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ERYTHROPOIETIN [EPO]: INTERVENTIONS FOR INCREASING EPO

Bill Misner Ph.D.*

There is a distinct relationship between illegitimate EPO-drug or blood doping misuse and legal dietary interventions accompanied by specified training protocols. EPO increases performance from its influence on blood-oxygen carrying capacity up to a point. Excessive substrates, dietary deficiencies, hormonal imbalances, and lack of specific hypoxic training stress may inhibit the endurance athlete from peaking naturally-induced optimal endogenous production of erythropoietin.

ERYTHROPOIETIN [EPO] is a naturally occurring hormone that stimulates the production of red blood cells (RBC). In the absence of erythropoietin, few RBC's are formed by the bone marrow. In normal adults, approximately 90% of human erythropoietin is produced in the kidneys. Endogenous production of erythropoietin is normally regulated by the level of tissue oxygenation. A reduction in the delivery of oxygen to the kidneys may occur when the hematocrit (Hct) is low, or as a result of changes in the way that hemoglobin (Hb) and oxygen interact. HYPOXIA and ANEMIA generally increase the production of erythropoietin, which in turn stimulates red blood cell production. Erythropoietin increases RBC production by stimulating the division and differentiation of specific cells in the bone marrow. An important effect of erythropoietin is to stimulate the production of "proerythroblasts." Erythropoietin causes these cells to mature rapidly, further accelerating the production of new RBCs. The regulation of red blood cell production resembles a complete feedback loop. ERYTHROPOIETIN [EPO] is released primarily by the kidneys in response to hypoxia, by sending a highly specific signal prompting cells in the bone marrow to produce RBCs. As a result, the oxygen-carrying capacity increases, the stimulus of hypoxia is alleviated, and the production of erythropoietin is decreased. Endogenous production of erythropoietin is normally regulated by the level of tissue oxygenation. Hypoxia and anemia generally increase the production of erythropoietin, which in turn stimulates erythropoiesis. In normal subjects, plasma erythropoietin levels range from 0.01 to 0.03 Units/mL, and increase up to 100- to 1000-fold during hypoxia or anemia. EPOETIN ALFA[PROCRIT] has been shown to stimulate erythropoiesis in anemic patients with CRF who do not require regular dialysis. The first evidence of a response to the three times weekly (T.I.W.) administration of the prescription drug EPOETIN ALFA[PROCRIT] is an increase in the reticulocyte count within 10 days, followed by increases in the red cell count, hemoglobin, and hematocrit, usually within 14-42 days. Because of the length of time required for erythropoiesis -- several days for erythroid progenitors to mature and be released into the circulation -- a clinically significant increase in hematocrit is usually not observed in less than 14 days and may require up to 42 days in some patients. Once the hematocrit reaches the suggested target range (30-36%), that level can be sustained by adequate nutrition in the absence of iron deficiency and concurrent illnesses. Interval training hypoxia enhances EPO levels by the same mechanism which the prescription drug, EPOETIN ALFA[PROCRIT] does. When Procrit is administered 1-3 times per week, subsequent increases in plasma erythropoietin levels are 100- to 1000-fold.[1] Because EPO increases the hematocrit, it enables more oxygen to flow to the skeletal muscles. Some distance runners and cyclists have used recombinant EPO to enhance their performance. A model for the regulation of erythropoietin production has been examined. This model proposes that a primary O2-sensing reaction in the kidney is initiated by a decrease in ambient PO2, a rapid decrease in gas exchange in the lung, a diminished oxygen-carrying capacity of hemoglobin, a molecular deprivation of oxygen, or a decrease in renal blood flow. Some of the agents that are thought to be released during hypoxia, which may trigger the EPO cascade, are adenosine (A2 activation), eicosanoids (PGE2, PGI2, and 6-keto PGE1), oxygen-free radicals (superoxide and H2O2), and catecholamines with beta-2 adrenergic receptor agonist properties. It is further proposed that an INCREASE IN INTRACELLULAR CALCIUM LEADS TO THE INHIBITION OF ERYTHROPOIETIN BIOSYNTHESIS AND/OR SECRETION AND A DECREASE IN INTRACELLULAR CALCIUM INCREASES ERYTHROPOIETIN PRODUCTION. THE SPECIFIC MECHANISM BY WHICH CALCIUM REGULATES ERYTHROPOIETIN BIOSYNTHESIS AND SECRETION IS NOT WELL UNDERSTOOD. However, a good correlation is seen with several agents that decrease intracellular calcium and increase erythropoietin production as well as with other agents that increase intracellular calcium and decrease erythropoietin production. When INOSITOL TRIPHOSPHATE levels are increased, an increase in the mobilization of intracellular calcium from the endoplasmic reticulum or another intracellular pool occurs. This increased INTRACELLULAR CALCIUM probably activates a calcium calmodulin kinase and produces a phosphoprotein that inhibits erythropoietin production/secretion.[2] Although recombinant EPO has exactly the same sequence of amino acids as the natural hormone, the sugars attached by the cells used in the pharmaceutical industry differ from those attached by the cells of the human kidney. This difference can be detected by a test of the athlete's urine.

ERYTHROPOIETIN (EPO) LEVELS INCREASE DURING HYPOXIC EXERCISE AND PLASMA VOLUME DEPLETION

Roberts et al., examined exercise-induced hypoxemia (EIH) and plasma volume contraction as modulators of serum ERYTHROPOIETIN (EPO) production. Five athletes cycled for 3 min at supra-maximal power outputs, at each of two different elevations (1,000 and 2,100 meters). Five subjects were exposed to normobaric hypoxia (F(I)O(2)=0.159), seven subjects underwent plasmapheresis to reduce plasma volume and eight subjects were time controls for Epo levels. Oxyhemoglobin saturation was significantly reduced during exercise and during normobaric hypoxia. The time period of haemoglobin oxygen saturation <91% was 24+/-29 s (mean+/-S.D., n=5) for exercise at 1000 m, 136+/-77 s (mean+/-S.D., n=5) for exercise at 2100 m and 178+/-255 s (mean+/-S.D., n=5) with resting hypoxic exposure. However, SIGNIFICANTLY INCREASED SERUM EPO LEVELS WERE OBSERVED ONLY FOLLOWING EXERCISE (21-27% at 1,000 m and 31-41% at 2,100 m). VOLUME CONTRACTION ALSO RESULTED IN INCREASED SERUM EPO 29-41% in spite of a significant rise in hematocrit of +2.2%. Despite similar degrees of arterial desaturation, ONLY THE HYPOXEMIA INDUCED BY EXERCISE WAS ASSOCIATED WITH AN INCREASE IN SERUM EPO. This finding indicates that other factors, in addition to hypoxemia, are important in modulating the production of Epo in response to exercise. VOLUME DEPLETION IN THE ABSENCE OF EXERCISE RESULTED IN INCREASES IN EPO LEVELS THAT WERE COMPARABLE WITH THOSE OBSERVED IN RESPONSE TO EXERCISE. The paradoxical responses of the increased hematocrit and the increase in Epo in subjects undergoing plasmapheresis suggests that PLASMA VOLUME MAY ALSO MODULATE THE PRODUCTION OF EPO.[3]

HOW DOES INTENSITY OF EXERCISE INCREASE ERYTHROPOIETIN RELEASE?

Roberts & Smith set out to determine if the hypoxaemic stimulus generated by intense exercise results in the physiological response of increased erythropoietin production. Twenty athletes exercised for 3 min at 106-112% maximal oxygen consumption. 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 h 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 h post-exercise. However, no significant changes in erythropoietin 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%). In conclusion, SHORT [3 MINUTES] SUPRAMAXIMAL EXERCISE CAN 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%.[4] Hence, fit athletes tend to gain more exercise-induced EPO from short 3-minute all-out intervals than do less fit athletes.

DIETARY INTERVENTIONS FOR INCREASING OXYGEN CARRYING CAPACITY AND REDUCING ANEMIA

COMMON CAUSES OF ANEMIA

Red blood cells that carry iron-rich hemoglobin, live only 120 days or four months. Unless there is a continual supply of iron, vitamin B12, vitamin C and folacin from either food or supplements, anemia will result in poorly formed red blood cells that are ineffective carriers of oxygen. Iron deficiency anemia is the most common form of anemia. Approximately 20% of women, 50% of pregnant women, and 3% of men are iron deficient. Iron is an essential component of hemoglobin, the oxygen carrying pigment in the blood. Iron is normally obtained through the food in the diet and by the recycling of iron from old red blood cells. The causes of iron deficiency are too little iron in the diet, poor absorption of iron by the body, and loss of blood (including heavy menstrual bleeding). It may also be related to lead poisoning or chemotherpy. Anemia develops slowly, after the normal stores of iron have been depleted in the body and in the bone marrow. Women, in general, have smaller stores of iron than men and have increased loss through menstruation, placing them at higher risk for anemia than men. In men and postmenopausal women, anemia is usually due to gastrointestinal blood loss associated with ulcers, the use of aspirin or nonsteroidal anti-inflammatory medications (NSAIDS), or colon cancer. High-risk groups include: women of child-bearing age who have blood loss through menstruation; pregnant or lactating women who have an increased requirement for iron; infants, children, and adolescents in rapid growth phases; and people with a poor dietary intake of iron through a diet of little or no meat or eggs for several years. Risk factors related to blood loss are peptic ulcer disease, long term aspirin use, colon cancer, or cancer-related chemotherapy treatment. Dietary sources of iron are red meat, liver, and egg yolks. Flour, bread, and some cereals are fortified with iron. If the diet is deficient in iron, iron should be taken orally and monitored by a physician.

The rate at which NATURAL ENDOGENOUS HEMATOCRIT increases varies with each subject but may be further enhanced when SPECIFIC DIETARY INTERVENTIONS ARE ADDED TO THE INTENSE HYPOXIC INTERVAL SESSIONS. The same dietary intervention observed to relieve Anemia symptoms is the ideal protocol for treating impaired blood oxygen capacity or increasing blood oxygen capacity of a normal-healthy endurance athlete. The most common cause is iron-deficiency anemia in red blood cells which are smaller than usual and pale in color due to improper amounts of hemoglobin (the molecule in red blood cells that binds to oxygen and carries it in the blood). This lack of iron for the production of hemoglobin is due to:

-Loss of iron from the body due to blood loss

-Poor absorption of iron from one's diet

-Lack of dietary iron

-Radiotherapy or Chemotherapy

-Anti-cancer drugs

-Certain types of viral infections

-Genetic reasons

-A result of malaria

-AIDS

-A deficiency of vitamin B-12.

-A deficiency of folic acid.

-An imbalance between the ratio of B-12 & Folate

SYMPTOMS OF ANEMIA

[Note: There may be no symptoms if anemia is mild.]

1. Tiredness and weakness

2. Lethargy

3. Dizziness, shortness of breath, and palpitations (rapid heart rate)

4. Headaches

5. Pale complexion

6. Brittle nails(due to lack of iron)

7. Irritability

8. Sore tongue

9. Unusual food cravings (called pica)

10. Decreased appetite

11. Headache - frontal

12. Blue tinge to sclerae (whites of eyes)

DIETARY INTERVENTIONS

PROTEIN ADEQUACY is a factor in erythropoietin (EPO) release mechanics. The erythroid response to Erythropoietin (EPO) is highly dependent on DIETARY PROTEIN. 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.[5] "ENOUGH PROTEIN" is 1.4-1.7 grams/kilogram body weight.

"ENOUGH FOOD", NOT FASTING is also a factor. In order to test the hypothesis that the early cessation of erythropoietin (Ep) production during hypobaric hypoxia is induced by lowered food intake, we have compared the plasma Ep titer of rats after exposure to continuous hypoxia (42.6 kPa = 7000 m altitude) for 4 days with that in FED OR FASTED RATS AFTER EXPOSURE TO DISCONTINUOUS HYPOXIA. We found that plasma Ep was rather low after 4 days of continuous hypoxia. However, the Ep titer significantly rose again, when rats were maintained normoxic for 18 h and then exposed to repeated hypoxia for 6 h. Because this was also found in rats which were deprived of food during the normoxic interval and the second hypoxic period, we conclude that the fall of the Ep titer during continuous hypoxia is not primarily due to reduced food intake. In addition, OUR FINDINGS SHOW THAT FASTING PER SE LOWERS THE EPO-RESPONSE TO HYPOXIA IN NORMAL RATS BUT NOT EXHYPOXIC RATS.[6] Maintaining caloric balance from exercise expense versus food intake is necessary for EPO-release.

OTHER HORMONAL AND CALORIC FACTORS INFLUENCE NATURAL EPO RATE

EPO production also has hormonal-dependant roots complexly related to glucose metabolism, and caloric adequacy. The effect of 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. ERYTHROPOIETIN 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 erythropoietin 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 it. THESE RESULTS INDICATE THAT CALORIC DEPRIVATION IS PRIMARILY RESPONSIBLE FOR THE DECREASED ERYTHROPOIETIN PRODUCTION INDUCED BY FASTING AND THAT THIS EFFECT IS PROBABLY MEDIATED BY BOTH A DECREASED LEVEL OF T3 AND A DECREASED RESPONSIVENESS TO IT. [7]

DIETARY IRON ABSORPTION INLUENCES ERYTHROPOIETIN

Dietary interventions may significantly advance nonheme IRON ABSORPTION during EPO production. It is most important to include foods that enhance nonheme iron absorption, when an iron loss are exceptionally high, or when no heme iron is consumed [vegan diet]. Absorption of heme iron is very efficient; the presence of red meat may increase absorption of non-heme iron four times. Only 1-7% of the nonheme iron in vegetable staples such as rice, maize, black beans, soybeans and wheat is absorbed when consumed by itself. Meat proteins and vitamin C will improve the absorption of nonheme iron. Diets that include a minimum of 5 servings of fruits and vegetables daily, provide adequate vitamin C to boost nonheme iron absorption. Calcium, polyphenols and tannins found in tea, and phytates, a component of plant foods such as legumes, rice and grains, inhibit the absorption of nonheme iron. Some of the proteins found in soybeans may inhibit nonheme iron absorption. Most healthy individuals maintain normal iron stores when the diet provides a wide variety of foods. However, 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. A favorable absorption of heme iron is further influenced by other foods in the diet such as foods containing vitamin C and an acid environment found in the stomach. The Recommended Dietary Allowance (RDA) for iron is 10 milligrams for adult males and postmenopausal females. Males (ages 11 to 18) need 12 milligrams of iron per day. Females (ages 11 to 50 years) need 15 milligrams. Most endurance athletes consume too much iron from their daily menu. Iron is fortified in breads, cereals, and a number of packaged products. I performed dietary analysis on 16 endurance athletes' and 9 non-endurance athlete's iron intake from their reported food intake in a series of computer-generated Dietary Analysis data collected over a 3 year period.

The results of this review are as follows:

AVERAGE MALE ENDURANCE ATHLETE'S DAILY IRON INTAKE FROM FOODS

N=9 AVERAGE=279%

AVERAGE FEMALE ENDURANCE ATHLETE'S DAILY IRON INTAKE FROM FOODS

N=7 AVERAGE=193%

AVERAGE MALE NON-ENDURANCE ATHLETE'S DAILY IRON INTAKE FROM FOODS

N=4 AVERAGE=158%

AVERAGE FEMALE NON-ENDURANCE ATHLETE'S DAILY IRON INTAKE FROM FOODS

N=5 AVERAGE=115%

Excessive iron overload is not healthy. Common side effects of iron overload include gastro-intestinal pain, constipation, nausea, and heartburn. Excess iron levels may generate a continuous low-grade infection. Foods are the best source to assure iron adequacy. 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 provide supplemental iron in the diet. Anemia may develop on a meat-free diet, if 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 is harmful to cardiovascular lipid health. 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 advancing dietary substrates to regenerate EPO levels. This is 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. [8] Hematocrit levels are restored by getting adequate substrates [list below] that support the body's natural mechanisms for producing the EPO it requires for handling imposed endurance exercise stress.

SUBSTRATES REQUIRED FOR ERYTHROPOIETIN [EPO] METABOLISM [9]

- Acidophilus - 2-8 Billion Count, Good Bacteria

- Coenzyme Q10 - 100-150 mg daily

- Garlic capsules - 2 capsules 3 x daily

- Germanium - 200 mg daily

- Kelp - 100-225 micrograms/day

- Vitamin B6 - 50 mg 1-3 daily

- Vitamin B12 - 200-1,000 mcg

- Folic Acid - 800 mcg

- Proteolytic enzymes - Bromelain & Papain

- Selenium - 200 mcg daily

- Vitamin A - 15,000 IU daily or Beta Carotene - 25,000 IU daily

- Vitamin B Complex - 50-100 mg/day

- Vitamin C plus Bioflavonoids - 1-3 grams daily [divided dose]

- Vitamin E - 400 IU daily

- Copper - 2 mg daily

- Zinc chelate or Picolinate- 50-80 mg daily ---->(Do not take zinc in amounts over 100 mg daily as it can impair the immune response.)

CONCLUSION

Nutritional imbalances imposed from caloric restriction, overhydration, excessive supplemental calcium or inositol, dietary oxalates or phytates from dark green leafy vegetables or whole cereal grains, and lack of hypoxic interval training are factors which may inhibit the optimal natural production of Erythropoietin [EPO]. Manipulating diet, hydration, supplements, exercise intensity, and rest in order to maximize EPO for optimal hematocrit and oxygen carrying capacity is not without risk when HCT is above 48%. Why limit hematocrit to 48%? When hematocrit levels exceed 48%, risk of insulin resistance syndrome and stroke exponentially increase. Men with hematocrits of 48 percent or higher have an fourfold-increased rate of non-insulin-dependent-diabetes mellitus, according to a study from Royal Free Hospital School of Medicine in London. They followed over 7,000 middle-aged men for more than 12 years, and discovered that the risk of diabetes increases as the hematocrit increases. [10] The upper recommended levels for a female is 45%.

Nutritional interventions and exercise balance are key to provoking optimal, not excessive levels of EPO. Nutritional and training interventions for resolving low EPO levels need to be periodically monitored to determine progress toward normal reference ranges of no higher than 48% in men, 45% in women. Regular physician-diagnostic blood labs are well advised to confirm if such strategies are appropriate for resolving deficiencies and/or preventing performance inhibition.

REFERENCES

[1]-CLINICAL PHARMACOLOGY OF PROCRIT from the World Wide Web, cited 2-14-2002 @: http://www.procrit.com/profonly/nephrology/what_is_procrit/clinical_pharmacology.html

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

[3]-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.

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

Barrio Rendo ME. Related Articles

[5]-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.

[6]-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.

[7]-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.

[8]-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.

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

[10]-Diabetes 45:576-579, 1997.

*Dr. Bill Misner Ph.D. is the Director of Research & Product Development for E-CAPS INC. & HAMMER NUTRITION LTD. 1-800-336-1977 E-Mail: askdrbill@e-caps.com

http://www.e-caps.com

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