ERYTHROPOIETIN (EPO)

ERYTHROPOIETIN (EPO) is a naturally occurring hormone that stimulates the production of red blood cells (RBC). EPO levels up to 48% safely improve performance in males, however beyond this level, the risk of compromised health increases.

Erythropoietin (EPO) is most commonly known as the cytokine secreted by the kidneys that stimulates red blood cell production and is used as a drug for the treatment of anemias. Epo is also secreted in the brain in response to hypoxia, such as ischemic stroke. Epo production in the brain is stimulated by the hypoxia-inducible transcription factor HIF-1 (see HIF pathway). Administration of Epo to the brain in rodents before hypoxic stress or other neuronal stresses is neuroprotective, preventing neuronal apoptosis. The erythropoietin receptor (EpoR) is known to associate with JAK kinases that phosphorylate and activate the STAT family of transcription factors (See Epo pathway). The neuroprotection by Epo involves cross-talk between Epo receptor and anti-apoptotic pathways through activation of NF-kB by the JAK2 kinase (see NF-kB pathway). Epo stimulates JAK2 phosphorylation of I-kB, releasing NF-kB to translocate into the nucleus and activate transcription of neuroprotective genes. Neuroprotective genes activated by NF-kB include the anti-oxidant enzyme manganese superoxide dismutase and calbindin-D(28k). The erythropoietin receptor is also essential for proper brain development in mice. The absence of EpoR causes high levels of neuronal apoptosis in the developing mouse brain, further confirming the important role of Epo as a neuroprotective agent.

What nutritional protocol safely increases natural production of EPO?

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. 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.[2] In the absence of erythropoietin, only a few RBC's are formed by the bone marrow. EPO increases the blood-oxygen carrying capacity but only up to a point, but beyond, it may compromise health and hinder blood flow dynamics with performance-limiting implications.

EXCESS EPO CAN BE LETHAL

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 Erythropoietin can cause elevated Hematocrit levels (i.e. thickened blood is difficult to pump). Elevated EPO increases the risk of heart attack (due to the increase in hematocrit). 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 (although its physiological effects prevail for several months).[3]

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[7] 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 increased hematocrit and increase in EPO in subjects undergoing plasmapheresis suggests that plasma volume may also modulate the production of EPO.[8]

does exercise intensity increase erythropoietin?

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. 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. 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]

Fitness of these athletes provides a physiological environment for increasing EPO naturally from short 3-minute all-out intervals.

DIETARY INTERVENTIONS REDUCE ANEMIA AND INCREASE OXYGEN CARRYING CAPACITY

COMMON CAUSES OF ANEMIA

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 appear in two forms:

1.      Low red blood cell count

2.      Malformed red blood cells.

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 dying "retired" red blood cells. The causes of iron deficiency are iron-poor food, lead poisoning, chemotherapy, dehydration, poor absorption of iron from food or supplements, and blood loss. Anemia develops slowly, after the normal stores of iron from the body tissues and bone marrow are reduced to low levels. Women, in general, have smaller stores of iron than men and experience increased blood loss through menstruation, placing them at higher risk for anemia than men. Runners are also reported to lose more blood during heel strike during gait motion than cyclists, whose impact riding is noticeably less than running. In men and postmenopausal women, anemia is usually due to gastrointestinal blood loss associated with ulcers, nonsteroidal anti-inflammatory medications (NSAIDS), or colon cancer.

High-risk groups include:

1.      Women of child-bearing age who have blood loss through menstruation

2.      Pregnant or lactating women who have an increased requirement for iron

3.      Infants, children, and adolescents in rapid growth phases

4.      People with poor dietary intake of iron through little or no eggs, meat for several years.

5.      Blood loss from peptic ulcer disease, long term aspirin/NSAIDS, colon cancer

6.      Cancer-related drug therapy & chemotherapy

7.      Athletes whose sport requires running

WHAT IS THE EFFECT OF EXERCISE ON EPO (HEMATOCRIT)?

The paradox of hematocrit in exercise physiology is that artificially increasing it by autotransfusion or erythropoietin doping improves VO2 max and performance, while in normal conditions there is a strong negative correlation between hematocrit and fitness, due to a training-induced "Autohemodilution". Brun et al. reported that in professional soccer footballers:

�        Physiological values of hematocrit in athletes were comprised between 36 and 48%

�        Low hematocrit (<40%) was associated with a higher aerobic capacity

�        Subjects with the higher hematocrits (>44.6%) were frequently overtrained and/or iron-deficient, and their blood viscosity (and red cell disaggregability) tended to be increased.[10]

Over the past 9 years several endurance athletes have complained of low hematocrit levels. In 6 elite endurance athletes ranging from 31-67 years age, hair lab analysis showed iron deficiency, in spite of a calorie-sufficient dietary iron intake. Proper nutrition permits the body to set optimal natural (EPO) hematocrit levels. The diet should contain specific blood-iron building blocks, first from whole foods, second from supplements. However, an athlete should not take supplemental iron unless prescribed and monitored by a physician.

SYMPTOM-SPECIFIC EPO DEFICIENCY

The rate hematocrit increases varying specific to the individual but it may be improved applying dietary interventions with hypoxic interval sessions. The same dietary intervention that relieves Anemia is the protocol for increasing blood oxygen capacity of any endurance athlete. The most common cause is iron-deficiency anemia in red blood cells, 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).

Lack of iron for hemoglobin

CAUSES:

1.      Loss of iron from the body due to blood loss

2.      Poor absorption of iron from one's diet

3.      Lack of dietary iron

4.      Radiotherapy or Chemotherapy

5.      Anti-cancer drugs

6.      Certain types of viral infections

7.      Genetic reasons

8.      A result of malaria

9.      AIDS

10.  A deficiency of Vitamin B-12

11.  A deficiency of folic acid

12.  An imbalanced ratio of B-12:Folate

SYMPTOMS OF ANEMIA

• Tiredness and weakness
• Lethargy
• Dizziness, shortness of breath, and palpitations(rapid heart rate)
• Headaches
• Pale complexion
• Brittle nails (due to lack of iron)
• Irritability
• Sore tongue
• Unusual food cravings (called pica)
• Decreased appetite
• Headache - frontal
• Blue tinge to sclerae (whites of eyes)
• There may be no symptoms if anemia is mild.

NUTRITION BUILDING BLOCKS INCREASE EPO

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.

Inadequate dietary 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.

Calorie inadequacy is a secondary factor in EPO production including red blood cell quality and quantity. 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 with that in fed or fasted rats after exposure to discontinuous hypoxia. They 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, they concluded that the fall of the Ep titer during continuous hypoxia is not primarily due to reduced food intake. In addition, these findings show that fasting per se lowers the EPO-response to hypoxia in normal rats but not exhypoxic rats.[12] 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.

HORMONE & GLUCOSE IMPACT EPO LEVELS

IRON ABSORPTION RATE EFFECTS ERYTHROPOIETIN RELEASED

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 collect follows:

GROUP	PERCENT DAILY IRON (RDI/RDA)
MALE ENDURANCE ATHLETE	279%
FEMALE ENDURANCE ATHLETE	193%
MALE SEDENTARY	158%
FEMALE SEDENTARY	115%

FOOD COMBINATIONS THAT INFLUENCE IRON ABSORPTION

Diet then likely provides enough iron, but 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 ASSIST ERYTHROPOIETIN [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)

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 vitamin C to a 3-4 ounce lean cut of red meat cooked in an iron skillet 1-2 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]

CONCLUSIONS

Nutritional imbalance from caloric restriction (or exercise related expense), dehydration, fluid intoxication, excess calcium, excess inositol, excess oxalates foods[17], excess phytic acid from cereal grains[18], or a lack of hypoxic (interval training) are factors that inhibit the natural production of Erythropoietin (EPO).

Manipulating diet for protein and total calorie adequacy, monitoring hydration, supplements, timing food combinations, adding weekly hypoxic exercise followed by easy or rest days increases the release of natural EPO for healthy maximal oxygen carrying capacity. When individual hematocrit exceeds 48%, the risk of insulin resistance syndrome and stroke exponentially increase. Men with hematocrits above 48 percent have a 400% increased risk of non-insulin-dependent-diabetes mellitus. This 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] The upper recommended levels for a female is slightly lower at 45%.

This nutritional intervention parallels exercise intensity s 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]

Source 1,