Increasing Your Natural EPO

By William Misner Ph.D.

What is EPO?

Erythropoietin (EPO) is a naturally occurring hormone that stimulates the production of red blood cells (RBC). Erythropoietin is a glycoprotein hormone produced in the kidneys, containing a 165-amino acids structure. Most erythropoietin is produced by the kidney's renal cortex, but some is also produced in the liver (mainly in the fetus), the brain and uterus.

Why is it important?

Erythropoietin production is stimulated by low oxygen levels in interstitial cells of the peritubular capillaries in the kidneys. Following its production in the kidneys, EPO travels to the bone marrow where it stimulates production of red blood cells (RBC's) [2]. EPO increases the body's blood-oxygen carrying capacity, but only up to a point. An overabundance may compromise health and hinder blood flow dynamics with performance-limiting implications. In the absence of EPO, only a few RBC's are formed by the bone marrow.

Why are RBC's important?

Red blood cells carry iron-rich hemoglobin for up to 120-days, then they die. Unless there is a continual supply of Iron, Vitamin B-12, Vitamin C and Folacin, anemia and reduced oxygen carrying capacity manifests in two ways:

1. Low red blood cell count
2. Malformed red blood cells.

How can one increase their oxygen carrying capacity?

There is a distinct difference between unethical, harmful, EPO-blood doping methods and the safe nutrition that effectively increases individual oxygen-carrying capacity. Once can improve their health and oxygen carrying capacity similar to EPO without compromising the athlete's health or integrity. EPO levels up to 48% safely improve performance in males, however beyond this level, the risk of compromised health increases. Look to dietary suggestions below regarding vitamins, minerals, proteins, and avoiding anemia to ensure oxygen carrying capacity.

Can excess EPO can be lethal?

Yes. The margin between effective and lethal quantities of EPO is very narrow. EPO use can be LETHAL. Many athletes seeking to derive its performance-enhancing effects have died from incorrectly-administered EPO. Inappropriate use of exogenous EPO can cause elevated hematocrit levels (i.e. thickened blood that is difficult to pump). Elevated EPO increases the risk of heart attack due to the increase in hematocrit. Choosing sustainable, healthy choices is preferred.

Exogenous EPO is totally cleared from the urine within 48 hours of its administration and is cleared from the blood within 72 hours of its administration but its physiological effects prevail for several months).[3] A look at EPO's complex pathway further illustrates a complex physiological process below, see PATHWAYS[4]. Research followed over 7,000 middle-aged men for more than 12 years, and discovered that the risk of diabetes increases proportionate to hematocrit increase.[19] [20]. Men with hematocrits above 48 percent have a 400% increased risk of non-insulin-dependent-diabetes mellitus. The upper recommended levels for a female is slightly lower at 45%.

This nutritional intervention parallels exercise intensitys effect for increasing EPO. Nutritional and training interventions for resolving low EPO levels during iron supplementation (only prescribed by a physician who should monitored progress) should not be permitted above a reference range of 48% in males and 45% in females. Similar research confirms this report.[21] [22] [23]

Does exercise intensity increase EPO?

It's complicated. Roberts & Smith measured the effects of exercise-induced hypoxia on the physiological production of erythropoietin. Twenty athletes exercised for 3 min at 106-112% maximal oxygen consumption. The fitness of these athletes provides a physiological environment for increasing EPO naturally from short 3-minute all-out intervals. Estimated oxyhemoglobin saturation was measured by reflective probe pulse oximetry (Nellcor N200) and was validated against arterial oxyhemoglobin saturation by CO-oximetry in eight athletes. Serum erythropoietin concentrations, as measured using the INCSTAR Epo-Trac radioimmunoassay, increased significantly by 19-37% at 24 hours post-exercise in 11 participants who also had an arterial oxyhemoglobin saturation < or = 91%. Decreased ferritin levels and increased reticulocyte counts were observed at 96 hours post-exercise. However, no significant changes in EPO levels were observed in nine non-desaturating athletes and eight non-exercise controls. Good agreement was shown between arterial oxyhemoglobin saturation and percent estimated oxyhaemoglobin saturation (limits of agreement = -3.9 to 3.7. They concluded that a short 3 minutes supramaximal exercise period could induce both hypoxemia and increased erythropoietin levels in well-trained individuals. The decline of arterial hypoxemia levels below 91% during exercise appears to be necessary for the exercise-induced elevation of serum erythropoietin levels. Furthermore, reflective probe pulse oximetry was found to be a valid predictor of percent arterial oxyhemoglobin saturation during supramaximal exercise when percent estimated oxyhemoglobin saturation > or = 86%.[9]

What naturally occuring, nutritional building blocks aid in EPO production?

Protein adequacy is a factor in erythropoietin (EPO) production. Inadequate protein nutrition can reduce the EPO produced. The erythroid response to Erythropoietin (EPO) is highly dependent on dietary protein adequacy and quality. The mouse spleen is an erythropoietic organ, which contains an EPO-responsive cell population that can be easily amplified by administration of the hormone. Researchers determined the effect of a protein-free diet offered freely to mice up to two days after injection of r-Hu EPO (1000mU/200 ul) on the response of the above population. Splenic cell suspensions from control and experimental mice were prepared in microwells containing 400 mU r-Hu EPO and appropriate medium. The response to EPO was evaluated in terms of 3H-thymidine uptake. The results obtained indicate that acutely induced protein restriction suppressed the response of the EPO-responsive splenic cell population to EPO when it was imposed on mice immediately after hormone injection, and suggest the appearance of deficient rates of differentiation of erythropoietic units by protein restriction.[11] Adequate dietary protein intake is 1.4-1.7 grams/kilogram body weight per day for an endurance athlete.

What other nutritional elements and processes affect the natural production of EPO and the body's oxygen carrying capacity?

Dietary Iron. To ensure oxygen carrying capacity, one should take the recommended daily value of iron. Food sources of iron are red meat, liver, and egg yolks. Most flour, bread, and cereals are iron-fortified. If the diet continues to be iron-deficient, only a physician should prescribe and supervise iron supplementation.

Calories. Calories are needed for EPO production. Calorie sufficiency (in spite of exercise expense) is required for optimal EPO-release. If training is causing weight loss, then EPO loss may be occurring. In order to test the hypothesis that the early cessation of erythropoietin (Ep) production during hypobaric hypoxia is induced by lowered food intake, researchers compared the plasma Ep titer of rats after exposure to continuous hypoxia (42.6 kPa = 7000 m altitude) for 4 days in fed or fasted rats after exposure to discontinuous hypoxia. They found that plasma Ep was rather low after 4 days of continuous hypoxia. Their findings showed that fasting lowers the EPO-response to hypoxia in normal rats [12].

Hormone and Glucose. EPO production also has hormonal-dependant roots complexly related to glucose metabolism, and calorie adequacy. The effect of Thyroid-T3 replacement and glucose supplementation on erythropoietin production was investigated in fasted hypoxic rats. It was found that 48 hr of fasting significantly reduced the circulating levels of thyroid hormones and the production of renal and extrarenal erythropoietin in response to hypoxia. These effects of fasting were completely abolished when the animals had free access to 25% glucose solution as drinking water, despite their lack of protein intake. Replacement doses of T3 (0.5 micrograms/100 gm per day) restored erythropoietin production in the fasted animals but also increased the response of the fed controls. To avoid the effect of endogenous T3, the experiments were repeated in thyroidectomized rats. EPO production in athyroid rats was found to be markedly decreased, with values equivalent to those found in normal fasted animals, and were not affected by fasting or glucose supplementation. Replacement doses of T3 increased EPO production in all three groups, but the fasted animals needed five times as much T3 to obtain a response similar to that observed in the fed group. Glucose supplementation enhanced the effect of T3 in the fasted animals but did not completely restore them. These results indicate that caloric deprivation is primarily responsible for the decreased EPO production induced by fasting and that this effect is probably mediated by both a decreased level of T3 and a decreased responsiveness to it.[13] A calorie deficit therefore requires 500% more Thyroid Hormone (T3) to maintain EPO levels. This is a good reason for monitoring calorie intake during high training calorie expense.

Iron absorbtion. Dietary interventions significantly advance nonheme iron absorption rate during EPO production. It is very important to include foods to enhance nonheme iron absorption, especially when an exercise-induced iron loss is high or when no heme iron is consumed, such as in a vegetarian diet. Absorption of heme iron is very efficient; the presence of red meat increases absorption of non-heme iron +400%. Only 1-7% of the nonheme iron in vegetable staples in rice, maize, black beans, soybeans, and wheat are absorbed consumed alone. Vitamin C improves the rate of absorption of nonheme iron from red meats. Diets that include a minimum of 5 servings of fruits and vegetables daily provide adequate vitamin C to boost nonheme iron absorption. Calcium, polyphenols, tannins from tea, and phytates (a component of plant foods), rice, and grains inhibit the absorption of nonheme iron. Some of the protein found in soybeans inhibits nonheme iron absorption. Most healthy individuals maintain normal iron stores when the diet provides a wide variety of foods. However, if the diet contains large amounts of oxalates and phytates from dark green leafy vegetables and whole cereal grains the absorption of iron decreases due to binding with iron in the gut. High absorption of heme iron is further advanced by foods containing vitamin C in an acid environment found of the stomach. The recommended for daily iron intake is between 10-18 milligrams for adult males and postmenopausal females. Most endurance athletes consume too much iron. Iron is added to breads, cereals, and most packaged foods.

From a computer-generated dietary analysis on 16 endurance athletes and 9 non-athletes, iron intake from their reported food intake was assessed.

The results of this data is as follows:

What are some food combinations that increase the absortion of iron?

How foods are combined may affect iron absorption rate. Excess iron overdose is unhealthy and should be avoided. Common side effects of acute iron overload are gastro-intestinal pain, constipation, nausea, and heartburn. Excess iron levels may generate a continuous low-grade infection. Foods are the best source of iron. The best food source of iron is liver and red meats. These foods contain heme iron, which is better absorbed than non-heme iron. Non-heme iron can be found in dark green, leafy vegetables (spinach, chard and kale) and whole cereal grains (bran and whole wheat bread). Include dark green, leafy vegetables and whole cereal grains in the daily diet. Oxalates and phytates found in dark green leafy vegetables and whole cereal grains decrease the absorption of iron because they bind with iron in the gastrointestinal tract. Iron fortified cereals increase iron from the diet. Anemia may develop on a meat-free diet and/or if the iron store or intake is low.

Red meat contains arachidonic acid, an EPO-precursor nutrient, but it also contains high levels of saturated fats and cholesterol suggesting a little (now and then) is good but too much will harmfully compromise cardiovascular lipid levels. Adding iron to the diet in supplemental form is not recommended except under the supervision of a physician who is monitoring blood serum levels for a specific outcome. It has been shown that eating red meat 1-2 per week may contribute to providing substrates known to regenerate EPO as shown in animal research. The ability of Arachidonic Acid (AA), the bisenoic prostaglandin precursor to stimulate erythropoiesis and Erythropoietin (EP) Production in exhypoxic polycythemic mice and the programmed isolated perfused canine kidney was found to stimulate erythropoiesis when administered to exhypoxic polycythemic mice in the lowest dose tested (50 microgram/kg i.p.). Endogenously synthesized prostaglandins, their intermediates and/or other products of AA metabolism, such as prostacyclin and prostaglandins play an important role in the control EPO production.[14] Hematocrit levels are restored through the supplying dietary or supplemental specific substrates to support the body's natural EPO-producing mechanisms during endurance exercise stress.

SUBSTRATES THAT ASSIST EPO METABOLISM[15]

1. Acidophilus - 15-30 Billion Count Probiotics
2. Coenzyme Q10 - 150-300 mg daily
3. Garlic - 2 cloves or 2 capsules up to 3 x day
4. Kelp - 100-225 micrograms
5. Vitamin B6 - 50-100 mg
6. Vitamin B12 - 200-1,000 mcg
7. Folic Acid - 800 mcg
8. Proteolytic enzymes - Bromelain & Papain
9. Selenium - 200 mcg
10. Vitamin A - 15,000 IU daily or Beta Carotene - 25,000 IU daily
11. Vitamin B Complex - 50-100 mg
12. Vitamin C plus Bioflavonoids - 1-3 grams (divided dose)
13. Vitamin E - 400 IU daily
14. Copper - 2 mg
15. Zinc 40 mg daily ---->(Do not take zinc in amounts over 40 mg daily as it may interfere with metabolism of iron and copper)

More DIetary Recommendations

There is a method to improve iron uptake in the absence of oxalate or phytate rich foods previously mentioned above. If hematocrit, hemoglobin, or ferritin blood lab measures are low, the athlete may add 1-gram of vitamin C to a 3-4 ounce lean cut of red meat cooked in an iron skillet one to two times each week. A complete dietary protocol for cancer patients going through chemotherapy and radiation was published and is applicable to over-trained endurance athletes who present low hematocrit levels.[16]

Conclusion

In normal adults, the kidneys produce EPO, which initiates approximately 90% of natural erythropoietin production. Tissue oxygenation exposure regulates the production of erythropoietin. Less oxygen saturation in the air we inhale (either by altitude or hypoxic interval training) stimulates the kidneys to activate the chemical messengers to instruct the bone marrow to increase the production of EPO to resolve the lack of oxygen exposure. Hypoxia or Anemia stimulates the kidney production of erythropoietin to increase production red blood cells. EPO released from the kidneys increases the rate of red blood cell division and differentiation of specific cells in the bone marrow.

Dietary deficiency of specific foods and micronutrients, hormone imbalance, and lack of specific hypoxic training stress inhibit the endogenous (natural) production of EPO. Additionally, nutritional imbalance from caloric restriction (or exercise related expense), dehydration, fluid intoxication, excess calcium, excess inositol, excess oxalates foods, excess phytic acid from cereal grains, or a lack of hypoxic interval training all inhibit the natural production of EPO also. [17] [18],

Manipulating diet for protein and total calorie adequacy, monitoring hydration, using supplements, timing food combinations, adding weekly hypoxic exercise followed by easy or rest days all increases the release of natural EPO for healthy maximal oxygen carrying capacity. Plus, there are many ways to use diet and wellness to ensure that the body's production of red blood cells is sound and that their oxygen carrying capacity is functioning.

[1] Director of Research & Product Development for HAMMER NUTRITION LTD. 1-800-336-1977, Whitefish, Montana.

[2] Courtesy of From Wikipedia, the free encyclopedia @: http://en.wikipedia.org/wiki/Main_Page

[3] In-Tele-Health 2002 (from Hyperhealth Pro CD-ROM)

[4] Courtesy of Biocarta @ http://www.biocarta.com/pathfiles/h_eponfkbPathway.asp

[5] CLINICAL PHARMACOLOGY OF PROCRIT@: http://www.procrit.com/profonly/nephrology/what_is_procrit/clinical_pharmacology.html

[6] Fisher JW. Pharmacologic modulation of erythropoietin production. Annu Rev Pharmacol Toxicol. 1988;28:101-22.

[7] Plasmapheresis is the process of separating certain cells from the plasma in the blood by a machine; only the cells are returned to the person. Plasmapheresis can be used to remove excess antibodies from the blood.

[8] Roberts D, Smith DJ, Donnelly S, Simard S., Plasma-volume contraction and exercise-induced hypoxaemia modulate erythropoietin production in healthy humans. Clin Sci (Lond). 2000 Jan;98(1):39-45.

[9] Roberts D, Smith DJ. Erythropoietin concentration and arterial haemoglobin saturation with supramaximal exercise. J Sports Sci. 1999 Jun;17(6):485-93.

[10] Brun JF, Bouchahda C, Chaze D, Benhaddad AA, Micallef JP, Mercier J. The paradox of hematocrit in exercise physiology: which is the "normal" range from a hemorheologist's viewpoint? Clin Hemorheol Microcirc. 2000;22(4):287-303.

[11] Depressed response of the erythropoietin-responsive splenic cell population to erythropoietin in acutely protein restricted mice. In Vivo. 1995 Jan-Feb;9(1):71-3.

[12] Jelkmann W, Kurtz A, Bauer C., Effects of fasting on the hypoxia-induced erythropoietin production in rats. Pflugers Arch. 1983 Feb;396(2):174-5.

[13] Caro J, Silver R, Erslev AJ, Miller OP, Birgegard G., Erythropoietin production in fasted rats. Effects of thyroid hormones and glucose supplementation. J Lab Clin Med. 1981 Dec;98(6):860-8.

[14] Foley JE, Gross DM, Nelson PK, Fisher JW. The effects of arachidonic acid on erythropoietin production in exhypoxic polycythemic mice and the isolated perfused canine kidney. J Pharmacol Exp Ther. 1978 Nov;207(2):402-9.

[15] As with any supplement, always confirm with your physician as to the appropriate level and selection prior to use.

[16] Nutritional Interventions for Reducing the Negative Side Effects of Chemotherapy, Bill Misner, Ph.D. http://www.cancure.org/Chemo_support.htm

[17] Oxalate-rich foods are: Spinach, Cereals, Green Beans (steamed), Potato (raw), Peanut Butter, Tea (brewed), Celery, Chocolate, Ravioli, and White Bread.

[18] Phytate-rich foods are Grains, Corn, Oats, Rice Bran, Wheat Bran, Legumes, Peanuts, Soybeans, and Seeds.

[19] Catalano C, Muscelli E, Natali A, Mazzoni A, Masoni A, Bernardini B, Seghieri G, Ferrannini E. Reciprocal association between insulin sensitivity and the haematocrit in man. Eur J Clin Invest. 1997 Jul;27(7):634-7.

[20] Wannamethee SG, Perry IJ, Shaper AG. Hematocrit and risk of NIDDM. Diabetes. 1996 May;45(5):576-9.

[21] Sit D, Kadiroglu AK, Yilmaz ME, Kara IH, Isikoglu B. The prevalence of insulin resistance and its relationship between anemia, secondary hyperparathyroidism, inflammation, and cardiac parameters in chronic hemodialysis patients. Ren Fail. 2005;27(4):403-7.

[22] Evrengul H, Dursunoglu D, Kaftan A, Kilicaslan F, Tanriverdi H, Kilic M. Relation of insulin resistance and left ventricular function and structure in non-diabetic patients with essential hypertension. Acta Cardiol. 2005 Apr;60(2):191-8.

[23] Amoah AG, Schuster DP, Gaillard T, Osei K. Insulin resistance, beta cell function and cardiovascular risk factors in Ghanaians with varying degrees of glucose tolerance. Ethn Dis. 2002 Fall;12(4):S3-10-7.