart rate, blood pressure, or urin­
ary catecholamine levels (285).
Immune and hemopoietic systems
LEPR is expressed in almost all immune cells (286, 287), and
its long form, which is considered to be fully capable of JAK/
STAT signaling, is expressed on natural killer cells and acti­
vated T-lymphocytes (287). Incubation with leptin has been
shown to activate B cells and induce the expression of cyto­
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kines and signaling molecules in macrophages and mono­
nuclear cells (288). When administered in fasted mice, leptin
reversed the starvation-induced suppression of T-lymphocyte
responses by increasing Th1 cells and downregulating Th2
cytokine production (289). In humans, leptin administration
in children with congenital leptin deficiency boosted T-cell re­
sponsiveness and increased CD4+ T-lymphocytes (273), and in
adults it boosted signals that stimulate chemotaxis and in­
crease CD4+ cell counts (290, 291).
In a study of 14 women with HA (6 treated with placebo and
8 with replacement-dose r-metHuLeptin for 36 weeks) and 13
healthy controls, individuals with HA had lower basal leptin
levels and T-cell counts compared with controls. Treatment
with r-MetHuLeptin improved CD4+ cell counts and their
proliferative responses following in vitro stimulation. Leptin
additionally boosted the expression of cell survival and hormo­
nal response genes and blunted apoptosis-related genes.
Finally, leptin activated cell proliferation and growth path­
ways within CD4+ T-lymphocytes, such as AMPK, STAT3,
and mTOR (291).
Leptin is also known to promote the proliferation, differen­
tiation, and activation of marrow hemopoietic cells, induce
bone marrow colonies, and interact with granulocyte precur­
sors (292-294). More recently, the presence of LEPR on hem­
atopoietic stem cells was identified as an indicator of
hematopoietic stem cell engrafting quality and capacity (295).
Bone Health
Loss of BMD constitutes 1 of the prime characteristics of the
Female Athlete Triad and is a pivotal feature of REDs. The sta­
tus of bone tissue is a direct reflection of human nutritional
status, including but not limited to calcium and vitamin D in­
take, and is regulated by PTH and other hormonal conduits,
including leptin, particularly in energy-insufficiency states
(296) (Fig. 4).
When elucidating the inner workings of bone regulation, it
is important to mention the roles of receptor-activator of nu­
clear factor κΒ ligand (RANKL) pathway signaling, osteopro­
tegerin (OPG), and sclerostin, among others, in regulating the
osteoblast-osteoclast equilibrium. Osteoclasts, responsible
for bone resorption, are activated through RANKL ligand
signaling, which is naturally inhibited by OPG, itself secreted
by osteoblasts (297). On the other hand, sclerostin, which is
also produced by osteocytes, binds to low-density lipoprotein
receptor-related protein receptors, which are involved in
WNT signaling and the regulation of bone mass (298).
Normally, WNT activation induces osteoblast activation,
whereas sclerostin inhibits lipoprotein receptor-related pro­
tein and WNT signaling, thus reducing bone formation
(298). Sex steroid hormones and estrogen directly regulate
OPG and RANKL production (299) and may influence
RANKL-induced osteoclast differentiation (300), whereas
Endocrine Reviews, 2024, Vol. 00, No. 0 15

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Figure 4. Functions and pathways of leptin in bone health. Arrows with plus signs indicate positive relationships or feedback; arrows with minus signs
indicate negative feedback. Physiologically, RANKL is critical for the differentiation of osteocytes into osteoclasts and is inhibited by osteoprotegerin
(OPG). Meanwhile, sclerostin binds to LRP receptors and antagonizes WNT signaling, which is key for osteoblast activation. Leptin’s role in bone ph­
ysiology can be discerned into indirect and direct. Leptin indirectly influences bone status by producing changes in hormone levels such as estrogens and
growth factors, especially IGF-1. Studies in animals and humans receiving leptin have demonstrated positive effects on bone mass through downre­
gulation of bone resorption and increased osteoblast formation and activity. Leptin may also act through CART to deactivate osteoblasts while it add­
itionally increases osteoprotegerin expression, which binds RANKL and thus deactivates osteoclasts in a manner similar to estrogen. This is evident in
human studies showcasing a downregulation of CTX, a marker of bone catabolism. On the other hand, leptin upregulates a series of important bone
formation factors, including TGF-B, collagen 1a, bone-specific alkaline phosphatase, and osteocalcin. Leptin may additionally influence PTH secretion,
while it also regulates vitamin D metabolism and activates FGF-23 in animal models, which is central to bone and mineral metabolism, yet does not impact
sclerostin, and only tends to increase osteoprotegerin (OPG) and decrease RANKL levels in humans. Intracellularly, leptin drives osteoblast proliferation
through cyclin D1, activated through the same molecular clock the hormone oversees. Overall, leptin demonstrates a tendency to improve cortical bone
integrity and thus may pinpoint a strategy to reduce SF risk in athletes and military personnel. Abbreviations: AP-1, activator protein 1; BAP, bone-specific
alkaline phosphatase; CART, cocaine and amphetamine regulated transcript; Col1A, collagen type I alpha 1; CTX, C-terminal telopeptide of collagen; CY,
cytochrome; E2, estradiol; FGF23, fibroblast growth factor-23; LPR, low-density lipoprotein receptor-related protein; OPG, osteoprotegerin; RANKL, r­
eceptor activator of nuclear factor kappa-Β ligand; VDR, vitamin D receptor.

in animals, estrogen targets and suppresses RANKL expres­
sion in bone lining cells (301).
High cortisol may additionally directly lead to increased
bone resorption by means of reducing OPG and increasing
RANKL expression, promoting osteoclast survival and de­
creased bone formation via inducing osteoblast apoptosis,
and by preferentially driving BM stromal cell differentiation
to adipocytes over osteocytes (253, 302-304). Moreover, cor­
tisol concentrations have been positively correlated with colla­
gen type 1 C-telopeptide (CTX), a bone resorption marker,
and inversely associated with LH pulsatility and procollagen
type 1 N-terminal propeptide (P1NP), a marker of bone colla­
gen deposition (110).
PTH aims to maintain and mobilize circulating calcium
from the bones, kidneys, and gut, while reducing the renal re­
absorption of phosphate. Vitamin D, on the other hand, stim­
ulates both calcium and phosphate metabolism, providing
adequate minerals for bone formation (305). In exercising hu­
mans, short-term exercise often increases circulating PTH,
whereas conflicting results are present in long-term exercising
cohorts, even displaying decreasing trends (306). On the other
hand, vitamin D deficiency is a frequent occurrence in athletes
and often correlated with increased fracture risk (307), pre­
cipitating therapeutic recommendations for supplementation
in amenorrhea with osteoporosis.
Estrogen promotes osteoblast proliferation and blocks
osteoclast differentiation (308). Thus, hypoestrogenism re­
sults in increased bone resorption with a relative deficit in
bone formation and is associated with low BMD (309-312).
Furthermore, androgens play important antiresorptive and
anabolic roles in bone for men and women by decreasing os­
teoclastogenesis and stimulating osteoclast apoptosis while in­
hibiting osteoblast apoptosis (313).
Low IGF-1 levels and activity are also culprits of compro­
mised BMD in LEA. IGF-1 has been positively correlated
with bone mass (314) and shown to stimulate osteoblast pro­
liferation and activity (315), is considered essential for the dif­
ferentiation of mesenchymal osteoprogenitors (316), has been
16
associated with bone resorption, formation, and healing, and
linked, alongside GH administration, to rapid clinical im­
provements in tibial fractures (317). IGFBPs also possess an
important anabolic role within the skeleton by directing the
actions of IGFs and particularly IGF-1 within bone tissue
(314).
The HPA axis, which responds to stress and LEA by excess
cortisol production, influences bone health as well. Cortisol
can inhibit osteoblast and osteoclast growth, hinder the ana­
bolic effects of growth hormone, and suppress IGF-1 synthesis
in skeletal cells (99, 318-320). Excess cortisol is also known to
suppress the HPG axis, which is pivotal for bone regulation
(12, 26, 36, 321).
Role of leptin in bone health
Leptin serves as a link between AT and bone both directly by
stimulating osteoblasts, chondrocytes, and BM stromal cells
and indirectly through alterations in neuroendocrine activity
(49, 322). At the molecular level, leptin regulates osteoblasts
by upregulating Ap-1 gene expression, which activates osteo­
blast proliferation through cyclin D1 (323). Leptin has also
been shown to promote osteoblast differentiation by upregu­
lating TGF-β, IGF-1, collagen-1α, alkaline phosphatase, and
osteocalcin mRNA in human iliac crest osteoblasts (324).
Osteocalcin, in particular, is known to be affected by leptin
via the hypothalamus and constitutes a notable orchestrator
of bone health, insulin sensitivity, and energy balance (325,
326). Moreover, leptin may also promote osteoblastogenesis
by upregulating CYP27B1, CYP27A1, and VDR, which are
mediators in vitamin D metabolism (327). In rodent models,
leptin also increases FGF-23 expression in bone, leading to
suppression of renal 1α-hydroxylase expression (328). It is
now accepted that leptin represses osteoclast differentiation
through cocaine- and amphetamine-regulated transcript and
acts in a similar way to estrogen, increasing OPG levels, which
binds to RANKL (329) and thus blunts osteoclast activity.
Finally, leptin also exerts beneficial effects on bone through
an overall amelioration of metabolism and neuroendocrine
health (49). In lean hypoleptinemic women, r-metHuLeptin
administration for 36 weeks markedly downregulated intact
PTH and RANKL to OPG ratio did not alter sclerostin,
dickkopf-1, and FGF-23 levels, but it nevertheless tended to
increase serum OPG and decreased serum RANKL (330).
This indicates differences in mechanisms of action between
humans and animal models.
Low leptin levels have also been observed among female
athletes with elevated bone turnover as indicated by levels of
CTX (331). Even though early animal models displayed in­
verse relationships with leptin concentrations and BMD, re­
porting predominantly antiosteogenic pathways through the
central hypothalamus as a result of intracerebroventricular
leptin infusions (284, 332), such pathways are not activated
in humans (42, 114). Although leptin levels have not been
linked to estrogens in healthy individuals with sufficient leptin
levels (333), leptin has an intricate relationship with the regu­
lation of sex steroid hormone production through its para­
mount influence on the HPG and other axes, particularly
when circulating leptin levels are low as in cases characterized
by acute or chronic energy deprivation (334, 335).
In vitro, leptin directly activates osteoblasts, chondrocytes,
and bone marrow stromal cells and promotes osteoblast dif­
ferentiation (49). Leptin-deficient mice present with increased
Endocrine Reviews, 2024, Vol. 00, No. 0
trabecular volume and BMD in axial bones, but diminished
length and mineralization, along with increased marrow
adiposity, in the peripheral skeleton (322, 336).
Intracerebroventricular leptin administration in ob/ob mice
inhibits bone formation and stimulates bone resorption
(284) to reduce vertebral trabecular bone volume but increase
femur length and bone volume, normalizing the bone pheno­
type (322). In several animal models, leptin administration
exerts positive effects on bone mass except at markedly ele­
vated doses, which may decrease body weight (49, 322, 337).
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A retrospective analysis of 1193 Japanese postmenopausal
women found that low leptin concentrations were associated
with a higher risk of long-bone osteoporotic fractures (hazard
ratio 0.70) (48), confirming the results of an older report in
men and women (51). Leptin replacement in leptin-deficient
individuals may improve bone health directly and indirectly
via restoration of the HPG axis, increased IGF-1 activity,
and decreased cortisol concentrations (46). In a randomized
controlled trial of 19 women with HA, 36 weeks of
r-metHuLeptin treatment upregulated osteocalcin levels, a
marker of bone formation, and prevented an increase in urin­
ary N-terminal telopeptide-to-creatinine ratio, a marker of
bone resorption, compared with placebo (45). Lumbar BMC
and BMD improved with r-metHuLeptin treatment (114).
The extension of treatment in 6 subjects for 1 additional
year increased BMC by 1.4% to 6.5% and BMD by 2.2%
to 10.8% from baseline at the lumbar spine and maintained
low levels of CTX, another marker of bone resorption
(114). These r-metHuLeptin-treated women with HA also
had increases in estradiol concentrations and resumed menses,
which would also contribute to decreased bone resorption
(114). In another randomized placebo-controlled trial, leptin
administration in women with hypothalamic amenorrhea
for 36 weeks did not influence circulating sclerostin or
FGF23 levels but markedly downregulated intact PTH and
tended to downregulate serum RANKL and increase OPG,
while also significantly decreasing the RANKL-to-OPG ratio
(330), indicating reduced bone resorption and osteoclastic ac­
tivity, which are beneficial to bone integrity.
The AFI Axis
Leptin significantly influences the energy-consuming process of
reproduction, as attested by the downregulation of the HPG
axis in energy-deprived hypoleptinemic states, leading to HA
and infertility (43). However, only 60% of patients with HA
improve their reproductive function with leptin replacement,
suggesting the presence of additional regulators. We have pro­
posed that the AFI axis may have a role in reproduction, as well
as muscle mass and metabolic processes, in energy-deficiency
states, that is independent of leptin (43, 338) (Fig. 2).
Activins and inhibins are members of the TGF-β superfamily,
chiefly functioning through SMAD signaling. They are impli­
cated in reproduction, muscle tissue growth and differentiation,
and energy metabolism (339). Under normal circumstances, ac­
tivins and inhibins bind to their receptors on pituitary, ovarian,
and testicular cells. Principally, inhibins suppress whereas acti­
vins upregulate FSH production from the anterior pituitary,
thus maintaining an equilibrium (339-341). Activins also in­
duce muscle atrophy and limit muscle mass alongside myosta­
tin (53, 342).
Follistatin and follistatin-like 3 (FSTL3), which increase
with LEA, suppress the bioactivity of activins by irreversibly
Endocrine Reviews, 2024, Vol. 00, No. 0
binding to them (339, 340). By neutralizing activins’ role in re­
production, follistatins shunt energy away from the repro­
ductive system (43, 54, 340). Follistatins also block the
catabolic function of activins and myostatin to preserve
muscle mass (339, 341).
Follistatins also mediate liver metabolic processes, lipid
homeostasis, and glucose metabolism (54). FSTL3 knockout
mice have reduced visceral fat, decreased insulin resistance, in­
creased pancreatic islet number and size, and improved glu­
cose tolerance (343). In humans, follistatin concentrations
are inversely correlated with insulin sensitivity and positively
associated with body mass index, fat mass, lipid profiles, and
blood pressure (43, 53, 54, 111).
Activin A and B concentrations are elevated in physically
active individuals (without known LEA), and exercise tends
to increase the levels of activins, but also follistatin, which
acts as a “binding protein” for activins and FSTL3 (53). In
contrast, acute energy deprivation by fasting in healthy males
results in decreased activin A and increased follistatin concen­
trations (37). In the context of chronic energy deficiency,
women with HA also have higher follistatin levels and lower
circulating levels of activins but lower FSTL3 levels compared
with healthy women (43). These changes would lead to sup­
pression of reproduction, preservation of muscle mass, and in­
sulin resistance, mainly at the level of the liver, which would
lead to higher availability of circulating levels of glucose and
lipids (ie, energy sources). Importantly, 72-hour crossover ex­
periments in lean men and women, as well as long-term
placebo-controlled leptin replacement in women with hypo­
thalamic amenorrhea attaining resumption of menses and re­
ductions in body fat, have shown that LEA-induced
alterations of the AFI axis are not influenced by leptin admin­
istration and thus mostly function independently of leptin (53,
54, 111, 338, 344) (Fig. 2).
Management of REDs
The management of REDs should be multidisciplinary and
undertaken by a team of sports and exercise professionals, in­
cluding nutritionists, physicians, psychologists, psychiatrists,
physiotherapists, and physiologists. However, REDs is often
misdiagnosed by health professionals, coaches, and athletes,
with studies demonstrating insufficient education, poor man­
agement, and prioritization of performance over health (345-
347). Initial recommendations start with specialized dietary
plans, nutritional education, and supplementation, followed
by mitigation of exercise, before proceeding with specialized
hormonal or pharmaceutical treatments.
Nonpharmacological Strategies
Nonpharmacological therapy is the preferred mainstay strat­
egy, which frequently results in the successful resolution of
most cases. The treatment of REDs should involve a multifa­
ceted approach, taking into account the complexity and indi­
vidual variability in each athlete’s nutritional needs and
recovery processes. Therefore, it is crucial to recognize the sig­
nificance of addressing the underlying cause of REDs rather
than solely focusing on treating its symptoms. Current con­
sensus statements and practice guidelines (6, 14, 19, 35) em­
phasize nutritional, behavioral, and lifestyle changes,
including an appropriate exercise regimen and the importance
of increasing dietary energy intake and/or reducing exercise
17
energy expenditure to improve EA for the prevention and
treatment of the clinical consequences of LEA and therefore
of the Female and Male Athlete Triad and REDs.
The IOC panel of experts also highlights the need for edu­
cational programs on nutritional options as well as the risks
and consequences in health from inadequate dietary patterns
(26). Besides, they describe the REDs clinical treatment as
based on realistic health-promoting goals for weight and
body composition (26). Patients are usually advised to in­
crease their daily calorie intake by 300 to 600 kcal (26) or
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to set energy intake at a minimum of 2000 kcal/day, depend­
ing on exercise energy expenditure (14), but there is no estab­
lished protocol for gradually increasing calorie consumption
(26). In addition, it is suggested to restore body weight at lev­
els that are correlated with the resumption of regular men­
strual cycles (14). It has been observed that resumption of
menses may occur after achieving approximately 90% of the
ideal body weight for age and height (348). However, the
timeframe for recovery typically spans several months, al­
though it can vary significantly and may even extend to years
in some cases (348, 349).
Moreover, it is crucial to emphasize that the relationship be­
tween body weight gain and the restoration of menstrual func­
tion is not a linear process, and additional factors may play a
role (350). Recovery can be complex, particularly in the con­
text of REDs, as intense physical activity may lead to the per­
sistence of amenorrhea (6, 30). Therefore, it is essential to
acknowledge both the complexity and individual variability
in the resumption of the menstrual cycle while emphasizing
the importance of personalized goals and targets in clinical
practice to facilitate menstrual function recovery. This
highlights that achieving a specific weight is not a universal so­
lution, and a “1-size-fits-all” approach may not be appropri­
ate and adjustments may be required over time.
Besides observational data (351), recently, the first random­
ized controlled trial (ie, REFUEL study) showed that increased
energy intake 20% to 40% above baseline energy require­
ments was associated with an improved menstrual function
in exercising women with oligomenorrhoea or amenorrhoea
(352). It is also important to focus on diet quality, ensuring
a proper balance of macronutrients and appropriate
consumption of micronutrients (such as iron, calcium, and
vitamin D) (14). In particular, vitamin D and calcium supple­
mentation, as needed, may promote bone health and prevent
SF with a potential benefit during the recovery phase (127,
296, 353-356), whereas an optimal daily intake of 1000 to
1300 mg of calcium and vitamin D concentrations within
the range of 32 to 50 ng/mL are recommended (14).
Additional factors such as the diversity of food choices, indi­
vidual taste, and the practicality of food availability (practical
aspects of food availability) should be considered while de­
signing a meal plan (14). As a result, potential challenges of
correcting the underlying LEA by altering energy intake and/
or exercise energy expenditure in individual athletes or sol­
diers (from difficulties in changing the antecedents that under­
pin LEA or noncompliance) should also be acknowledged.
Finally, the European College of Sport Science and the
American College of Sports Medicine consensus also highlight
resting, adequate sleeping, adjusting dietary patterns, and de­
creasing training as important treatment factors (357).
Regarding eating disorders, treatments for medically stable
and unstable patients differ but also require multidisciplinary
treatment. Although cognitive behavioral therapy is a first-line
18
treatment option, each patient evaluation should consider the
need for an inpatient hospitalization, outpatient care, or day
programs based on their stability, associated complications,
and comorbidities (358). Specifically, for anorexia nervosa,
it can be attempted to be treated with cognitive behavioral
therapy, which has been expanded to females with HA and
shown to normalize leptin, TSH, and cortisol concentrations
(probably because body weight and fat mass increased)
(353, 359). More precisely, its first-line management should
include weight restoration with nutritional rehabilitation. It
should include restoring a structured meal routine, supervised
meals, and psychotherapy to address dysfunctional thoughts
and behaviors (358, 360). Of note, nutritional repletion might
restore several related endocrine abnormalities but is not com­
monly sufficient by itself (361, 362).
Several ongoing (Table 2) and recently completed trials
have investigated risk assessment for REDs, as well as
pharmacological and nonpharmacological lifestyle modifica­
tion strategies for REDs and related disorders. One study en­
rolled 481 female college athletes who were assigned to a
comprehensive lifestyle modification termed the Female
Athlete Body Project, a behavioral eating disorder risk factor
reduction program, or a control arm, and found benefit in
body perception-related outcomes through the Female
Athlete Body Project (363). Under the same principles, the
Male Athlete Body Project has also been investigated up to 1
month follow-up (364); yet, these studies chiefly pertain to
DE and do not specifically address outcomes on endocrine
REDs markers. Another more recent study implementing a
food and nutrition learning program intervention of online
lectures applied to a multinational cohort alongside a control
intervention, demonstrated improvements in REDs symp­
toms, particularly menstrual function and, to a lesser extent,
gastrointestinal issues, in athletes who underwent the FUEL
intervention, with these benefits persisting up to 12 months
after intervention (365). Another study in healthy females
under low energy availability led to decreased P1NP levels in­
dicative of bone resorption, which were prevented through the
incorporation of high-impact jumping, indicated by stable
β-CTx levels, suggesting a protective effect on bone health
(366). On the other hand, in male cyclists, 4 weeks of intensive
endurance interval training was shown to improve aerobic
performance and testosterone but produced reductions in
RMR, T3, and increases in cortisol, all of which constituted
risk markers of REDs (367).
Pharmacological Strategies
Targeting underlying causes of LEA incorporating nutritional,
behavioral, and lifestyle alterations is the front-line treatment
approach. However, pharmacological management could be
considered, especially in specific cases regarding the treatment
of problematic LEA-related symptoms. The nonpharmacolog­
ical approach should continue along with the initiation of
pharmacological treatment.
Despite recommendations for treatment of FHA with estro­
gen with or without calcium and vitamin D, a recent meta-
analysis on estradiol treatment in premenopausal women
with FHA and low BMD found no significant improvements
in lumbar BMD overall, though there may be a benefit with
transdermal estradiol (309). A recent randomized controlled
study in young, amenorrheic female athletes demonstrated ro­
bust improvements in spine, femoral neck, and hip BMD with
Endocrine Reviews, 2024, Vol. 00, No. 0
12 months of transdermal estradiol treatment, compared
with oral estradiol or no treatment (368). Unlike transder­
mal estrogen, oral formulations of estrogen can decrease
IGF-1 activity (369), reduce free testosterone concentrations
(by increasing SHBG levels), and as a result, the potential
anabolic testosterone-induced effects on bone (370, 371).
The Endocrine Society suggests against using oral contra­
ceptives to improve BMD if the underlying energy deficit is
not addressed (78). However, the 2014 Female Athlete
Triad Coalition recommended considering transdermal es­
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tradiol if BMD Z-scores are ≤−2.0, there are ongoing risk
factors, and an adequate response has not been achieved
after 1 year of lifestyle modification (ie, BMD loss or new
fracture) (14).
PTH analogs are used for the treatment of osteoporosis and
are extremely effective at reducing vertebral fractures.
Teriparatide, an injectable synthetic recombinant human
parathyroid hormone analog, has been shown to markedly in­
crease BMD in women with anorexia nervosa after 6 months
of treatment (372) and is stipulated by the Endocrine Society’s
guidelines for HA-associated delayed fracture healing and low
BMD (78). Two ongoing clinical trials (Table 2) are currently
investigating its use in military populations to prevent SF.
Romosozumab, an anti-sclerostin antibody, has proven
fracture reduction benefits in postmenopausal women with
osteoporosis and improve bone profiles in men, albeit with
some potential cardiovascular side effects, chiefly myocardial
infarction and stroke (373). Currently, there is only 1 small
trial examining BMD changes in premenopausal women
with idiopathic osteoporosis (NCT04800367). Denosumab
has also been studied for 12 and 24 months in 32 women
with premenopausal idiopathic osteoporosis following a
treatment course of 24-month teriparatide, attaining marked
increases in lumbar, hip, and femoral BMD (374). These med­
ications have yet to be studied in energy-deficient cohorts of
athletes or soldiers. Moreover, it should be noted that the
Endocrine Society does not recommend bisphosphonates, de­
nosumab, testosterone, or leptin for bone health based on lim­
ited evidence, and these therapies are only reserved for
individuals who have failed or have contraindications to es­
trogen replacement. Recombinant parathyroid hormone is
suggested in cases of delayed fracture healing and markedly
low BMD (78).
Given the reduced GH activity associated with LEA, GH
and IGF-1 therapies have been tried in women with anorexia
nervosa. Although treatment with GH does not seem effective
because of GH resistance, recombinant IGF-1 treatment with
oral contraceptives has been shown to modestly increase spine
BMD in women with anorexia (195, 375). Growth hormone
secretagogues are currently being investigated, but not in co­
horts with REDs. LUM201, also known as ibutamoren or
MK-677, is a GH secretagogue currently being investigated
for pediatric GH deficiency (NCT04614337). MK-677 has
been shown to increase serum levels of GH, IGF-1, and
IGFBP-3, as well as lean body mass in a 2-month study in
obese patients (376). MK-677 additionally increased both
markers of bone formation and resorption, elevating CTX
by 23% and procollagen III by 28% in early stages of treat­
ment and osteocalcin at later stages (377). A randomized con­
trolled trial in 165 older adults with hip fractures found
marked increases in IGF-1 levels but no improvements in func­
tional or performance metrics (378). In another trial of elderly
patients with hip fracture, MK-677 was found to improve gait
Endocrine Reviews, 2024, Vol. 00, No. 0 19

Table 2. Ongoing studies, as of November 2023, investigating the pathophysiology and treatment of LEA-, REDs-, and the Female Athlete Triad-associated
conditions in athletic, training, healthy, and energy-deficient populations

Registered trials investigating prevalence, risk or mechanisms, and characteristics of LEA, REDs, and the Female Athlete Triad

Identifier Design Participants Arms Outcomes Time frame

NCT05649267 Prospective/ 10 Judoka athletes, 1. Year 1—Energy deficit, 1. Body weight and composition including 3y
cross-sectional aged 18-30 y, dietary risk BMD
training ≥4 times/ 2. Years 2 and 3—effect of 2. Food intake
week for at least 2 h carbohydrates and protein

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on function and
performance
NCT04821076 Prospective Females, aged 18-30 Trained population: 1. Changes in muscle protein synthesis 10 d
RCT y, BMI 18.5-30, 1. Low-calorie diet + exercise rate
normally 2. Energy-balanced diet + 2. Muscle and adipose tissue biopsies,
menstruating: exercise anthropometrics, ergometric
1. 30 trained Recreationally active assessment, hormones, inflammatory
2. 30 recreationally population: markers, cardiovascular indices
active 1. Low-calorie diet
2. Energy-balanced diet
NCT02858336 Crossover 150 females ages 1. Neutral energy availability 1. LH pulse frequency 5d
18-28 y, BMI (45 kcal/kg lean body 2. Levels of hormones, adipokines,
18.5-27, normal mass/d) assessment of glucose homeostasis
menstruation 2. Deficient energy
availability (20 kcal/kg
lean body mass/d)
NCT04910724 Prospective Individuals, ages Energy deficit resulting from a 1. Whole body protein balance (leucine 2d
18-35 y, BMI < 30, combination of exercise and isotope)
stable weight for 2 diet: 2. Muscle protein synthesis (phenylalanine
months 1. Energy deficit (20% of isotope)
daily requirements) 3. Carbohydrate oxidation (glucose
2. Energy deficit (40% of isotope)
daily requirements)
3. Energy deficit (60% of
daily requirements)
NCT04900701 Prospective 36 individuals, aged 1. Hypocaloric energy status 1. Muscle protein fractional synthetic rate 6d
35-65 y 2. Energy balance 2. Muscle morphology
3. Hypercaloric energy status
NCT05259969 Prospective 25 competitive male Observational study 1. Energy intake, expenditure and fat-free 1 y, (visits on
cohort athletes aged 18-40 examining a series of mass baseline, 6
y markers across the sport 2. Resting metabolic rate, body mass and mo, 12 mo)
seasons to assess the risk of composition, iron status markers,
LEA in male adult athletes. thyroid markers, testosterone, cortisol,
1. Preparation phase (peak LEAM-Q, eating attitude and disorder
exercise workload) questionnaires, inflammation markers,
2. Competition phase ghrelin, GH, gut microbiota,
3. transition phase (lowest metabolites and performance markers,
exercise workload) lipid profiles, leptin concentrations,
IGF-1
NCT03593382 Cross-sectional Female endurance Energy availability 1. Resting energy metabolism 6 wk to 6 mo
athlete exercising at 2. Secondary outcomes include: work after
least 5 times/week, efficiency, substrate utilization, bone inclusion
18-39 y mineral content and density, hormonal
measurements, lipid profile, vital signs,
dietary and activity questionnaires
NCT04254900 Prospective Athletes from a Energy availability evaluation 1. Energy intake, exercise energy 7 consecutive
national team in expenditure and fat-free mass and days during
wheelchair sports, using the following formula: energy preseason
18-60 y availability = (energy intake – exercise
energy expenditure)/fat-free mass)
NCT05587270 Prospective Swedish climbers on Web-based surveys and DXA 1. Eating disorders based on the Eating 3y
elite or subelite Disorders Examination-Questionnaire
levels of 2. Basic symptoms indicative of REDs,
competition, >13 y questionnaires on meals, menstruation,
injuries
(continued)
20 Endocrine Reviews, 2024, Vol. 00, No. 0

Table 2. Continued

Registered trials investigating prevalence, risk or mechanisms, and characteristics of LEA, REDs, and the Female Athlete Triad

Identifier Design Participants Arms Outcomes Time frame

3. Sleep quality; depression, anxiety, and
stress assessment; body image;
compulsive exercise and perfectionism
behaviors; overuse injuries

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Registered interventional trials investigating treatments for energy-deficiency related disorders in healthy and unhealthy leanness, athletes, and soldiers

Identifier Design Phase Participants Arms Outcomes Time frame

Behavioral modifications and dietary supplementation

NCT04748250 Prospective RCT N/A 60 female adolescent 1. Acupuncture Bone mineral density—DXA 3 mo
gymnasts with 2. Soy phytoestrogens
diagnosed Female 3. Acupuncture + soy
Athlete Triad, phytoestrogens
particularly
osteoporosis
NCT05390346 Cross-sectional, N/A 100 male or female college 1. Evaluation of subjects’ 1. Energy availability Up to 21 mo
prospective athletes energy availability and 2. REDs-CAT risk scores,
risk stratification improvements in energy
2. Intervention through availability after nutrition
nutrition education education
NCT04766203 Prospective N/A 2000 athletes or 1. REDs screening 1. REDs CAT, menstrual 6 mo
nonrandomized para-athletes >15 y 2. REDs screening function, sex hormone Treatment arm:
(blood draw) + levels, biochemical blood 3-6 mo
follow-up tests, RMR and
3. REDs screening ergometric capacities,
(DXA scan, RMR IGF-1, BMD,
and exercise testing) + cardiovascular parameters
follow-up 2. Anthropometrics,
4. Treatment of REDs complete blood counts,
using a holistic glucose homeostasis,
treatment arm through hormones, vitamin D,
individualized questionnaires
nutrition plans and
counselling
NCT04823156 Prospective RCT N/A 45 females, ages 18-36 y, 1. Daily calcium + 1. Urine calcium isotopes 2 wk
BMI 18-30, stable vitamin D 2. At rest and during load
weight over 2 mo supplementation carriage: calcium isotopes,
2. LEA (45 kcal/kg lean P1NP, calcium
body mass/d for 7 metabolism, reproductive
days proceeding to and metabolic hormones,
15 kcal/kg lean body muscle strength,
mass/d thereafter) + anthropometrics, BMD
vitamin D
3. LEA + calcium +
vitamin D
NCT03963128 Prospective N/A 4450 male soldiers, ages 1. Vitamin D3 1. SF risk reduction 32 wk
RCT 16-32 y supplementation 2. Skin, soft tissue, and
(800 IU/d) respiratory infection,
2. Placebo vitamin D and hormone
levels, bone turnover
markers
NCT05341700 Cross-sectional N/A 15 females, ages 18-30 y, 1. Impact loading 1. Changes in osteocalcin, 5d
with regular menstrual exercises sclerostin, CTX, PTH,
cycles, exercising at 2. No impact load estrogen, IGF-1,
least 5 days per week exercises hepcidin, insulin, thyroid
hormones, 24-h glucose
patterns
2. Running economy—
oxygen consumption,
change in body weight
NCT05709678 Randomized N/A Physically active (training, 1. General nutrition and 1. Platform to Evaluate 3 wk
sport nutrition with Athlete Knowledge of
(continued)
Endocrine Reviews, 2024, Vol. 00, No. 0 21

Table 2. Continued

Registered interventional trials investigating treatments for energy-deficiency related disorders in healthy and unhealthy leanness, athletes, and soldiers

Identifier Design Phase Participants Arms Outcomes Time frame

competition-level) athlete testimonials on Sports Nutrition
adults aged 18-40 y impacts of REDs on Questionnaire (Peak-Nq)
health 2. Carbohydrate intake
2. Control group 3. Food frequency
questionnaire

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NCT05589077 Interventional N/A Females aged 18-25 y, 1. Behavioral: Education 1. Change in Knowledge, Cross-sectional
that participate in on Female Athlete Confidence, and Impact
organized sport Nutritional Concerns Scores
NCT05709639 Prospective N/A 8 tier 4 and 5 elite Individualized counselling 1) Nutrition knowledge 12 wk
Olympic and in nutrition 2) Change in carbohydrate
paralympic athletes, intake
aged ≥ 18 years old
NCT06116097 Interventional N/A 100 competitive female 1. Experimental: 1. Energy availability 6 mo
endurance athletes aged Nutrition education 2. LEAF-Q
14-18 y training (behavioral) 3. Sports nutrition
minimum 6 h weekly intervention group knowledge questionnaire
(not taking a break from 2. No intervention: (SNKQ), Eating Attitude
sports for more than 3 Control group Test, Dietary intake,
mo) Energy Expenditure,
BMR, body composition
NCT06220240 Interventional N/A Professional female 1. Eccentric muscle 1. Energy intake and 2 wk
basketball players aged contraction modified availability, RED-S
18-35 y with a BMI training program CAT, biomechanics,
18.5-25, energy 2. Routine training running speed, activity
deficient. program 2. Hormones (gonadal,
thyroid, adrenal)
Pharmacological options for BMD loss in soldiers and athletes
NCT04196855 Prospective RCT 3 136 individuals 1. Teriparatide 20 μg/d 1. Radiological healing of SF 8, 10, 12, 14,
undergoing military 2. No intervention, 2. Time to healing, 16, 20, 24 wk
training, aged 18-40 y, standard SF care rehabilitation, pain
with lower limb SF quantification, quality of
life, adverse effects, P1NP,
CTX
NCT04589819 Prospective RCT 4 183 soldiers, diagnosed 1. Teriparatide 20μg/d 1. Time to return to full 3y
with tibial SF 2. Placebo activity
2. Long-term side effects,
injury recurrence, effects
on bone stress injuries
NCT05382026 Prospective N/A 114 adolescent athletes 1. Chocolate milk 1. Changes in lean mass 6 mo
RCT aged 12-17 y, having supplement (DXA)
reached menarche and 2. Pea-based beverage 2. Changes in fat mass,
performing resistance supplement lumbar BMD, hip BMD,
training 3x/wk 3. Placebo supplement bench press strength,
squat strength

Abbreviations: BMD, bone mineral density; BMI, body mass index; BMR, basal metabolic rate; DXA, dual-energy X-ray absorptiometry; LEA, low energy availability;
LEAF-Q, low energy availability in females questionnaire; N/A, not applicable; P1NP, pro-peptide of type 1 collagen; RCT, randomized controlled trial; REDs CAT,
relative energy deficiency in sport clinical assessment tool; RMR, resting metabolic rate; SF, stress fracture; β-CTX, β-carboxyl-terminal cross-linked telopeptide of type 1
collagen.

speed but not other performance measures and did not signifi­
cantly reduce falls (379). However, it is important to clarify
that GH, IGF-1, and GH secretagogues are considered forms
of doping and therefore are prohibited for use by competitive
athletes.
Bimagrumab, an antibody blocking the activin type II recep­
tor, has been shown to increase lean body mass in older men
and women with sarcopenia and in older patients with recent
hip fractures (380, 381). However, no improvements were
seen in physical performance. Another randomized controlled
trial in adults with type 2 diabetes and obesity found that bima­
grumab over 48 weeks decreased fat mass by a mean of 20.5%
(7.5 kg), waist circumference, and hemoglobin A1c (382).
Whether bimagrumab may have a role in maintaining muscle
mass in lean, energy-deficient cohorts remains to be seen.
On the basis of improving performance, testosterone ad­
ministration has been recently assessed in a controlled study
of 48 young female athletes. Therein, daily application of tes­
tosterone cream led to marked enhancements in aerobic cap­
acity and total lean mass, but not anaerobic performance or
muscle strength. Although this trial assessed circulating testos­
terone and performance-specific characteristics, it did not spe­
cifically address potential improvements in REDs-related
markers, warranting further research (383).
22
According to findings from studies on college athletes,
weight gain was identified as the most important indicator
of normal menstrual function restoration (351, 384). The se­
verity of energy deficiency and the duration of the menstrual
disturbances affect the timeline of the menstrual cycle resump­
tion (385). Although not REDs-specific, according to the 2017
Endocrine Society Clinical Practice Guidelines, the adminis­
tration of GnRH analogs is considered the first line of treat­
ment for patients with FHA who wish to conceive, followed
by gonadotropin therapy and ovulation induction with clomi­
phene citrate (78). Short-term use of transdermal estradiol
with cyclic oral progesterone is suggested for those who
have not resumed menses after 6 to 12 months of lifestyle
modifications, but all these have a limited effect in normaliz­
ing only a small part of the big picture (78).
Leptin as a Potential Approach for REDs
Current pharmacological options for the Female Athlete Triad
and REDs fail to address the complete physiological picture.
GnRH analogs, estradiol, bone active agents, and GH analogs,
as outlined previously, only contend with the endocrine
changes downstream of leptin. Based on available data regard­
ing the efficacy of leptin in reversing FHA and remedying
LEA-induced neuroendocrine perturbations in experimental
and small clinical settings, leptin could hypothetically consti­
tute an effective candidate treatment for the broader family
of REDs-related disorders, especially in individuals with clinic­
ally low concentrations of leptin. Thus, from a pharmacologic­
al perspective, administering leptin, which is suppressed under
LEA conditions (113, 115, 116, 386, 387), could potentially
serve as a complementary treatment strategy that could ad­
dress problematic LEA-related pathophysiological alterations
(eg, FHA, compromised bone health). However, leptin re­
placement therapy is currently not recommended by consensus
guidelines for individuals with hypothalamic amenorrhea or
during low energy availability because its safety and effective­
ness require further investigation for confirmation.
Leptin administration in energy-deficient individuals over­
rides the energy conservation milieu that hinders the HPG axis
in REDs (36, 45, 46), reversing gonadotropin pulsatility in males
(42) and inducing ovulation, restoring menstruation, and thus
resolving HA in lean energy-deficient females as discussed
previously (36, 45-47). Moreover, leptin replacement in
energy-deprived amenorrheic women increased osteocalcin
levels, decreased CTX levels, and increased lumbar BMC
and BMD (45, 114) while also decreasing intact PTH levels
and tending to diminish the RANKL/OPG ratio indicative of
osteoclast differentiation and activity (330). Notwithstanding
favorable results, because no large clinical trials beyond our
proof-of-concept studies have been performed, the safety and ef­
ficacy of leptin have not been adequately evaluated and thus lep­
tin cannot be recommended at this time as a definitive treatment
for HA. A major physiological caveat to the use of leptin in hy­
poleptinemic individuals is weight loss from overtreatment,
which can lead to supraphysiological circulating leptin levels
(62, 388). Although leptin treatment reduces caloric intake
when administered in supraphysiological levels in lean individu­
als, it does not affect resting metabolic rate or physical activity,
nor does it prevent the metabolomic shift from carbohydrate to
fatty acid metabolism (285). At this time, it is unknown if anti­
bodies with any neutralizing effects may develop in subjects
with REDs in response to therapy with anti-r-metHuLeptin or
Endocrine Reviews, 2024, Vol. 00, No. 0
leptin analogues currently in development (388, 389). Large,
randomized phase 3 clinical trials investigating the effects of lep­
tin in women and men with energy-deficiency-related disorders
are warranted. Thus far, r-metHuLeptin has only been approved
for patients with CLD or congenital or acquired generalized lip­
odystrophy (390, 391).
In contrast to its effects to normalize immune and neuroendo­
crine function when leptin administration leads to normalization
of the low leptin levels seen in energy deprivation states, leptin
might exert anorexigenic properties and therefore suppress appe­
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tite when administered in supraphysiological doses and only
when circulating levels exceed the upper physiological range
(392-394). Moreover, according to studies conducted on
women with FHA, recombinant leptin administration has been
associated with significant weight loss and fat mass reduction
when doses exceeded the upper limit of normal (45, 46, 114).
Therefore, as previously highlighted, leptin is not currently rec­
ommended for treating REDs-related health consequences be­
cause randomized clinical trials on leptin administration with
doses within the normal range (ie, beyond the proof of concept
studies discussed previously) have not been performed. The po­
tential role of leptin in specific athletic and military populations
experiencing problematic LEA as a pharmacological approach
should be explored and confirmed in larger clinical trials
involving both females and males with problematic LEA and
REDs-related health consequences.
Conclusions
REDs is a frequently overlooked constellation of disorders
stemming from LEA in diverse exercising populations of ei­
ther biological sex, resulting in various physiological conse­
quences and impaired health and overall performance.
Addressing the underlying causes of LEA by incorporating nu­
tritional, behavioral, and lifestyle modifications is currently
the primary treatment approach.
As the principal arbiter of energy homeostasis, leptin may con­
stitute a key neuroendocrine conduit for several REDs-related
disturbances. The AFI system also seems to contribute to the
pathophysiology of REDs. Decades of investigation have offered
valuable insight into the potential therapeutic implications of
leptin and the AFI axis, which exert a wide array of
pro-metabolic effects (37, 254), including direct and indirect os­
teoprotective mechanisms (49).
Furthermore, the practicality and feasibility of routinely
measuring leptin levels or AFI in clinical practice for REDs re­
mains a significant consideration. However, it is important to
recognize that REDs is a multifaceted disorder involving vari­
ous physiological and psychological factors, underscoring the
need for a more comprehensive understanding of REDs,
which includes exploring other contributing factors. This
has paved the way for new observational studies, prospective
cohorts, and randomized controlled trials in athletes and mili­
tary personnel, which should aim to encompass a broader
range of factors impacting REDs for a more holistic approach
to treatment and understanding.
Additional Information
Review criteria: The authors consulted the relevant position
statements of the American College of Sports Medicine and
the IOC. Each author queried PubMed, Clinicaltrials.gov, tri­
al registries accepted by the International Committee of
Endocrine Reviews, 2024, Vol. 00, No. 0
Medical Journal Editors, and Google Scholar using the terms
“energy deficiency,” “RED-S,” “REDs,” “female athlete tri­
ad,” “anorexia,” “low energy availability,” “hypothalamic
amenorrhea,” “bone,” “stress fractures,” “leptin,” “activin,”
“follistatin,” “adipose,” “soldier,” and “military.” The au­
thors also reviewed relevant references cited within retrieved
articles. Cumulative results were presented as summaries in
tabular format, to be screened, assessed, and selected for in­
clusion in the current manuscript based on topic relevance,
conciseness, and study quality by the authors. Of note, for
the completeness of this review, the authors searched the lit­
erature for both Triad and REDs syndromes. The use of
each term inside the manuscript depends on the findings of
the original paper.
Author Contributions
C.S.M. conceptualized the review. K.S. and C.S.M. performed
the initial search and wrote the first draft. A.M.A. performed
extensive review of the first draft and A.M.A. and K.S. wrote
the manuscript. All coauthors (A.M.A., K.S., S.H.C., L.V.V.,
D.G.G., K.D., K.N., C.B., P.T., A.K., H.A.P., and C.S.M.)
performed literature searches, wrote sections of the text, con­
tributed to the discussion of the content, edited, corrected, ex­
tended, and reappraised all versions of the manuscript. All
authors have approved the final version of the submitted
manuscript.
Disclosures
No funding sources or conflicts of interest pertaining to the
present work were reported from the authors. This review is
not funded, and none of the authors have received any funding
or nonfinancial support relevant to its completion. Other un­
related disclosures are as follows: A.K. reports grants and ad­
visory services for Novo Nordisk, advisory services for Eli
Lilly, Bausch Health, Sanofi-Aventis, MSD, AstraZeneca,
Elpen Pharmaceuticals, Boehringer-Ingelheim, Galenica,
Ethicon, and Epsilon Health. None is related to the work pre­
sented herein. C.S.M. reports grants through his institution
from Merck, Massachusetts Life Sciences Center, and
Boehringer Ingelheim, has been a shareholder of and has re­
ceived grants through his institution and personal consulting
fees from Coherus Inc. and AltrixBio; he reports personal con­
sulting fees and support with research reagents from Ansh
Inc., collaborative research support from LabCorp Inc., re­
ports personal consulting fees from Genfit, Lumos, Amgen,
Corcept, Aligos, Intercept, 89 Bio, Madrigal, and
Regeneron, reports travel support and fees from TMIOA,
Elsevier, and the Cardio Metabolic Health Conference.
None is related to the work presented herein. The other au­
thors have nothing to disclose.
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