After an initial iron profile, athletes were assigned to one of three supplementation groups. Group allocation was performed by an independent researcher, with groups balanced by initial serum ferritin [Hb] and Hbmass. Treatment groups included the following:
- (i) ORAL: oral iron, placebo IV: oral iron supplement daily (325 mg ferrous sulfate, 562 mg sodium ascorbate, in a clear locked gelatin capsule) and two to three IV bolus injections of normal saline (2–4 mL).
- (ii) IV: intravenous iron; oral placebo, two to three IV iron injections (Ferinject: 2–4 mL [100–200 mg] bolus injection, ferric carboxymaltose) and a glucose tablet daily (450 mg microcrystalline cellulose, 0.04 mg red food coloring, in a clear locked gelatin capsule).
- (iii) PLA: placebo oral; placebo IV: the placebo group received both a glucose tablet daily (450 mg microcrystalline cellulose, 0.04 mg red food coloring, in a clear locked gelatin capsule) and two to three IV bolus injections of normal saline (2–4 mL).
For IV iron delivery, ferric carboxymaltose (Ferinject; Vifor Pharma, UK) was administered as a bolus IV injection (2–4 mL, 100–200 mg). All injections were performed in a medical clinic under the supervision of a sports physician. Facilities for cardiopulmonary resuscitation were available at all times during administration, and subjects remained under medical supervision for 30 min after administration. No adverse reactions to the injection were observed. Subjects were blinded to the treatment provided; thus, all subjects received both an injection (Ferinject or saline) and an oral supplement (ferrous sulfate or placebo). A shroud was placed over the arm to be injected to prevent participants from observing the injection. Only medical personnel responsible for the injections were privy to group allocations during the study. The principal investigator who was responsible for Hbmass measures, V˙O2peak testing and blood collection, was blinded to group allocations until the completion of the data collection period.
Supplementation commenced 2 wk before altitude exposure (after an initial blood iron profile assessment) and continued throughout the 3 wk of altitude exposure. Injections were performed on up to three occasions: (i) 2 wk before altitude exposure, (ii) immediately before altitude exposure, and (iii) on day 10 of altitude exposure. All injections were performed after blood collection and Hbmass testing had been completed (B1 [day −14] and B2 [day −1]). Ferric carboxymaltose was only administered to athletes with serum ferritin <160 μg·L−1 for women and <250 μg·L−1 for men. If serum ferritin exceeded these limits on the day of injection, a saline injection was administered. Replacement saline injections were required on two occasions in two different athletes.
Hbmass and venous blood sampling
The time course and magnitude of the erythropoietic in response to altitude exposure and iron supplementation was assessed via measurement of total Hbmass using the 2-min carbon monoxide (CO) rebreathing method (16). Briefly, a CO bolus (1.2 mL·kg−1 body mass) was rebreathed with 3 L 100% oxygen through a glass spirometer for 2 min. Carboxyhemoglobin (HbCO) concentration of capillary blood was measured in quintuplet before and at minute 7 using an OSM 3 hemoximeter (Radiometer, Copenhagen, Denmark). Hbmass was calculated from the mean change in HbCO as described previously (16). The typical error of measurement expressed as a CV from duplicate baseline measures was 1.5% (90% confidence interval [CI] = 1.2%–1.9%). Hbmass was assessed at the following time points (Fig. 1): baseline (day −14, B1), immediately before altitude exposure (day −1, B2), weekly during altitude exposure (days 8 [A8] and 15 [A15]), and immediately, 1, 3, and 6 wk after the completion of altitude exposure (days 22 [P1], 28 [P7], 42 [P21], and 63 [P42]).
Venous blood was sampled after each Hbmass measurement, with an additional time point on the third day of altitude (A3) exposure (Fig. 1). Specifically, participants were rested, with no prior exercise for at least 2 h, and seated for at least 10 min before three vacutainers (3 mL K2EDTA whole blood, two 8.5 mL serum separator) were obtained by an experienced phlebotomist from an antecubital forearm vein. Five participants reported previous dizziness and fainting with blood drawn in a seated position; thus, all blood draws for these participants were performed in a supine position. A full blood count with reticulocytes was performed on whole blood immediately using a Sysmex XT-2000i automated hematology analyzer (Sysmex Corporation, Kobe, Japan). Iron profiles (ferritin, transferrin, iron, and tranferrin saturation) were performed after centrifugation of the serum separator tubes, on a COBAS Integra 400 (Roche Diagnostics, Switzerland). The instruments used for analysis underwent regular internal and external quality control procedures as required by the Royal College of Pathologists of Australasia Quality Assurance Program with both machines meeting or exceeding the required standards. Remaining serum was aliquoted and stored at −80° for subsequent batch analysis of hepcidin and erythroferrone (ERFE). Hepcidin was measured by competitive enzyme-linked immunosorbent assay (17) (Intrinsic Life Sciences, La Jolla, CA). ERFE was measured using a recently validated rabbit monoclonal antibody-based sandwich immunoassay (18). The lower limit of detection was 1.5 ng·mL−1.
Aerobic power (V˙O2peak)
Peak aerobic power (V˙O2peak) was assessed during the week pre- and the week postaltitude exposure (Fig. 1), using an incremental test to exhaustion performed on either a custom-built, motorized treadmill (Australian Institute of Sport, Canberra, Australia) (5) or stationary bike (Lode Excalibur sport, Netherlands), depending on the athlete’s preference. The running and cycling protocols used have been described previously (5,19). The typical error for V˙O2peak in our laboratory is 2% (20).
All data were analyzed using linear mixed models and the nlme package of the R statistical programming language, with time (days of altitude exposure) entered as a fixed effect and subject ID entered as a random effect. The difference in Hbmass, iron parameters (serum iron, ferritin, transferrin, and transferrin saturation) and iron regulatory hormones (hepcidin and ERFE) from baseline for each experimental group (PLA, ORAL and IV) was conducted in three parts: baseline (−14 to −1, B1 to B2), during altitude exposure (days 0–21, B2 to P1), and after altitude exposure (days 28–42, P7 to P42). Because two baseline measurements were taken for each participant and iron supplementation was administered between the first and second measurement, the second baseline measurement (B2) was used as the value for comparison during and after altitude exposure. All iron parameters were log-transformed before analysis to stabilize the variance. Data were back-transformed to allow differences to be expressed as percentages. Where appropriate, linear or nonlinear mixed models were fitted with heterogeneous variances for supplement groups. Temporal autocorrelation was addressed by fitting an exponential covariance structure.
Hbmass is known to increase rapidly from baseline values during the first week of altitude exposure and then approach a plateau after many weeks of altitude exposure (7). Therefore, the change in log Hbmass from baseline values was modeled separately in each supplement group using a nonlinear exponential growth model with a plateau (equation 1):
In this equation, α is the intercept term, k is a constant term, d refers to the number of days of altitude exposure, and β refers to the regression coefficient. Furthermore, an exponential decay model was fit to estimate the decrease in Hbmass after altitude exposure (equation 2):
In addition, the relationships between serum ferritin, hepcidin, and ERFE at B1 were examined via linear and polynomial regression. Because athletes had not yet received iron supplementation or undertaken altitude exposure at B1, data from all experimental groups were pooled for analysis. Thereafter, linear, quadratic, and cubic regression models were fit to these data and compared using the corrected Akaike information criteria, where the model with the lowest corrected Akaike information criteria was considered parsimonious. Linear regression models were validated using fivefold cross validation in the DAAG package. In all models, two-tailed statistical significance was accepted as a type I alpha level of 0.10. The imprecision of model parameter estimates was estimated using 90% CI.
The change in peak aerobic power for each supplement group after the altitude block was assessed using a paired two-tailed t-test. Further, the relationship between the change in Hbmass (B1 vs P1) and the change in V˙O2peak (pre- or postaltitude) across all groups was examined by linear regression (Graphpad Prism, version 7.01), as was the relationship between baseline serum ferritin (B1) and change in Hbmass after altitude exposure (P1).
A detailed description of changes in [Hb] and reticulocytes of each supplement group over the course of the study can be found in our companion article (21). Of note here is the absence of a reticulocyte response in PLA during the altitude phase.
In all groups, Hbmass was similar between B1 and B2 (IV: 780 ± 194 vs 783 ± 192 g; ORAL: 764 ± 209 vs 772 ± 221 g; PLA 902 ± 243 vs 915 ± 257 g), such that 2 wk of iron supplementation did not result in a measureable Hbmass change (χ22 = 0.81, P = 0.67).
A significant, three-way time–supplement group–sex effect (χ22 = 8.93, P = 0.01) was present for serum ferritin; therefore, the difference in serum ferritin levels between B1 and B2 for males and females was examined via separate models. In females, the change in ferritin from B1 to B2 was (mean % [90% CI]) 728% [256–1826] and 401% [47–1616] higher in IV compared with PLA and ORAL, respectively. In comparison, the change in serum ferritin levels from B1 to B2 was 92% [29–184] and 47% [5–104] in IV compared with PLA and ORAL in males. No significant interaction effect existed between B1 and B2 for transferrin, transferrin saturation, iron, hepcidin, or ERFE (all P > 0.10).
At B1, a moderate, positive linear relationship existed between serum ferritin levels and hepcidin levels (F1, 30 = 17.7, r = 0.61, 90% CI = 0.38–0.77, adjusted R2 = 0.35) (Fig. 2A). A subsequent fivefold cross validation demonstrated a mean squared error for the linear model of 0.18%. Furthermore, a significant cubic relationship existed between ERFE and serum ferritin levels at B1 (F3, 28 = 3.47, P = 0.03, adjusted R2 = 0.19) (Fig. 2B). A quadratic model best estimated the relationship between ERFE and hepcidin compared with a linear and cubic model, respectively; however, the quadratic model did not reach statistical significance (F2, 29 = 1.7, P = 0.20, adjusted R2 = 0.04).
Hbmass significantly increased in IV and ORAL after 21 d of altitude exposure. Compared with B2, Hbmass was 3.2% [2.2–4.2]) and 3.7% [2.8–4.7]) higher at P1 in ORAL and IV, respectively (Fig. 3). By comparison, Hbmass at P1 was not significantly higher than B2 in PLA (0.1% [−1.4 to 1.7]).
Serum ferritin was 32% [6–51] and 34% [2–56] higher than B2 in IV compared with PLA at A8 and A15 of altitude exposure, respectively (Fig. 4A). Further, the change in serum ferritin relative to B2 was higher in ORAL compared with PLA at both A8 (28% [2–47]) and A15 (30% [−2 to 52]). The change in serum iron levels from B2 was 12% [2–24], 26% [4–53], and 41% [5–89] greater in PLA compared with IV at A8, A15, and P1, respectively (Fig. 4B). The change in transferrin saturation from B2 was 12% [1–23], 24% [3–51], and 39% [4–86] higher in PLA compared with IV at A8, A15, and P1, respectively (Fig. 4D). No significant differences existed between the change in transferrin saturation from B2 in IV and ORAL at any time point during altitude exposure (all P > 0.10, Fig. 4D). No interaction effect was present for transferrin, hepcidin, or ERFE (Fig. 4C, 4E, and 4 F).
Hbmass remained 2.9% [1.5–4.3] and 1.2% [−0.2 to 2.6] above B2 at P7 and P21 after altitude exposure in ORAL (Fig. 3). In comparison, Hbmass remained 3.6% [2.1–5.1] and 3.0% [1.5–4.6] higher than B2 at P7 and P21 days after altitude exposure in IV but was not significantly different from B2 at P42. In addition, Hbmass was not significantly different from B2 at any time point after altitude exposure in PLA.
A significant quadratic time–supplement group effect was present for the difference in serum ferritin relative to B2 after altitude exposure (χ26 = 20.33, P < 0.01). In IV, serum ferritin was 37.0% [21.8–49.2] lower than B2 at P42 but was not significantly different from B2 at any other time point after altitude exposure (Fig. 4A). In addition, serum ferritin in ORAL and PLA was not significantly different from B2 at any time point (P > 0.10). The decrease in serum ferritin relative to B2 was 65% [17–134] and 45% [1–108] larger in IV and ORAL compared with PLA at P42, respectively. Transferrin levels were significantly lower than B2 at all time points after altitude exposure (P = 0.06), decreasing to 6.6% [1–12] below B2 at P42. In comparison, transferrin levels were not different from B2 at any time point in PLA and ORAL (all P > 0.10) (Fig. 4C). No significant interaction effect was present for serum iron, transferrin saturation, hepcidin, or ERFE after altitude exposure (all P > 0.10) (Fig. 4D, 4E, and 4 F).
Four female athletes (two IV, two ORAL) had serum ferritin values <20 μg·L−1 at B1. The relationship between serum ferritin at B1 and change in Hbmass after altitude exposure was not statistically significant (F1, 32 = 1.1, R2 = 0.03, P = 0.31).
Two subjects (one PLA, one ORAL) were unable to complete the posttest within the required time frame due to technical and personal constraints. Thus, complete data were collected for 32 subjects and presented for analysis. Mean V˙O2peak increased in IV after the altitude phase (61.4 ± 10.1 vs 63.6 ± 10.0 mL·kg−1·min−1, P = 0.004) but not in ORAL (60.6 ± 6.2 vs 61.0 ± 5.2 mL·kg−1·min−1, P = 0.53) or PLA (62.7 ± 9.8 vs 63.1 ± 10.6 mL·kg−1·min−1, P = 0.54).
There was a significant positive relationship between the percent change in Hbmass and the percent change in V˙O2peak for the three groups combined (F1, 30 = 7.2, r = 0.44, R2 = 0.19, P = 0.01), with a slope (90% CI) of 0.44 (0.10–0.78) when the intercept was free to vary and a slope of 0.31 (0.06–0.55) when the intercept was constrained through the origin (Fig. 5).
The main finding of the present study was the absence of an increase in Hbmass in the non–iron-supplemented “placebo” group in response to 3 wk (~880 km·h−1) of simulated hypoxic exposure. By comparison, the type and the route of iron supplementation administered did not appear to influence the magnitude of the erythropoietic response, although the elevated Hbmass persisted longer in the IV-supplemented group during the postaltitude phase.
Hbmass was not altered by iron supplementation in the 2-wk baseline phase. Large increases in ferritin were observed in the IV group consequent to the iron injection, confirming previous observations that IV iron is a fast and effective method of raising iron stores (5). However, in the absence of iron deficiency anemia or an external erythropoietic stimulus, supplementation of iron-replete individuals is unlikely to induce changes in Hbmass (5,22).
Although significant changes in hepcidin or ERFE were not observed during the baseline phase, their relationships with ferritin at the start of the study are of interest. Hepcidin production is predominantly determined by whole body iron stores, erythropoietic activity, and inflammation (23). For example, when body iron stores are high, hepcidin regulates iron metabolism by internalizing and degrading ferroportin (24). Conversely, low iron stores (17) and hypoxia serve to suppress hepcidin (25) to maximize iron absorption from the gut and iron recycling from splenic macrophages. Thus, the linear relationship observed in the present study between ferritin and hepcidin is consistent with previous observations (18), confirming that hepcidin is suppressed in athletes with low serum ferritin levels (17) but is positively regulated by high iron stores (26).
ERFE is a recently discovered regulatory hormone within the iron metabolism pathway (27), which has been shown to mediate hepcidin suppression during stress-related erythropoiesis (i.e., after hemorrhage) (27). ERFE is produced by erythroblasts in a dose-dependent response to erythropoietin (28). ERFE, in turn, acts on the liver to downregulate hepcidin production (29). Ganz et al. (18) reported a twofold increase in ERFE in male blood donors, 2.5 d after blood donation, which peaked after 9 d. Hepcidin was suppressed during this period and inversely correlated to ERFE. Here, the cubic model of ERFE and ferritin infers a high ERFE when ferritin is low, consistent with concomitantly suppressed hepcidin.
Contrary to our hypothesis, and despite having significantly greater ferritin stores upon commencing altitude exposure, the IV group did not exhibit a greater Hbmass response, nor an apparently altered time course of erythropoiesis, compared with the ORAL-supplemented group. Indeed the magnitude of the Hbmass increase observed in both iron-supplemented groups was in line with that expected, according to the hypoxic dose administered (7,30). Rather, the more striking finding was the lack of Hbmass response in the placebo group, given an equivalent hypoxic dose and with iron stores being similar to the ORAL group throughout the study.
The stable iron stores of the ORAL group, despite supplementation, coupled with the increase in Hbmass implies the supplemented iron was used for erythropoiesis, allowing iron stores to remain stable. By comparison, the somewhat delayed rise in transferrin and iron throughout altitude exposure in the placebo group suggests that the ferrokinetics (although upregulated) may have been insufficient to support an accelerated erythropoiesis, with EPO levels likely at or below baseline levels (31) by the time sufficient iron had been mobilized. Further evidence of a blunted erythropoietic response in the placebo group is provided by the absence of an increase in reticulocytes during the altitude phase (21). Together, these results suggest that iron bioavailability plays a key role in the altitude induced erythropoietic pathway.
However, our findings are in contrast to Ryan et al. (32), who observed a 5.5% increase in Hbmass in nonsupplemented females after 16 d of exposure to 5260 m, a much higher hypoxic dose than administered here, with ferritin levels dropping by ~65% in the same period. No significant correlation between ferritin levels upon initial exposure to altitude and the percent change in absolute Hbmass after exposure was observed (in accordance with our present findings), and even those subjects with the lowest ferritin values were able to increase Hbmass. Of note, however, was that subjects with ferritin values <20 μg·L−1 at baseline were supplemented orally for 3 wk before exposure, with perhaps this prior availability of iron sufficient to support an accelerated erythropoiesis.
Alternatively, it could be postulated that the lack of an Hbmass response in the placebo group was due to a slightly higher Hbmass in this group before altitude exposure, and thus these athletes may have less scope for erythropoietic adaptation. However, our group (7) and others (33) have observed positive Hbmass responses to altitude training in athletes with similar or higher baseline values. Similarly, other inhibitors to erythropoietic adaptation, such as hypoxic dose (7), low energy availability (8), illness (9), and injury (10), are unlikely to explain the difference because athletes across all three groups lived and trained together, with no noteworthy injuries or illnesses occurring. Further, the large variation in our results (as indicated by the large SD of each group) highlights the individual response to altitude reported previously (20,31).
In hypoxia, a cyclical relationship of iron regulation exists whereby iron levels control EPO, which regulates ERFE expression, which controls hepcidin synthesis, which controls ferroportin, ultimately controlling iron levels (28). Such a response is homeostatic in nature, to allow greater iron availability in response to the accelerated erythropoietic drive. Although significant differences in ERFE and hepcidin were not observed in the present study (see Limitations section), the time course of ERFE was reminiscent of the well-documented spike of EPO within 48 h of exposure (31), whereas hepcidin showed a tendency to decrease, particularly in the placebo group. We recently reported that two nights of simulated LHTL altitude exposure decreased resting hepcidin levels by ~70% in well-trained distance runners, with the hormone remaining suppressed (59%–63% of baseline levels) after 14 d of stimulus (13). Clearly, more investigation into the interactions of these iron regulatory hormones during altitude training in athletes is required.
Surprisingly, despite a similar Hbmass response in both the IV and the ORAL groups, V˙O2peak was significantly increased only in the IV-supplemented group. It is possible that the greater iron availability afforded by IV supplementation contributed to this increase of V˙O2peak independent of Hbmass, perhaps via iron-dependent protein synthesis involved in energy production (34). However, previous studies have not detected an improvement in 3000-m run-time after IV supplementation (22), nor an increase in V˙O2max after a single injection (35). Overall, our results confirm the relationship between changes in Hbmass and changes in V˙O2max after altitude exposure described previously (36). However, several athletes across all three groups experienced a decrease in V˙O2peak after the altitude phase, often despite an increase in Hbmass. Because V˙O2peak was only measured once, within a week postaltitude, it is possible that some athletes were unable to use the additional Hbmass due to residual fatigue from the altitude block. Thus, our results possibly reflect individual variation in the optimal time for peak performance after altitude training (37).
The rate of decay of altitude-induced increases in Hbmass is not completely understood. Evidence of neocytolysis (38) after LHTL and LHTH has been reported in athletes upon return to sea level, mostly after relatively short duration exposures (2–4 wk) (31,39), whereas Robertson et al. (20) reported that a 6-wk washout period between altitude exposures was sufficient for Hbmass to return to baseline levels after an identical simulated LHTL protocol. In the present study, the elevated Hbmass levels of the IV group persisted slightly longer than the ORAL group, returning to prealtitude levels by 6 wk postexposure, compared with 3 wk postexposure in the ORAL group. V˙O2peak was not measured at this time; thus, the potential benefits pertaining to the longer persistence of Hbmass postaltitude cannot be determined. Ferritin levels remained stable or slightly decreased during the postexposure period and thus do not point toward neocytolysis (31). Recent modeling by Gore et al. (30) indicates a ~3% increase in Hbmass for up to 20 d postsimulated LHTL exposure; however, 61% of the data set used in the meta-analysis was collected within the first 7 d postaltitude. Thus, in the absence of weekly Hbmass assessments collected during the postaltitude phase, it is not possible to ascertain the exact time course of the Hbmass decay.
It must also be acknowledged that iron supplementation ceased in both supplemented groups upon cessation of the altitude exposure (the last IV injection was administered midway through the exposure). In the case of any subjects with a degree of iron deficiency at the start of the study (four subjects had serum ferritin <20 μg·L−1 at the start of the study), the supplementary iron may have stimulated erythropoiesis before altitude exposure. Therefore, in the absence of additional iron, the erythropoietic stimulus may be downregulated in addition to the removal of the hypoxic stimulus. Indeed, the effect of prior altitude exposure and iron supplementation on iron regulatory hormones requires further investigation, particularly in athletes at risk of developing iron deficiency.
ERFE has been suggested as a potential biomarker for athletic adaptation. Although the present study is one of only a few to report data in athletic settings, there remains a clear need for further investigation. The large variance observed in ERFE and hepcidin throughout the present study likely contributed to the lack of any significant differences in these parameters. Furthermore, the degree of erythropoietic stimulus arising from the hypoxic dose administered is much smaller than that associated with pathological conditions in which the assays were developed (blood loss, thalassemia, etc. [17,18]); thus, the magnitude of any perturbations remained within the “normal range.” In this context, serum EPO measurement may also have been beneficial. Nonetheless, the LHTL protocol used in the present study is a popular training protocol among athletes and remains practically relevant In addition, whereas the Hbmass response evoked by hypobaric hypoxia is expected to be similar to a matched dose of normobaric hypoxia (40). Future research should investigate the responses of ERFE and hepcidin during both simulated and natural altitude training camps.
Although modern IV iron preparations are certainly attractive in a variety of clinical fields (4), their use with iron-replete athletic populations engaged in altitude training should not be widely advocated. If the logistics and risks associated with IV supplementation are compared with traditional oral supplementation practices (e.g., medical staff required for administration, prescription only medication, and potential side effects), then the cost–benefit ratio points toward oral supplementation as a more viable option in an altitude context, particularly in light of the present findings, which do not suggest a greater erythropoietic response in iron-replete athletes. Further, from an ethical standpoint, it is important to consider the appropriateness of IV supplementation, particularly in sports which have adopted a “no needle” policy.
Iron supplementation appears necessary for optimal erythropoietic adaptation to altitude exposure, even when prealtitude stores are within normal range. As such, supplementation 2 wk before the commencement of, and throughout altitude exposure, is recommended, particularly in athletes with low ferritin stores. Of note, IV iron supplementation offers no additional benefit in terms of the magnitude of the erythropoietic response to 3 wk of simulated LHTL altitude training compared with standard oral iron supplementation practices. However, the time course of Hbmass decay in the postaltitude phase after different forms of iron supplementation warrants further investigation.
The authors wish to acknowledge the technical assistance of Ms. Leslee Zaja, Ms. Alice Wallett, Ms. Ruth Fazakerley, Ms. Helen Browning, Ms. Robynn Broadbent, Ms. Nicole Townsend, Ms. Lauren Kajewski, and Mr. Jamie Plowman during the data collection phase of this study.
The authors declare no conflicts of interest. Funding for this study was received from a Partnership for Clean Competition Research Grant (cleancompetition.org). The results of the present study do not constitute endorsement by the American College of Sports Medicine. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.
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Keywords:© 2018 American College of Sports Medicine
FERRIC CARBOXYMALTOSE; ERYTHROFERRONE; HEPCIDIN; HEMOGLOBIN MASS; ALTITUDE TRAINING