Available online at www.sciencedirect.
com Current Opinion in
ScienceDirect
Review
Endocrine and metabolic repercussions of relative energy
deficiency in sport
Lauren M. McCall1 and Kathryn E. Ackerman1,2
Abstract
Low energy availability (EA), caused by insufficient caloric
intake for daily energy expenditure, is detrimental to an ath-
lete’s performance and long-term health. Male and female
athletes are at considerable risk for low EA and relative energy
deficiency in sport because of intense training regimens, po-
tential lack of nutrition education, and pressures associated
with “ideal” body type for performance. This review summa-
rizes the endocrine and metabolic changes observed in ath-
letes with low EA with an emphasis on the most recent
research findings. While awareness of relative energy defi-
ciency in sport has significantly increased, further investigation
is needed in the advancement of a sensitive diagnostic tool
across populations.
Addresses
1
Female Athlete Program, Division of Sports Medicine, Boston Chil-
dren’s Hospital, Boston, MA, USA
2
Neuroendocrine Unit, Massachusetts General Hospital, Harvard
Medical School, Boston, MA, USA
Corresponding author: Ackerman, Kathryn E. (kathryn.ackerman@
childrens.harvard.edu)
Current Opinion in Endocrine and Metabolic Research 2019,
9:56–65
This review comes from a themed issue on Sports Endocrinology
Edited by Fabio Lanfranco
For a complete overview see the Issue and the Editorial
Available online 18 July 2019
https://doi.org/10.1016/j.coemr.2019.07.005
2451-9650/© 2019 Elsevier Ltd. All rights reserved.
Keywords
Low energy availability, Exercise-hypogonadal male condition, Female
athlete triad.
Abbreviations
EA, Energy availability; RED-S, Relative Energy Deficiency in Sport;
GnRH, Gonadotropin-releasing hormone; LH, Luteinizing hormone;
FSH, Follicle-stimulating hormone; AUC, Area under the curve; EHMC,
Exercise-hypogonadal male condition; RMR, Resting metabolic rate;
T3, Triiodothyronine; T4, Thyroxine; TSH, Thyroid-stimulating hormone;
GH, Growth hormone; IGF-1, Insulin-like growth factor 1; SEAQ-I,
Sport-specific Energy Availability Questionnaire and Interview; FFM,
Fat-free mass; PYY, Peptide YY; AN, Anorexia nervosa; ACTH, Adre-
nocorticotropic hormone; BMD, Bone mineral density; LEAF-Q, Low
Energy Availability in Females Questionnaire; BMI, Body mass index.
Current Opinion in Endocrine and Metabolic Research 2019, 9:56–65
Endocrine and Metabolic Research
Introduction
Relative energy deficiency in sport (RED-S) is a syn-
drome observed in athletes characterized by impaired
physiological functioning, as reflected in a constellation of
symptoms affecting numerous organ systems (Figures 1
and 2) [1]. The underlying cause of RED-S is low
energy availability (EA) [1]. EA is defined as an in-
dividual’s energy expenditure during exercise subtracted
from total caloric intake, divided by fat-free mass [2,3].
The result identifies the residual energy for normal
physiological functioning, with low EA typically charac-
terized as <30 kcal kg 1 FFMday 1 [4]. This review
focuses specifically on the endocrine effects of RED-S,
which includes metabolic, menstrual function, bone
health, and endocrine consequences, highlighting the
most recent research and updates in the field.
Hypothalamic-pituitary-gonadal axis
Energy is diverted away from the reproductive axis as a
survival mechanism to function with inadequate energy
[5]. Disruption of gonadotropin-releasing hormone
secretion and alterations in other sex hormones in male
and female athletes result in a range of disturbances
detrimental to an athlete’s health or performance [6e
10]. While there are some inconsistencies in luteiniz-
ing hormone (LH) and follicle-stimulating hormone
(FSH) changes in states of low EA, Gordon et al. (2017),
among others, have described a decrease in LH con-
centration and pulsatility in amenorrheic athletes
compared with eumenorrheic athletes and nonathletes
[6,7,9e11]. Recent studies have found that while LH
pulsatility is reduced in response to low EA, regardless
of whether low EA is achieved through diet and/or ex-
ercise manipulation, there is not a particular EA
threshold that ensures menstrual dysfunction [12,13].
Additionally, within-day energy deficiency has been
associated with menstrual dysfunction and lower estra-
diol in female elite endurance athletes, suggesting the
importance of timing of caloric intake relative to
expenditure [14,15]. Figure 3 shows a diagnostic algo-
rithm for causes of amenorrhea.
Findings of the effect of RED-S on testosterone in fe-
males are inconsistent. In a study of female athletes
with menstrual disorders and lower EA, Łagowska and
Kapczuk reported higher testosterone levels in dancers
www.sciencedirect.com

Figure 1
Proposed health consequences of RED-S including the Female Athlete Triad. Adapted from Mountjoy et al. [1].
compared with other athletes and in association with
decreased daily fat, protein, and carbohydrate intake and
lower EA [16]. Other studies of female athletes have
found reduced or unchanged levels of testosterone in
response to low EA, confirming that further research is
needed to better understand testosterone in females
with low EA [5].
Research on the hypothalamic-pituitary-gonadal axis in
males with RED-S is more limited than in women. LH
pulse frequency, amplitude, and area under the curve
(AUC) have been reported to increase, decrease, and
not change in males with low EA while FSH has been
shown to be reduced immediately following an ultra-
endurance race [17e21]. Another study of long dis-
tance male runners with exercise-hypogonadal male
condition found no significant difference compared
with nonactive controls in LH concentration, pulse
www.sciencedirect.com
Endocrine Sequelae of RED-S McCall and Ackerman 57
frequency, pulse amplitude, or in FSH levels [8]. In a
study of collegiate male athletes, estradiol was lower in
runners (a leanness sport) compared with golfers and
out of season wrestlers (less likely energy deficient)
and was associated with reduced body fat mass [22]. In
elite male distance runners and race walkers, lower EA
was strongly correlated with reduced testosterone
levels [8,15,23,24]. There is also a lack of research on
progesterone levels in male athletes with low EA [5].
Overall, male athletes participating in sports where
leanness is perceived to be advantageous for perfor-
mance are at increased risk for low testosterone.
However, lower testosterone has been reported in
nonleanness sports, as well [15].
Hypothalamic-pituitary-adrenal axis
Enhanced activation of the HPA axis may be induced
through physiological or psychological stress (including
Current Opinion in Endocrine and Metabolic Research 2019, 9:56–65
58 Sports endocrinology
Figure 2
Proposed performance effects of RED-S. Adapted from Mountjoy et al. [1].
extreme eating and exercise behavior) and may result in
chronic exposure of tissues to increased serum cortisol.
This may be detrimental to athletic performance in
addition to having particularly deleterious effects on
bone [5,6].
Studies of caloric restriction and of women with anorexia
nervosa (AN) have revealed elevated cortisol levels
compared with overweight individuals and normal
weight controls [25,26]. Higher cortisol levels were re-
ported in elite endurance athletes with amenorrhea
relative to eumenorrheic athletes and were correlated
with poorer neuromuscular performance [27]. Another
study found that before and after controlling for body
fat, amenorrheic athletes had higher cortisol pulse
amplitude, mass, half-life, and AUC compared with
eumenorrheic athletes and nonexercisers [6]. This in-
crease was inversely associated with fat mass and with
Current Opinion in Endocrine and Metabolic Research 2019, 9:56–65
LH pulsatility, independent of the appetite-regulating
hormones, ghrelin and leptin [6]. In a within-day energy
deficiency study, elite endurance athletes with men-
strual dysfunction spent a longer time in a catabolic
state with elevated cortisol compared with eumenor-
rheic athletes despite similar total daily EA between
groups [14].
In a small study of long-distance male runners with
exercise-hypogonadal male condition, high volume of
exercise was significantly correlated with reduced
testosterone whereas there were no significant changes
in one-time measures of cortisol [8]. Torstveit et al.
(2018) also measured within-day EA in 1 h intervals in
male cyclists, triathletes, and long-distances runners
and reported a higher cortisol:insulin ratio in response
to low EA [28]. Additionally, males with suppressed
resting metabolic rate (RMR) were energy deficient
www.sciencedirect.com

Figure 3
Diagnostic algorithm for amenorrhea. Functional hypothalamic amenorrhea can arise secondary to an energy deficiency. DHEA/S, dehydroepiandros-
terone sulfate; FHA, functional hypothalamic amenorrhoea; hCG, human chorionic gonadotropin; PCOS, polycystic ovarian syndrome; TSH, thyroid-
stimulating hormone. Adapted from De Souza et al. [81].
longer than those with normal RMR despite equivalent
daily total EA; RMR suppression was associated with
higher cortisol and a lower testosterone:cortisol ratio
[29].
Hypothalamic-pituitary-thyroid axis
The hypothalamic-pituitary-thyroid axis adapts to
reduced energy by altering levels of triiodothyronine
(T3) and thyroxine (T4) [30]. Studies of low EA
consistently demonstrate lower T3, whereas the effects
of RED-S on thyroid stimulating hormone (TSH) and
T4 are less consistent [15,27,31e33]. T3 and free T3
decreased over 4 days in eumenorrheic nonathletes
conditioned to an EA between 19 and 25 kcal kg 1
FFM$d 1 while T4 and reverse T3 (rT3) increased at a
lower threshold of EA (10.8e19 kcal kg 1 FFM$d 1)
[34]. While the reduction in T3 was consistent with a
prior study of athletes with menstrual dysfunction, the
www.sciencedirect.com
Endocrine Sequelae of RED-S McCall and Ackerman 59
effects of low EA on T4 and rT3 remain inconclusive,
with some studies reporting reduced levels [15,35].
More recently, Tornberg et al. (2017) reported no
change in TSH in female athletes with amenorrhea
compared with eumenorrheic athletes, consistent with
prior findings [27,35,36].
T3 is significantly lower in male athletes with low
testosterone (likely secondary to low EA) [15,37]. Along
with reduced T3, Skolnick et al. (2016) reported no
change in TSH and a decrease in T4 in males with AN
[37]. In power-sprint athletes and marathon runners,
the TSH-free T3 ratio was reduced relative to sedentary
controls [38]. These findings support an under-
performing metabolic axis in an energy-restricted
setting. Collectively, these studies suggest that T3
may be a more useful marker of low EA than other
thyroid function tests.
Current Opinion in Endocrine and Metabolic Research 2019, 9:56–65
60 Sports endocrinology
Growth hormone and insulin-like growth
factor-1
Growth hormone (GH) is an anabolic hormone whose
effects are predominantly mediated by insulin-like
growth factor 1 (IGF-1) produced by the liver. In
eumenorrheic females subjected to caloric restriction
and in females with AN, GH has been reported to in-
crease while IGF-1 decreases, consistent with GH
Figure 4
Example of a DXA body composition measurement of an amenorrheic female athlete. Percent body fat Z-score = −2.0.
Current Opinion in Endocrine and Metabolic Research 2019, 9:56–65
resistance [5,30,39,40]. Papageorgiou et al. (2018) also
noted reduced IGF-1 levels in active eumenorrheic
women who were subjected to a low EA condition
compared with an adequate energy condition [32]. A
conflicting study found no changes in IGF-1 in amen-
orrheic athletes compared with eumenorrheic athletes;
however, the specific duration of amenorrhea was un-
clear [15].
www.sciencedirect.com

While prior research indicates an increase in GH in male
athletes in response to low EA and in males with AN,
Maestu et al. (2010) found that GH levels remained
stable while IGF-1 followed the expected pattern of
decrease [41e43]. Additionally, IGF-1 was suppressed
in male cyclists during an ultraendurance event, and
changes in IGF-1 were positively correlated with EA
[44]. Male bodybuilders engaged in an eleven-week
energy-restricted program exhibited reduced IGF-1
levels compared with unrestricted athletic controls
[41]. Male soldiers under conditions of high-energy
expenditure and caloric restriction also demonstrated
lower IGF-1 [45]. In contrast, another study found no
change in IGF-1 in low testosterone male athletes
compared with normal testosterone male athletes, but
“low testosterone” males in the study still had testos-
terone levels within the normal clinical range (lowest
quartile) and the duration of low testosterone was not
reported [15].
Body composition and metabolic rate
Inadequate energy may substantially influence the
body composition of athletes; amenorrheic athletes
have demonstrated lower lean mass, fat mass, and body
mass index (BMI) compared with age-matched
eumenorrheic athletes; however, this is not always the
case (Figure 4) [6,27,46]. In one study of collegiate
swimmers, those with ovarian suppression had greater
BMI and fat mass compared with eumenorrheic ath-
letes after a 12-week competitive training season [31].
Amenorrheic athletes also have a reduced RMR relative
to eumenorrheic athletes [27]. This trend has been
observed in several populations, including elite female
endurance athletes, and in a within-day energy defi-
ciency study, energy deficiency was associated with
reduced RMR in female endurance athletes with
menstrual dysfunction [14,29].
In male cyclists, Keay et al. (2018) found that lower EA,
assessed through a Sport-specific Energy Availability
Questionnaire and Interview, was strongly associated
with lower total fat percentage [23]. Reduced RMR was
reported in a male mixed martial arts athlete undergoing
extreme weight cutting and in association with male
endurance athletes conditioned to within day energy
deficiency [28,47]. Male jockeys experience reduced
RMR compared with female jockeys, likely a result of
more frequent mandatory weigh-ins [48]. Suppressed
RMR was also associated with low EA in some profes-
sional male and female ballet dancers [49,50].
Energy homeostasis, metabolism, and
appetite
Changes in body composition associated with RED-S
and suboptimal nutrient intake impact appetite regu-
lation through altered anorexigenic and orexigenic hor-
mone levels. Leptin, an anorexigenic hormone that
www.sciencedirect.com
Endocrine Sequelae of RED-S McCall and Ackerman 61
signals satiety to the brain, decreases in male and female
athletes with inadequate energy and strongly correlates
with fat mass and sex hormone concentration [7]. In
habitual exercisers, fasting leptin was 53e56% lower in
the EA condition of 15 kcal kg 1 FFM$day 1 while
exercisers with an EA of 40 kcal kg 1 FFM$day 1 did
not exhibit such fluctuations [51]. Lower leptin levels
have been found in overtrained athletes and those in
energy deficit, as well as in men with exercise addiction
(thought to have relatively low EA) after adjusting for
body fat [52,53]. Lower leptin levels were also reported
in male Olympic athletes competing in leanness sports
relative to men competing in nonleanness sports
[54,55]. Similarly, active eumenorrheic women
randomly assigned to an EA of 15 kcal kg 1 FFM$d 1
exhibited significantly lower leptin concentrations than
those with an EA of 45 kcal kg 1 FFM$d 1, indepen-
dent of whether low EA was achieved through diet or
exercise manipulation [32,56].
Peptide YY (PYY) acts to decrease appetite. Interest-
ingly, PYY is elevated in amenorrheic athletes compared
with eumenorrheic athletes [30,57e59]. PYY is also
higher in males with AN while other studies report
mixed findings on whether the hormone is increased or
decreased in females with AN [60e62]. Adiponectin,
another anorexigenic adipokine, is elevated in some
amenorrheic athletes, in dancers with low EA, and in
exercisers compared with nonathletes; however, the
correlations between the hormone and BMI, lean mass,
and body fat are inconsistent [57,63e65].
The orexigenic hormone, ghrelin, is thought to affect
the secretion of gonadotropin-releasing hormone,
ACTH, LH, and FSH, with higher levels of the hormone
considered an indication of lower EA [7,66,67]. Amen-
orrheic athletes exhibited more frequent overnight
ghrelin pulsatile secretion and larger pulse amplitude,
pulse mass, and AUC consistent with the association
between increased ghrelin and decreased fat mass and
with suppressed LH and FSH pulsatility [7,30]. In
studies of competitive male rowers, increased ghrelin
was associated with acute insufficient energy [68,69].
However, this finding is inconsistent across studies, and
male athletes with AN and male habitual exercisers with
low EA did not have altered ghrelin levels when
compared with controls with adequate EA [51,60].
Insulin is an anabolic hormone that regulates energy
storage. A study of elite distance athletes found no
significant difference in insulin levels in amenorrheic
versus eumenorrheic athletes or in males with low
testosterone versus males with normal testosterone
[15]. One study reported a decrease in serum insulin
levels in exercising men in a low EA condition (achieved
through diet or exercise manipulation) relative to the
adequate EA condition; this reduction was independent
of whether low EA was caused by diet or exercise
Current Opinion in Endocrine and Metabolic Research 2019, 9:56–65
62 Sports endocrinology
changes [51]. This is consistent with other findings in
both males and females [4,41,56,70].
Bone health
The previously mentioned modifications of metabolic
hormones associated with RED-S directly impact skel-
etal health. Bone serves as a major endocrine target, and
consequently, bone microarchitecture and turnover are
impaired, bone mineral density (BMD) and strength are
reduced, and fracture rate is increased in some male and
female athletes with reduced EA [46,71e73]. Further-
more, maintaining adequate EA may be the most
effective solution to reduce the risk of injury in athletes
[74]. Bone formation markers were studied in men and
women in low EA conditions (15 kcal kg FFM 1$d 1)
achieved through diet or exercise manipulation for 5
days. Bone formation markers were significantly reduced
in low EA versus normal EA (45 kcal kg LBM 1$d 1)
female athletes; however, no differences were noted in
the males [56]. In active, eumenorrheic women
subjected to the prior normal EA versus low EA protocol,
low EA achieved through exercise manipulation did not
significantly impact bone metabolism while low EA
achieved through caloric restriction significantly
decreased bone formation. There were significant
changes in hormone concentrations regardless of dietary
or exercise manipulation [32]. The negative effects of
RED-S on bone have also been determined to be
influenced by low EA and by estrogen independently, as
well as by a combination of the two [75]. In a study
stratifying athletes as high, moderate, or low risk for
Triad, those classified as “high-risk” and “moderate-
risk”, were four and two times more likely, respectively,
to sustain a bone stress injury than “low-risk” athletes
[76]. Another study reported that the rate of bone in-
juries was 4.5-fold greater in world class male athletes
with low testosterone and in female athletes with
amenorrhea compared with controls; the hormonally
suppressed athletes also had significantly lower BMD
[15].
Male cyclists and distance runners, among others with
inadequate EA, have also demonstrated quantifiable
effects on bone, with EA being the main determinant of
low lumbar spine BMD (other risk factors: weighing
<85% expected weight, >30 miles running distance per
week) [23,77,78]. Additionally, studies have (2018) re-
ported significantly reduced BMD in male jockeys
[79,80].
Conclusion
This review briefly summarizes the most recent
research and highlights what is currently known about
endocrine effects of RED-S in various athletic popula-
tions. Many hormones are modulated in relation to an
energy deficit; however, further understanding is still
needed, particularly in male athletes. Though there has
Current Opinion in Endocrine and Metabolic Research 2019, 9:56–65
been increased awareness of causes and consequences of
RED-S, there remains the difficulty of measuring EA. It
is important to note that the majority of studies cited in
this review used surrogate markers of RED-S, such as
low BMI, participation in leanness sports, and dysfunc-
tion of the reproductive axis. While these markers and
use of screening tools (e.g., Low Energy Availability in
Females Questionnaire and RED-S Clinical Assessment
Tool) may be more effective in assessing risk of low EA
compared with food/training logs, the effects of low EA
needs to be further investigated using direct measure-
ments. The need for a standard protocol and sensitive
tool for RED-S assessment has been amplified because
of its high association with athlete injury. Because of the
important role endocrinology plays in sports health and
performance, future research needs to focus on the
complex hormonal changes in states of low EA.
Furthermore, a greater understanding of hormonal
pathways leading to specific health and performance
consequences will help advance our understanding of
appropriate hormonal ranges for healthy athletes
compared with nonathletes.
Conflict of interest statement
Nothing declared.
References
Papers of particular interest, published within the period of review,
have been highlighted as:
* of special interest
* * of outstanding interest
1. Mountjoy M, Sundgot-Borgen J, Burke L, et al.: The IOC
consensus statement: beyond the female athlete triad–rela-
tive energy deficiency in sport (RED-S). Br J Sports Med 2014,
48:491–497, https://doi.org/10.1136/bjsports-2014-093502.
2. Loucks AB: Low energy availability in the marathon and other
endurance sports. Sports Med Auckl NZ 2007, 37:348–352,
https://doi.org/10.2165/00007256-200737040-00019.
3. Loucks AB: Energy balance and energy availability. In The
encyclopaedia of sports medicine. John Wiley & Sons, Ltd; 2013:
72–87, https://doi.org/10.1002/9781118692318.ch5.
4. Loucks AB, Thuma JR: Luteinizing hormone pulsatility is
disrupted at a threshold of energy availability in regularly
menstruating women. J Clin Endocrinol Metab 2003, 88:
297–311, https://doi.org/10.1210/jc.2002-020369.
5. Elliott-Sale KJ, Tenforde AS, Parziale AL, Holtzman B,
** Ackerman KE: Endocrine effects of relative energy deficiency
in sport. Int J Sport Nutr Exerc Metab 2018, 28:335–349, https://
doi.org/10.1123/ijsnem.2018-0127.
This review describes the endocrine effects of Relative Energy Defi-
ciency in Sport (RED-S) in female and male athletes, focusing on al-
terations in various hormonal pathways and changes in body
composition and bone health
6. Ackerman KE, Patel KT, Guereca G, Pierce L, Herzog DB,
Misra M: Cortisol secretory parameters in young exercisers in
relation to LH secretion and bone parameters. Clin Endocrinol
(Oxf). 2013, 78:114–119, https://doi.org/10.1111/j.1365-
2265.2012.04458.x.
7. Ackerman KE, Slusarz K, Guereca G, et al.: Higher ghrelin and
lower leptin secretion are associated with lower LH secretion
in young amenorrheic athletes compared with eumenorrheic
athletes and controls. Am J Physiol Endocrinol Metab 2012,
302:E800–E806, https://doi.org/10.1152/ajpendo.00598.2011.
www.sciencedirect.com

8. Hooper DR, Kraemer WJ, Saenz C, et al.: The presence of
symptoms of testosterone deficiency in the exercise-hypo-
gonadal male condition and the role of nutrition. Eur J Appl
Physiol 2017, 117:1349–1357, https://doi.org/10.1007/s00421-
017-3623-z.
9. Gordon CM, Ackerman KE, Berga SL, et al.: Functional hypo-
thalamic amenorrhea: an endocrine society clinical practice
guideline. J Clin Endocrinol Metab 2017, 102:1413–1439, https://
doi.org/10.1210/jc.2017-00131.
10. Iwasa T, Matsuzaki T, Yano K, et al.: Effects of low energy
availability on reproductive functions and their underlying
neuroendocrine mechanisms. J Clin Med 2018, 7:166, https://
doi.org/10.3390/jcm7070166.
11. Scheid JL, De Souza MJ, Hill BR, Leidy HJ, Williams NI:
Decreased luteinizing hormone pulse frequency is associ-
ated with elevated 24-hour ghrelin after calorie restriction and
exercise in premenopausal women. Am J Physiol Endocrinol
Metab 2013, 304:E109–E116, https://doi.org/10.1152/
ajpendo.00360.2012.
12. Lieberman JL, De MS, Wagstaff DA, Williams NI: Menstrual
* disruption with exercise is not linked to an energy availability
threshold. Med Sci Sport Exerc 2018, 50:551–561, https://
doi.org/10.1249/MSS.0000000000001451.
This study demonstrates that while a decrease in energy availability
corresponds with a linear increase in menstrual disturbance, there is
not a specific threshold of energy availability that induces exercise-
associated menstrual disturbances.
13. Reed JL, De Souza MJ, Mallinson RJ, Scheid JL, Williams NI:
Energy availability discriminates clinical menstrual status in
exercising women. J Int Soc Sport Nutr 2015, 12:11, https://
doi.org/10.1186/s12970-015-0072-0.
14. Fahrenholtz IL, Sjödin A, Benardot D, et al.: Within-day energy
deficiency and reproductive function in female endurance
athletes. Scand J Med Sci Sport 2018, 28:1139–1146, https://
doi.org/10.1111/sms.13030.
15. Heikura IA, Uusitalo ALT, Stellingwerff T, Bergland D, Mero AA,
* Burke LM: Low energy availability is Difficult to assess but
outcomes have Large impact on bone injury rates in elite
distance athletes. Int J Sport Nutr Exerc Metab 2018, 28:
403–411, https://doi.org/10.1123/ijsnem.2017-0313.
This publication investigates various diagnostic tools used to identify
low energy availability and RED-S and reports current reproductive
function as the most accurate marker for estimating energy availability.
16. Łagowska K, Kapczuk K: Testosterone concentrations in
female athletes and ballet dancers with menstrual disorders.
Eur J Sport Sci 2016, 16:490–497, https://doi.org/10.1080/
17461391.2015.1034786.
17. Berg U, Enqvist JK, Mattsson CM, et al.: Lack of sex differences
in the IGF-IGFBP response to ultra endurance exercise.
Scand J Med Sci Sport 2008, 18:706–714, https://doi.org/
10.1111/j.1600-0838.2007.00758.x.
18. Hackney AC, Sinning WE, Bruot BC: Reproductive hormonal
profiles of endurance-trained and untrained males. Med Sci
Sport Exerc 1988, 20:60–65.
19. Hackney AC, Fahrner CL, Gulledge TP: Basal reproductive
hormonal profiles are altered in endurance trained men. J
Sport Med Phys Fit 1998, 38:138–141.
20. Hackney AC, Moore AW, Brownlee KK: Testosterone and
endurance exercise: development of the “exercise-hypo-
gonadal male condition. Acta Physiol Hung 2005, 92:121–137,
https://doi.org/10.1556/APhysiol.92.2005.2.3.
21. McColl EM, Wheeler GD, Gomes P, Bhambhani Y, Cumming DC:
The effects of acute exercise on pulsatile LH release in high-
mileage male runners. Clin Endocrinol (Oxf). 1989, 31:617–621.
22. Ackerman KE, Skrinar GS, Medvedova E, Misra M, Miller KK:
Estradiol levels predict bone mineral density in male colle-
giate athletes: a pilot study. Clin Endocrinol (Oxf). 2012, 76:
339–345, https://doi.org/10.1111/j.1365-2265.2011.04212.x.
23. Keay N, Francis G, Hind K: Low energy availability assessed
by a sport-specific questionnaire and clinical interview
indicative of bone health, endocrine profile and cycling
www.sciencedirect.com
Endocrine Sequelae of RED-S McCall and Ackerman 63
performance in competitive male cyclists. BMJ Open Sport
Exerc Med 2018, 4, e000424, https://doi.org/10.1136/bmjsem-
2018-000424.
24. Melin AK, Heikura IA, Tenforde A, Mountjoy M: Energy avail-
* ability in athletics: health, performance, and physique. Int J
Sport Nutr Exerc Metab 2019, 29:152–164, https://doi.org/
10.1123/ijsnem.2018-0201.
This review summarizes the performance and health outcomes of
Relative Energy Deficiency in Sport (RED-S) in athletes and identifies
screening, prevention, and treatment options for clinical application.
25. Nakamura Y, Walker BR, Ikuta T: Systematic review and meta-
analysis reveals acutely elevated plasma cortisol following
fasting but not less severe calorie restriction. Stress Amst
Neth 2016, 19:151–157, https://doi.org/10.3109/
10253890.2015.1121984.
26. Schorr M, Lawson EA, Dichtel LE, Klibanski A, Miller KK: Cortisol
measures across the weight spectrum. J Clin Endocrinol
Metab 2015, 100:3313–3321, https://doi.org/10.1210/JC.2015-
2078.
27. Tornberg ÅB, Melin A, Koivula FM, et al.: Reduced neuromus-
cular performance in amenorrheic elite endurance athletes.
Med Sci Sport Exerc 2017, 49:2478–2485, https://doi.org/
10.1249/MSS.0000000000001383.
28. Torstveit MK, Fahrenholtz I, Stenqvist TB, Sylta Ø, Melin A:
Within-day energy deficiency and metabolic perturbation in
male endurance athletes. Int J Sport Nutr Exerc Metab 2018, 28:
419–427, https://doi.org/10.1123/ijsnem.2017-0337.
29. Melin A, Tornberg ÅB, Skouby S, et al.: Energy availability and
the female athlete triad in elite endurance athletes. Scand J
Med Sci Sport 2015, 25:610–622, https://doi.org/10.1111/
sms.12261.
30. Misra M, Klibanski A: Endocrine consequences of anorexia
nervosa. Lancet Diabetes Endocrinol 2014, 2:581–592, https://
doi.org/10.1016/S2213-8587(13)70180-3.
31. Vanheest JL, Rodgers CD, Mahoney CE, De MS: Ovarian sup-
pression impairs sport performance in junior elite female
swimmers. Med Sci Sport Exerc 2014, 46:156–166, https://
doi.org/10.1249/MSS.0b013e3182a32b72.
32. Papageorgiou M, Dolan E, Elliott-Sale KJ, Sale C: Reduced
energy availability: implications for bone health in physically
active populations. Eur J Nutr 2018, 57:847–859, https://doi.org/
10.1007/s00394-017-1498-8.
33. Harber VJ, Petersen SR, Chilibeck PD: Thyroid hormone con-
centrations and muscle metabolism in amenorrheic and
eumenorrheic athletes. Can J Appl Physiol Rev Can Physiol
Appl 1998, 23:293–306.
34. Loucks AB, Heath EM: Induction of low-T3 syndrome in exer-
cising women occurs at a threshold of energy availability. Am
J Physiol 1994, 266:R817–R823, https://doi.org/10.1152/
ajpregu.1994.266.3.R817.
35. Loucks AB, Laughlin GA, Mortola JF, Girton L, Nelson JC,
Yen SS: Hypothalamic-pituitary-thyroidal function in eume-
norrheic and amenorrheic athletes. J Clin Endocrinol Metab
1992, 75:514–518, https://doi.org/10.1210/jcem.75.2.1639953.
36. Berga SL, Mortola JF, Girton L, et al.: Neuroendocrine aberra-
tions in women with functional hypothalamic amenorrhea. J
Clin Endocrinol Metab 1989, 68:301–308, https://doi.org/10.1210/
jcem-68-2-301.
37. Skolnick A, Schulman RC, Galindo RJ, Mechanick JI: The
endocrinopathies of male anorexia nervosa: case series.
AACE Clin Case Rep 2016, 2:e351–e357, https://doi.org/
10.4158/EP15945.CR.
38. Perseghin G, Lattuada G, Ragogna F, Alberti G, La Torre A,
Luzi L: Free leptin index and thyroid function in male highly
trained athletes. Eur J Endocrinol 2009, 161:871–876, https://
doi.org/10.1530/EJE-09-0569.
39. Estour B, Germain N, Diconne E, et al.: Hormonal profile het-
erogeneity and short-term physical risk in restrictive
anorexia nervosa. J Clin Endocrinol Metab 2010, 95:
2203–2210, https://doi.org/10.1210/jc.2009-2608.
Current Opinion in Endocrine and Metabolic Research 2019, 9:56–65
64 Sports endocrinology
40. Ackerman KE, Holtzman B, Cooper KM, et al.: Low energy
* availability surrogates correlate with health and performance
consequences of Relative Energy Deficiency in Sport. Br J
Sports Med June 2018, https://doi.org/10.1136/bjsports-2017-
098958. bjsports-2017-098958.
The results of a questionnaire administered to 1000 female athletes
between the ages of 15 and 30 revealed significance between low
energy availability and heightened risk of health issues, including poor
bone health and menstrual dysfunction, as well as decreased
performance.
41. Mäestu J, Eliakim A, Jürimäe J, Valter I, Jürimäe T: Anabolic and
catabolic hormones and energy balance of the male body-
builders during the preparation for the competition. J Strength
Cond Res 2010, 24:1074–1081, https://doi.org/10.1519/
JSC.0b013e3181cb6fd3.
42. Thienpont E, Bellemans J, Samson I, Fabry G: Stress fracture of
the inferior and superior pubic ramus in a man with anorexia
nervosa and hypogonadism. Acta Orthop Belg 2000, 66:
297–301.
43. Roemmich JN, Sinning WE: Weight loss and wrestling training:
effects on growth-related hormones. J Appl Physiol Bethesda
Md 1985, 82(6):1760–1764, https://doi.org/10.1152/
jappl.1997.82.6.1760.
44. Geesmann B, Gibbs JC, Mester J, Koehler K: Association be-
tween energy balance and metabolic hormone suppression
during ultraendurance exercise. Int J Sports Physiol Perform
2017, 12:984–989, https://doi.org/10.1123/ijspp.2016-0061.
45. Henning P, Margolis L, P. McClung J, Young A, Pasiakos S: High
protein diets do not attenuate decrements in testosterone
and IGF-I during energy deficit. Metabolism 2014, 63, https://
doi.org/10.1016/j.metabol.2014.02.007.
46. Ackerman KE, Cano Sokoloff N, DE Nardo Maffazioli G,
Clarke HM, Lee H, Misra M: Fractures in relation to menstrual
status and bone parameters in young athletes. Med Sci Sport
Exerc 2015, 47:1577–1586, https://doi.org/10.1249/
MSS.0000000000000574.
47. Kasper AM, Crighton B, Langan-Evans C, et al.: Case study:
extreme weight making causes relative energy deficiency,
dehydration and acute kidney injury in a male mixed martial
arts athlete. Int J Sport Nutr Exerc Metab July 2018:1–20, https://
doi.org/10.1123/ijsnem.2018-0029.
48. Wilson G, Hill J, Sale C, Morton JP, Close GL: Elite male Flat
jockeys display lower bone density and lower resting meta-
bolic rate than their female counterparts: implications for
athlete welfare. Appl Physiol Nutr Metab Physiol Appl Nutr Metab
2015, 40:1318–1320, https://doi.org/10.1139/apnm-2015-0354.
49. Staal S, Sjödin A, Fahrenholtz I, Bonnesen K, Melin AK: Low
RMRratio as a surrogate marker for energy deficiency, the
choice of predictive equation vital for correctly identifying
male and female ballet dancers at risk. Int J Sport Nutr Exerc
Metab 2018, 28:412–418, https://doi.org/10.1123/ijsnem.2017-
0327.
50. Schofield KL, Thorpe H, Sims ST: Resting metabolic rate pre-
diction equations and the validity to assess energy defi-
ciency in the athlete population. Exp Physiol 2019, 104:
469–475, https://doi.org/10.1113/EP087512.
51. Koehler K, Hoerner NR, Gibbs JC, et al.: Low energy availability
in exercising men is associated with reduced leptin and in-
sulin but not with changes in other metabolic hormones. J
Sport Sci 2016, 34:1921–1929, https://doi.org/10.1080/
02640414.2016.1142109.
52. Roupas ND, Mamali I, Maragkos S, et al.: The effect of
prolonged aerobic exercise on serum adipokine levels during
an ultra-marathon endurance race. Horm Athens Greece 2013,
12:275–282.
53. Joro R, Uusitalo A, DeRuisseau KC, Atalay M: Changes in cy-
tokines, leptin, and IGF-1 levels in overtrained athletes during
a prolonged recovery phase: a case-control study. J Sport Sci
2017, 35:2342–2349, https://doi.org/10.1080/
02640414.2016.1266379.
54. Hagmar M, Berglund B, Brismar K, Hirschberg AL: Body
composition and endocrine profile of male Olympic athletes
Current Opinion in Endocrine and Metabolic Research 2019, 9:56–65
striving for leanness. Clin J Sport Med Off J Can Acad Sport
Med 2013, 23:197–201, https://doi.org/10.1097/
JSM.0b013e31827a8809.
55. Lichtenstein MB, Andries A, Hansen S, Frystyk J, Støving RK:
Exercise addiction in men is associated with lower fat-
adjusted leptin levels. Clin J Sport Med Off J Can Acad Sport
Med 2015, 25:138–143, https://doi.org/10.1097/
JSM.0000000000000110.
56. Papageorgiou M, Elliott-Sale KJ, Parsons A, et al.: Effects of
* reduced energy availability on bone metabolism in women
and men. Bone 2017, 105:191–199, https://doi.org/10.1016/
j.bone.2017.08.019.
This study compared the effect of low energy availability on bone
turnover markers in female and male athletes, reporting no significant
differences between genders in markers associated with bone forma-
tion and resorption.
57. Russell M, Stark J, Nayak S, et al.: Peptide YY in adolescent
athletes with amenorrhea, eumenorrheic athletes and non-
athletic controls. Bone 2009, 45:104–109, https://doi.org/
10.1016/j.bone.2009.03.668.
58. Scheid JL, Williams NI, West SL, VanHeest JL, De Souza MJ:
Elevated PYY is associated with energy deficiency and
indices of subclinical disordered eating in exercising women
with hypothalamic amenorrhea. Appetite 2009, 52:184–192,
https://doi.org/10.1016/j.appet.2008.09.016.
59. Scheid JL, De Souza MJ: Menstrual irregularities and energy
deficiency in physically active women: the role of ghrelin,
PYY and adipocytokines. Med Sport Sci 2010, 55:82–102,
https://doi.org/10.1159/000321974.
60. Misra M, Katzman DK, Cord J, et al.: Bone metabolism in
adolescent boys with anorexia nervosa. J Clin Endocrinol
Metab 2008, 93:3029–3036, https://doi.org/10.1210/jc.2008-0170.
61. Utz AL, Lawson EA, Misra M, et al.: Peptide YY (PYY) levels and
bone mineral density (BMD) in women with anorexia nervosa.
Bone 2008, 43:135–139, https://doi.org/10.1016/
j.bone.2008.03.007.
62. Germain N, Galusca B, Grouselle D, et al.: Ghrelin and
obestatin circadian levels differentiate bingeing-purging from
restrictive anorexia nervosa. J Clin Endocrinol Metab 2010, 95:
3057–3062, https://doi.org/10.1210/jc.2009-2196.
63. Donoso MA, Muñoz-Calvo MT, Barrios V, Garrido G, Hawkins F,
Argente J: Increased circulating adiponectin levels and
decreased leptin/soluble leptin receptor ratio throughout
puberty in female ballet dancers: association with body
composition and the delay in puberty. Eur J Endocrinol 2010,
162:905–911, https://doi.org/10.1530/EJE-09-0874.
64. O’Donnell E, De Souza MJ: Increased serum adiponectin
concentrations in amenorrheic physically active women are
associated with impaired bone health but not with estrogen
exposure. Bone 2011, 48:760–767, https://doi.org/10.1016/
j.bone.2010.12.018.
65. MA SK and S. Effects of exercise on adiponectin: a systematic
review. - PubMed – NCBI. https://www.ncbi.nlm.nih.gov/pubmed/
18239630. Accessed April 23, 2019.
66. Christo K, Cord J, Mendes N, et al.: Acylated ghrelin and leptin
in adolescent athletes with amenorrhea, eumenorrheic ath-
letes and controls: a cross-sectional study. Clin Endocrinol
(Oxf). 2008, 69:628–633, https://doi.org/10.1111/j.1365-
2265.2008.03237.x.
67. Misra M, Miller KK, Kuo K, et al.: Secretory dynamics of ghrelin
in adolescent girls with anorexia nervosa and healthy ado-
lescents. Am J Physiol Endocrinol Metab 2005, 289:E347–E356,
https://doi.org/10.1152/ajpendo.00615.2004.
68. Jürimäe J, Jürimäe T, Purge P: Plasma ghrelin is altered after
maximal exercise in elite male rowers. Exp Biol Med Maywood
NJ 2007, 232:904–909.
69. Jürimäe J, Mäestu J, Jürimäe T, Mangus B, von Duvillard SP:
Peripheral signals of energy homeostasis as possible
markers of training stress in athletes: a review. Metabolism
2011, 60:335–350, https://doi.org/10.1016/
j.metabol.2010.02.009.
www.sciencedirect.com

70. Rickenlund A, Thorén M, Carlström K, von Schoultz B,
Hirschberg AL: Diurnal profiles of testosterone and pituitary
hormones suggest different mechanisms for menstrual dis-
turbances in endurance athletes. J Clin Endocrinol Metab 2004,
89:702–707, https://doi.org/10.1210/jc.2003-030306.
71. Mountjoy M, Sundgot-Borgen J, Burke L, et al.: International
* * olympic committee (IOC) consensus statement on relative
energy deficiency in sport (RED-S): 2018 update. Int J Sport
Nutr Exerc Metab 2018, 28:316–331, https://doi.org/10.1123/
ijsnem.2018-0136.
This consensus statement provides an updated summary of the recent
advancements in the understanding of Relative Energy Deficiency in
Sport (RED-S) in female and male athletes; including the health and
performance consequences, identification, screening, prevention, and
treatment.
72. Tenforde AS, Barrack MT, Nattiv A, Fredericson M: Parallels
with the female athlete triad in male athletes. Sports Med
Auckl NZ 2016, 46:171–182, https://doi.org/10.1007/s40279-
015-0411-y.
73. Gibbs JC, Nattiv A, Barrack MT, et al.: Low bone density risk is
higher in exercising women with multiple triad risk factors.
Med Sci Sport Exerc 2014, 46:167–176, https://doi.org/10.1249/
MSS.0b013e3182a03b8b.
74. Close GL, Sale C, Baar K, Bermon S: Nutrition for the pre-
vention and treatment of injuries in track and field athletes. Int
J Sport Nutr Exerc Metab 2019, 29:189–197, https://doi.org/
10.1123/ijsnem.2018-0290.
75. Southmayd EA, Mallinson RJ, Williams NI, Mallinson DJ, De
Souza MJ: Unique effects of energy versus estrogen defi-
ciency on multiple components of bone strength in exer-
cising women. Osteoporos Int 2017, 28:1365–1376, https://
doi.org/10.1007/s00198-016-3887-x.
www.sciencedirect.com
Endocrine Sequelae of RED-S McCall and Ackerman 65
76. Tenforde AS, Carlson JL, Chang A, et al.: Association of the
female athlete triad risk assessment stratification to the
development of bone stress injuries in collegiate athletes. Am
J Sports Med 2017, 45:302–310, https://doi.org/10.1177/
0363546516676262.
77. Barrack MT, Fredericson M, Tenforde AS, Nattiv A: Evidence of a
cumulative effect for risk factors predicting low bone mass
among male adolescent athletes. Br J Sports Med 2017, 51:
200–205, https://doi.org/10.1136/bjsports-2016-096698.
78. Burke LM, Close GL, Lundy B, Mooses M, Morton JP,
* Tenforde AS: Relative energy deficiency in sport in male
athletes: a commentary on its presentation among selected
groups of male athletes. Int J Sport Nutr Exerc Metab 2018, 28:
364–374, https://doi.org/10.1123/ijsnem.2018-0182.
This commentary highlights the complexity of Relative Energy Defi-
ciency in Sport (RED-S) in male athlete populations, centering on
numerous factors unique to specific sports that contribute to the
severity of outcomes.
79. Poon ET-C, O’Reilly J, Sheridan S, Cai MM, Wong SH-S:
Markers of bone health, bone-specific physical activities,
nutritional intake, and quality of life of professional jockeys in
Hong Kong. Int J Sport Nutr Exerc Metab 2018, 28:440–446,
https://doi.org/10.1123/ijsnem.2016-0176.
80. Jackson KA, Sanchez-Santos MT, MacKinnon AL, et al.: Bone
density and body composition in newly licenced professional
jockeys. Osteoporos Int 2017, 28:2675–2682, https://doi.org/
10.1007/s00198-017-4086-0.
81. De Souza MJ, Nattiv A, et al.: Female athlete triad coalition
consensus statement on treatment and return to play of the
female athlete triad: 1st international conference held in san
francisco, California, may 2012 and 2nd international con-
ference held in indianapolis, Indiana, may 2013. Br J Sports
Med. 2014 2014, 1:289. 48.
Current Opinion in Endocrine and Metabolic Research 2019, 9:56–65