Iron supplementation for athletic populations is not a new concept (26). Investigation of the effect of iron supplementation on performance has drawn differing conclusions (37), and despite more than 20 yr of research, no consensus exists among the sporting community as to who can benefit from supplementation (41). Advocates of the importance of iron for athletic performance have suggested that “relative” anemia may exist among athletes with low iron stores, but the threshold ferritin level at which this occurs is undetermined, as is the optimal level for whole body iron metabolism (6,7). Results have often been clouded by study design and supplementation protocol (37). However, recent developments in parenteral iron preparations present an opportunity to revisit the topic by offering an effective, safe, and simple avenue for supplementation (30), which avoids potential absorption issues by bypassing the gut (29).
Recently, a double-blind placebo-controlled study of nonanemic women reported significant improvements in fatigue scores after treatment with intravenous (IV) iron (III)–hydroxide sucrose (24). More specifically, the treatment was found to be most effective in patients with baseline ferritin levels <15 μg·L−1, indicating a possible threshold for benefit. Most interestingly, however, was the observation that values of hemoglobin concentration ([Hb]) did not change, suggesting that iron-related processes that were not related to erythropoiesis were responsible for the improved fatigue levels. Indeed, early research using rat models hints at a differentiation between total hemoglobin and iron per se on exercise capacity (10), and indeed, one of the only human studies to report improved performance after iron supplementation in athletes did not find a concomitant increase in total hemoglobin (12).
Optimization of the measurement of hemoglobin mass (Hbmass) via carbon monoxide (CO) rebreathing (38,44) has also altered the way the efficacy of iron supplementation can be quantified. Using the rebreathing method, it is now possible to detect subtle but worthwhile changes in Hbmass, which traditional methods such as [Hb] may not be sensitive enough to detect. Garvican et al. (17) report quite dramatic changes in Hbmass induced by iron deficiency and subsequent supplementation. Of note is the continued rise in Hbmass in the latter stages of supplementation despite a relatively constant [Hb]. These results question the usefulness of [Hb] in the assessment of iron deficiency and efficacy of supplementation.
The combination of newly available IV iron complexes that provide greater bio-availability (28,34), coupled with a reliable, sensitive, and accurate method for measuring Hbmass (and indirectly oxygen carrying potential), presents an opportunity to revisit the effect of iron supplementation in endurance athletes. The purpose of this study was therefore to assess the efficacy of iron supplementation in athletes by comparing the effects of IV and oral supplementation on Hbmass (via CO rebreathing) and running physiology in nonanemic distance runners with low ferritin levels. If oxygen transport capacity (Hbmass) is compromised in distance runners because of serially low ferritin levels, then the greater bioavailability afforded by supplementation via the IV route may assist to “normalize” Hbmass levels and subsequently enhance V˙O2max.
Highly trained distance runners, with baseline ferritin values of ≤65 μg·L−1, were supplemented with either an oral iron supplement or IV iron injections for 6 wk. Hbmass, iron status, and markers of erythropoiesis were monitored throughout the supplementation period while indices of running physiology were assessed before and after supplementation. The study was approved by the AIS human ethics committee, and all athletes provided written informed consent before participating.
Twenty-seven highly trained distance runners (Table 1) were recruited from local distance running squads (14 men and 13 women). All athletes had been training consistently for at least 2 yr before the study and competed at state level or above.
Before inclusion in the study, full blood count and duplicate iron profile were performed on each athlete at rest. Athletes with ferritin levels ≤65 μg·L−1 and [Hb] >12 g·dL−1 were examined by a medical doctor to determine their suitability for inclusion in the study. Athletes with anemia not caused by simple iron deficiency, bronchial asthma, previously documented hypersensitivity to iron, iron overload (hemochromatosis and hemosiderosis), pregnancy, severe infection or inflammation of the kidney or liver, or low iron binding capacity were excluded from the study. In addition, any athletes who had engaged in altitude training or iron supplementation within 4 wk were excluded from participating.
Athletes were pair-matched and assigned to either an oral (ORAL) or IV supplement group. Within each treatment group, athletes were further subdivided according to iron status at baseline into either a low ferritin group (LOW: ferritin ≤35 μg·L−1 + transferrin saturation (TSAT) <20% or ferritin ≤15 μg·L−1) or a suboptimal ferritin group (SUB: ferritin >15 μg·L−1 + TSAT >20%) to assess the influence of baseline values on the efficacy of treatment. The four subgroups were therefore ORAL LOW, ORAL SUB, IV LOW, and IV SUB.
ORAL supplementation consisted of one (SUB) or two (LOW) tablets daily of Ferrogradumet (305 mg ferrous sulfate and 105 mg elemental iron; Abbott, Botany, Australia) to be taken in the morning before food. Athletes were encouraged to consume with vitamin C if possible. IV supplementation consisted of two to four injections of ferric carboxymaltose solution (Ferinject®; Vifor International, Switzerland) spaced evenly for 6 wk. The total cumulative dose of IV, which could be administered during the course of the study, was calculated as per the manufacturer’s instructions using the Ganzoni (13) formula as follows:
where the previous known “normal” [Hb] for subject = 150 g·L−1 (when ferritin > 30 μg·L−1); factor 0.24 = 0.0034 × 0.07 × 1000, where 0.0034 is the iron content of hemoglobin at 0.34%, 0.07 is the blood volume at 7% of body weight, and 1000 is the conversion factor 1 g·L−1 =1000 mg·L−1; and the depot iron for body weight 35 kg and above = 500 mg.
Each dose of Ferinject® was injected by a medical practitioner via an indwelling cannula inserted into a forearm vein and flushed with 2 mL of 0.9% saline. Athletes remained under observation for 60 min, with blood pressure, oxygen saturation, and heart rate recorded every 15 min. Athletes were not given subsequent injections until ferritin values were <160 μg·L−1 in women and <300 μg·L−1 in men. The mean number of injections given was 3 ± 1 for both IV groups. The total dose given was 550 ± 171 mg (11 ± 0.4 mL) for the IV LOW group and 375 ± 39 mg (7.5 ± 0.8 mL) for the IV SUB group, with the mean number of days between injections 17 ± 4 and 16 ± 3 for the LOW and SUB groups, respectively.
Hematological profiles of venous blood were performed at baseline and at weeks 1, 2, 4, and 6 of supplementation and 2 wk after (week 8) for determination of [Hb], percent reticulocytes (%retics), soluble transferrin receptor (sTfR), and serum erythropoietin concentration ([EPO]). Venous blood was drawn from an antecubital forearm vein by a trained phlebotomist. A total of 10 mL was drawn on each occasion, totaling 60 mL for 8 wk and equating to <10 g of Hbmass. Whole blood was analyzed using a Sysmex XT-2000i (Sysmex Corporation, Japan) within 4 h of collection. Iron profiles (serum ferritin, sTfR, iron, transferrin, and % transferrin saturation) were conducted using an Integra 400 (Roche Diagnostics, Switzerland) automated biochemistry analyzer. The remaining serum was stored at –80°C and analyzed as a single batch. [EPO] analysis was performed using an Immulite automated solid-phase, sequential chemiluminescent Immulite assay (Diagnostic Product Corporation, Los Angeles, CA).
Hbmass was measured in duplicate before supplementation and at weeks 1, 2, 4, 6, and 8 using the CO-monoxide rebreathing method of Schmidt and Prommer (44) with some modifications (2,15,38). Specifically, a CO bolus of 1.2 mL·kg−1 was rebreathed through a closed system for 2 min. The percent carboxyhemoglobin of capillary blood was measured before and 7 min after rebreathing using a CO-oximeter (OSM3; Radiometer, Copenhagen, Denmark). At least five replicates of each sample were performed where possible. The typical error calculated from duplicate baseline measures at the start of the study was 1.6% (90% confidence interval [CI] = 1.3%–2.2%).
Maximal aerobic power (V˙O2max), lactate threshold, and running economy were assessed before and after the 6-wk supplementation period (after running test performed at ~week 7). After a brief warm up, athletes performed four to five submaximal running stages of 4 min in duration, separated by 1 min of standing recovery, with speed increasing 1 km·h−1 each stage. The starting speed was selected based on each athlete’s current level of fitness such that the final stage aimed to elicit a blood lactate response of >4 mmol·L−1. On the occasion that blood lactate values were <4 mmol·L−1 after the fourth stage then a fifth stage was completed. However, the same running speeds and protocol duration were adopted in the posttest regardless of blood lactate values.
On completion of the submaximal part of the test, athletes were given 5 min to recover before commencing the maximal stage. Starting at a running speed of 4 km·h−1 less than their finishing speed in the submaximal test, athletes were instructed to run continuously until exhaustion. Speed was increased by 0.5 km·h−1 every 30 s for 4 min (until the final submaximal speed was reached), after which the treadmill gradient was increased by 0.5% every 30 s. The time to exhaustion during the incremental portion of the treadmill test was used as maximal treadmill performance time.
Expired gas was measured continuously using a custom-built automated Douglas bag system with associated in-house software (Australian Institute of Sport, Belconnen, Australia) as described previously (40). Oxygen uptake (V˙O2) values were calculated using standard algorithms for consecutive 30-s periods, with V˙O2max determined as two times the highest 30-s value recorded. Running economy was derived from steady-state V˙O2 during the last 60 s of each submaximal stage of the treadmill test, to determine V˙O2 for a given velocity. Comparisons of economy were made from pooled individual data from the four to five submaximal running speeds. Lactate threshold was determined as the speed at which 4 mmol·L−1 lactate concentration was reached via the speed-versus-lactate curve. The lactate threshold was measured as a velocity (km·h−1). Typical error established in our laboratory on a separate group of endurance trained athletes was 2.4% for submaximal V˙O2 and 2.1% for V˙O2max (40).
Heart rate was monitored continuously (Polar heart rate monitor; Polar Electro, Kempele, Finland), with the peak heart rate (HRpk) recorded. Blood lactate concentration (Lactate Pro, Akray, Japan) was measured via capillary sampling from a fingertip, during the recovery period between each submaximal stage and 1 min after completion of the maximal test.
Training and lifestyle
Athletes were asked to record all training in a training diary for the duration of the study. They were also instructed to continue their usual dietary practices, in particular with regard to the consumption of iron-rich foods.
Athletes were monitored for 1 h after each injection with heart rate, blood pressure, temperature, and breathing rate recorded every 15 min. Any adverse events were recorded by the study physician.
A contemporary approach to statistics was adopted because small changes in performance can be meaningful in athletes (21). Differences and associated 90% CI, in hematological and physiological changes between the IV and the ORAL supplemented groups, were estimated to define the practical significance of the results, as opposed to a traditional significance and hypothesis testing approach. The magnitude of difference over time as well as between groups was expressed as a standardized mean difference (Cohen effect sizes) computed as the difference in the mean divided by the between-subject SD, where a small effect is >0.2, moderate >0.6, and a large effect >1.2. The smallest worthwhile change was set to 0.2 of the between-subject SD at baseline. Effects were deemed unclear if the CI overlapped the thresholds for the smallest positive and negative effects. Clear effects >75% likely positive were considered substantial, with the following descriptors attributed accordingly: 75%–95%, likely; 95%–99%, very likely; and >99%, almost certainly (21). Data are expressed as the mean and SD unless otherwise stated. Data in graphs are presented as percent changes from baseline measures.
Twenty-eight distance runners were recruited into the study, but one athlete in the ORAL group withdrew because of work commitments, leaving data for n = 27 (IV LOW: 1 male and 6 females; ORAL LOW: 2 males and 4 females; IV SUB: 5 males and 2 females; and ORAL SUB: 6 males and 1 female). Two subjects sustained acute injuries at the end of the study period and were not able to complete the final treadmill test; thus, only their hematological data were included in the analysis.
At baseline, there were no substantial differences between the IV and the ORAL groups for Hbmass, V˙O2max, or iron status (Table 1). V˙O2max, Hbmass, and iron status were very likely lower in the LOW versus the SUB groups but were not substantially different between the treatment groups (IV LOW vs ORAL LOW and IV SUB vs ORAL SUB).
IV versus oral
Both IV and ORAL supplementation resulted in increased serum ferritin levels (Table 2). Serum ferritin levels of IV-treated athletes were almost certainly higher than ORAL from week 1 onward (change scores, 90% CI; week 1: +361%, 231%–543%; week 2: +175%, 93%–292%; week 4: +194%, 113%–305%; week 6: +174%, 94%–288%; week 8: +149%, 86%–234%). By the end of supplementation, both IV and ORAL displayed decreased levels of sTfR and increased % transferrin saturation, consistent with improved iron status (Table 2). Changes in [Hb] were likely trivial in both groups. ORAL supplementation had trivial effects on Hbmass; however, likely substantial increases in Hbmass were observed at weeks 6 and 8 in IV-treated athletes.
V˙O2max likely increased in IV only (+1.9; 0.4%–3.5%), with the difference in the change score before and after (+2.5%, −0.1% to 5.2%) likely higher than ORAL. Similarly, maximal running time increased in IV (+5.6, 1.0%–10.4%), with the relative change 3.7% (−5.0% to 13.2%) higher than ORAL. Differences in other running parameters were trivial with the exception of maximal blood lactate concentration [La] and average heart rate, which were unclear.
Efficacy of Iron treatment in subgroups
Hematological parameters at each time point are shown by subgroup in Table 3 and Figure 1. [Hb] did not substantially change in any group (Fig. 1). Hbmass substantially increased only in IV LOW (change scores, 90% CI; week 6: 4.9%, 1.1%–8.9%; week 8: 4.0%, 0.9%–7.2%) (Fig. 1). Differences in the change in Hbmass of IV LOW were likely higher than ORAL LOW (week 6: 5.2%, 0.8%–9.8%; week 8: 4.8%, 0.7%–9.0%) and IV SUB (week 6: 4.4%, 0.1%–9.0%; week 8: 4.2%, 0.4%–8.0%). V˙O2max and time to exhaustion during the treadmill running test likely increased in IV LOW only (V˙O2max: 3.3%, 0.4%–6.3%; max time: 9.3%, 0.9%–18.3%), with the change scores for V˙O2max (2.1%, 90% CI = −3.3% to 7.7%) and max time (6.0%, 90% CI = −12.8% to 28.7%) higher than ORAL LOW. There were unclear differences for measures of economy (Table 4).
After 6 wk of supplementation, 85%–100% of athletes in the IV (LOW and SUB) and ORAL SUB groups displayed ferritin levels exceeding the study inclusion criteria (i.e., ferritin >65 μg·L−1, transferrin saturation >20%). The improved iron status was maintained at 2 wk follow-up in both IV groups but decreased in ORAL SUB. Ferritin values exceeded 65 μg·L−1 in only 33% of ORAL LOW athletes. All athletes maintained an [Hb] level higher than 12 g·dL−1 for the duration of the study.
No adverse events were reported in either the ORAL or IV treatment group. Six subjects in the IV group received one less injection than planned due to ferritin levels exceeding the study cutoff limit.
The main finding of the present study was an increase in Hbmass and V˙O2max after 6 wk in nonanemic distance runners after IV iron supplementation. However, similar to the findings of Krayenbuehl et al. (24), we observed greater efficacy in the IV LOW group (ferritin <35 μg·L−1 and transferrin saturation <20%, or ferritin <15 μg·L−1) than that in the IV SUB group, indicating that supplementation is more effective when iron stores are most compromised. Six weeks of oral iron supplementation increased serum ferritin levels in both the ORAL LOW and the ORAL SUB groups but was not accompanied by an increase in Hbmass or V˙O2max.
Early studies of the performance benefits of iron supplementation in athletes drew mixed results, which may largely be attributed to varying supplementary protocols (length, dosage) and different cutoff values for iron deficiency (37). The majority of studies that did report a performance benefit were accompanied by an increase in [Hb] (25,31,42), indicating that the subjects were slightly anemic at the start of the study. We recruited subjects with apparent “normal” [Hb] (>12 g·dL−1 for females and >13 g·dL−1 for males) but ferritin values lower than 65 μg·L−1. The optimal level for ferritin stores in athletes is widely debated (7,32,50), but a target level similar to this has been suggested (35). Furthermore, in our experience, highly trained female distance runners rarely maintain values higher than 50 μg·L−1 with males rarely >100 μg·L−1. Our subgroups were created based on recommendations that “controlled iron supplementation” should be implemented in all athletes with serum ferritin <35 μg·L−1 (35). In addition, because serum ferritin alone does not always present a complete profile of iron status (8), percent transferrin saturation was also taken into account when subdividing the treatment groups.
Recently, Krayenbuehl et al. reported improved fatigue scores after iron supplementation in nonathletic populations (fatigued nonanemic women), which were not associated with changes in [Hb] (9,24), indicating the potential importance of iron metabolism for well-being independent of erythropoiesis. However, the sensitivity of [Hb] to measure subtle changes in total Hb may be questioned. A case study of an iron-deficient female distance runner demonstrates that Hbmass may still increase despite [Hb] levels remaining constant (17). Further, because [Hb] is influenced by changes in plasma volume, values obtained from athletes engaged in heavy training or competition may be artificially low (6,16,46). Anemia is typically described as [Hb] <12 g·L−1, but it has been suggested that some athletes with apparent “normal” [Hb] levels may in fact be relatively anemic “for them” (7) and the level at which ferritin stores begin to compromise total Hb is not known. If total Hb levels are indeed compromised in many endurance athletes due to iron deficiency, then restoring iron levels to an “optimal level” may also serve to increase Hbmass. The measurement of Hbmass (via CO rebreathing), as opposed to [Hb], therefore provides a more sensitive method for detecting small but meaningful changes in total body Hb (39,44).
In the present study, baseline values of Hbmass and [Hb] were not different between the LOW groups (IV LOW vs ORAL LOW). [Hb] did not change, yet substantial increases in Hbmass were observed in the IV-treated group. A possible explanation for a rise in Hbmass in the IV group only related to the time course of iron replenishment because of the differences in the bioavailability of the two treatment regimens. Assuming 10% of oral iron consumed is absorbed (43), the ORAL LOW group absorbed approximately 800 mg of iron during the 6 wk—approximately 20 mg·d−1. This is compared with doses in the IV group of 100–200 mg every few weeks of which 99% is bioavailable (3). Hence, although the total amount of bioavailable iron was similar, the bolus delivery of iron in the IV group may be more conducive for Hb formation.
Although it may be argued that 6 wk is not a sufficient timeframe for oral supplementation (20) to raise serum ferritin levels to optimal amounts, the mean ferritin of the ORAL-LOW exceeded 50 μg·L−1 after 4 wk and approached 60 μg·L−1 by the end of the study period (the target value suggested by Nielsen and Nachtigall ). Changes in Hbmass induced by accelerated erythropoiesis (as in the case of altitude training, rhEPO use ) can be observed in as little as 10 d (14,19), which indicates that a minimum threshold for iron stores must be reached before erythropoiesis is “switched on.” The flood of iron into the system via the IV route may therefore be sufficient to activate the erythropoietic system, whereas 6 wk of oral supplementation was not sufficient to reach this threshold. However, it should also be noted that an increase in [EPO] typically observed in conjunction with accelerated erythropoiesis (14) was not observed in any group.
Our observation of an enhanced Hbmass may be of importance in an athletic setting if iron deficiency is revealed within 6 wk of an important competition or training block (e.g., altitude exposure). Although oral iron supplementation may be suitable under normal circumstances when the time afforded for change is >3 months (20), IV supplementation may present a rapid source of iron which facilitates physiological improvements (i.e., increase in Hbmass) within a shorter period of weeks (28,49).
Of course, iron is also needed for a number of metabolic processes not related to Hb formation (5), and this may also help explain why an increase in Hbmass was not observed in the ORAL LOW group. When iron stores are below optimal, competition demands for iron use are placed on the functional iron compartment (47), with a “trade-off” likely at some point. In the case of our subjects, we speculate that supplementary iron was first sequestered to improve mitochondrial electron transport and muscle function as well as to replenish mitochondrial enzymes until stores were raised sufficiently to divert to Hb formation.
Nonhematological effects of iron
In the present study, subjects in the suboptimal groups (IV SUB and ORAL SUB) did not display changes in Hbmass, indicating that serum ferritin levels between 35 and 65 μg·L−1 do not compromise the erythropoietic system. Although this finding was largely predicted, we were nonetheless interested in the potentially positive nonhematological effects of iron in this group.
Within a human setting, researchers have found it difficult to distinguish the hematological effects of iron compared with those associated with cellular function. Using a rat model, Finch et al. (10) demonstrated that the running time of iron-deficient versus healthy rats was impaired despite a constant [Hb]. Furthermore, parenteral iron therapy using iron dextran resulted in exercise capacity returning to normal within 4 d—a time frame too short for erythropoiesis to manifest. Rates of oxidative phosphorylation in skeletal muscle were linked to iron deficiency, with some substrates showing improvement with iron replacement therapy. Iron deficiency has also been linked to reduced enzyme activity in mitochondrial electron transport and muscle function, again in animals (1,33), and one of the few studies to report endurance benefits in athletes after iron supplementation (200 mg·d−1 for 12 wk) without concomitant changes in Hbmass suggests changes to muscle oxidative capacity as a potential mechanism (12).
In contrast to Friedmann et al. (12), substantial changes in endurance capacity were not observed in either IV SUB or ORAL SUB. Unfortunately, our testing battery did not include a true measure of performance per se, and without invasive measures assessing muscle enzyme activity, we are not able to comment on whether the additional iron enhanced muscle function at a cellular level. Furthermore, one of the many complaints from athletes diagnosed with iron deficiency is the general feeling of lethargy, combined with a decreased motivation to train, and the feeling that they are unable to recover fully between training sessions. Again, our study design does not allow us to comment on this issue, but in light of the findings of Krayenbuehl et al. (24), future investigations in athletes should attempt to measure subjective and objective indicators of training load and fatigue.
The present study is limited by the lack of a placebo group. We instead chose to use the current practice model of oral iron supplementation as a control—a model that has been accepted in prior clinical trials (28,49). Although it is possible that IV supplementation may have been associated with an increased belief effect, the key outcome measures of Hbmass and ferritin cannot be readily altered by motivation or belief. However, of interest in future studies would be an objective measure of fatigue, training recovery, and motivation for which a placebo-controlled double-blind design as per Krayenbuehl et al. (24) is essential. From our results, it is also not possible to fully ascertain the impact of iron supplementation on performance and training.
Another limitation of the study is that the dietary intake of iron was not controlled. Instead, the athletes were instructed to continue their normal dietary practice. One study suggested that a diet high in “muscle foods” was more effective in preserving [Hb] and ferritin status in exercising women than as 50 mg·d−1 taken as an oral supplement (27). However, in their study, the diet of the iron-supplemented group were purposefully instructed not to eat foods containing greater than 2 mg of iron per serving, whereas those in the high iron diet group were asked to intentionally select those foods. In practice, distance runners will gravitate toward a low fat, high carbohydrate diet to support nutritional needs, and vast changes in dietary practices would be required to confound total iron intake during our study (4). In addition, although not measured, it is likely that hepcidin levels were upregulated in the IV group, thereby reducing dietary absorption of iron (36). Thus, differences in outcome measures seen between the IV and the ORAL groups may in fact be lessened due to a slight bias in favor of increased dietary iron intake in the orally treated group.
The menstrual cycle phase in the female subjects was not controlled, and thus the potential impact on cycle phase on indices of iron status must be acknowledged as a further limitation of the study (23). However, although iron parameters may be lower during menses, V˙O2max and Hbmass, our key outcome variables, are not substantially altered by menstrual cycle phase (11,18,22,48). We were also unable to control the training performed by athletes in the study, and hence athletes completed training sessions on a number of different surfaces at a range of intensities. The impact of surface, the number of quality sessions, and the total distance covered on the iron and Hbmass response therefore warrant further investigation.
Iron supplementation using ferric carboxymaltose via the IV route resulted in rapid increases in serum ferritin compared with oral iron supplementation. Increases in Hbmass and V˙O2max were observed in highly trained nonanemic iron-deficient runners (ferritin <35 μg·L−1 and transferrin saturation <20%, or ferritin <15 μg·L−1) after a series of IV injections for a 6-wk period. Ferric carboxymaltose may be an effective short-term treatment for athletes presenting with low ferritin levels with near major competition. Finally, Hbmass appears a more sensitive tool for monitoring iron deficiency in humans than [Hb].
The assistance of the students and staff within AIS Physiology and AIS Medicine during data collection is gratefully acknowledged. We also thank the athletes for their involvement in the study.
Funding for the present study was received from the Australian Institute of Sport Performance Research Centre and the University of Canberra External Collaborative Research Scheme Grant.
The authors declare no conflicts of interest.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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