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Abstract and Figures

Iron plays a significant role in the body, and is specifically important to athletes, since it is a dominant feature in processes such as oxygen transport and energy metabolism. Despite its importance, athlete populations, especially females and endur-ance athletes, are commonly diagnosed with iron deficiency, suggesting an association between sport performance and iron regulation. Although iron deficiency is most common in female athletes (~ 15–35% athlete cohorts deficient), approximately 5–11% of male athlete cohorts also present with this issue. Furthermore, interest has grown in the mechanisms that influ-ence iron absorption in athletes over the last decade, with the link between iron regulation and exercise becoming a research focus. Specifically, exercise-induced increases in the master iron regulatory hormone, hepcidin, has been highlighted as a contributing factor towards altered iron metabolism in athletes. To date, a plethora of research has been conducted, including investigation into the impact that sex hormones, diet (e.g. macronutrient manipulation), training and environmental stress (e.g. hypoxia due to altitude training) have on an athlete’s iron status, with numerous recommendations proposed for considera-tion. This review summarises the current state of research with respect to the aforementioned factors, drawing conclusions and recommendations for future work.
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Vol.:(0123456789)
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European Journal of Applied Physiology
https://doi.org/10.1007/s00421-019-04157-y
INVITED REVIEW
Iron considerations fortheathlete: anarrative review
MarcSim1,2· LauraA.Garvican‑Lewis3,4· GregoryR.Cox5· AndrewGovus6· AlannahK.A.McKay7,8·
TrentStellingwer9,10· PeterPeeling7,8
Received: 19 March 2019 / Accepted: 2 May 2019
© Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract
Iron plays a significant role in the body, and is specifically important to athletes, since it is a dominant feature in processes
such as oxygen transport and energy metabolism. Despite its importance, athlete populations, especially females and endur-
ance athletes, are commonly diagnosed with iron deficiency, suggesting an association between sport performance and iron
regulation. Although iron deficiency is most common in female athletes (~ 15–35% athlete cohorts deficient), approximately
5–11% of male athlete cohorts also present with this issue. Furthermore, interest has grown in the mechanisms that influ-
ence iron absorption in athletes over the last decade, with the link between iron regulation and exercise becoming a research
focus. Specifically, exercise-induced increases in the master iron regulatory hormone, hepcidin, has been highlighted as a
contributing factor towards altered iron metabolism in athletes. To date, a plethora of research has been conducted, including
investigation into the impact that sex hormones, diet (e.g. macronutrient manipulation), training and environmental stress (e.g.
hypoxia due to altitude training) have on an athlete’s iron status, with numerous recommendations proposed for considera-
tion. This review summarises the current state of research with respect to the aforementioned factors, drawing conclusions
and recommendations for future work.
Keywords Iron deficiency· Anaemia· Hepcidin· Exercise
Abbreviations
ΔHbmass Change in haemoglobin mass
DMT-1 Divalent metal transporter 1
DCytB Duodenal cytochrome b
ERFE Erythroferrone
EPO Erythropoietin
FSH Follicle stimulating hormone
GI Gastro-intestinal
Hb Haemoglobin
Hbmass Haemoglobin mass
HIF Hypoxia-inducible factor
IL-6 Interleukin-6
IV Intravenous
Fe Iron
ID Iron deficiency
IDA Iron deficiency anaemia
IDNA Iron deficient non-anaemia
LHTL Live high, train low
LCHF Low carbohydrate, high fat
LEA Low energy availability
Communicated by Michael Lindinger.
* Peter Peeling
peter.peeling@uwa.edu.au
1 School ofMedical andHealth Sciences, Edith Cowan
University, Joondalup, WA, Australia
2 Medical School, Royal Perth Hospital Unit, The University
Western Australia, Perth, WA, Australia
3 Australian Institute ofSport, Canberra, ACT , Australia
4 Mary MacKillop Institute forHealth Research, Australian
Catholic University, Melbourne, VIC, Australia
5 Faculty ofHealth Sciences andMedicine, Bond University,
GoldCoast, QLD, Australia
6 Department ofRehabilitation, Nutrition andSport, School
ofAllied Health, La Trobe University, Melbourne, VIC,
Australia
7 School ofHuman Sciences (Exercise andSport Science), The
University ofWestern Australia, Crawley, WA, Australia
8 The Western Australian Institute ofSport, MtClaremont,
WA, Australia
9 Canadian Sport Institute-Pacific, Victoria, BritishColumbia,
Canada
10 Department ofExercise Science, Physical andHealth
Education, University ofVictoria, Victoria,
BritishColumbia, Canada
European Journal of Applied Physiology
1 3
LH Luteinising hormone
VO2max Maximal oxygen uptake
mRNA Messenger ribonucleic acid
OCC Oral contraceptive cycle
OCP Oral contraceptive pill
RDI Recommended dietary intake
RED-S Relative energy deficiency in sport
sTfR Soluble transferrin receptor
TfR Transferrin receptor
TfR-2 Transferrin receptor-2
vVO2peak Velocity at peak oxygen uptake
Introduction
Iron is a fundamental mineral used by the body for numer-
ous processes such as oxygen transport and energy produc-
tion at a cellular level (Beard 2001). Clearly, these processes
are imperative in the support of athletic pursuit, hence, the
provision, utilisation and storage of iron is extremely impor-
tant to an athlete. Despite the biological importance, iron
deficiency (ID) is a widely reported issue in athlete popula-
tions, with the documented prevalence reported at ~ 15–35%
of female and ~ 3–11% of male athletes (Fallon 2004, 2008;
Malczewska etal. 2001; Parks etal. 2017). However, smaller
cohort studies report higher rates of compromised iron stores
across a variety of sports settings, with the prevalence
reported as > 50% in female, and up to 30% in male athletes
(Koehler etal. 2012; Tan etal. 2012).
Of note, female athletes tend to experience a greater inci-
dence of ID (Beard and Tobin 2000), potentially a result of
increased iron demand to account for menses (Pedlar etal.
2018). However, low energy intake, vegetarian diets and
endurance exercise have also been proposed as potential
factors impacting both male and female athletes’ iron stores
(Castell etal. 2019). The symptoms of compromised iron
status include lethargy, fatigue and negative mood states
(Pasricha etal. 2010; Patterson etal. 2001; Nielsen and
Nachtigall 1998), with more severe cases (i.e. iron deficiency
anaemia; IDA) also compromising work capacity (Woodson
etal. 1978). Such symptoms may impact the athlete’s ability
to train appropriately and to produce competitive perfor-
mances (Garvican etal. 2011). Consequently, it is impor-
tant that the iron status of an athlete is routinely monitored,
and that appropriate action is taken should correction of a
deficiency be required. However, to assess an athlete’s iron
status, and to determine an appropriate course of action, an
understanding of the mechanisms that influence iron absorp-
tion is needed, since contemporary research has established
a clear link between iron regulation and exercise. Further-
more, numerous research papers have explored the impact
of diet, training and environmental stress on an athlete’s iron
status over the past decade, with many recommendations
proposed for consideration. Therefore, this review will
attempt to summarise the current state of play with respect to
the aforementioned factors of interest, drawing conclusions
and recommendations for future work in this area.
How dowe dene aniron deciency
inathletes?
Debate currently exists as to the most appropriate haema-
tological variables (and their cut-off values) that should
be measured in the assessment of an athlete’s iron status;
however, the reader is directed to a succinct summary of
these various measures by Clenin etal. (2015). Despite a
plethora of variables available to practitioners, the current
(minimum) routine clinical assessment of ID includes analy-
sis of the blood markers; ferritin, haemoglobin concentra-
tion (Hb) and transferrin saturation. In an attempt to classify
the various stages of ID using these three haematological
variables, Peeling etal. (2007) proposed the following for
athletic populations:
Stage 1—iron deficiency (ID): iron stores in the bone
marrow, liver and spleen are depleted (ferritin < 35μg/L,
Hb > 115g/L, transferrin saturation > 16%).
Stage 2—iron-deficient non-anaemia (IDNA): erythro-
poiesis diminishes as the iron supply to the erythroid
marrow is reduced (ferritin < 20 μg/L, Hb > 115 g/L,
transferrin saturation < 16%).
Stage 3—iron-deficient anaemia (IDA): Hb produc-
tion falls, resulting in anaemia (ferritin < 12μg/L,
Hb < 115g/L, transferrin saturation < 16%).
Additionally, serum-soluble transferrin receptor (sTfR)
levels of 2.5mg/L could be considered a reasonable thresh-
old for identification of IDA (Koulaouzidis etal. 2009). Of
note, it appears that depleted iron stores (stage 1) may have
a minimal impact on physical performance; however, early
correction of iron depletion is likely to prevent the issue
from further progressing into stages 2 and 3. For example,
despite unchanged Hb concentration in IDNA, training and
performance outcomes may be compromised (DellaValle
and Haas 2011). Furthermore, Garvican-Lewis etal. (2016a)
reported that supplementing athletes with low pre-altitude
iron stores (< 35µg/L) with 210mg supplemental iron per
day over 3weeks of moderate altitude exposure was associ-
ated with an increased haematological response compared
to no supplementation, suggesting an essential role of iron
in the adaptation process. Regardless, as noted by Clenin
etal. (2015), a number of limitations are associated with
the use of ferritin as a marker of iron status, such as its role
as an acute phase protein, and the fact that ferritin levels are
increased during periods of inflammation and after intensive
European Journal of Applied Physiology
1 3
exercise. Furthermore, measures of Hb are also affected by
shifts in plasma volume, which, when unaccounted for, may
present issues such as pseudo-anaemia (see Bartsch etal.
1998): also commonly referred to as sports anaemia (Sim
etal. 2013), which does not appear to have any negative
effects on performance. Considering training and/or heat
adaptions can induce hypervolaemia (Taylor 2011; Voss
etal. 2014), these factors should be considered to avoid
underestimating the concentrations of plasma iron and red
cell parameters. Additionally, blood collection standardisa-
tion is imperative prior to assessing an athlete’s iron sta-
tus, and consideration must be given to the time of day, the
hydration state of the athlete and their prior activity levels
leading to the blood assessment (Castell etal. 2019). Of
note, muscle damaging exercise (e.g. eccentric) should not
be performed 2–3days prior to the assessment, since this
type of activity can induce high levels of systemic inflam-
mation (Peake etal. 2005), which may impact on the blood
picture captured. Ultimately, blood for such purposes should
be collected in the morning, with the athlete in a rested (i.e.
24 + h post-training) and hydrated state (preferably assessed
via waking urinary specific gravity of < 1.025; Armstrong
etal. 2010) after an overnight fast (Fig.1).
What are thecontributing factors toiron
deciency inathlete populations?
Given the high incidence of ID reported in athletes, it
is likely that exercise, and/or dietary/energy availability,
can influence iron metabolism in this population. Previ-
ous reviews exploring the underlying mechanisms of iron
deficiency in athlete populations have considered pros-
pects such as haemolysis exacerbated by ground impact
forces (e.g. foot strike; Telford etal. 2003) and muscle
contraction (e.g. eccentric muscle damaging exercise;
Theodorou etal. 2010), haematuria, gastro-intestinal
(GI) bleeding, sweating and inflammatory/iron regula-
tory hormone (hepcidin) responses (for review see Peel-
ing etal. 2008). Over the past decade, a strong focus of
Considerations and frequency of iron blood screening forathletes*
AnnuallyBiannually Quarterly
No history of iron deficiency
No history of irregular/excessive
menses or amenorrhea
No reports of fatigue after extended
rest
Strength/power-based sports with
minimal endurance component
No iron-related dietary restrictions
No evidence of low energy
availability
No intention to undertake hypoxic
training in the next 12 months
No underlying pathology
(e.g. coeliac or Crohn’s disease)
Female
Previous history (≥ 24 months) of
iron depletion (e.g. Stage 1#)
Previous history (≥ 24 months) of
irregular/excessive menses
Intention to undertake high training
loads especially in endurance and
team-based sports
Minimal (or zero) reports of
prolonged fatigue after extended rest
No iron-related dietary restrictions
(e.g. non-vegetarian, non-vegan)
No evidence of low energy
availability
Intention to undertake hypoxic
training in the next 12 months
Any recent history (<24 months) of
iron depletion/deficiency (Stage 1, 2
or 3#) irrespective of sex
Any evidence of irregular/excessive
menses or amenorrhea
High training loads in team and
endurance-based sports
Reporting prolonged
fatigue/lethargy even after extended
rest
Reduced work capacity during
training
Unexplained poor athletic
performance
Individuals restricting sources of
dietary iron (e.g., vegetarian and
vegan) or overall caloric intake
Any evidence of low energy
availability
Intention to undertake hypoxic
training in the next 6 months
Variables to be considered
Minimum: Serum ferritin, hemoglobin concentration, transferrin
saturation
Desirable: Serum soluble transferrin receptor, hemoglobin mass,
C-reactive protein
Standardisation of blood collection
Time of day: Preferably in the morning
Hydration state: hydrated preferably assessed by waking urinary
specific gravity (< 1.025)
Low to moderate activity in the proceeding 24 hours, including no
muscle-damaging exercise (e.g. eccentric) in the 2-3 days prior
No signs of sickness or infection
Fig. 1 Framework of considerations for the frequency of iron blood
screening in athlete populations. Asterisk indicates this framework
requires the expertise of trained professionals including sports phy-
sicians, dietitians and physiologists. # indicates stages of iron defi-
ciency are defined by Peeling etal. (2007)
European Journal of Applied Physiology
1 3
the literature has been placed on this latter mechanism,
with numerous papers showing that exercise has a tran-
sient impact on increasing levels of the master iron regu-
latory hormone, hepcidin (for 3–6h post-exercise), likely
a result of the well-documented exercise-induced inflam-
matory response and associated increases in the cytokine
interleukin-6 (IL-6) (Peeling etal. 2008; Roecker etal.
2005; Newlin etal. 2012). Increases in hepcidin activ-
ity result in a decrease in iron absorption and recycling
from the gut and scavenging macrophages, respectively.
As such, it is likely that there exists a transient window
of altered iron metabolism after exercise where nutri-
tion strategies could be exploited to manipulate the out-
come (i.e. strategic feeding times to avoid the window of
decreased iron absorption). Regardless, it is understood
that the function of hepcidin is homeostatic in nature and,
therefore, it has been noted that the hepcidin response to
exercise is attenuated in iron-deficient athletes (Peeling
etal. 2014, 2017), likely a result of the body signalling
an increased iron need. The problem exists that exercise-
induced elevations in the hormone response are evident
in athletes with ‘healthy’ iron stores, including those that
present with values at the borderline of the above-men-
tioned cutoff values (i.e. ferritin 30µg/L). Therefore, ath-
letes that tend to sit on the verge of having compromised
iron stores seem to be in a vicious cycle of being unable
to ‘get on top’ of their iron status. As such, strategies to
rapidly increase iron stores may be required to overcome
this issue (discussed further in the supplement strategies
section below).
In addition to these core mechanisms, there is also
a likely link to the relative energy deficiency in sport
(RED-S) concept (Mountjoy etal. 2014), whereby over-
all low energy availability (LEA) and energy intake in
athlete populations may relate to either an overall deficit
in dietary iron intake and/or dysfunction in its subse-
quent absorption. Such events may reduce an athlete’s
chance of meeting the increased iron demands, where an
additional ~ 1–2mg iron/day may be required to replen-
ish exercise-related iron losses (Nielsen and Nachtigall
1998). Finally, there exists the added burden of menstrual
blood losses in female athletes (Pedlar etal. 2018) and the
decreased iron bioavailability in vegetarian diets (Vend-
erley and Campbell 2006) that can add to the cumulative
effect of compromised iron stores in athlete populations.
As such, it is essential that practitioners are aware of, and
assess, the multitude of factors that contribute towards
ID when working with athletes who struggle to maintain
iron balance. Furthermore, future research is required
to explore these interactions and the best approaches to
improving the iron status of athletes that struggle to main-
tain optimal iron stores.
How does iron deciency impact athletic
performance?
Iron-dependent metabolic pathways involve (1) Hb and
myoglobin for oxygen transport to the exercising skeletal
muscle; and (2) the oxidative production of adenosine
triphosphate at the electron transport chain that is highly
reliant on non-heme iron sulphur enzymes and heme-
containing cytochromes (Beard and Tobin 2000). Iron
deficiency is typically associated with impaired aerobic
power, with the magnitude of the expected performance
reduction related to the severity of the ID. Specifically,
aerobic performance is likely to be most severely affected
when iron stores are depleted and Hb production is com-
promised (e.g. IDA; stage 3 of ID) (Myhre etal. 2016).
Consequently, reduced oxygen transport to the exercising
skeletal muscle may place higher demands on anaerobic
metabolism (Gardner etal. 1977), which could negatively
influence performance (e.g. lower blood pH, depletion of
muscle glycogen). Given the reliance on aerobic metabo-
lism and high prevalence of ID in endurance athletes, this
population is often studied (Rubeor etal. 2018).
Despite the importance of iron, supplementing iron to
athletes without ID does not appear to improve endurance
performance (Garvican etal. 2014a, b; Powell and Tucker
1991; Tsalis etal. 2004). Furthermore, evidence for the
negative influence that IDNA (stage 1 and 2) has on endur-
ance performance is also equivocal, with both no effect
and negative effects reported (Rubeor etal. 2018; Burden
etal. 2015a). Specifically, as oxygen transport capacity is
unchanged in IDNA (stages 1 and 2), any negative influ-
ence that IDNA has on endurance performance may be
associated with impaired function of oxidative enzymes
and respiratory proteins (Haas and Brownlie 2001). How-
ever, as we cannot exclude other potential negative effects
that IDNA has on health, preventing further declines to
iron status must be prioritised. A combination of regu-
lar screening tests alongside dietary assessments should
be scheduled periodically throughout the year to identify
the need for iron supplementation (discussed in other sec-
tions). Such propositions have led research to investigate
the role of iron supplements on endurance performance
in IDNA athletes. For instance, in 165 IDNA female
rowers (Hb > 120g/L), lower ferritin stores (< 20µg/L
vs. ≥ 20µg/L) was retrospectively associated (2–3months
prior) with slower (~ 21s) 2km rowing TT ergometer
performance (DellaValle and Haas 2011). In a follow-up
randomised controlled trial conducted in a similar popu-
lation (n = 31, IDNA female rowers), despite unchanged
4km rowing TT performance, daily iron supplements
(100mg/day) over 6weeks were shown to decrease energy
expenditure and increase energy efficiency during the TT
European Journal of Applied Physiology
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(Dellavalle and Haas 2014). The authors hypothesised
that physiological adaptions (e.g. increase in oxidative
enzymes, red cell volume) typically associated with endur-
ance training may only be maximised in the presence of
adequate iron stores. For example, greater iron bioavail-
ability may favour adaptations leading to better exercise
economy. However, such propositions remain to be con-
firmed by future research.
Similar sentiments to those above were echoed in a
meta-analysis reporting that iron supplementation in IDNA
athletes could lead to improved aerobic performance (Bur-
den etal. 2015a). Here, Burden etal. (2015a) explored the
efficacy of iron treatments (injection or oral supplements)
on iron status and aerobic capacity (assessed by maximal
oxygen uptake; VO2max) in IDNA individuals (12 studies,
n = 443, 82% female). Here, iron treatment had a large effect
on ferritin, and a moderate effect on both Hb and VO2max.
However, no improvements in VO2max were reported across
eight studies, while the greatest changes in aerobic power
were observed in studies with less-trained individuals
(VO2max < 40mL/kg/min). Another recent meta-analysis
(18 trials and 2 companion papers, n = 1170 individuals)
by Houston etal. (2018) reported that iron supplementa-
tion in IDNA adults (combing both trained and untrained
populations) did not improve physical capacity (assessed
by VO2max and other timed-exercise tests) despite improved
perceived measures of fatigue. However, such findings may
be different if only well-trained or elite endurance athletes
were considered. Accordingly, Rubeor et al. concluded
in their systemic review (12 studies, n = 283 participants,
91% female) that 50% of studies found no performance
improvements for IDNA athletes after iron supplementa-
tion (Rubeor etal. 2018). However, unlike the meta-anal-
ysis where aerobic power was assessed using VO2max, per-
formance was quantified using a range of tests differing in
their metabolic demands (e.g. shuttle run, 3000m run, time
to fatigue), which complicates the interpretation of results.
Of note, when ferritin stores are substantially compromised
(≤ 20µg/L) in IDNA athletes, Rubeor etal. (2018) reported
that iron supplementation can improve performance. Col-
lectively, these meta-analyses highlight that a definitive
relationship between IDNA and compromised performance
remains ambiguous in elite athlete populations, although it
is perhaps the bioavailability of iron (as indicated by ferritin)
that is likely to be a contributing factor when performance
decrements are evident.
Alternatively, for IDA, the benefits of iron supplements
to improve iron status and performance are well documented
and widely recognised. IDA is estimated to affect up to 18%
and 7% of female and male athletes across a variety of sports
(see Parks etal. 2017 for review). However, the extent of
IDA could be higher during intense physical preparation,
with 29% of elite female soccer players (from a single team)
diagnosed with IDA 6 months prior to the FIFA Women’s
World Cup (Landahl etal. 2005). Of interest, a case study
of an elite female endurance athlete (19years of age) pre-
senting with anaemia (ferritin 9.9μg/L, Hb 88g/L) found
that an initial intramuscular injection (100mg Fe), fol-
lowed by twice daily oral supplements (100mg, elemental
Fe) over 15weeks substantially improved iron status (fer-
ritin 27.0μg/L, Hb 130g/L) (Garvican etal. 2011). Here,
a marked and rapid increase in absolute haemoglobin mass
(Hbmass; measured via the carbon monoxide rebreathing
method; Schmidt and Prommer 2005) was recorded in the
first ~ 2weeks after the iron injection (389g to 580g) and
continued to rise over the next 13weeks (710g). Improved
iron status enabled the athlete to gradually increase her
training load, which likely contributed to a 3000m personal
best run time ~ 8 weeks after iron treatment commenced.
Although results from case studies cannot be generalised,
this work highlights the benefits of a well-devised iron sup-
plementation framework. Under similar scenarios, the afore-
mentioned framework should be considered by support staff
(i.e. sports medicine, nutrition and physiology) when dealing
with athletes presenting with IDA.
In summary, despite a lack of definitive evidence that
IDNA compromises performance, the iron status of athletes
should be monitored consistently throughout the training
year. Early detection of low iron stores and subsequent
supplementation may reverse (or limit) further declines in
iron status (e.g. the progression to IDA), where a range of
other negative effects (e.g. compromised immune function,
lethargy, weakness) can exacerbate performance declines.
Furthermore, it is possible that compromised iron stores
could have other unknown negative influences on numer-
ous training (e.g. enzymes involved in energy production,
muscle physiology/function) and recovery adaptions in ath-
letes. Such prospects require further investigation by future
work. Finally, as highlighted in Fig.1, blood screening needs
to consider a range of factors (discussed subsequently) and
should be performed (1) annually for athletes with no symp-
toms (or history of ID), or (2) quarterly (or at least biannu-
ally) for ‘at risk’ individuals.
Are there any sex dierences relevant toiron
deciency?
An estimated 11% of male and 35% of female athletes suffer
from ID (Malczewska etal. 2001; Dubnov and Constan-
tini 2004). In the general population, IDA is estimated to
affect 3–5% of women and < 1% of men. For IDNA, this
affects approximately 12–16% of premenopausal adult
women and 2% of men (Looker etal. 1997). Active women
are estimated to be twice as likely to present with IDNA
compared to sedentary women (Sinclair and Hinton 2005),
European Journal of Applied Physiology
1 3
with 24–47% of exercising women experiencing IDNA
(Rowland 2012). In 193 elite young (< 25years) German
athletes (mean age 16.2years, ~ 50% female) across 24 dif-
ferent sports, the prevalence of low ferritin (< 35 ug/L) was
almost double in females compared to males (57% vs. 31%)
(Koehler etal. 2012). However, the incidence of low Hb
(< 120g/L or < 130g/L for females and males, respectively)
was similar (6.2% vs 7.3%). Although sex-specific cut-points
for biomarkers related to ID have been proposed (Looker
etal. 1997), such methods have been met with criticism.
Specifically, as current practice used to establish reference
ranges (for serum ferritin, Hb and transferrin saturation) for
women contained a large proportion of individuals with sub-
optimal iron status from the general population, the lower
limits may be set too low (Rushton etal. 2001). Therefore,
at present, the universal cut-points established in the iron
deficiency definition section above are generally used for
athlete populations.
With the aforementioned guidelines in mind, IDA
as defined by Dubnov and Constantini (2004) (ferri-
tin < 12μg/L, transferr in saturation < 16%) was observed
among 7% of elite basketball players (n = 103, 64% male).
Of the IDA athletes, 3% were male and 14% were female.
These findings highlight the frequency of poor iron status
in athletic populations, which may be related to a combina-
tion of factors including: (1) the aforementioned exercise-
induced mechanisms; (2) inadequate dietary iron and/or
energy intake; (3) an influence of sex hormones on iron
metabolism; and (4) menses. For example, in regularly men-
struating women, ~ 30–50mL of blood is lost during menses
(Dasharathy etal. 2012), with ~ 40mL of blood resulting
in an average loss of 1.6mg of iron (Jacob etal. 1965). Of
concern, consecutive menstrual blood loss of greater than
60mL can compromise iron stores (Andrade etal. 1991).
Given the differences in sex hormones between males and
females, this section will focus on the interaction between
sex hormones, hepcidin and iron parameters that may con-
tribute towards impaired iron metabolism.
The predominant circulating gonadal sex steroid hor-
mones after puberty are androgens in males and oestrogens
in females (Sims and Heather 2018). Both testosterone and
oestrogen can influence iron metabolism via their suppres-
sive effects on the hepcidin–ferroportin axis (Bachman etal.
2010, 2013; Hou etal. 2012; Yang etal. 2012). For athletes,
it is possible that high training loads may alter an individu-
al’s hormonal profile (Warren and Perlroth 2001), thereby
suppressing gonadotropin-releasing hormone (GnRH), a
precursor for sex hormones. In women, this can lead to sup-
pressed luteinising hormone (LH), follicle stimulating hor-
mone (FSH; to a lesser extent) and consequently oestrogen.
Such events likely contribute to secondary amenorrhoea,
which has previously been reported in recreational runners
(De Souza etal. 1998).
Few studies to date have investigated the specific effects
of sex hormones such as oestrogen, progesterone and tes-
tosterone on hepcidin and iron status in exercising popula-
tions. Of these hormones, only the role of testosterone is
well established in erythropoiesis. For example, in young
strength-trained healthy males (n = 12), weekly testoster-
one injections (600mg) resulted in a ~ 10% increase in Hb
concentration over 20weeks (Bhasin etal. 2001). Poten-
tial mechanisms including erythropoietin (EPO) secre-
tion and the stimulation of erythroid progenitor cells have
been proposed (Moriyama and Fisher 1975). An investiga-
tion in males of varying ages (aged 19–35years, n = 53;
59–75years, n = 56) reported that testosterone enanthate
supplementation (using a range of doses 25, 50, 125, 300
and 600mg) over 20weeks suppressed basal serum hepci-
din concentration by more than 50% (Bachman etal. 2010).
In younger men (19–35years), hepcidin suppression was
more pronounced, while appearing dose dependent in older
individuals (59–75years). The proposed mechanisms for
hepcidin down-regulation by testosterone appears multi-
factorial, including its stimulatory effect on erythropoiesis,
modulation of bone morphogenetic protein signalling by the
androgen receptor and alterations in epidermal growth factor
receptor signalling (Li etal. 2016; Guo etal. 2013; Latour
etal. 2014). Lower circulating (~ 40%) and production rates
of testosterone (~ 20–30%) resulting from altered hypotha-
lamic–pituitary–testicular axis has been demonstrated in
endurance-trained men compared to age-matched sedentary
controls (Hackney etal. 2003). Unsurprisingly, endurance
exercise completed over extended periods has also been
implicated with lower circulating testosterone levels in men
(Hackney 1996). Albeit an extreme example of acute endur-
ance exercise, testosterone levels were reduced by ~ 58%
in 38 trained males (aged ~ 32years) after completing an
Ironman triathlon race (swim 3.8km, cycle 180 km and
run 42.2km) (Ginsburg etal. 2001). Comparable findings
have also been reported after less demanding exercise, as
reviewed previously (Hackney 2001). Consequently, chronic
suppression of testosterone may be linked to higher hepcidin
levels in male athletes, potentially impairing iron regulation,
and thereby helping to explain the incidence of ID among
this sex. In women, although lower levels of testosterone
are present, its importance in iron metabolism should not be
ignored. For example, higher testosterone levels have been
associated with lower risk for anaemia in both healthy older
women (n = 509) and men (n = 396) (Ferrucci etal. 2006).
Of note, the primary female sex hormones oestrogen and
progesterone (and their synthetic forms oestradiol and pro-
gestogens) have been implicated in hepcidin and iron regula-
tion (Sim etal. 2014).
Currently, evidence exists for oestradiol supplementa-
tion to down-regulate hepcidin production (Hou etal. 2012;
Yang etal. 2012). Specifically, a link between oestrogen and
European Journal of Applied Physiology
1 3
hepcidin mRNA in mice has been uncovered, where oestro-
gen deficiency resulted in lower iron stores (in the liver and
spleen) and higher transcription of hepcidin mRNA (Hou
etal. 2012). Another investigation examined the relation-
ship between oestrogen and hepcidin in women undertak-
ing invitro fertilisation treatment who had their oestrogen
suppressed using buserelin (GnRH agonist) (Lehtihet etal.
2016). In this study, when an FSH injection was provided to
stimulate oestrogen production, hepcidin levels decreased
by 40% (median hepcidin: 4.85–1.43ng/mL). These results
indicate that large amounts of endogenous oestrogen can
suppress basal hepcidin levels. When examining synthetic
sex hormones, positive effects of an oral contraceptive pill
(OCP) use on iron status have been reported, as OCP users
have higher serum ferritin, iron, total iron binding capac-
ity and lower menstrual blood loss (~ 50%) compared to
non-users (Frassinelli-Gunderson etal. 1985; Larsson etal.
1992). Evidence also exists that after commencing OCP use,
ferritin increases (~ 21–29%) in women with poor iron stores
(ferritin < 10μg/L) (Larsson etal. 1992).
Although ID is often studied in female athlete popula-
tions, the interaction of the aforementioned sex hormones
with hepcidin and iron metabolism remains unclear. For
example, besides an inverse link between progesterone and
IL-6 (a primary mediator of hepcidin) (Angstwurm etal.
1997), relatively little is known about the potential role of
progesterone (and its synthetic form progestogens) on iron
metabolism. To our knowledge, only one study has exam-
ined the role of oestradiol in combination with progestogens
for their acute effects on hepcidin and iron metabolism in
exercising young women (Sim etal. 2015). In that study, ten
active females on OCP performed two separate 40min run
trials at 75% of the velocity attained at peak oxygen uptake
(vVO2peak) during specific phases of the oral contraceptive
cycle (OCC): (a) day 2–4, representing a hormone-free with-
drawal period (D−0); (b) day 12–14, representing the end
of the first week of active hormone therapy (D + 7). Exer-
cise performed during the different phases (D−0 vs. D + 7)
did not alter exercise-induced IL-6 or hepcidin production.
Specifically, serum hepcidin concentration was significantly
elevated 3h post-exercise in both trials. Of interest, serum
iron remained significantly elevated 3h post-exercise as
compared to baseline only during D − 0 (not D + 7). Of note,
higher oestradiol levels are hypothesised to reduce oxida-
tive stress (Stirone etal. 2005), which is known to exacer-
bate haemolysis (indicated by serum iron), thereby likely
explaining why serum iron levels return to baseline by 3h
post-exercise at D + 7, but not D 0.
Similar basal serum iron, hepcidin, IL-6 and transfer-
rin saturation levels have also been reported during dif-
ferent phases of an OCC (e.g. D−0 vs. D + 7) in young
active women (Sim etal. 2017). Only serum ferritin was
significantly higher at D + 7 compared to D−0 (69.4 vs.
61.1µg/L), suggesting that a combination of oestradiol and/
or progestogens from the OCP can influence iron stores.
Considering the high prevalence of ID in female athletes
and active women, numerous questions remain regarding the
potential interaction between oestrogen, progesterone and
iron metabolism. Since knownlinks between oestradiol (or
oestrogen) and iron regulation exist, future studies should
examine both the acute post-exercise hepcidin response and
its longitudinal influence on markers of iron status in OCP
users vs non-users (including different phases of the men-
strual cycle). This work should also consider the influence
that sex hormones might have on menstrual blood loss and
oxidative stress-induced haemolysis, and the implications
for exercise-induced ID.
What istheimpact ofdiet ontheiron status
ofathletes?
The current recommended dietary intake (RDI) for elemen-
tal iron is 8mg for males and 18mg for females (Trumbo
etal. 2001), with the higher intake in women attributed to
the iron losses associated with menses (McClung 2012).
However, given the aforementioned mechanisms of iron loss
that occur as a result of exercise, it is likely that athletes
have a higher iron requirement than the general population.
For instance, despite consuming iron at the RDI (13–18mg/
day), a block of intensified training was shown to reduce fer-
ritin concentrations by 25–40% in a group of international-
level endurance athletes (McKay etal. 2019a). This sug-
gests that the current iron recommendations for the ‘general
population’ may not be sufficient for athletes, supporting the
case for athlete-specific recommendations to be developed
(Thomas etal. 2016).
Developing appropriate RDIs for athletes is important,
since iron cannot be synthesised by the body and is attained
solely from dietary sources, primarily in the form of whole
grain cereals, fish, poultry and meat. For reference, a com-
prehensive list of the iron content for various foods can be
found on the United States Department of Agriculture Food
Composition Database (USDA 2015), while a condensed list
of iron-rich food has been prepared by the British Dietetic
Association (Gill 2017). The timing, amount and source of
dietary iron, in combination with the overall iron compo-
sition of the diet, are all important factors for practition-
ers to consider, since they collectively influence total iron
absorption. For instance, it is well known that heme iron
sources (from meat) exhibit greater absorptive capacity
(~ 5–35%) than non-heme sources (~ 2–20%) from a single
meal (Beard and Tobin 2000). Furthermore, the presence of
various dietary components such as vitamin C, meat, poultry
and fish can enhance non-heme iron absorption, whereas
substances such as polyphenols, phytates or calcium that are
European Journal of Applied Physiology
1 3
part of tea, coffee, whole grains, legumes and dairy products
can decrease the amount of non-heme iron absorbed from
a given meal (Saunders etal. 2013). With this in mind, it is
clear that athletes should be working with trained dietitians
and nutrition experts when planning their meal composition
to optimise dietary iron absorption.
Notwithstanding the dietary composition, it might also
be considered that the aforementioned transient increases
in hepcidin activity may require strategic thinking relevant
to the timing of post-exercise iron intake for athletes, with
impaired iron absorption likely to occur during the post-
exercise window. However, to add another layer of com-
plexity, hepcidin activity also shows a strong diurnal varia-
tion, with the lowest levels observed in the morning, and a
steady increase reported throughout the day (Schaap etal.
2013). Therefore, it may be that optimal iron ingestion
should occur as far away from exercise as possible, in an
attempt to maximise its absorption, with a preference for the
morning, compared to evening consumption. However, the
impact of exercise, coupled with typically higher breakfast
calcium intake, and the diurnal variation of hepcidin present
a logistical challenge for the elite athlete population, who
often complete multiple training sessions on each day, and
likely consume their highest iron-containing meals in the
evening, when hepcidin levels are naturally elevated. As a
result, literature is lacking when it comes to the appropriate
timing of iron consumption for the elite athlete population.
Interestingly, recent work from our laboratory (McCormick
etal. 2019) indicates a potential open window of opportu-
nity if the iron is consumed within 60min of completing
exercise in the morning, likely a result of the iron reaching
the gut within the 3-h period before transient hepcidin eleva-
tions take effect. However, further work is required to fully
elucidate the prospects of such a window, and whether this
strategy is applicable to elite-level athletes with full training
schedules.
What istheinuence ofcontemporary
nutritional strategies oniron regulation?
Recent interest in iron metabolism has focused on nutri-
tional strategies where select exercise sessions are delib-
erately undertaken with low muscle glycogen stores, with
the primary goal of increasing transcriptional activation
of enzymes involved in carbohydrate (CHO) and fat oxi-
dation, as well as greater mitochondrial biogenesis (Burke
etal. 2018; Impey etal. 2018). While these strategies may
promote endurance adaptation, they may also interfere
with post-exercise iron metabolism. Given IL-6’s role as
an energy sensor for contracting muscle, this explains aug-
mented post-exercise IL-6 concentrations when training
under conditions of low CHO availability (Hennigar etal.
2017). Furthermore, as IL-6 is a key cytokine involved in the
up-regulation of hepcidin levels post-exercise, training with
low muscle glycogen stores may also amplify hepcidin levels
following exercise. Such events potentially prolong the post-
exercise period of impaired iron absorption and metabolism.
Investigations of acute CHO supplementation have found
minimal influence on iron-regulation (Dahlquist etal. 2017;
Robson-Ansley etal. 2011; Sim etal. 2012), however, it
appears that diet-training strategies that target depleting
muscle glycogen stores may have a greater impact. For
instance, Badenhorst etal. (2015) demonstrated that both
IL-6 and hepcidin concentrations were elevated in response
to exercise after 24h of a low (3g/kg), compared to high
CHO (8g/kg) diet. Interestingly, when this diet was extended
across 7days, no differences in iron-regulation were evident
(Badenhorst etal. 2016). However, the programing of a rest
day prior to the exercise test on day 7, combined with the
increased protein consumption in the low CHO condition,
likely minimised any differences in muscle glycogen stores
between dietary conditions. Further research in this area,
using elite athletes adhering to a low CHO high fat (LCHF)
diet for 3weeks (< 50g CHO/day), observed increased IL-6
and hepcidin levels (3h post-exercise) following a 2h bout
of race walking, compared to athletes consuming a CHO-
rich diet (McKay etal. 2019a). However, differences in the
baseline iron status of the athletes in this investigation may
have been a confounding factor when interpreting changes
to hepcidin concentrations (McKay etal. 2019b; Peeling
etal. 2014). In light of these recent findings, it is evident
that the macronutrient composition of an athletes’ diet may
impact on post-exercise iron metabolism. As a result, we
currently suggest that the use of nutritional approaches that
restrict CHO should be carefully considered, particularly
for athletes with increased iron requirements (e.g. growth,
altitude, females or endurance athletes) or those consuming
low dietary iron intakes (e.g. vegetarians, weight category
athletes). Finally, a greater understanding of the relationship
between the dietary macronutrient composition, current iron
status, inflammatory responses to exercise and subsequent
hepcidin activity is warranted to further our understanding
of the true influence of contemporary nutritional strategies
on iron metabolism.
Is there animpact ofoverall energy
availability?
Low energy availability occurs in athletes when a mismatch
between energy intake and energy expenditure is evident
(Loucks etal. 2011). RED-S is an umbrella term used to
describe the health and performance consequences asso-
ciated with LEA in athletes. Of note, ID is an associated
haematological outcome of RED-S (Mountjoy etal. 2018),
European Journal of Applied Physiology
1 3
with a retrospective questionnaire-based investigation of
1000 female athletes reporting that LEA was associated
with greater risk (64%) for haematologic dysfunction (char-
acterised by a history of anaemia, low Hb, iron or ferritin)
(Ackerman etal. 2018). Recent work supports these find-
ings, with significantly higher Hbmass (7.9%) recorded in
eumenorrhoeic (n = 22) versus amenorrhoeic (n = 13) elite
females runners, indicating the importance of long-term
energy availability for relevant health outcomes (Heikura
etal. 2018). One explanation is that athletes with LEA are
in energy deficit and do not reach the RDI for dietary iron.
A typical Western diet is shown to provide ~ 6mg of iron
per ~ 4200kJ (Beard and Tobin 2000). Therefore, reduced
energy intake may result in low dietary iron consumption,
subsequently having negative implications for an athlete’s
iron status. Additionally, many negative health outcomes
associated with RED-S can be exacerbated by ID. For exam-
ple, low iron stores are known to perturb thyroid function,
decrease appetite and impair metabolic efficiency; altera-
tions of which can lead to reduced energy intake, increased
energy expenditure and potentially contribute to LEA in
athletes (Petkus etal. 2017). Therefore, it appears that ID
can be a negative consequence of LEA; however, ID itself
may also augmentsome of the other undesirable outcomes
(e.g. weakness and extreme fatigue) associated with RED-S.
With this in mind, studies directly linking LEA and ID are
lacking, and further research is required to understand this
relationship. Perhaps, low iron stores may be an early indica-
tion of LEA, and supplementation should be considered to
minimise other health consequences associated with RED-S.
However, first and foremost, targeted nutrition counselling
focusing on adequate energy and nutrient intake should be
emphasised to correct energy availability. Notably, future
work examining the implications of RED-S and/or LEA on
hepcidin expression and iron metabolism is warranted. Such
work could provide direct evidence for the mechanistic inter-
action between RED-S and ID. Finally, since the physiology
of elite athletes, in combination with high training loads,
makes such populations unique, the inclusion of healthy
recreationally active controls as part of this work should be
considered.
What are thestrategies toaddress aniron
deciency?
Given the increased iron demand placed on an athlete, an
adequate exogenous iron supply is imperative to maintaining
appropriate iron levels. With the inability to endogenously
replace taxed iron stores, supplemental sources of iron are
an important consideration for athletes and their support
team. When faced with an ID, there are three primary strat-
egies for iron supplementation (Castell etal. 2019); these
include (a) increasing dietary iron intake (b) supplemental
oral iron or (c) parenteral iron administration. In determining
the most appropriate strategy, the athlete and support team
must first consider the severity of the ID, the typical indi-
vidual response to a given supplement preparation, the time
required for iron repletion via the strategy chosen (generally
in context of the training phase) and, of course, any legali-
ties of supplement choice in respect to the sport’s governing
body and anti-doping authority. Furthermore, it is important
to ascertain and treat any potential causes of ID (e.g. under-
lying pathophysiology), as this could facilitate the efficacy
of iron supplementation and prevent future reoccurrence.
The initial and most conservative strategy to approaching
an ID is a full dietary assessment by a qualified sports dieti-
tian, with a subsequent eating plan that focuses on increasing
dietary iron intake from food. Considering the aforemen-
tioned superior absorption of heme compared to non-heme
iron, vegetarian athletes presenting with compromised iron
stores are a more complex case when approaching the issue
via this strategy. An additional complexity when consider-
ing diet as a primary means to address an ID are the con-
current absorption enhancers and/or inhibitors that may be
consumed with the iron source (Saunders etal. 2013). As
such, careful planning is required when manipulating the
diet to increase iron absorption, and factors other than total
iron intake must be considered.
The second strategy to addressing compromised iron
stores requires the use of oral iron supplements, commonly
consumed as either tablet or liquid preparations. Oral iron
supplements are generally provided in the ferrous form
(fumarate, sulphate or gluconate); however, ferric prepara-
tions are also available, although the GI tolerance for ferric
iron supplements appears low (Brittenham 2018). Of note,
in a comparative review of ferrous versus ferric oral iron
formulations (Santiago 2012), slow-release ferrous sul-
phate preparations remained the established and standard
treatment of ID, resulting from their acceptable tolerability,
adequate bioavailability and overall efficacy of effect. How-
ever, it should be noted that a generally high incidence of
GI disturbance from oral iron supplementation is commonly
reported (Tolkien etal. 2015) and, in such cases, considera-
tion of iron polymaltose preparations or using enteric tablet
coating may be helpful.
Generally, the overall response to oral iron supplementa-
tion in athlete cohorts appears positive (40–80% increases to
ferritin) when consumed over an 8- to 12-week time frame,
utilising doses of ~ 100mg per day (Garvican etal. 2014a,
b; Dawson etal. 2006). However, alternate day supplemen-
tation may increase the efficacy of effect via an improve-
ment in the fractional absorption of iron from a given dose,
which, over time, results in a greater cumulative response
(Stoffel etal. 2017). Such regimens, in combination with
iron absorption enhancers such as vitamin C, should be
European Journal of Applied Physiology
1 3
considered. Furthermore, under extreme environmental
stress (e.g. exposure to altitude), a greater dose of oral iron
may be required to sustain iron stores and assist in the hae-
matological adaptation (as discussed in detail below).
The final method of addressing an iron deficiency comes
in the form of parenteral iron preparations via intramuscular
or intravenous (IV) administration. Previous literature has
shown both approaches to be very effective at improving
an athlete’s iron status, with 200–400% increases in ferritin
levels reported from 300 to 550mg of iron delivered over
a 1- to 42-day period (Dawson etal. 2006; Garvican etal.
2014a, b; Woods etal. 2014; Burden etal. 2015b). Mod-
ern advances in IV preparations (Macdougall 2009) have
increased the safety and accessibility of IV supplementa-
tion, with injections or infusions commonly delivered in an
outpatient setting. As such, IV administration has largely
superseded intra-muscular administration that is commonly
associated with soreness and staining around the injection
site. The clear benefit of an IV supplement strategy is the
speed and magnitude of the response, without GI upset, in
comparison to the aforementioned approaches of dietary
modification or oral supplementation. This is likely a result
of such administration methods by-passing the gut where
key issues of iron absorption exist. With this in mind, par-
enteral supplement methods may be of great importance
when a situation requires rapid improvement in iron stores,
or when gut issues appear to render more traditional methods
of iron therapy impractical and ineffective. Regardless, the
use of these administration methods do come with some
risks of adverse reactions, which may manifest as a mild
rash through to anaphylaxis (in very rare cases; Rampton
etal. 2014).
Also worth considering is the concept of maximising
iron stores through supplementation during periods of lower
activity (e.g. off-season). Inevitably, as training load and
iron demands increase during the competitive season, higher
iron reserves may limit the negative influence that exercise
training has on the bioavailability of iron. In conclusion,
the decision to supplement, and the administration strategy
used,should be made by the sports physician, in consulta-
tion with the support team (i.e. dietitian). Furthermore, care
should be taken to ensure that the method of supplement
delivery is acceptable and consistent with the sport’s govern-
ing body and the anti-doping authorities.
Does iron play asignicant role
inadaptation tohypoxic environments?
Prolonged (> 2week) exposure to low (1000–2000m) and
moderate (2000–3000m) simulated or terrestrial altitudes
(Bärtsch etal. 2008) is associated with several haematologi-
cal (increased Hbmass) and non-haematological adaptations
(increased iron-dependent oxidative and glycolytic enzyme
concentrations) that assist aerobic exercise performance
(see Hahn and Gore 2001) for a comprehensive review).
The magnitude of the change in Hbmass during live high,
train low (LHTL) altitude training depends upon the hypoxic
dose (defined in kilometre hours (km/h) = (m/1000) × h), and
is characterised by an exponential increase, followed by an
eventual plateau after ~ 4 to 5weeks (Garvican-Lewis etal.
2016b). Although large intra- and inter-individual variabil-
ity exists in the Hbmass response (Siebenmann etal. 2015),
hypoxic exposure of 1000km/h (e.g. 21days at 2,000m) is
associated with a ~ 3–4% increase in Hbmass. Of note, altitude
training places a large demand on an athlete’s iron stores,
since, in addition to the aforementioned ~ 1–2mg iron/day
required to replenish exercise-related iron losses (Nielsen
and Nachtigall 1998), altitude exposure increases erythroid
iron demand by three- to fivefold (Reynafarje etal. 1959).
Therefore, low iron availability during prolonged altitude
exposure may blunt haematological adaptations (Stray-
Gundersen etal. 1992; Garvican-Lewis etal. 2018), in turn
decreasing the potential performance benefits that may be
gained from altitude exposure.
How isiron metabolism regulated
inhypoxia?
Oxygen sensing and the regulation of iron metabolism dur-
ing altitude exposure are linked by three distinct isoforms of
hypoxia-inducible factor (HIF-1α, HIF-2α and HIF-3α), with
the HIF-2α isoform stimulating EPO production (Kapitsinou
etal. 2010). Continuous hypoxic exposure causes plasma
EPO to increase within ~ 90min (Rodríguez etal. 2000),
peaking usually within 48h and returning to baseline lev-
els (or below) after 1 week (Garvican etal. 2012). EPO
principally acts upon receptors located on erythroid pro-
genitor cells in the bone marrow, stimulating the differen-
tiation of proerythroblasts into basophilic, polychromatic
and orthochromatic forms. Iron supply to differentiating
erythroid cells is met almost entirely by diferric transferrin
(Leimberg etal. 2008). Proerythroblasts then enucleate to
form reticulocytes, which are expelled into the blood plasma
as mature red blood cells. These adaptations typically mani-
fest as measurable changes in Hbmass after approximately
10days (Garvican etal. 2012).
Several changes in systemic iron metabolism occur to
support accelerated erythropoiesis in hypoxia, including
increased iron efflux from storage sites (reticuloendothe-
lial macrophages, hepatocytes and enterocytes), increased
iron transport to the erythron and increased intestinal iron
absorption (see Chepelev and Willmore 2011 for review).
Hypoxic stress has been shown to strongly inhibit liver
hepcidin production within 15h of exposure (Ravasi etal.
European Journal of Applied Physiology
1 3
2018), thereby promoting iron release from (predominantly)
reticuloendothelial macrophages in the bone marrow to sup-
port erythropoiesis. Hepcidin suppression in hypoxia is not
directly mediated by EPO (Canali etal. 2016); instead, the
hormone erythroferrone (ERFE) is released by proeryth-
roblasts and acts to suppress hepcidin expression (Kautz
etal. 2014). Simultaneously, during early hypoxic expo-
sure, several growth factors in the bone marrow (but not
the spleen or liver) may also play a role in hypoxic hepci-
din suppression (Ravasi etal. 2018). However, since these
growth factors and ERFE are down-regulated within 48h,
alternative mechanisms have been suggested to regulate the
later phases of hepcidin suppression in hypoxia (Ravasi etal.
2018). These mechanisms include erythroid iron demand
as indicated by the current plasma transferrin receptor-2
(TfR-2) concentration. TfR-2 is highly expressed by eryth-
roblasts and involved in sensing plasma diferric transferrin
concentration, in turn modulating EPO receptor signalling.
In addition to hepcidin suppression, hypoxic stabilisation of
HIF-2α up-regulates divalent metal transporter 1 (an iron
import protein; DMT-1) and duodenal cytochrome b (a fer-
ric reductase; DCytB) expression on duodenal enterocytes,
thereby increasing intestinal iron absorption (Goetze etal.
2013) from ~ 15–20% in normoxia to ~ 20–25% in hypoxia
(Reynafarje etal. 1959). Additionally, hypoxic stabilisation
of HIF-1α promotes increased iron transport to the erythron
by increasing TfR expression within ~ 16–40h of hypoxic
exposure (Piperno etal. 2010).
Are there specic iron supplementation
strategies ataltitude foranoptimised
outcome?
Athletes need sufficient iron stores to support accelerated
erythropoiesis and to replenish exercise-related iron losses
associated with daily training during prolonged altitude
exposure. Athletes typically receive oral iron supplements
before and during altitude exposure to maintain iron bal-
ance (Garvican-Lewis etal. 2018). However, despite several
different serum ferritin cutoff values being used to guide
iron supplementation during altitude exposure (Constantini
etal. 2017; Garvican-Lewis etal. 2018; Hauser etal. 2018),
the optimal iron supplementation strategy, including timing,
dose and administration route (i.e. oral versus intravenous),
to maximise haematological adaptations is still emerging.
The decision to provide iron supplementation to athletes
undertaking altitude exposure should be made by a sports
physician following a review of their pre-exposure blood
profile. Blood screening should be performed 3–6 weeks
before exposure, and should include a full blood count (but
preferably Hbmass via the carbon monoxide-rebreathing
method, since it is not affected by the plasma volume shifts
that occur at altitude), iron profile (including serum iron,
serum ferritin and transferrin saturation) and C-reactive
protein assessment (reflecting systemic inflammation over
the previous ~ 24–48h). This enables the size of the red cell
compartment, iron storage pool and the presence of inflam-
mation, to be quantified, respectively. Based upon their pre-
exposure serum ferritin concentration, athletes are usually
prescribed iron supplements to avoid the development of an
ID and to support erythropoiesis (Govus etal. 2015). On a
cautionary note, pre-exposure serum ferritin concentration
appears to be a weak predictor of Hbmass changes at altitude
in individuals with otherwise healthy iron stores (Hauser
etal. 2018; Ryan etal. 2014). Other factors, such as the rate
of iron efflux from bone marrow and splenic macrophages,
in addition to the rate of iron transport to the erythron (indi-
cated by the transferrin saturation) during early adaptation,
likely exert a greater influence on the resulting haemato-
logical adaptation. In practical terms, the adequacy of an
athlete’s iron storage pool for a prolonged altitude sojourn
likely depends both on the overall hypoxic dose (Garvican-
Lewis etal. 2016b) (with larger hypoxic doses, such as
longer duration and higher elevations requiring more iron
owing to the potentially greater haematological response),
the volume of training performed and the preparation time
available.
Of note, oral iron supplements remain the most common
form of iron used for altitude training, and are typically
administered daily for 2–6 weeks before, and throughout
exposure, to ensure that athletes can maintain a sufficient
iron balance over time. In a retrospective analysis of athletes
undertaking simulated LHTL altitude training, Hbmass was
improved even in athletes with low pre-exposure iron stores
(considered by the authors as serum ferritin: < 35μg/L) who
were supplemented with oral iron supplements for 2 weeks
before, and for the duration of the altitude exposure (Govus
etal. 2015). In fact, athletes with a pre-exposure serum fer-
ritin concentration < 20μg/L, who were supplemented with
210mg elemental iron/day, not only increased their Hbmass
(+ 4.0%), but also increased their iron stores, indicating that
the oral iron dose exceeded bone marrow iron uptake. As
such, hypoxic-mediated changes in iron metabolism during
altitude exposure (e.g. suppression of hepcidin, increased
iron absorption, transport and the mobilisation of iron from
storage sites) may improve the efficacy of oral iron supple-
mentation, assisting in the haematological adaptation to the
environmental stress.
The timing and dose of oral iron supplements during pro-
longed altitude exposure may affect intestinal iron absorp-
tion and subsequent incorporation by the erythron, in turn
affecting haematological adaptations to prolonged altitude
exposure. For example, Hall etal. (2019) found that a single
nightly dose of oral iron supplement (200mg elemental iron/
day delivered nightly), rather than a split dose of oral iron
European Journal of Applied Physiology
1 3
supplement (2 × 100mg elemental iron/day delivered in the
morning and evening, respectively), was associated with a
higher Hbmass response in athletes exposed to 2106m ter-
restrial altitude for ~ 3weeks. Of note, both doses allowed
athletes to maintain or increase their pre-exposure serum
ferritin concentration. However, GI discomfort, a common
side effect of oral iron supplements, was higher in the sin-
gle compared with the split dose group, decreasing by the
third week of exposure. As such, a single dose of oral iron
supplement may be superior to a split dose (of the same con-
centration) during prolonged altitude exposure to maximise
Hbmass adaptations.
In contrast to oral iron supplements, IV iron preparations
allow athletes to rapidly increase their iron stores and are
not associated with GI discomfort, instead delivering iron
directly into the splenic macrophages (Girelli etal. 2018).
We recently reported that both IV iron supplementation and
oral iron supplementation augment ΔHbmass (%) in endur-
ance-trained athletes who undertook 3weeks of simulated
LHTL altitude training (Garvican-Lewis etal. 2018). Nota-
bly, the ΔHbmass (%) was not greater than the coefficient of
variation for the CO-rebreathing method (1.5%) in the non-
iron supplemented group. Of note, Hbmass decay was less
rapid post-altitude exposure in the IV group as compared to
the oral group. Therefore, IV iron supplementation may be
useful to prepare athletes for prolonged sojourns at moder-
ate altitudes (~ 2000–3000m) when athletes have little time
to adequately prepare for the altitude exposure. However,
given the greater logistical (i.e. medical assistance required),
financial (IV iron is more expensive than oral iron) and ethi-
cal concerns (some sports have a “no needle policy”) asso-
ciated with IV iron supplements, oral iron supplementation
should be considered as the first choice iron supplementation
strategy to prepare athletes for prolonged altitude sojourns.
Summary
This review summarises evidence regarding the regulation
and increased demands of iron in athletic populations. We
have covered key topics related to athletes’ iron regulation
including (1) the effects and severity of ID on performance;
(2) sex and the implications of sex hormones on iron param-
eters; (3) diet, including macronutrient manipulation and
RED-S; and finally (4) the demands and influence of hypoxia
as part of altitude exposure. Collectively, we also highlight
the multifactorial causes of exercise-induced ID and pre-
vention strategies (e.g. dietary intake or supplements) and
provide suggestions for future work and practical informa-
tion that should be considered by athletes and their support
staff (sports dietitians, physiologists and physicians). We
propose that the iron status of athletes are monitored closely
throughout the training year, and that particular attention
should be paid insituations linked with increased iron loss
and/or demands, such as chronically high training loads and
environmental factors (altitude), respectively. Although the
influence of IDNA on athletic performance remains unclear,
early detection of low iron stores and subsequent supplemen-
tation may reverse (or limit) further declines to iron status.
As detailed in Fig.1, we propose that blood screening should
be performed regularly for athletes, while also considering
a diverse range of circumstances. On a positive note, sub-
stantial progress has been made in understanding the role of
iron, mechanisms of its regulation and the strategies used to
correct a deficiency/optimise adaptation; however, contin-
ued research is required to further our ability to reduce the
burden of an iron deficit in athlete populations.
Author contributions All authors on this review contributed to each
section equitably. The literature search, idea development, writing,
reviewing and editing for each section were completed as a collective.
Furthermore, all authors have provided specific insight on key aspects
relevant to each sub-heading.
Compliance with ethical standards
Conflict of interest The authors have no conflicts of interest to dis-
close.
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... Multiple factors influence the manifestation of ID, including sex, age, diet, exercise, pregnancy, altitude exposure, smoking and the presence of chronic disease [70,71]. Additionally, ferritin is an acute-phase protein, meaning levels increase in response to inflammation, such as during illness or in response to exerciseinduced inflammation [13]. Shifts in blood plasma volume in response to training, known as 'pseudo-anaemia', may also affect Hb measurements [13]. ...
... Additionally, ferritin is an acute-phase protein, meaning levels increase in response to inflammation, such as during illness or in response to exerciseinduced inflammation [13]. Shifts in blood plasma volume in response to training, known as 'pseudo-anaemia', may also affect Hb measurements [13]. These factors have made the comprehensive designation of specific values defining ID somewhat complex, hence the lack of universal consensus regarding these values. ...
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... Iron deficiency (ferritin < 20 ng/mL) is frequently observed among endurance athletes, and reduces endurance capacity (Beard and Tobin 2000;Eliakim et al. 2002;Sim et al. 2019). Although several factors have been suggested to explain iron deficiency, iron loss through exercise training (Mclnnis et al. 1998;Babic et al. 2001;DeRuisseau et al. 2002) and insufficient dietary iron intake (Hinton 2014) strongly affect higher risk of iron deficiency. ...
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... We did not note any changes in ferritin levels in the current study. Changes in ferritin levels, especially their reduction, are frequently observed among athletes and indicate iron store depletion [40]. Ferritin levels positively correlate with tissue iron stores, including the bone marrow, and hence, they are a good indicator of iron reserves in the body [41]. ...
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Background: Iron is a trace mineral that plays a significant role in oxygen transport and energy production during exercise. In deficiency, iron can have a significant negative impact on sports performance. Due to its relative simplicity, supplementation is a common treatment to combat deficiency. However, there is a paucity of analyses combining supplementation with dietary education as a method of treatment. Objective: To assess the effectiveness of a systematic iron intervention combining nutrition education and supplementation stages to combat low ferritin levels in collegiate runners. Methods: Twenty four distance runners (13 women; 11 men; 19.5 ± 0.8 years of age) were measured for serum ferritin, daily iron, calcium and vitamin C intake at the start of the fall semester and again after 100 days of supplementation. A dependent groups t-test was applied to delineate changes in Ferritin levels and iron, vitamin C and calcium intake. Alpha levels were maintained a priori at p < 0.05. Results: Ferritin levels averaged 40.0 ± 22.6 ng/mL in Fall and 33.7 ± 14.7 ng/mL in Spring. There were no statistical differences in ferritin levels from Fall to Spring (p = 0.074). Weekly Iron intake (# of foods) significantly increased from Fall (110.8 ± 43.1) to Spring (123.3 ± 43.9), (p = 0.028). There were no significant changes in Vitamin C or Calcium intake between time points (p = 0.441), (p = 0.901). Conclusion: We found no significant differences in serum ferritin measures but dietary intake of iron increased as a result of the intervention.
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Micronutrient deficiency is prevelant in both high income and low-income countries globally causing major health issues, especially iron deficiency which causes hypoproliferative microcytic anemia. Iron deficieny anemiais effecting more than two billion population on earth especially pregnant woman, infants and woman of reproductive. Iron plays a key role in the formation of red blood cells and reactions occurring in the human body. Food is one of the best and safe options to prevent and cure iron deficiency anemia. In the present study, we highlighted different foods with special reference to plant-based foods for the treatment and prevention of iron deficiency anemia. Literature revealed that major cereal flours, cumin seeds, green leafy vegetables, moringa leaves, papaya with supplements, beet root, apples, pomegranate, bael, sugar molasses and berries are best sources of iron due to presence of ascorbic acid. Prebiotics and probiotics fortification can also increase the iron absorption in the gut by providing optimum pH for absorption. In addition to change in dietary patterns, fortification of major crops, flours and salt should be made mandatory by as in many countries. Moreover, Iron fortified formulas, complementary food, beverages, baked items (cookies) and confectionary are best ways to prevent and cure iron deficiency anemia in children and adults. Similarly, sugar molasses from sugar industry is one of the superabundant sources of iron which can be used as supplement for value addition. However, human research is required to check the efficacy of fortified products to prevent iron deficiency anemia in future generations.
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The immune function is closely related to iron (Fe) homeostasis and allostasis. The aim of this bioinformatics-assisted review was twofold; (i) to update the current knowledge of Fe metabolism and its relationship to the immune system, and (ii) to perform a prediction analysis of regulatory network hubs that might serve as potential biomarkers during stress-induced immunosuppression. Several literature and bioinformatics databases/repositories were utilized to review Fe metabolism and complement the molecular description of prioritized proteins. The Search Tool for the Retrieval of Interacting Genes (STRING) was used to build a protein-protein interactions network for subsequent network topology analysis. Importantly, Fe is a sensitive double-edged sword where two extremes of its nutritional status may have harmful effects on innate and adaptive immunity. We identified clearly connected important hubs that belong to two clusters: (i) presentation of peptide antigens to the immune system with the involvement of redox reactions of Fe, heme, and Fe trafficking/transport; and (ii) ubiquitination, endocytosis, and degradation processes of proteins related to Fe metabolism in immune cells (e.g., macrophages). The identified potential biomarkers were in agreement with the current experimental evidence, are included in several immunological/biomarkers databases, and/or are emerging genetic markers for different stressful conditions. Although further validation is warranted, this hybrid method (human-machine collaboration) to extract meaningful biological applications using available data in literature and bioinformatics tools should be highlighted.
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Purpose: This study examined postexercise inflammatory, hepcidin, and iron absorption responses to endurance exercise performed in the morning versus the afternoon. Methods: Sixteen endurance-trained runners (10 male, 6 female) with serum ferritin (sFer) < 50 μg·L completed a 90-min running protocol (65% vV˙O2max) in the morning (AM), or the afternoon (PM), in a crossover design. An iron-fortified fluid labeled with stable iron isotopes (Fe or Fe) was administered with a standardized meal 30 min following the exercise and control conditions during each trial, serving as a breakfast and dinner meal. Venous blood samples were collected before, immediately after, and 3 h after the exercise and control conditions to measure sFer, serum interleukin-6 (IL-6), and serum hepcidin-25. A final venous blood sample was collected 14 d after each trial to determine the erythrocyte iron incorporation, which was used to calculate iron absorption. Linear mixed-modeling was used to analyze the data. Results: Overall, exercise significantly increased the concentrations of IL-6 (4.938 pg·mL; P = 0.006), and hepcidin-25 concentrations significantly increased 3 h after exercise by 0.380 nM (P < 0.001). During the PM trial, hepcidin concentrations exhibited diurnal tendency, increasing 0.55 nM at rest (P = 0.007), before further increasing 0.68 nM (P < 0.001) from prerun to 3 h postrun. Fractional iron absorption was significantly greater at breakfast after the AM run, compared with both the rested condition (0.778%; P = 0.020) and dinner in the AM run trial (0.672%; P = 0.011). Conclusions: Although exercise resulted in increased concentrations of IL-6 and hepcidin, iron was best absorbed in the morning after exercise, indicating there may be a transient mechanism during the acute postexercise window to promote iron absorption opposing the homeostatic regulation by serum hepcidin elevations.
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Objectives: Adhering to a low carbohydrate (CHO) high fat (LCHF) diet can alter markers of iron metabolism in endurance athletes. This investigation examined the re-introduction of CHO prior to, and during exercise on the iron-regulatory response to exercise in a homogenous (in regard to serum ferritin concentration) group of athletes adapted to a LCHF diet. Design: Parallel groups design. Methods: Three weeks prior to the exercise trials, twenty-three elite race walkers adhered to either a CHO-rich (n = 14) or LCHF diet (n = 9). A standardised 19–25 km race walk was performed while athletes were still adhering to their allocated dietary intervention (Adapt). A second test was performed three days later, where all athletes were placed on a high CHO diet (CHO Restoration). Venous blood samples were collected pre-, post- and 3 h post-exercise and measured for interleukin-6 (IL-6) and hepcidin-25. Results: The post-exercise IL-6 increase was greater in LCHF (p < 0.001) during both the Adapt (LCHF: 13.1-fold increase; 95% CI: 5.6–23.0, CHO: 8.0-fold increase; 5.1–11.1) and CHO Restoration trials (LCHF: 18.5-fold increase; 10.9–28.9, CHO: 6.3-fold increase; 3.9–9.5); outcomes were not different between trials (p = 0.84). Hepcidin-25 concentrations increased 3 h post-exercise (p < 0.001), however, they did not differ between trials (p = 0.46) or diets (p = 0.84). Conclusions: The elevated IL-6 response in athletes adapted to a LCHF diet was not attenuated by an acute increase in exogenous CHO availability. Despite diet-induced differences in IL-6 response to exercise, post-exercise hepcidin levels were similar between diets and trials, indicating CHO availability has minimal influence on post-exercise iron metabolism.
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The main focus of this review is illness among elite athletes, how and why it occurs, and whether any measures can be taken to combat it or to prevent its onset. In particular, there is particular interest in exercise-induced immunodepression, which is a result of the immune system regarding exercise (e.g., prolonged, exhaustive exercise) as a challenge to its function. This promotes the inflammatory response. There is often a high incidence of illness in athletes after undertaking strenuous exercise, particularly among those competing in endurance events, not only mainly in terms of upper respiratory tract illness, but also involving gastrointestinal problems. It may well be that this high incidence is largely due to insufficient recovery time being allowed after, for example, a marathon, a triathlon, or other endurance events. Two examples of the incidence of upper respiratory tract illness in moderate versus endurance exercise are provided. In recent years, increasing numbers of research studies have investigated the origins, symptoms, and incidence of these bouts of illness and have attempted to alleviate the symptoms with supplements, sports foods, or immunonutrition. One aspect of the present review discusses iron deficiency, which has been primarily suggested to have an impact upon cell-mediated immunity. Immunonutrition is also discussed, as are new techniques for investigating links between metabolism and immune function.
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Purpose: The short-term restriction of carbohydrate (CHO) can potentially influence iron regulation via modification of post-exercise interleukin-6 (IL-6) and hepcidin levels. This study examined the impact of a chronic ketogenic low CHO-high fat (LCHF) diet on iron status and iron-regulatory markers in elite athletes. Methods: International-level race walkers (n=50) were allocated to one of three dietary interventions; i) a high CHO diet (HCHO; n=16), ii) periodized CHO availability (PCHO; n=17) or iii) a LCHF diet (n=17) while completing a periodized training program for 3 weeks. A 19-25 km race walking test protocol was completed at baseline and following adaptation, and changes in serum ferritin, IL-6 and hepcidin concentrations were measured. Results from HCHO and PCHO were combined into one group (CHO; n=33) for analysis. Results: The decrease in serum ferritin across the intervention period was substantially greater in the CHO group (37%) compared to the LCHF (23%) group (p=0.021). After dietary intervention, the post-exercise increase in IL-6 was greater in LCHF (13.6-fold increase; 95% CI 7.1-21.4), than athletes adhering to a CHO-rich diet (7.6-fold increase; 5.5-10.2; p=0.033). While no significant differences occurred between diets, confidence intervals indicate 3 h post-exercise hepcidin concentrations were lower after dietary intervention compared to baseline in CHO (β=-4.3; -6.6, -2.0), with no differences evident in LCHF. Conclusion: Athletes who adhered to a CHO-rich diet experienced favorable changes to the post-exercise IL-6 and hepcidin response, relative to the LCHF group. Lower serum ferritin after 3 weeks of additional dietary CHO might reflect a larger more adaptive hematological response to training.
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New findings: What is the topic of this review? We review methodological considerations for the inclusion of women in sex and menstrual cycle phase comparison studies. What advances does it highlight? Improving the methodological design for studies exploring sex differences, menstrual cycle phase differences and/or endogenous versus exogenous female sex hormones will help to close the gap in our understanding of the effects of endogenous and exogenous hormones on exercise science and sports medicine outcomes. Abstract: In recent years, the increase in scientific literature exploring sex differences has been beneficial to both clinicians and allied health science professionals, although female athletes are still significantly under-represented in sport and exercise science research. Women have faced exclusion throughout history though the complexities of sociocultural marginalization and biomedical disinterest in women's health. These complexities have contributed to challenges of studying women and examining sex differences. One underlying complexity to methodological design may be hormonal perturbations of the menstrual cycle. The biphasic responses of oestrogen and progesterone across the menstrual cycle significantly influence physiological responses, which contribute to exercise capacity and adaptation in women. Moreover, oral contraceptives add complexity through the introduction of varying concentrations of circulating exogenous oestrogen and progesterone, which may moderate physiological adaptations to exercise in a different manner to endogenous ovarian hormones. Thus, applied sport and exercise science research focusing on women remains limited, in part, by poor methodological design that does not define reproductive status. By highlighting specific differences between phases with regard to hormone perturbations and the systems that are affected, methodological inconsistencies can be reduced, thereby improving scientific design that will enable focused research on female athletes in sports science and evaluation of sex differences in responses to exercise. The aims of this review are to highlight the differences between endogenous and exogenous hormone profiles across a standard 28-32 day menstrual cycle, with the goal to improve methodological design for studies exploring sex differences, menstrual cycle phase differences and/or endogenous versus exogenous female sex hormones.
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The effects of testosterone and erythropoietin (ESF) on erythroid colony formation in normal human bone marrow cultures were studied in vitro using a methyl cellulose gel system. Testosterone was found to produce a significant increase in erythroid colony formation at concentrations of 10–4–10-4M in vitro. In this system, the numbers of erythroid colonies formed per plate increased in direct proportion to the increase in the number of erythroid precursors inoculated as well as to the increase in the dose of ESF in vitro. In addition, a synergistic effect of a combination of testosterone and ESF on erythroid colony formation was seen when ESF was present at high concentrations. These data suggest that a greater number of erythropoietin-responsive cells are available for ESF to differentiate into the nucleated erythroid cell line in the presence of testosterone, indicating that the effect of a combination of testosterone and ESF is greater in enhancing erythropoiesis than the additive effects of either agent alone.
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Purpose: To determine if a single versus a split equivalent daily dose of elemental iron was superior for haemoglobin mass (Hbmass) gains at altitude, while minimizing gastrointestinal (GI) discomfort. Methods: Twenty-four elite runners attended a 3.1 ± 0.3 week training camp (Flagstaff, AZ; 2106 m). A two-group design, randomized and stratified to baseline Hbmass, sex and ferritin (>30 μ/L), was implemented daily as: 1) single dose of 1 x 200 mg (PM only, SINGLE) vs; 2) split dose of 2 x 100 mg (AM & PM; SPLIT) elemental iron (ferrous fumarate). Hbmass and venipuncture assessments were completed upon arrival and departure (± 2 days) from camp for ferritin, hepcidin and erythroferrone (ERFE) concentrations. Validated food frequency (FFQ), GI-distress, menstrual blood loss (MBL) and training questionnaires were implemented throughout. Univariate analysis was used to compare Hbmass; with baseline ferritin, dietary iron intake, MBL and training volume used as covariates. Results: Both conditions increased Hbmass from baseline (p<0.05), with SINGLE (867.3 ± 47.9 g) significantly higher than SPLIT (828.9 ± 48.9 g) (p=0.048). GI-scores were worse in SINGLE for weeks 1 & 2 combined (SINGLE: 18.0 ± 6.7 points, SPLIT: 11.3 ± 6.9 points, p=0.025), however, GI-scores improved by week 3, resulting in no between group differences (p=0.335). Hepcidin significantly decreased over time (p=0.043) in SINGLE, with a non-significant decrease evident in SPLIT (~22%). ERFE significantly decreased in both groups (~28.5%; p<0.05). No between group differences existed for ERFE, hepcidin, FFQ, MBL or daily training outcomes (p>0.05). Conclusion: A single nightly 200 mg dose of elemental iron was superior to a split dose for optimizing Hbmass changes at altitude in runners over a ~3 week training camp.
Article
From the breakthrough studies of dietary carbohydrate and exercise capacity in the 1960s through to the more recent studies of cellular signaling and the adaptive response to exercise in muscle, it has become apparent that manipulations of dietary fat and carbohydrate within training phases, or in the immediate preparation for competition, can profoundly alter the availability and utilization of these major fuels and, subsequently, the performance of endurance sport (events >30 min up to ∼24 hr). A variety of terms have emerged to describe new or nuanced versions of such exercise-diet strategies (e.g., train low, train high, low-carbohydrate high-fat diet, periodized carbohydrate diet). However, the nonuniform meanings of these terms have caused confusion and miscommunication, both in the popular press and among the scientific community. Sports scientists will continue to hold different views on optimal protocols of fuel support for training and competition in different endurance events. However, to promote collaboration and shared discussions, a commonly accepted and consistent terminology will help to strengthen hypotheses and experimental/experiential data around various strategies. We propose a series of definitions and explanations as a starting point for a more unified dialogue around acute and chronic manipulations of fat and carbohydrate in the athlete's diet, noting philosophies of approaches rather than a single/definitive macronutrient prescription. We also summarize some of the key questions that need to be tackled to help produce greater insight into this exciting area of sports nutrition research and practice.