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Regulation of Red Blood Cell Volume with Exercise Training

David Montero, Carsten Lundby

10.1002/cphy.c180004

Source: Volume 9, Issue 1, January 2019

Published online: December 2018

Full Article on Wiley Online Library



ABSTRACT

Hypervolemia is a hallmark of endurance training (ET) and manifests by similar elevations in plasma (PV) and red blood cell volume (RBCV) so that hematocrit largely remains unaltered following weeks/months of training. While the mechanisms facilitating PV expansion with ET have been previously reviewed extensively this is not the case for RBCV. Endurance champions may have 40% more RBCV than controls and RBCV may increase up to 10% following months of regular exercise training in healthy individuals. Such adaptations are the main factor leading to concomitant changes in maximal oxygen uptake. The increase in RBCV is preceded by that of PV after few ET sessions, which in turn transiently decreases the hematocrit. The “critmeter” theory suggests that O2 sensors located within the juxtamedullary apparatus regulate the hematocrit via modulation of renal erythropoietin (EPO) production according to arterial O2 content‐dependent changes in tissue O2 pressure. Hence, the initial decrease in hematocrit can be considered as a primary mechanism facilitating RBCV expansion with ET. Furthermore, after a single endurance exercise bout blood volume‐regulating hormones ANGII and VPN increase transiently. Both stimulate renal EPO production. Catecholamines and cortisol, stress hormones acutely increased by endurance exercise, may facilitate the release of red blood cells from the bone marrow, thus possibly contributing to ET‐induced erythropoiesis. These and other endocrine effects could be enhanced by the hyperplasia of the hematopoietic bone marrow observed in endurance athletes. © 2019 American Physiological Society. Compr Physiol 9:149‐164, 2019.

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Figure 1. Figure 1. Relationship of hemoglobin mass and blood volumes with aerobic capacity. Aerobic capacity, represented by maximal oxygen consumption (VO2max), is closely associated with blood volumes in humans along the continuum of VO2max from healthy young untrained individuals to Olympic champions in endurance disciplines. The strongest determinants of VO2max are red blood cell volume (RBCV) and hemoglobin mass (nHb), followed by blood volume (BV) and plasma volume (PV). The concentration of hemoglobin in blood ([Hb]) is not associated with VO2max, underlining the importance of volumetric variables facilitating cardiac output over relatively uniform [Hb] values.
Figure 2. Figure 2. Changes in blood volumes with endurance training. This figure presents absolute (A) and relative (B) changes in blood volume (BV) (circles), red blood cell volume (RBCV) (squares), and plasma volume (PV) (triangles) throughout 8 weeks of a typical endurance training program (3‐4 × 60 min, moderate‐to‐high intensity cycle ergometry sessions per week) in healthy young untrained individuals. Endurance training elicits substantial increases in RBCV from week 4, preceded by marked PV expansion during the initial weeks, resulting in reduced hematocrit. At week 8, RBCV is further increased while PV expansion is slightly attenuated, thus approaching normal hematocrit levels.
Figure 3. Figure 3. Acute effect of endurance exercise on circulating erythropoietin (EPO). This figure shows plasma EPO concentration from 7 to 10 AM in healthy young untrained individuals following a session of endurance exercise (1‐h of cycle ergometry at 55% of maximal power output) (filled circles) or 1‐h rest (open circles). Plasma EPO concentration acutely increases following endurance exercise. This increase is accentuated 3 h after stopping exercise, independently of exercise‐induced hemoconcentration.
Figure 4. Figure 4. Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): the critmeter hypothesis. Endurance exercise‐induced plasma volume expansion lowers hematocrit and arterial O2 content, resulting in decreased tissue O2 pressure in the juxtamedullary region of the cortical labyrinth in the kidney, stimulating EPO‐producing cells (peritubular fibroblast‐like cells). Augmented circulating EPO enhance erythropoiesis in the bone marrow, increasing red blood cell volume and hence tending to restore hematocrit and arterial O2 content, closing a negative feedback loop.
Figure 5. Figure 5. Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): baroreflex‐endocrine responses to reduced central venous pressure. Central venous pressure, which reflects the filling state of the cardiovascular system, is reduced for several hours after endurance exercise, in part due to peripheral vasodilation. The reduction in central venous pressure is sensed by cardiopulmonary and arterial baroreceptors, triggering the release of blood volume (BV)‐regulating hormones such as angiotensin II (ANGII) and vasopressin (VPN). These hormones stimulate renal EPO production via direct activation of renal receptors as well as through the increase of sodium reabsorption leading to decreased tissue O2 pressure in peritubular fibroblast‐like cells. Ultimately, the EPO‐induced enhancement of red blood cell volume contributes, along with plasma volume expansion, to blood pressure homeostasis with endurance training.
Figure 6. Figure 6. Acute effect of endurance exercise on endocrine factors modulating bone marrow erythropoiesis. Besides erythropoietin, several hormones possessing erythropoietic activity are transiently elevated with endurance exercise. Catecholamines augment the release of hematopoietic stem cells from the bone marrow, mediated by chemokine stromal cell derived factor‐1 (SDF‐1). Another stress hormone, cortisol, stimulates differentiation, and mobilization of erythroid progenitor cells (EPCs) via Notch signaling pathways. Furthermore, growth hormone (GH) and its mediator insulin‐like growth factor 1 (IGF‐1) can induce erythroid cell growth and differentiation in the bone marrow. Overall, endurance exercise enhances plasma erythropoietic activity via redundant endocrine pathways.


Figure 1. Relationship of hemoglobin mass and blood volumes with aerobic capacity. Aerobic capacity, represented by maximal oxygen consumption (VO2max), is closely associated with blood volumes in humans along the continuum of VO2max from healthy young untrained individuals to Olympic champions in endurance disciplines. The strongest determinants of VO2max are red blood cell volume (RBCV) and hemoglobin mass (nHb), followed by blood volume (BV) and plasma volume (PV). The concentration of hemoglobin in blood ([Hb]) is not associated with VO2max, underlining the importance of volumetric variables facilitating cardiac output over relatively uniform [Hb] values.


Figure 2. Changes in blood volumes with endurance training. This figure presents absolute (A) and relative (B) changes in blood volume (BV) (circles), red blood cell volume (RBCV) (squares), and plasma volume (PV) (triangles) throughout 8 weeks of a typical endurance training program (3‐4 × 60 min, moderate‐to‐high intensity cycle ergometry sessions per week) in healthy young untrained individuals. Endurance training elicits substantial increases in RBCV from week 4, preceded by marked PV expansion during the initial weeks, resulting in reduced hematocrit. At week 8, RBCV is further increased while PV expansion is slightly attenuated, thus approaching normal hematocrit levels.


Figure 3. Acute effect of endurance exercise on circulating erythropoietin (EPO). This figure shows plasma EPO concentration from 7 to 10 AM in healthy young untrained individuals following a session of endurance exercise (1‐h of cycle ergometry at 55% of maximal power output) (filled circles) or 1‐h rest (open circles). Plasma EPO concentration acutely increases following endurance exercise. This increase is accentuated 3 h after stopping exercise, independently of exercise‐induced hemoconcentration.


Figure 4. Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): the critmeter hypothesis. Endurance exercise‐induced plasma volume expansion lowers hematocrit and arterial O2 content, resulting in decreased tissue O2 pressure in the juxtamedullary region of the cortical labyrinth in the kidney, stimulating EPO‐producing cells (peritubular fibroblast‐like cells). Augmented circulating EPO enhance erythropoiesis in the bone marrow, increasing red blood cell volume and hence tending to restore hematocrit and arterial O2 content, closing a negative feedback loop.


Figure 5. Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): baroreflex‐endocrine responses to reduced central venous pressure. Central venous pressure, which reflects the filling state of the cardiovascular system, is reduced for several hours after endurance exercise, in part due to peripheral vasodilation. The reduction in central venous pressure is sensed by cardiopulmonary and arterial baroreceptors, triggering the release of blood volume (BV)‐regulating hormones such as angiotensin II (ANGII) and vasopressin (VPN). These hormones stimulate renal EPO production via direct activation of renal receptors as well as through the increase of sodium reabsorption leading to decreased tissue O2 pressure in peritubular fibroblast‐like cells. Ultimately, the EPO‐induced enhancement of red blood cell volume contributes, along with plasma volume expansion, to blood pressure homeostasis with endurance training.


Figure 6. Acute effect of endurance exercise on endocrine factors modulating bone marrow erythropoiesis. Besides erythropoietin, several hormones possessing erythropoietic activity are transiently elevated with endurance exercise. Catecholamines augment the release of hematopoietic stem cells from the bone marrow, mediated by chemokine stromal cell derived factor‐1 (SDF‐1). Another stress hormone, cortisol, stimulates differentiation, and mobilization of erythroid progenitor cells (EPCs) via Notch signaling pathways. Furthermore, growth hormone (GH) and its mediator insulin‐like growth factor 1 (IGF‐1) can induce erythroid cell growth and differentiation in the bone marrow. Overall, endurance exercise enhances plasma erythropoietic activity via redundant endocrine pathways.
References
 1.Altehoefer C, Schmid A, Buchert M, Ghanem NA, Heinrich L, Langer M. Characterization of hematopoietic bone marrow in male professional cyclists by magnetic resonance imaging of the lumbar spine. J Magn Reson Imaging 16: 284‐288, 2002.
 2.Arlettaz A, Portier H, Lecoq AM, Rieth N, De Ceaurriz J, Collomp K. Effects of short‐term prednisolone intake during submaximal exercise. Med Sci Sports Exerc 39: 1672‐1678, 2007.
 3.Astrand PO, Saltin B. Plasma and red cell volume after prolonged severe exercise. J Appl Physiol 19: 829‐832, 1964.
 4.Bacon AP, Carter RE, Ogle EA, Joyner MJ. VO2max trainability and high intensity interval training in humans: A meta‐analysis. PLoS One 8: e73182, 2013.
 5.Baschetti R. Chronic fatigue syndrome: A form of Addison's disease. J Intern Med 247: 737‐739, 2000.
 6.Bauer A, Tronche F, Wessely O, Kellendonk C, Reichardt HM, Steinlein P, Schütz G, Beug H. The glucocorticoid receptor is required for stress erythropoiesis. Genes Dev 13: 2996‐3002, 1999.
 7.Beardwell CG, Geelen G, Palmer HM, Roberts D, Salamonson L. Radioimmunoassay of plasma vasopressin in physiological and pathological states in man. J Endocrinol 67: 189‐202, 1975.
 8.Bergmann M, Gornikiewicz A, Sautner T, Waldmann E, Weber T, Mittlböck M, Roth E, Függer R. Attenuation of catecholamine‐induced immunosuppression in whole blood from patients with sepsis. Shock 12: 421‐427, 1999.
 9.Bie P, Secher NH, Astrup A, Warberg J. Cardiovascular and endocrine responses to head‐up tilt and vasopressin infusion in humans. Am J Physiol 251: R735‐R741, 1986.
 10.Bonne TC, Doucende G, Fluck D, Jacobs RA, Nordsborg NB, Robach P, Walther G, Lundby C. Phlebotomy eliminates the maximal cardiac output response to six weeks of exercise training. Am J Physiol Regul Integr Comp Physiol 306: R752‐R760, 2014.
 11.Bonsignore MR, Morici G, Riccioni R, Huertas A, Petrucci E, Veca M, Mariani G, Bonanno A, Chimenti L, Gioia M, Palange P, Testa U. Hemopoietic and angiogenetic progenitors in healthy athletes: Different responses to endurance and maximal exercise. J Appl Physiol (1985) 109: 60‐67, 2010.
 12.Bonsignore MR, Morici G, Santoro A, Pagano M, Cascio L, Bonanno A, Abate P, Mirabella F, Profita M, Insalaco G, Gioia M, Vignola AM, Majolino I, Testa U, Hogg JC. Circulating hematopoietic progenitor cells in runners. J Appl Physiol (1985) 93: 1691‐1697, 2002.
 13.Borovka M, Teruya S, Alvarez J, Helmke S, Maurer MS. Differences in blood volume components between hyporesponders and responders to erythropoietin alfa: The heart failure with preserved ejection fraction (HFPEF) anemia trial. J Card Fail 19: 685‐691, 2013.
 14.Bragadottir G, Redfors B, Nygren A, Sellgren J, Ricksten SE. Low‐dose vasopressin increases glomerular filtration rate, but impairs renal oxygenation in post‐cardiac surgery patients. Acta Anaesthesiol Scand 53: 1052‐1059, 2009.
 15.Brandenberger G, Weibel L. The 24‐h growth hormone rhythm in men: Sleep and circadian influences questioned. J Sleep Res 13: 251‐255, 2004.
 16.Bratosin D, Mazurier J, Tissier JP, Estaquier J, Huart JJ, Ameisen JC, Aminoff D, Montreuil J. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review. Biochimie 80: 173‐195, 1998.
 17.Breymann C, Rohling R, Huch A, Huch R. Intraoperative endogenous erythropoietin levels and changes in intravascular blood volume in healthy humans. Ann Hematol 79: 183‐6, 2000.
 18.Brotherhood J, Brozovic B, Pugh LG. Haematological status of middle‐ and long‐distance runners. Clin Sci Mol Med 48: 139‐145, 1975.
 19.Bunt JC, Boileau RA, Bahr JM, Nelson RA. Sex and training differences in human growth hormone levels during prolonged exercise. J Appl Physiol (1985) 61: 1796‐1801, 1986.
 20.Calbet JA, Lundby C, Koskolou M, Boushel R. Importance of hemoglobin concentration to exercise: Acute manipulations. Respir Physiol Neurobiol 151: 132‐140, 2006.
 21.Caldemeyer KS, Smith RR, Harris A, Williams T, Huang Y, Eckert GJ, Slemenda CW. Hematopoietic bone marrow hyperplasia: Correlation of spinal MR findings, hematologic parameters, and bone mineral density in endurance athletes. Radiology 198: 503‐508, 1996.
 22.Claustres M, Chatelain P, Sultan C. Insulin‐like growth factor I stimulates human erythroid colony formation in vitro. J Clin Endocrinol Metab 65: 78‐82, 1987.
 23.Colao A, Cuocolo A, Marzullo P, Nicolai E, Ferone D, Florimonte L, Salvatore M, Lombardi G. Effects of 1‐year treatment with octreotide on cardiac performance in patients with acromegaly. J Clin Endocrinol Metab 84: 17‐23, 1999.
 24.Collomp K, Arlettaz A, Portier H, Lecoq AM, Le Panse B, Rieth N, De Ceaurriz J. Short‐term glucocorticoid intake combined with intense training on performance and hormonal responses. Br J Sports Med 42: 983‐988, 2008.
 25.Connell JM, Whitworth JA, Davies DL, Lever AF, Richards AM, Fraser R. Effects of ACTH and cortisol administration on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man. J Hypertens 5: 425‐433, 1987.
 26.Convertino VA. Blood volume response to physical activity and inactivity. Am J Med Sci 334: 72‐79, 2007.
 27.Convertino VA, Keil LC, Bernauer EM, Greenleaf JE. Plasma volume, osmolality, vasopressin, and renin activity during graded exercise in man. J Appl Physiol Respir Environ Exerc Physiol 50: 123‐128, 1981.
 28.Convertino VA, Mack GW, Nadel ER. Elevated central venous pressure: A consequence of exercise training‐induced hypervolemia? Am J Physiol 260: R273‐R277, 1991.
 29.Costa RJ, Jones GE, Lamb KL, Coleman R, Williams JH. The effects of a high carbohydrate diet on cortisol and salivary immunoglobulin A (s‐IgA) during a period of increase exercise workload amongst Olympic and Ironman triathletes. Int J Sports Med 26: 880‐885, 2005.
 30.Coyle EF, Hemmert MK, Coggan AR. Effects of detraining on cardiovascular responses to exercise: Role of blood volume. J Appl Physiol (1985) 60: 95‐99, 1986.
 31.Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH. Growth hormone treatment in growth hormone‐deficient adults. II. Effects on exercise performance. J Appl Physiol (1985) 70: 695‐700, 1991.
 32.Cupps TR, Fauci AS. Corticosteroid‐mediated immunoregulation in man. Immunol Rev 65: 133‐155, 1982.
 33.Christ ER, Cummings MH, Westwood NB, Sawyer BM, Pearson TC, Sönksen PH, Russell‐Jones DL. The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency. J Clin Endocrinol Metab 82: 2985‐2990, 1997.
 34.Damsgaard R, Munch T, Morkeberg J, Mortensen SP, Gonzalez‐Alonso J. Effects of blood withdrawal and reinfusion on biomarkers of erythropoiesis in humans: Implications for anti‐doping strategies. Haematologica 91: 1006‐1008, 2006.
 35.Dar A, Schajnovitz A, Lapid K, Kalinkovich A, Itkin T, Ludin A, Kao WM, Battista M, Tesio M, Kollet O, Cohen NN, Margalit R, Buss EC, Baleux F, Oishi F, Fujii N, Larochelle A, Dunbar CE, Broxmeyer HE, Frenette PS, Lapidot T. Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4‐dependent SDF‐1 release from bone marrow stromal cells. Leukemia 25: 1286‐1296, 2011.
 36.Davidson RJ, Robertson JD, Galea G, Maughan RJ. Hematological changes associated with marathon running. Int J Sports Med 8: 19‐25, 1987.
 37.de la Chapelle A, Traskelin AL, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci U S A 90: 4495‐4499, 1993.
 38.De Lisio M, Parise G. Characterization of the effects of exercise training on hematopoietic stem cell quantity and function. J Appl Physiol (1985) 113: 1576‐1584, 2012.
 39.Dhabhar FS. Enhancing versus suppressive effects of stress on immune function: Implications for immunoprotection and immunopathology. Neuroimmunomodulation 16: 300‐317, 2009.
 40.Dill DB, Braithwaite K, Adams WC, Bernauer EM. Blood volume of middle‐distance runners: Effect of 2,300‐m altitude and comparison with non‐athletes. Med Sci Sports 6: 1‐7, 1974.
 41.Donnelly S. Why is erythropoietin made in the kidney? The kidney functions as a critmeter. Am J Kidney Dis 38: 415‐425, 2001.
 42.Dressendorfer RH, Wade CE. Effects of a 15‐d race on plasma steroid levels and leg muscle fitness in runners. Med Sci Sports Exerc 23: 954‐958, 1991.
 43.Duclos M, Tabarin A. Exercise and the hypothalamo‐pituitary‐adrenal axis. Front Horm Res 47: 12‐26, 2016.
 44.Dunn A, Lo V, Donnelly S. The role of the kidney in blood volume regulation: The kidney as a regulator of the hematocrit. Am J Med Sci 334: 65‐71, 2007.
 45.Egan B, Grekin R, Ibsen H, Osterziel K, Julius S. Role of cardiopulmonary mechanoreceptors in ADH release in normal humans. Hypertension 6: 832‐836, 1984.
 46.Ehmke H, Just A, Eckardt KU, Persson PB, Bauer C, Kirchheim HR. Modulation of erythropoietin formation by changes in blood volume in conscious dogs. J Physiol 488(Pt 1): 181‐191, 1995.
 47.Eliakim A, Nemet D, Cooper DM. Exercise, training and the GH–IGF‐I axis. In: WJ Kraemer, AD Rogol editors. The Endocrine System in Sports and Exercise. Massachusetts, USA: Blackwell Publishing, 2005, pp. 165‐179.
 48.Engan HK, Lodin‐Sundstrom A, Schagatay F, Schagatay E. The effect of climbing Mount Everest on spleen contraction and increase in hemoglobin concentration during breath holding and exercise. High Alt Med Biol 15: 52‐57, 2014.
 49.Engel A, Pagel H. Increased production of erythropoietin after application of antidiuretic hormone. A consequence of renal vasoconstriction? Exp Clin Endocrinol Diabetes 103: 303‐307, 1995.
 50.Epperson WL, Burton RR, Bernauer EM. The influence of differential physical conditioning regimens on simulated aerial combat maneuvering tolerance. Aviat Space Environ Med 53: 1091‐1097, 1982.
 51.Erkelens DW, Statius van Eps LW. Bartter's syndrome and erythrocytosis. Am J Med 55: 711‐719, 1973.
 52.Fisher JW. Increase in circulating red cell volume of normal rats after treatment with hydrocortisone or corticosterone. Proc Soc Exp Biol Med 97: 502‐505, 1958.
 53.Florit EA, Hadad F, Rodriguez Cubillo B, De la Flor JC, Valga F, Perez Flores I, Calvo Romero N, Valero San Cecilio R, Barrientos Guzman A, Sanchez Fructuoso A. Anemia in kidney transplants without erythropoietic agents: Levels of erythropoietin and iron parameters. Transplant Proc 44: 2590‐2592, 2012.
 54.Freudenthaler SM, Lucht I, Schenk T, Brink M, Gleiter CH. Dose‐dependent effect of angiotensin II on human erythropoietin production. Pflugers Arch 439: 838‐844, 2000.
 55.Freudenthaler SM, Schreeb K, Korner T, Gleiter CH. Angiotensin II increases erythropoietin production in healthy human volunteers. Eur J Clin Invest 29: 816‐823, 1999.
 56.Galbo H. Hormonal and Metabolic Adaptation to Exercise. New York: Georg Thieme Verlag, 1983.
 57.Gardner FH, Nathan DG, Piomelli S, Cummins JF. The erythrocythaemic effects of androgen. Br J Haematol 14: 611‐615, 1968.
 58.Gasser C. [Aplastic anemia (chronic erythroblastophthisis) and cortisone]. Schweiz Med Wochenschr 81: 1241‐1242, 1951.
 59.Gauer OH, Henry JP. Circulatory basis of fluid volume control. Physiol Rev 43: 423‐481, 1963.
 60.Gibney J, Healy ML, Sonksen PH. The growth hormone/insulin‐like growth factor‐I axis in exercise and sport. Endocr Rev 28: 603‐624, 2007.
 61.Gillen CM, Lee R, Mack GW, Tomaselli CM, Nishiyasu T, Nadel ER. Plasma volume expansion in humans after a single intense exercise protocol. J Appl Physiol (1985) 71: 1914‐1920, 1991.
 62.Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti‐inflammatory effects of exercise: Mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 11: 607‐615, 2011.
 63.Godfrey RJ, Madgwick Z, Whyte GP. The exercise‐induced growth hormone response in athletes. Sports Med 33: 599‐613, 2003.
 64.Gossmann J, Burkhardt R, Harder S, Lenz T, Sedlmeyer A, Klinkhardt U, Geiger H, Scheuermann EH. Angiotensin II infusion increases plasma erythropoietin levels via an angiotensin II type 1 receptor‐dependent pathway. Kidney Int 60: 83‐86, 2001.
 65.Gozdz A, Szczepanska‐Sadowska E, Szczepanska K, Maslinski W, Luszczyk B. Vasopressin V1a, V1b and V2 receptors mRNA in the kidney and heart of the renin transgenic TGR(mRen2)27 and Sprague Dawley rats. J Physiol Pharmacol 53: 349‐357, 2002.
 66.Groenveld HF, Januzzi JL, Damman K, van Wijngaarden J, Hillege HL, van Veldhuisen DJ, van der Meer P. Anemia and mortality in heart failure patients a systematic review and meta‐analysis. J Am Coll Cardiol 52: 818‐827, 2008.
 67.Gunga HC, Kirsch K, Baartz F, Maillet A, Gharib C, Nalishiti W, Rich I, Röcker L. Erythropoietin under real and simulated microgravity conditions in humans. J Appl Physiol (1985) 81: 761‐773, 1996.
 68.Gunga HC, Kirsch KA, Rocker L. Central venous pressure and erythropoietin after spaceflight. Aviat Space Environ Med 65: 274, 1994.
 69.Gursoy A, Dogruk Unal A, Ayturk S, Karakus S, Nur Izol A, Bascil Tutuncu N, Guvener Demirag N. Polycythemia as the first manifestation of Cushing's disease. J Endocrinol Invest 29: 742‐744, 2006.
 70.Guyton AC. An overall analysis of cardiovascular regulation: Fifteenth annual Baxter‐Travenol lecture. Anesth Analg 56: 761‐768, 1977.
 71.Hackney AC. Endurance exercise training and reproductive endocrine dysfunction in men: Alterations in the hypothalamic‐pituitary‐testicular axis. Curr Pharm Des 7: 261‐273, 2001.
 72.Hamilton T, Coyle D. The Secret Race. Inside the Hidden World of the Tour de France. New York: Bantam, 2013.
 73.Hartley LH. Growth hormone and catecholamine response to exercise in relation to physical training. Med Sci Sports 7: 34‐36, 1975.
 74.Haskell A, Gillen CM, Mack GW, Nadel ER. Albumin infusion in humans does not model exercise induced hypervolaemia after 24 hours. Acta Physiol Scand 164: 277‐284, 1998.
 75.Haskell A, Nadel ER, Stachenfeld NS, Nagashima K, Mack GW. Transcapillary escape rate of albumin in humans during exercise‐induced hypervolemia. J Appl Physiol (1985) 83: 407‐413, 1997.
 76.Hattangady NG, Olala LO, Bollag WB, Rainey WE. Acute and chronic regulation of aldosterone production. Mol Cell Endocrinol 350: 151‐162, 2012.
 77.Heinicke K, Wolfarth B, Winchenbach P, Biermann B, Schmid A, Huber G, Friedmann B, Schmidt W. Blood volume and hemoglobin mass in elite athletes of different disciplines. Int J Sports Med 22: 504‐512, 2001.
 78.Helgerud J, Hoydal K, Wang E, Karlsen T, Berg P, Bjerkaas M, Simonsen T, Helgesen C, Hjorth N, Bach R, Hoff J. Aerobic high‐intensity intervals improve VO2max more than moderate training. Med Sci Sports Exerc 39: 665‐671, 2007.
 79.Hellsten Y, Nyberg M. Cardiovascular Adaptations to Exercise Training. Compr Physiol 6: 1‐32, 2015.
 80.Holmberg HC, Rosdahl H, Svedenhag J. Lung function, arterial saturation and oxygen uptake in elite cross country skiers: Influence of exercise mode. Scand J Med Sci Sports 17: 437‐444, 2007.
 81.Hopper MK, Coggan AR, Coyle EF. Exercise stroke volume relative to plasma‐volume expansion. J Appl Physiol (1985) 64: 404‐408, 1988.
 82.Horn PL, Pyne DB, Hopkins WG, Barnes CJ. Lower white blood cell counts in elite athletes training for highly aerobic sports. Eur J Appl Physiol 110: 925‐932, 2010.
 83.Hu M, Lin W. Effects of exercise training on red blood cell production: Implications for anemia. Acta Haematol 127: 156‐164, 2012.
 84.Hunter RW, Ivy JR, Bailey MA. Glucocorticoids and renal Na+ transport: Implications for hypertension and salt sensitivity. J Physiol 592: 1731‐1744, 2014.
 85.Jacobs RA, Lundby C. Mitochondria express enhanced quality as well as quantity in association with aerobic fitness across recreationally active individuals up to elite athletes. J Appl Physiol (1985) 114: 344‐350, 2013.
 86.Jahromi AS, Zar A, Ahmadi F, Krustrup P, Ebrahim K, Hovanloo F, Amani D. Effects of endurance training on the serum levels of tumour necrosis factor‐alpha and interferon‐gamma in sedentary men. Immune Netw 14: 255‐259, 2014.
 87.Jelkmann W. Regulation of erythropoietin production. J Physiol 589: 1251‐1258, 2011.
 88.Jelkmann W, Lundby C. Blood doping and its detection. Blood 118: 2395‐2404, 2011.
 89.Jepson J, McGarry EE. Polycythemia and increased erythropoietin production in a patient with hypertrophy of the juxta‐glomerular apparatus. Blood 32: 370‐375, 1968.
 90.Jepson JH, McGarry EE, Lowenstein L. Erythropoietin excretion in a hypopituitary patient. Effects of testosterone and vasopressin. Arch Intern Med 122: 265‐70, 1968.
 91.Kanaley JA, Weatherup‐Dentes MM, Jaynes EB, Hartman ML. Obesity attenuates the growth hormone response to exercise. J Clin Endocrinol Metab 84: 3156‐3161, 1999.
 92.Kanaley JA, Weltman JY, Pieper KS, Weltman A, Hartman ML. Cortisol and growth hormone responses to exercise at different times of day. J Clin Endocrinol Metab 86: 2881‐2889, 2001.
 93.Kanstrup IL, Ekblom B. Acute hypervolemia, cardiac performance, and aerobic power during exercise. J Appl Physiol Respir Environ Exerc Physiol 52: 1186‐1191, 1982.
 94.Karvonen J, Saarela J. Hemoglobin changes and decomposition of erythrocytes during 25 hours following a heavy exercise run. J Sports Med Phys Fitness 16: 171‐176, 1976.
 95.Kelly JJ, Martin A, Whitworth JA. Role of erythropoietin in cortisol‐induced hypertension. J Hum Hypertens 14: 195‐198, 2000.
 96.Kim TS, Hanak M, Trampont PC, Braciale TJ. Stress‐associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells. J Clin Invest 125: 3965‐3980, 2015.
 97.Kim YC, Mungunsukh O, McCart EA, Roehrich PJ, Yee DK, Day RM. Mechanism of erythropoietin regulation by angiotensin II. Mol Pharmacol 85: 898‐908, 2014.
 98.Kirsch K, Risch WD, Mund U, Röcker L, Stosoy H. Low pressure system and blood volume regulating hormones after prolonged exercise. In: SB AG editor. Metabolic Adaptation to Prolonged Physical Exercise. Lausanne 1975, pp. 315‐321.
 99.Kirsch KA, Rocker L, von Ameln H, Hrynyschyn K. The cardiac filling pressure following exercise and thermal stress. Yale J Biol Med 59: 257‐265, 1986.
 100.Kjellberg SR, Rudhe U, Sjöstrand T. Increase of the amount of hemoglobin and blood volume in connection with physical training. Acta Physiol Scand 19: 146‐151, 1949.
 101.Klein E, Brossaud J, Gatta B, Corcuff JB. Erythropoietin levels in endocrinopathies. J Endocrinol Invest 34: 427‐430, 2011.
 102.Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, Sugawara A, Totsuka K, Shimano H, Ohashi Y, Yamada N, Sone H. Cardiorespiratory fitness as a quantitative predictor of all‐cause mortality and cardiovascular events in healthy men and women: A meta‐analysis. JAMA 301: 2024‐2035, 2009.
 103.Kortenoeven ML, Pedersen NB, Rosenbaek LL, Fenton RA. Vasopressin regulation of sodium transport in the distal nephron and collecting duct. Am J Physiol Renal Physiol 309: F280‐F299, 2015.
 104.Koshimizu TA, Nasa Y, Tanoue A, Oikawa R, Kawahara Y, Kiyono Y, Adachi T, Tanaka T, Kuwaki T, Mori T, Takeo S, Okamura H, Tsujimoto G. V1a vasopressin receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity. Proc Natl Acad Sci U S A 103: 7807‐7812, 2006.
 105.Kurtz A, Eckardt KU. Erythropoietin production in chronic renal disease before and after transplantation. Contrib Nephrol 87: 15‐25, 1990.
 106.Kurtz A, Zapf J, Eckardt KU, Clemons G, Froesch ER, Bauer C. Insulin‐like growth factor I stimulates erythropoiesis in hypophysectomized rats. Proc Natl Acad Sci U S A 85: 7825‐7829, 1988.
 107.Le Hir M, Eckardt KU, Kaissling B, Koury ST, Kurtz A. Structure‐function correlations in erythropoietin formation and oxygen sensing in the kidney. Klin Wochenschr 69: 567‐575, 1991.
 108.Le Panse B, Thomasson R, Jollin L et al. Short‐term glucocorticoid intake improves exercise endurance in healthy recreationally trained women. Eur J Appl Physiol 107: 437‐443, 2009.
 109.Levine BD. VO2max: What do we know, and what do we still need to know? J Physiol 586: 25‐34, 2008.
 110.Liu H, Bravata DM, Olkin I, Friedlander A, Liu V, Roberts B, Bendavid E, Saynina O, Salpeter SR, Garber AM, Hoffman AR. Systematic review: The effects of growth hormone on athletic performance. Ann Intern Med 148: 747‐758, 2008.
 111.Lodish H, Flygare J, Chou S. From stem cell to erythroblast: Regulation of red cell production at multiple levels by multiple hormones. IUBMB Life 62: 492‐496, 2010.
 112.Lorentz A, Eckardt KU, Osswald PM, Duchow JR. Erythropoietin levels in patients depositing autologous blood in short intervals. Ann Hematol 64: 281‐285, 1992.
 113.Luetkemeier MJ, Flowers KM, Lamb DR. Spironolactone administration and training‐induced hypervolemia. Int J Sports Med 15: 295‐300, 1994.
 114.Lundby C, Montero D. CrossTalk opposing view: Diffusion limitation of O2 from microvessels into muscle does not contribute to the limitation of VO2max. J Physiol 593: 3759‐3761, 2015.
 115.Lundby C, Montero D, Joyner M. Biology of VO2max: Looking under the physiology lamp. Acta Physiol (Oxf) 2016.
 116.Lundby C, Robach P. Performance enhancement: What are the physiological limits? Physiology (Bethesda) 30: 282‐292, 2015.
 117.Lundby C, Robach P, Saltin B. The evolving science of detection of ‘blood doping’. Br J Pharmacol 165: 1306‐1315, 2012.
 118.Lundby C, Thomsen JJ, Boushel R, Koskolou M, Warberg J, Calbet JA, Robach P. Erythropoietin treatment elevates haemoglobin concentration by increasing red cell volume and depressing plasma volume. J Physiol 578: 309‐314, 2007.
 119.Lundgren KM, Karlsen T, Sandbakk O, James PE, Tjonna AE. Sport‐specific physiological adaptations in highly trained endurance athletes. Med Sci Sports Exerc 47: 2150‐2157, 2015.
 120.MacConnie SE, Barkan A, Lampman RM, Schork MA, Beitins IZ. Decreased hypothalamic gonadotropin‐releasing hormone secretion in male marathon runners. N Engl J Med 315: 411‐417, 1986.
 121.Mack GW. The body fluid and hemopoietic systems. In: C Tipton, MN Sawka, C Tate, T Terjung, editors. ACSM's Advanced Exercise Physiology. Philadelphia, PA: Lippincott Williams & Wilkins, 2006, pp. 501‐520.
 122.Mack GW, Yang R, Hargens AR, Nagashima K, Haskell A. Influence of hydrostatic pressure gradients on regulation of plasma volume after exercise. J Appl Physiol (1985) 85: 667‐675, 1998.
 123.Mairbaurl H, Humpeler E, Schwaberger G, Pessenhofer H. Training‐dependent changes of red cell density and erythrocytic oxygen transport. J Appl Physiol Respir Environ Exerc Physiol 55: 1403‐1407, 1983.
 124.Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P, Bernstein KE. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 375: 247‐250, 1995.
 125.Mathur N, Pedersen BK. Exercise as a mean to control low‐grade systemic inflammation. Mediators Inflamm 2008: 109502, 2008.
 126.McCarthy JP, Bamman MM, Yelle JM, LeBlanc AD, Rowe RM, Greenisen MC, Lee SM, Spector ER, Fortney SM. Resistance exercise training and the orthostatic response. European Journal of Applied Physiology and Occupational Physiology 76: 32‐40, 1997.
 127.McMahon M, Gerich J, Rizza R. Effects of glucocorticoids on carbohydrate metabolism. Diabetes Metab Rev 4: 17‐30, 1988.
 128.Means RT, Jr. Pathogenesis of the anemia of chronic disease: A cytokine‐mediated anemia. Stem Cells 13: 32‐37, 1995.
 129.Melin B, Eclache JP, Geelen G, Annat G, Allevard AM, Jarsaillon E, Zebidi A, Legros JJ, Gharib C. Plasma AVP, neurophysin, renin activity, and aldosterone during submaximal exercise performed until exhaustion in trained and untrained men. Eur J Appl Physiol Occup Physiol 44: 141‐151, 1980.
 130.Menuki K, Mori T, Sakai A, Sakuma M, Okimoto N, Shimizu Y, Kunugita N, Nakamura T. Climbing exercise enhances osteoblast differentiation and inhibits adipogenic differentiation with high expression of PTH/PTHrP receptor in bone marrow cells. Bone 43: 613‐620, 2008.
 131.Meurrens J, Steiner T, Ponette J, Hans Antonius J, Monique R, Jon Peter W, Philippe V, Louise D. Effect of repeated whole blood donations on aerobic capacity and hemoglobin mass in moderately trained male subjects: A randomized controlled trial. Sports Med Open 2: 43, 2016.
 132.Miller ME, Cronkite EP, Garcia JF. Plasma levels of immunoreactive erythropoietin after acute blood loss in man. Br J Haematol 52: 545‐549, 1982.
 133.Mobius‐Winkler S, Hilberg T, Menzel K, Golla E, Burman A, Schuler G, Adams V. Time‐dependent mobilization of circulating progenitor cells during strenuous exercise in healthy individuals. J Appl Physiol (1985) 107: 1943‐1950, 2009.
 134.Montero D, Breenfeldt‐Andersen A, Oberholzer A, Haider T, Goetze JP, Meinild‐Lundby AK, Lundby C. Erythropoiesis with endurance training: Dynamics and mechanisms. Am J Physiol Regul Integr Comp Physiol 312: R894‐R902, 2017.
 135.Montero D, Cathomen A, Jacobs RA, Flück D, de Leur J, Keiser S, Bonne T, Kirk N, Lundby AK, Lundby C. Haematological rather than skeletal muscle adaptations contribute to the increase in peak oxygen uptake induced by moderate endurance training. J Physiol 593: 4677‐4688, 2015.
 136.Montero D, Lundby C. Red cell volume response to exercise training: Association with aging. Scand J Med Sci Sports 27: 674‐683, 2016.
 137.Montero D, Lundby C. Refuting the myth of non‐response to exercise training: ‘Non‐responders’ do respond to higher dose of training. J Physiol 595: 3377‐3387, 2017.
 138.Montero D, Lundby C. Arterial O2 content regulates plasma erythropoietin independently of arterial O2 tension: A blinded crossover study. Kidney Int In revision:2018.
 139.Montero D, Rauber S, Goetze JP, Lundby C. Reduction in central venous pressure enhances erythropoietin synthesis: Role of volume‐regulating hormones. Acta Physiol (Oxf) 218: 89‐97, 2016.
 140.Morici G, Zangla D, Santoro A, Pelosi E, Petrucci E, Gioia M, Bonanno A, Profita M, Bellia V, Testa U, Bonsignore MR. Supramaximal exercise mobilizes hematopoietic progenitors and reticulocytes in athletes. Am J Physiol Regul Integr Comp Physiol 289: R1496‐R1503, 2005.
 141.Moriyama Y, Fisher JW. Effects of testosterone and erythropoietin on erythroid colony formation in human bone marrow cultures. Blood 45: 665‐760, 1975.
 142.Morkeberg J. Detection of autologous blood transfusions in athletes: A historical perspective. Transfus Med Rev 26: 199‐208, 2012.
 143.Nagashima K, Cline GW, Mack GW, Shulman GI, Nadel ER. Intense exercise stimulates albumin synthesis in the upright posture. J Appl Physiol (1985) 88: 41‐46, 2000.
 144.Nagashima K, Mack GW, Haskell A, Nishiyasu T, Nadel ER. Mechanism for the posture‐specific plasma volume increase after a single intense exercise protocol. J Appl Physiol (1985) 86: 867‐873, 1999.
 145.Nagashima K, Wu J, Kavouras SA, Mack GW. Increased renal tubular sodium reabsorption during exercise‐induced hypervolemia in humans. J Appl Physiol (1985) 91: 1229‐1236, 2001.
 146.Nakamoto H, Kanno Y, Okada H, Suzuki H. Erythropoietin resistance in patients on continuous ambulatory peritoneal dialysis. Adv Perit Dial 20: 111‐116, 2004.
 147.Nass R, Huber RM, Klauss V, Muller OA, Schopohl J, Strasburger CJ. Effect of growth hormone (hGH) replacement therapy on physical work capacity and cardiac and pulmonary function in patients with hGH deficiency acquired in adulthood. J Clin Endocrinol Metab 80: 552‐527, 1995.
 148.Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone‐marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460: 259‐63, 2009.
 149.Ogawa T, Spina RJ, Martin WH, III, Kohrt WM, Schechtman KB, Holloszy JO, Ehsani AA. Effects of aging, sex, and physical training on cardiovascular responses to exercise. Circulation 86: 494‐503, 1992.
 150.Ogoh S, Volianitis S, Nissen P, Wray DW, Secher NH, Raven PB. Carotid baroreflex responsiveness to head‐up tilt‐induced central hypovolaemia: Effect of aerobic fitness. J Physiol 551: 601‐608, 2003.
 151.Olsen NV, Aachmann‐Andersen NJ, Oturai P, Munch‐Andersen T, Bornø A, Hulston C, Holstein‐Rathlou NH, Robach P, Lundby C. Erythropoietin down‐regulates proximal renal tubular reabsorption and causes a fall in glomerular filtration rate in humans. J Physiol 589: 1273‐1281, 2011.
 152.Panebianco RA, Stachenfeld N, Coplan NL, Gleim GW. Effects of blood donation on exercise performance in competitive cyclists. Am Heart J 130: 838‐840, 1995.
 153.Papanek PE, Raff H. Physiological increases in cortisol inhibit basal vasopressin release in conscious dogs. Am J Physiol 266: R1744‐R1751, 1994.
 154.Parisotto R. Blood Sports: The inside dope on drugs in sport. Hardie Grant: Prahran 2006.
 155.Pearce JW. A current concept of the regulation of blood volume. Br Heart J 23: 66‐74, 1961.
 156.Pedersen BK, Fischer CP. Beneficial health effects of exercise‐–the role of IL‐6 as a myokine. Trends Pharmacol Sci 28: 152‐156, 2007.
 157.Pedersen BK, Hoffman‐Goetz L. Exercise and the immune system: Regulation, integration, and adaptation. Physiol Rev 80: 1055‐1081, 2000.
 158.Pereira RM, Delany AM, Durant D, Canalis E. Cortisol regulates the expression of Notch in osteoblasts. J Cell Biochem 85: 252‐258, 2002.
 159.Perrault H, Cantin M, Thibault G, Brisson GR, Brisson G, Beland M. Plasma atrial natriuretic peptide during brief upright and supine exercise in humans. J Appl Physiol (1985) 66: 2159‐2167, 1989.
 160.Peschle C, Sasso GF, Mastroberardino G, Condorelli M. The mechanism of endocrine influences on erythropoiesis. J Lab Clin Med 78: 20‐29, 1971.
 161.Petraglia F, Barletta C, Facchinetti F, Spinazzola F, Monzani A, Scavo D, Genazzani AR. Response of circulating adrenocorticotropin, beta‐endorphin, beta‐lipotropin and cortisol to athletic competition. Acta Endocrinol (Copenh) 118: 332‐336, 1988.
 162.Pickering TR, Bunn HT. The endurance running hypothesis and hunting and scavenging in savanna‐woodlands. J Hum Evol 53: 434‐438, 2007.
 163.Piepoli M, Coats AJ, Adamopoulos S, Bernardi L, Feng YH, Conway J, Sleight P. Persistent peripheral vasodilation and sympathetic activity in hypotension after maximal exercise. J Appl Physiol (1985) 75: 1807‐1814, 1993.
 164.Piepoli MF, Conraads V, Corra U, Dickstein K, Francis DP, Jaarsma T, McMurray J, Pieske B, Piotrowicz E, Schmid JP, Anker SD, Solal AC, Filippatos GS, Hoes AW, Gielen S, Giannuzzi P, Ponikowski PP. Exercise training in heart failure: From theory to practice. A consensus document of the Heart Failure Association and the European Association for Cardiovascular Prevention and Rehabilitation. Eur J Heart Fail 13: 347‐357, 2011.
 165.Pirofsky B. The determination of blood viscosity in man by a method based on Poiseuille's law. J Clin Invest 32: 292‐298, 1953.
 166.Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González‐Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37: 2129‐2200, 2016.
 167.Pratt MC, Lewis‐Barned NJ, Walker RJ, Bailey RR, Shand BI, Livesey J. Effect of angiotensin converting enzyme inhibitors on erythropoietin concentrations in healthy volunteers. Br J Clin Pharmacol 34: 363‐365, 1992.
 168.Pritzlaff CJ, Wideman L, Blumer J, Jensen M, Abbott RD, Gaesser GA, Veldhuis JD, Weltman A. Catecholamine release, growth hormone secretion, and energy expenditure during exercise vs. recovery in men. J Appl Physiol (1985) 89: 937‐946, 2000.
 169.Prommer N, Ehrmann U, Schmidt W, Steinacker JM, Radermacher P, Muth CM. Total haemoglobin mass and spleen contraction: A study on competitive apnea divers, non‐diving athletes and untrained control subjects. Eur J Appl Physiol 101: 753‐759, 2007.
 170.Prommer N, Heckel A, Schmidt W. Timeframe to detect blood withdrawal associated with autologous blood doping. Med Sci Sports Exerc 39(5 Suppl): 2007.
 171.Pugh LG. Blood volume changes in outdoor exercise of 8‐10 hour duration. J Physiol 200: 345‐351, 1969.
 172.Remy I, Wilson IA, Michnick SW. Erythropoietin receptor activation by a ligand‐induced conformation change. Science 283: 990‐993, 1999.
 173.Robach P, Boisson RC, Vincent L, Lundby C, Moutereau S, Gergelé L, Michel N, Duthil E, Féasson L, Millet GY. Hemolysis induced by an extreme mountain ultra‐marathon is not associated with a decrease in total red blood cell volume. Scand J Med Sci Sports 24: 18‐27, 2014.
 174.Saltin B, Calbet JA. Point: In health and in a normoxic environment, VO2max is limited primarily by cardiac output and locomotor muscle blood flow. J Appl Physiol (1985) 100: 744‐745, 2006.
 175.Sander‐Jensen K, Secher NH, Astrup A, Christensen NJ, Giese J, Schwartz TW, Warberg J, Bie P. Hypotension induced by passive head‐up tilt: Endocrine and circulatory mechanisms. Am J Physiol 251: R742‐R748, 1986.
 176.Sandri M, Adams V, Gielen S, Linke A, Lenk K, Kränkel N, Lenz D, Erbs S, Scheinert D, Mohr FW, Schuler G, Hambrecht R. Effects of exercise and ischemia on mobilization and functional activation of blood‐derived progenitor cells in patients with ischemic syndromes: Results of 3 randomized studies. Circulation 111: 3391‐3399, 2005.
 177.Sawka MN, Convertino VA, Eichner ER, Schnieder SM, Young AJ. Blood volume: Importance and adaptations to exercise training, environmental stresses, and trauma/sickness. Med Sci Sports Exerc 32: 332‐348, 2000.
 178.Scoon GS, Hopkins WG, Mayhew S, Cotter JD. Effect of post‐exercise sauna bathing on the endurance performance of competitive male runners. J Sci Med Sport 10: 259‐262, 2007.
 179.Schmidt W, Heinicke K, Rojas J, Manuel Gomez J, Serrato M, Mora M, Wolfarth B, Schmid A, Keul J. Blood volume and hemoglobin mass in endurance athletes from moderate altitude. Med Sci Sports Exerc 34: 1934‐1940, 2002.
 180.Schmidt W, Maassen N, Trost F, Boning D. Training induced effects on blood volume, erythrocyte turnover and haemoglobin oxygen binding properties. Eur J Appl Physiol Occup Physiol 57: 490‐498, 1988.
 181.Schmidt W, Prommer N. Effects of various training modalities on blood volume. Scand J Med Sci Sports 18(Suppl 1): 57‐69, 2008.
 182.Schobersberger W, Tschann M, Hasibeder W, Steidl M, Herold M, Nachbauer W, Koller A. Consequences of 6 weeks of strength training on red cell O2 transport and iron status. Eur J Appl Physiol Occup Physiol 60: 163‐168, 1990.
 183.Schrier RW. Effects of adrenergic nervous system and catecholamines on systemic and renal hemodynamics, sodium and water excretion and renin secretion. Kidney Int 6: 291‐306, 1974.
 184.Schuler B, Arras M, Keller S, Rettich A, Lundby C, Vogel J, Gassmann M. Optimal hematocrit for maximal exercise performance in acute and chronic erythropoietin‐treated mice. Proc Natl Acad Sci U S A 107: 419‐423, 2010.
 185.Schumacher YO, Schmid A, Grathwohl D, Bultermann D, Berg A. Hematological indices and iron status in athletes of various sports and performances. Med Sci Sports Exerc 34: 869‐875, 2002.
 186.Segar WE, Moore WW. The regulation of antidiuretic hormone release in man: I. Effects of change in position and ambient temperature on blood ADH levels. J Clin Invest 47: 2143‐2151, 1968.
 187.Selleri C, Maciejewski JP, Sato T, Young NS. Interferon‐gamma constitutively expressed in the stromal microenvironment of human marrow cultures mediates potent hematopoietic inhibition. Blood 87: 4149‐4157, 1996.
 188.Sellers TL, Jaussi AW, Yang HT, Heninger RW, Winder WW. Effect of the exercise‐induced increase in glucocorticoids on endurance in the rat. J Appl Physiol (1985) 65: 173‐178, 1988.
 189.Senay LC, Jr. Movement of water, protein and crystalloids between vascular and extra‐vascular compartments in heat‐exposed men during dehydration and following limited relief of dehydration. J Physiol 210: 617‐635, 1970.
 190.Senturk UK, Gunduz F, Kuru O, Koçer G, Ozkaya YG, Yesilkaya A, Bor‐Küçükatay M, Uyüklü M, Yalçin O, Baskurt OK. Exercise‐induced oxidative stress leads hemolysis in sedentary but not trained humans. J Appl Physiol (1985) 99: 1434‐1441, 2005.
 191.Shahani S, Braga‐Basaria M, Maggio M, Basaria S. Androgens and erythropoiesis: Past and present. J Endocrinol Invest 32: 704‐716, 2009.
 192.Shahidi NT. Androgens and erythropoiesis. N Engl J Med 289: 72‐80, 1973.
 193.Shellock FG, Morris E, Deutsch AL, Mink JH, Kerr R, Boden SD. Hematopoietic bone marrow hyperplasia: High prevalence on MR images of the knee in asymptomatic marathon runners. AJR Am J Roentgenol 158: 335‐338, 1992.
 194.Shemin D, Rittenberg D. The life span of the human red blood cell. J Biol Chem 166: 627‐636, 1946.
 195.Shephard RJ. Responses of the human spleen to exercise. J Sports Sci 34: 929‐936, 2016.
 196.Siebenmann C, Robach P, Jacobs RA, Rasmussen P, Nordsborg N, Diaz V, Christ A, Olsen NV, Maggiorini M, Lundby C. “Live high‐train low” using normobaric hypoxia: A double‐blinded, placebo‐controlled study. J Appl Physiol (1985) 112: 106‐117, 2012.
 197.Singhal V, Maffazioli GD, Cano Sokoloff N, Ackerman KE, Lee H, Gupta N, Clarke H, Slattery M, Bredella MA, Misra M. Regional fat depots and their relationship to bone density and microarchitecture in young oligo‐amenorrheic athletes. Bone 77: 83‐90, 2015.
 198.Skarda ST, Burge MR. Prospective evaluation of risk factors for exercise‐induced hypogonadism in male runners. West J Med 169: 9‐12, 1998.
 199.Sohmiya M, Kato Y. Human growth hormone and insulin‐like growth factor‐I inhibit erythropoietin secretion from the kidneys of adult rats. J Endocrinol 184: 199‐207, 2005.
 200.Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL‐6 infusion inhibit endotoxin‐induced TNF‐alpha production in humans. FASEB J 17: 884‐886, 2003.
 201.Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK. IL‐6 enhances plasma IL‐1ra, IL‐10, and cortisol in humans. Am J Physiol Endocrinol Metab 285: E433‐E437, 2003.
 202.Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O'Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ, RED‐HF Committees, RED‐HF Investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med 368: 1210‐1219, 2013.
 203.Swinburn CR, Wakefield JM, Newman SP, Jones PW. Evidence of prednisolone induced mood change (‘steroid euphoria’) in patients with chronic obstructive airways disease. Br J Clin Pharmacol 26: 709‐713, 1988.
 204.Takahashi Y, Kipnis DM, Daughaday WH. Growth hormone secretion during sleep. J Clin Invest 47: 2079‐90, 1968.
 205.Takeda Y, Miyamori I, Yoneda T, Hatakeyama H, Inaba S, Furukawa K, Mabuchi H, Takeda R. Regulation of aldosterone synthase in human vascular endothelial cells by angiotensin II and adrenocorticotropin. J Clin Endocrinol Metab 81: 2797‐2800, 1996.
 206.Telford RD, Sly GJ, Hahn AG, Cunningham RB, Bryant C, Smith JA. Footstrike is the major cause of hemolysis during running. J Appl Physiol (1985) 94: 38‐42, 2003.
 207.Thijssen DH, Vos JB, Verseyden C, van Zonneveld AJ, Smits P, Sweep FC, Hopman MT, de Boer HC. Haematopoietic stem cells and endothelial progenitor cells in healthy men: Effect of aging and training. Aging Cell 5: 495‐503, 2006.
 208.Thrasher TN. Baroreceptor regulation of vasopressin and renin secretion: Low‐pressure versus high‐pressure receptors. Front Neuroendocrinol 15: 157‐196, 1994.
 209.Uhrikova I, Lacnakova A, Tandlerova K, Kuchařová V, Řeháková K, Jánová E, Doubek J. Haematological and biochemical variations among eight sighthound breeds. Aust Vet J 91: 452‐459, 2013.
 210.USADA. Report on proceedings under the world anti‐doping code and the USADA protocol united states anti‐doping agency, claimant, v. Lance Armstrong, respondent. Reasoned decision of the USADA. 2012.
 211.Van Cauter E, Plat L. Physiology of growth hormone secretion during sleep. J Pediatr 128: S32‐S37, 1996.
 212.Van Remoortel H, De Buck E, Compernolle V, Deldicque L, Vandekerckhove P. The effect of a standard whole blood donation on oxygen uptake and exercise capacity: A systematic review and meta‐analysis. Transfusion 57: 451‐462, 2016.
 213.van Uum SH, Houben AJ, Hermus AR, Kroon AA, Walker BR, Sweep CG, Smits P, de Leeuw PW, Lenders JW. Acute intrarenal administration of cortisol has no effect on renal blood flow in hypertensive individuals. J Hypertens 20: 2275‐2283, 2002.
 214.Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, Meerpohl J, Karlsson S, Liu JM, Leblanc T, Paley C, Kang EM, Leder EJ, Atsidaftos E, Shimamura A, Bessler M, Glader B, Lipton JM, Participants of Sixth Annual Daniella Maria Arturi International Consensus Conference. Diagnosing and treating Diamond Blackfan anaemia: Results of an international clinical consensus conference. Br J Haematol 142: 859‐876, 2008.
 215.Vogt S, Altehoefer C, Bueltermann D, Pottgiesser T, Prettin S, Schmid A, Roecker K, Schmidt W, Heinicke K, Heinrich L. Magnetic resonance imaging of the lumbar spine and blood volume in professional cyclists. Eur J Appl Physiol 102: 411‐416, 2008.
 216.WADA [Internet].
 217.Wade CE, Claybaugh JR. Plasma renin activity, vasopressin concentration, and urinary excretory responses to exercise in men. J Appl Physiol Respir Environ Exerc Physiol 49: 930‐936, 1980.
 218.Warburton DE, Haykowsky MJ, Quinney HA, Blackmore D, Teo KK, Taylor DA, McGavock J, Humen DP. Blood volume expansion and cardiorespiratory function: Effects of training modality. Med Sci Sports Exerc 36: 991‐1000, 2004.
 219.Wardyn GG, Rennard SI, Brusnahan SK, McGuire TR, Carlson ML, Smith LM, McGranaghan S, Sharp JG. Effects of exercise on hematological parameters, circulating side population cells, and cytokines. Exp Hematol 36: 216‐223, 2008.
 220.Webster JI, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity. Annu Rev Immunol 20: 125‐163, 2002.
 221.Weight LM, Byrne MJ, Jacobs P. Haemolytic effects of exercise. Clin Sci (Lond) 81: 147‐152, 1991.
 222.Weltman A, Weltman JY, Roy CP, Wideman L, Patrie J, Evans WS, Veldhuis JD. Growth hormone response to graded exercise intensities is attenuated and the gender difference abolished in older adults. J Appl Physiol (1985) 100: 1623‐1629, 2006.
 223.Weltman A, Weltman JY, Schurrer R, Evans WS, Veldhuis JD, Rogol AD. Endurance training amplifies the pulsatile release of growth hormone: Effects of training intensity. J Appl Physiol (1985) 72: 2188‐2196, 1992.
 224.Weltman A, Weltman JY, Womack CJ, Davis SE, Blumer JL, Gaesser GA, Hartman ML. Exercise training decreases the growth hormone (GH) response to acute constant‐load exercise. Med Sci Sports Exerc 29: 669‐676, 1997.
 225.Weltman AL, Wideman L, Y. WJ, Veldhuis JD. The growth hormone response to acute and chronic aerobic exercise. In: WJ Kraemer, AD Rogol editors. The Endocrine System in Sports and Exercise. Massachusetts, USA: Blackwell Publishing, 2005, pp. 122‐133.
 226.Wenger RH, Kurtz A. Erythropoietin. Compr Physiol 1: 1759‐1794, 2011.
 227.Widdowson WM, Gibney J. The effect of growth hormone replacement on exercise capacity in patients with GH deficiency: A metaanalysis. J Clin Endocrinol Metab 93: 4413‐4417, 2008.
 228.Yang RC, Mack GW, Wolfe RR, Nadel ER. Albumin synthesis after intense intermittent exercise in human subjects. J Appl Physiol (1985) 84: 584‐592, 1998.
 229.Young AJ, Sawka MN, Quigley MD, Cadarette BS, Neufer PD, Dennis RC, Valeri CR. Role of thermal factors on aerobic capacity improvements with endurance training. J Appl Physiol (1985) 75: 49‐54, 1993.
 230.Zaccaria M, Varnier M, Piazza P, Noventa D, Ermolao A. Blunted growth hormone response to maximal exercise in middle‐aged versus young subjects and no effect of endurance training. J Clin Endocrinol Metab 84: 2303‐2307, 1999.
 231.Zaldivar F, Eliakim A, Radom‐Aizik S, Leu SY, Cooper DM. The effect of brief exercise on circulating CD34+ stem cells in early and late pubertal boys. Pediatr Res 61: 491‐495, 2007.
 232.Zouhal H, Jacob C, Delamarche P, Gratas‐Delamarche A. Catecholamines and the effects of exercise, training and gender. Sports Med 38: 401‐423, 2008.

 

Teaching Material

D. Montero, C. Lundby. Regulation of Red Blood Cell Volume with Exercise Training. Compr Physiol 9: 2019, 149-164.

Didactic Synopsis

Major Teaching Points:

  • Hemoglobin mass and/or red blood cell volume (RBCV) are major determinants of maximal oxygen uptake (VO2max).
  • Endurance athletes may have up to 40% greater RBCV than healthy untrained individuals.
  • Endurance training facilitates RBCV expansion and thereby also VO2max improvement.
  • Prior to RBCV expansion endurance training leads to an about 10% increase in plasma volume (PV), which decreases hematocrit transiently.
  • The initial drop in hematocrit is proposed being sensed by kidney O2 sensors located in the juxtamedullary apparatus, which stimulate the release of erythropoietin (EPO).
  • Transient post-endurance exercise rises in blood volume-regulating hormones contributing to PV expansion (angiotensin II, vasopressin) directly induce renal EPO production.
  • Circulating hormones enhanced during and after endurance exercise such as catecholamines, cortisol and growth hormone may facilitate proliferation, differentiation, and/or release of red blood cells from the hematopoietic bone marrow.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Relationship of hemoglobin mass and blood volumes with aerobic capacity. Teaching points: Aerobic capacity, represented by maximal oxygen consumption (VO2max), is closely associated with blood volumes in humans along the continuum of VO2max from healthy young untrained individuals to Olympic champions in endurance disciplines. The strongest determinants of VO2max are red blood cell volume (RBCV) and hemoglobin mass (nHb), followed by blood volume (BV) and plasma volume (PV). The concentration of hemoglobin in blood ([Hb]) is not associated with VO2max, underlining the importance of volumetric variables facilitating cardiac output over relatively uniform [Hb] values.

Figure 2 Changes in blood volumes with endurance training. Teaching points: This figure presents absolute (A) and relative (B) changes in blood volume (BV) (circles), red blood cell volume (RBCV) (squares), and plasma volume (PV) (triangles) throughout 8 weeks of a typical endurance training program (3-4 × 60 min, moderate-to-high intensity cycle ergometry sessions per week) in healthy young untrained individuals. Endurance training elicits substantial increases in RBCV from week 4, preceded by marked PV expansion during the initial weeks, resulting in reduced hematocrit. At week 8, RBCV is further increased while PV expansion is slightly attenuated, thus approaching normal hematocrit levels.

Figure 3 Acute effect of endurance exercise on circulating erythropoietin (EPO). Teaching points: This figure shows plasma EPO concentration from 7 to 10 AM in healthy young untrained individuals following a session of endurance exercise (1-h of cycle ergometry at 55% of maximal power output) (filled circles) or 1-h rest (open circles). Plasma EPO concentration acutely increases following endurance exercise. This increase is accentuated 3 hours after stopping exercise, independently of exercise-induced hemoconcentration.

Figure 4 Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): the critmeter hypothesis. Teaching points: Endurance exercise-induced plasma volume expansion lowers hematocrit and arterial O2 content, resulting in decreased tissue O2 pressure in the juxtamedullary region of the cortical labyrinth in the kidney, stimulating EPO-producing cells (peritubular fibroblast-like cells). Augmented circulating EPO enhance erythropoiesis in the bone marrow, increasing red blood cell volume and hence tending to restore hematocrit and arterial O2 content, closing a negative feedback loop.

Figure 5 Mechanisms underlying the effect of endurance exercise on circulating erythropoietin (EPO): baroreflex-endocrine responses to reduced central venous pressure. Teaching points: Central venous pressure, which reflects the filling state of the cardiovascular system, is reduced for several hours after endurance exercise, in part due to peripheral vasodilation. The reduction in central venous pressure is sensed by cardiopulmonary and arterial baroreceptors, triggering the release of blood volume (BV)-regulating hormones such as angiotensin II (ANGII) and vasopressin (VPN). These hormones stimulate renal EPO production via direct activation of renal receptors as well as through the increase of sodium reabsorption leading to decreased tissue O2 pressure in peritubular fibroblast-like cells. Ultimately, the EPO-induced enhancement of red blood cell volume contributes, along with plasma volume expansion, to blood pressure homeostasis with endurance training.

Figure 6 Acute effect of endurance exercise on endocrine factors modulating bone marrow erythropoiesis. Teaching points: Besides erythropoietin, several hormones possessing erythropoietic activity are transiently elevated with endurance exercise. Catecholamines augment the release of hematopoietic stem cells from the bone marrow, mediated by chemokine stromal cell derived factor-1 (SDF-1). Another stress hormone, cortisol, stimulates differentiation and mobilization of erythroid progenitor cells (EPCs) via Notch signaling pathways. Furthermore, growth hormone (GH) and its mediator insulin-like growth factor 1 (IGF-1) can induce erythroid cell growth and differentiation in the bone marrow. Overall, endurance exercise enhances plasma erythropoietic activity via redundant endocrine pathways.

 


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Article Title: Regulation of Red Blood Cell Volume with Exercise Training
 

How to Cite

David Montero, Carsten Lundby. Regulation of Red Blood Cell Volume with Exercise Training. Compr Physiol 2018, 9: 149-164. doi: 10.1002/cphy.c180004