1. Iron Status & Fatigue in the Endurance Athlete
Andy asked me to talk about my approach to fatigue C
and to discuss the role of iron status in the process.
Should I get a serum ferritin?

2. Example Case RJ Dimeff. Clin J Sports Med 2000
I don’t see a lot of these athletes anymore, so we will use a case from Bob Dimeff. P
Briefly, a woman runner wasn’t doing well, was normal except for a low ferritin
He gave her iron, she got better, a similar sequence happened later.
He recommended screening for ferritin and treating the athlete if it’s low.
RJ Dimeff. Clin J Sports Med 2000
Female college middle-distance runner
CC: Fatigue, abdominal cramping
History, exam, labs unremarkable...
Low Ferritin with a “normal” Hb/Hct
Rx: Ferrous sulfate, iron-rich foods
Slowly gets better
Same song, second verse the following year

3. Rowland, et al. (1989) This study was very poorly done...
The notion of iron deficiency as a cause of fatigue got started about 20 years back.
Tom Rowland did a study using inadequate exercise tests and a heterogeneous population.
They concluded that iron deficiency was contributory, but the study was badly flawed. C
This study was very poorly done...
but was a catalyst for the concept of using Fe++
supplements in endurance athletes
Convenience sample of girl H.S. runners
Pre-season & post-season
Traditional max tests (ramp protocol)
Time to volitional exhaustion
No control of training programs

4. Fatigue Work-Up History (>90% in athletes) Exam (<5%)
I won’t discuss the work-up of fatigue.
In passing, I’ll comment that in an athlete with overtraining, the clue will be in the history.
Take a good history on the last 3 (to 6) months.
On exam, look for illnesses that make people tired.
History (>90% in athletes)
Exercise/Rest Provocative or Palliative?
Anxiety & Depression
Meds/Substance Abuse
Exam (<5%)
Infection/Inflammatory/Metabolic
Cardiopulmonary/Neuromuscular
Malignancy (PM/DM)

5. James Beard did a nice review of iron metabolism in 2001.
What is the feeling of fatigue as a symptom of iron deficiency?
Quite a range of things, some of which sound a little like overtraining syndrome.
JL Beard. J. Nutr. 131: 568S–580S, 2001.

6. Fatigue Work-Up Labs (5-10%) CBC UA Complete Metabolic Profile TSH
Get the usual screening labs.
I would be hard pressed do an ECG/CXR/OGTT in an athlete complaining of fatigue and no other symptoms.
Do an inflammatory screen, however.
When all are normal (99% of the time), you’ll be left wondering...
Labs (5-10%)
CBC UA
Complete Metabolic Profile
TSH
Consider ECG / CXR / OGTT
Rheum screen
ESR, CK, Rheumatoid Factor, ANA

7. Overtraining...or maybe Iron?
...about overtraining and iron.
Definition of fatigue vs endurance
Quantifying fatigue in the physiology lab
Studies of iron supplementation & fatigue
Iron metabolism
Fear & loathing (hemochromatosis)
A (not so) final analysis

8. What is Fatigue?
Before we take a look at iron, what is fatigue?
Fatigue is a vague trait, the inverse of endurance.
Exercise physiologists study it through in vivo or in vitro preparations.
A variety of factors influence fatigue.
Christensen, E.H Muscular work and fatigue, in Muscle as a Tissue, eds. K.Rodahl, S.M.Horvath, New York, McGraw-Hill.
Physical fatigue: a state of disturbed homeostasis attributable to work and to work environment.

9. What is Endurance?
What is endurance?
Exercise physiologists have not defined endurance very well.
Here is a suggestion.
Åstrand, P.-O., Rodahl, K., Dahl, H.A., Strømme, S.B Textbook of Work Physiology, 4th edition. Champaign, IL.
No definition of endurance
Physical endurance - GEM definition:
A state of prolonged homeostasis despite elevated levels of external physical work; resistance to physical fatigue.

10. A diagram of mass transport in energy metabolism.
Homeostasis (endurance) requires mass transport steady-state.

11. A diagram of O2 transport as measured by exercise spirometry.
Metabolic homeostasis is maintained to the left of the dotted line, and not maintained to the right.
The point described by the dotted line can thus be conceived as the maximal steady-state, or the highest level of external work that can be sustained for a prolonged period of time.

12. What is Fatigue? Characterization of exertional fatigue:
Before we take a look at iron, what is fatigue?
Fatigue is a vague trait, the inverse of endurance.
Exercise physiologists study it through in vivo or in vitro preparations.
A variety of factors influence fatigue.
The final common pathway is smooth endoplasmic reticulum calcium channels.
Covering that would take an hour so you’ll just have to believe me.
Characterization of exertional fatigue:
Muscle fatigue = 1/endurance
In situ / In vitro preparations
Multiple parameters needed to quantify
Highly sensitive to independent parameters
N.B.: SERCA the likely final common pathway

13. A diagram of a modified Van-Slyke preparation.
This prep allows examination of the roles of passive and active tension / type of electrical stimulation / O2 delivery regulated by pump perfusion / sympathetic stimulation via carotid baroreceptors.

14. Muscles have an optimal length, called Lo, at which they generate maximal force.
Lo is found using twitches (instantaneous pulses of current).
Passive tension has to be precisely adjusted; if the muscle is at <Lo, it will not generate good force and will not fatigue. Note the force output is ~100 g/g of muscle.

15. Tetanic contraction are where the spikes come so frequently that the tensions “fuse” into a smooth waveform. This happens at about 30 Hz; studies that use tetanic contractions typically use 50 Hz twitches, in order to be well into tetany.
The top contraction was at the time, per Bill Ameredes, the highest force ever generated in a Van-Slyke prep. Few labs do this prep anymore, so it likely remains the World Indoor Record.

16. This graph shows the strain gauge output, illustrating the classic parameters of muscle fatigue.
Contractility
Lusitropy
1/2 Rt
Fast component of fatigue
Slow component of fatigue

17. In this slide, focus on the FAP, Force, and Qactive tracings
In this slide, focus on the FAP, Force, and Qactive tracings. This a 12 minute study.
Initial FAP was 75 mm Hg, the increase at 3 min is to 150 mm Hg. Note the increase in blood flow (i.e., O2 delivery) and resulting cessation of fatigue and even some recovery.

18. What is Fatigue? Loss of muscle contractility & lusitropy
These, then, are major determinants of fatigue in skeletal muscle.
Loss of muscle contractility & lusitropy
Highly sensitive to independent parameters:
Tpass
Stimulation frequency (twitch vs tetanic)
O2 supply (ml O2 / min, not just Hb/Hct)
Other (e.g., sympathetic stimulation, pressors)

19. This is a muscle biopsy from my leg, back when I was a sub-2:20 marathoner.
The blue stain shows muscle fibers, the black ulex-B stain binds to capillary endothelium.
Note the high capillary to fiber ratio.

20. Dr Richard Taylor’s major contribution to exercise science: symmorphosis.
Symmorphosis is a close linkage in the matching of components in the O2 transport pathway. This represents some regulating process that matches tissue types - capillaries to mitochondria.
Taylor showed that this linear relationship exist throughout the O2 transport chain.

21. Gayeski, Connett, and Honig, at the University of Rochester, used a freeze-clamp technique to show that the impedance to transfer of oxygen is in the “carrier free region”. Mitochondrial machinery generates an immense gradient; the PO2 in the mitochondria is in the P50 region of myoglobin and the cytochromes (<1 torr). The P50 of hemoglobin is about 30 torr.
Mitochondrial oxidative capacity is in great excess over the flux capability of the capillaries. The rate limiting step in oxygen uptake is at the capillary-myofiber interface.

22. The putative rationale for measuring ferritin and iron is that the iron-dependent mitochondrial machinery might be “too weak” to generate this capillary-myofiber pO2 gradient.
Unfortunately, there remain no easy ways to reduce enzymatic activity in isolation of hemoglobin. It seems likely, however, that these deficiencies remain ~ 2-fold in excess of capillary O2 transport capacity. Five-fold excess enzymatic capacity down to 30% of initial value, is STILL 1.5 FOLD OF CAPACITY.
JL Beard. J. Nutr. 131: 568S–580S, 2001.

23. Beard’s reviewed iron metabolism in 2001, noting the metabolic enzyme/Hb/VO2 relationship.
The only ways to change Hb in isolation are phlebotomy and transfusion.
JL Beard. J. Nutr. 131: 568S–580S, 2001.

24. This figure is from a review I did with Trish Painter, on O2 transport in dialysis patients.
For normals, note the highly linear increase in VO2max as one increases or decreases hemoglobin through transfusion or phlebotomy.
Key point: one must very carefully control for changes in arterial O2 content in a longitudinal study of iron supplementation.

25. Again, Fatigue is... Loss of contractility and lusitropy
In sum, muscle physiologist’s view fatigue as a loss of the ability to pull and the ability to let go.
These losses are highly sensitive to O2 supply.
Calcium handling is the final common pathway (data not presented); other cytosolic and mitochondrial iron-dependent activities are not rate-limiting.
By deduction, a serum ferritin has no direct connection to fatigue as a symptom of overtraining.
Loss of contractility and lusitropy
Highly sensitive to O2 supply
TCA cycle and Ox Phos pathways are not rate-limiting in the O2 transport chain and are in excess capacity,
It is unlikely that skeletal muscle iron-dependent compounds are related to fatigability during exercise
therefore...

26. OK...What About Humans?
In the human exercise lab, it’s much more difficult to measure fatigue or endurance. There is no gold standard.
Basic approaches:
Aerobic tests to some standard measure of volitional exhaustion.
Isometric/isokinetic tests measuring loss of contractility.
No good technique to measure relaxation in humans - the main characteristic in muscle fatigue.
In the cardiology lab, the echocardiographer with tissue doppler can measure diastolic dysfunction; as an aside, we did this in our CHF dogs and those data were highly correlated with our gastrocnemius data (corroborating other literature suggesting that fatigue in cardiac and skeletal muscles are medicated by calcium channels).
One problem with contractile failure in the human lab is the volitional component; this can be alleviated with use of facilitated contractions (i.e., an electrically stimulated assist).
Problem: no good objective measure of “muscle failure”
Volitional exhaustion
Relative intensity a critical factor
Max steady-state (i.e., Vt, [La]4 mM, etc.)
Poor control of non-oxidative energy contribution
Failure of contractility
Rhythmic isometric/isokinetic contractions
Low %MVC, low duty cycle
1 contraction / 5 sec, electrical stimulation, etc.

27. Fatigue in Humans? Longitudinal studies are very problematic
Longitudinal studies looking at fatigue as an outcome measure are very difficult, because so many factors influence fatigue.
One must make extensive effort at regulating O2 supply, since this is the dominant variable.
Also, if there is any training effect, i.e., the muscle getting stronger, then one really must accommodate for that change.
Most investigators use the pre-intervention intensity and aim for showing a prolongation of function; one could (and I think should) match relative intensity, but few do this. Almost nobody (notably the Rowland paper) controls for changes in total non-oxidative capacity.
A major problem in the low ferritin / iron supplementation literature is that most investigators have done two interventions that would change fatigability. As exercise research goes, I find the literature we’re about to review as awful - not worthy of print.
Longitudinal studies are very problematic
Constant O2 supply?
Increase in Hb increases O2 delivery
Constant fitness?
Constant absolute vs relative intensity?
Constant non-oxidative contribution?
Existing studies do two interventions
Training
Iron supplementation

28. Haas, et al. Examine effect of Fe++ supplements on running economy
The more recent literature has been from a nutrition science group, led by Dr. Jere Haas.
The Haas group, to their credit, is getting better and better. I suspect critiques of their manuscripts has led them to get better physiology advice. We will look at four papers from this group (one is from a protégé), which are actually the main citations in much of the clinical sports medicine literature. Note that they started off measuring economy, graduated to an aerobic measure of fatigue, and then to a contractile measure.
Examine effect of Fe++ supplements on running economy
Examine effect of Fe++ supplements and training on virtual time-trial performance
Examine effect of Fe++ supplements on isokinetic contractility of knee extensors (not electrically stimulated)
Examine effect of Fe++ supplements on ventilatory threshold in trained subjects

29. There is a statistically significant change in hemoglobin.
In the first paper, they tried to study the effect of iron supplementation to improve ferritin on aerobic economy in running.
There is a statistically significant change in hemoglobin.
Full stop. End of any conclusions about ferritin and fatigue.
By the way, they found no effect on aerobic economy.
Haas group. Am J Clin Nutr :

30. The next effort was better, looking the effect of iron supplementation on virtual time-trial performance (stationary cycle ergometer). Unfortunately, they couldn’t resist doing a little exercise training too.
They problems of skewed data, and even worse, the placebo group Hb went down, and the supplement group went up.
Hinton et al., (Haas group). JAP :

31. Nonetheless, they went ahead and claimed that the supplement group got better on a vTT.
As a reviewer, I want to see an analysis showing that the difference here is not an effect of the opposite trends in Hb between the two groups. They don’t present such an analysis.
Hinton et al., (Haas group). JAP :

32. Rather than do the right statistics, they did a bunch of multiple regressions. Scrutinize Model 5.
It finds the strongest effect of all the models (ß), and this model is driven by their baseline vTT performance and hemoglobin.
The conclusion notes that they could not confirm the role of ferritin because of this relationship with hemoglobin.
Hinton et al., (Haas group). JAP :

33. These subjects are a group of women in Mexico
These subjects are a group of women in Mexico. They did refrain from training them, and did get iron changes; the placebo group dropped their hemoglobin insignificantly. Much better, they got the kind of changes you want to see.
I am concerned there may still be a difference in O2 content, since the hemoglobin assays are colorimetric indirect spectrophotometric measures of Hb. It’s important to remember that O2 is the important parameter, and in none of these protocols is anyone actually measuring O2 content or O2 delivery to the muscle. To do that, one must obtain ABG’s and arterial blood flow, which is more than most labs can muster in human research.
I was fortunate to spend several years in such labs, and we did that for a reason - if Hb were good enough, we wouldn’t have done that invasive work. I’m not saying one can’t learn from data like this, only reminding you what it is and what it isn’t to maintain your skepticism.
Brutsaert et al. (Haas group). Am J Clin Nutr :

34. Next, Haas et al., went to a better model of fatigue, more reproducible than aerobic endurance tests, which is aerobic rhythmic isometric contractions.
To orient you: this is an MVC of grams, by a say 5000 gram muscle, or 7 g/g of resultant force; note that the work cycle was 1 contraction / 5 sec at 15% of MVC and fatigues to 50% of MVC in 6 minutes.
Brutsaert et al. (Haas group). Am J Clin Nutr :

35. Here is the group fatigue data
Here is the group fatigue data. Panel A is placebo group, Panel B is iron supplement; filled circles are baseline data, the open circles post-test data. N of 10 in each group, except there were missing data from 2 subjects in the intervention group for the last 2 MVC measurements.
I have problems with finding significance when it’s only the samples with missing data. I further have problems in that both the control group measures look like the post-test data in the iron supplement group. If this were my data, I would interpret the vast majority of the data as showing no difference, and that it’s most likely that my statistical analysis represents sampling bias in a small group. They said it was a significant difference.
Brutsaert et al. (Haas group). Am J Clin Nutr :

36. FYI: this dog muscle started at 100% of MVC and after 12 minutes of 1 contraction/sec is still above 50% of Finit.
Dogs are far stronger and can run far longer than humans. Lawrence Taylor is scary, but a dog the size of LT is terrifying. Now you know why!

37. Lastly, Pamela Hinton (a Dr Haas protégé) looked at ventilatory threshold before and after iron supplementation. They learned not to train the subjects.
Remember that Vt is a control variable because of it’s role in relative intensity. It is not a measure of fatigue, but rather it is the highest work rate at which one can observe homeostasis. In the lab, it would be a good choice of where to set the work rate from which to observe fatigue/endurance.
I’m not sure where this is headed, other than that I fear this is a misguided concept of fatigue. I haven’t talked about measuring Vt, which is a bit of a tricky endpoint variable with a couple of protocols to quantify it and the nature of progression in the exercise intensity influences the calculations. A lot of people equate it with maximal steady state, which it is not but is closely related to. If I were going to do this type of work, I would measure MSS, which is much more annoying and difficult to do. Anyway, they are suggesting a small difference; note there is some weirdness in the Hb/Hct data, where the MCHC seems to be decrease in the Fe supplement group....again it would be nice to see O2 being measured directly.
If Vt does in fact change, and it is associated with something a runner could sense, then perhaps a link between ferritin and fatigue could exist, but it’s not clear to me what the physiologic mechanism would be as I don’t know of any linkage between ferritin and respiratory drive. I suppose they are hypothesizing a non-oxidative component and therefore increased lactate / ammonia.
More to come, I’m sure.
Hinton & Sinclair. Eur J Clin Nutr :30-39.

38. Iron / Fatigue Research
In summary, the physiological data connecting ferritin to fatigue are weak to non-existent.
The literature doesn’t support the notion, except for highly flawed studies. I note the Haas group are primarily nutritionists sponsored by supplement manufacturers.
I further note that this type of work belongs in physiology journals, not nutrition journals. Beware of research that is published in the wrong place, it was probably rejected by the right journals, and the referees accepted it probably aren’t adequately trained to critique the study methods.
I conclude there is no convincing evidence to support exertional fatigue as a symptom of a low ferritin.
Difficult studies, but fatally-flawed designs
Hb increases with Fe++ supplements
Little/no control of relative intensity
Various inequalities between groups
Multiple interventions (exercise and Fe++)
Volitional fatigue
Vt effect? - possibly but Vt ≠ fatigue

39. Iron Metabolism
But that is just from an O2 transport view, perhaps there is another linkage between ferritin and subjective sense of fatigue?
Not muscle fatigue, the FEELING of fatigue.
Unfortunately, there are very few data from that angle.
Could sub-normal iron metabolism contribute to fatigue via non-O2 transport mechanisms?
What does ferritin do, anyway?!

40. Uh oh. Aside from O2 transport, iron does a lot of things.
JL Beard. J Nutr 2001; 131: 568S–580S.

41. Iron is poorly absorbed.
Essentially all absorbed iron is bound to proteins or enzymes.
Total body iron is about 4 grams, about 2/3 as hemoglobin, 1/4 as ferritin, the rest divided
Transferrin cycles about 10 times a day, 5-10 times more rapidly than ferritin, though transferrin is quantitatively lower in serum.
JL Beard. J Nutr. 2001; 131: 568S–580S.

42. Essentially all cells have transferrin receptors, and there are a variety of intracellular pathways that direct the fate of iron.
Ferritin is not involved in these pathways. Ferritin is the “waste basket” for cellular iron.
When radiolabeled iron (59Fe) is bound to ferritin and re-injected, radiolabel does not end up in heme.
Repeat, ferritin is not metabolically involved in synthetic pathways related to O2 transport.
Ponka, et al. Semin Hematol. 1998; 35:35-54.

43. Ferritin is believed to take up iron mainly in this step of heme degradation.
As heme is broken down to biliverdin and bilirubin, iron is liberated. Though it is known that ferritin has active transporters in the protein structures, it is not known how cells get free iron into the ferritin. Inside ferritin are small molecules of rust.
Ferritin is the wastebasket for iron being liberated from iron-containing compounds. Ferritin encapsulates the iron atoms, protecting the body from forming peroxide and other free radicals.
Ferritin is the recycling bin for body iron. It is believed that ferritin transports waste iron to liver, but the fate of ferritinic iron after that is not well known.
Repeat, ferritin is not directly related to iron involved in O2 transport; not in hemoglobin, nor myoglobin, nor in the cytochromes. It is therefore difficult to fantasize how ferritin could be directly related to exertional fatigue.
EC Thiel. J Nutr. 2003; 133:1549S-1553S.
Ryter & Tyrrell. Free Rad Bio Med. 2000; 28:

44. The more iron you have, the more you will be breaking it down
The more iron you have, the more you will be breaking it down. Necessitating more wastebaskets for iron. Thus, ferritin synthesis is driven by a protein called IRP1, that stimulates synthesis of ferritin light and heavy chain when tissue iron is high. IRP1 actively binds to the ferritin and transferrin mRNA, and IRP1 is inactivated by iron.
When ferritin mRNA is bound by IRP1, the 5’ end binds to the IRP1 and translation is blocked. As iron levels rise, more IRP1 is inactivated by Fe, and the 5’ end is exposed allowing translation of ferritin mRNA. Therefore, ferritin levels are regulated in proportion to iron levels.
When transferrin mRNA is bound by IRP1, it stabilizes the mRNA molecule and allows for translation to proceed. As iron levels rise, and more IRP1 is inactivated by Fe, there is insufficient IRP1 able to bind to transferrin mRNA and the mRNA becomes unstable and is degraded. Thus, transferrin levels are regulated in inverse proportion to iron levels.
This common mechanism is why transferrin and ferritin levels go up and down in opposition of each other.
Ponka, et al. Semin Hematol. 1998; 35:35-54.

45. This is the function of ferritin.
In summary, ferritin is a wastebasket for body iron. It is not clear how, or how much, ferritinic iron is recycled.
The main function of ferritin is to protect the body from the free-radical formation that occurs if tissues are exposed to free iron. Even the iron in heme is very toxic in forming free radicals. Iron is extremely reactive, which is critically important in bioenergetics, but it also means that iron must be carefully sequestered away from everything.
This is the function of ferritin.
Ryter & Tyrrell. Free Rad Bio Med. 2000; 28:

46. It is then apparent why ferritin is an acute phase reactant.
Anything that traumatizes tissue, causing cell necrosis, liberating iron-containing proteins, will increase the synthesis of ferritin as a clean-up response to increasing levels of “free” iron.
Smith & Roberts. Clin Chem :

47. Forget About Ferritin?
So if ferritin is just a reactive component, maybe we should forget about it?
Well, no. P
It is unclear whether or not hemochromatosis is a risk to runners (and other endurance athletes).
Well,...no. It can be dangerous.
Hemochromatosis genotypes (HFE mutations) are highly prevalent in the population - one of the most common congenital mutations.
There continue to be no case-reports of a runner with phenotypic hemochromatosis.
Never is a long time.

48. Athletes: 50 pro cyclists + 15 “Olympic class endurance runners”
Two recent studies have shown that endurance athletes have a higher than expected prevalence of genotypic hemochromatosis - that carry the genetic mutations that cause hemochromatosis.
Both publications suggest we should have heightened scrutiny for clinical (i.e., phenotypic hemochromatosis) in endurance athletes.
Do they have it backwards?
Athletes: 50 pro cyclists + 15 “Olympic class endurance runners”
(vs only cyclists in Deugnier et al. MSSE. 2002; 34: )
Chicharro, et al. Br J Sports Med. 2004; 38:

49. Forget About Ferritin? Ferritin gene knockout - lethal in utero
Perhaps the gene selects for endurance superiority, not by virtue of hemochromatosis, but because iron losses are very high in runners.
If humans evolved to run (rather than sit in their car), a gene that improves endurance would be a selective advantage. A mutation that causes disease but is present in 50% of endurance athletes MUST be advantageous, or it would not persist.
Note that ferritin is critically important in life. Murine models of ferritin knockouts are lethal in utero; a-ferritinemia is not compatible with life. C
I would hypothesize that heterozygosity for hemochromatosis confers a selective evolutionary advantage to endurance runners, because it offsets the increased iron losses in endurance runners. As is sickle cell trait to malaria resistance, so perhaps the hemochromatosis gene resists iron losses in endurance runners.
Ferritin gene knockout - lethal in utero
Population prevalence of HFE - 33%
Athlete prevalence of HFE - 50%
Could the hemochromatosis gene be protective against iron-deficiency in runners?

50. Non-O2 Transport Fe++? CNS structures that contain Fe++
Well, if iron in the O2 transport pathways is not involved in fatigue, maybe there are other pathways that can cause fatigue.
Indeed, a number of CNS pathways and structures involve iron, and these pathways even can be imagined as mediating a sense of fatigue!
Unfortunately, very very little is known about how these pathways are involved in the sensation of fatigue. We simply do not know.
CNS structures that contain Fe++
Cortex, striatum, cerebellum, thalamus
Fe++ a co-factor in myelination
Dopaminergic regions “affected” ≥15% low
Mesolimbic & striatonigral tracts
Motor control, perception, motivation
Serotonin/Norepinephrine - not affected

51. A (Not So) Final Analysis
In conclusion, I have three main points.
First, iron-deficient non-anemic is a laboratory statistical phenomenon, not a biological reality.
You saw that our investigators had great trouble manipulating ferritin without affecting the hemoglobin. They are so closely linked, with ferritin as the wastebasket for heme, that you there really is no such thing as iron-deficient non-anemic.
James Beard on iron deficiency:
“Thus, although it is convenient at times to categorize individuals as iron-deficient anemic vs iron-deficient non- anemic, this is not a biological reality”.

52. A (Not So) Final Analysis
If you’re uncertain about something in sports science, ask Ian.
A low ferritin is a relative indication for iron supplementation in athletes. Period.
If the body is low on iron, and if it isn’t YET anemic, there’s a risk of anemia.
Anemia very definitely causes exertional fatigue because it reduces O2 delivery.
Ian Shrier on iron deficiency:
“Low ferritin with hemoglobin in the mid- to upper normal range is at best a relative indication for iron supplementation: low ferritin with hemoglobin in the low normal range is a stronger, yet still relative, indication for iron supplementation in athletes”.

53. A (Not So) Final Analysis
We don’t know whether or not a low ferritin is associated with the sense of fatigue through other non-O2 transport pathways.
There are several plausible pathways, and we simply don’t know whether or not they are involved.
Ferritin still could be related to fatigue through CNS- mediated pathways
Motor control
Motivation
Thermoregulation
Other?

54. Should Runners Take Iron?
Lastly, my personal view to a question everyone wants to know...should distance runners take iron?!
Only if they want to win.
I would not lose a second of sleep worrying about hemochromatosis in a menstruating woman distance runner.
I might worry a little in a male distance runner, but I would still get a great night’s sleep. Someday I might check a ferritin to exclude phenotypic hemochromatosis, but even in a male runner it is not something I would lose sleep over.
If that runner is using EPO or (more likely) an altitude tent, I’m not sure if I would check a ferritin or not. Frankly, I regard both techniques as cheating (but I regret that won’t make it go away).
Thanks.
All things being equal, if your competitor has a higher arterial O2 content than you, your only hope is that they will have a bad day...
Competitive distance runners should probably take an iron supplement and/or eat iron-containing foods, i.e., red meats, unless not winning doesn’t bother them
Menstruating Women - very low risk of hemochromatosis
Men - also at low risk?
Someday...check a ferritin. If it’s not high, forget about it
(at least while they’re a competitive runner)