Importance of Testosterone on Adaptation at High Altitude
Main Article Content
Abstract
Adaptation or natural acclimatization results from the interaction between genetic variations and acclimatization resulting in individuals with ability to live and reproduce without problems at high altitudes. Testosterone is a hormone that increases erythropoiesis and inhibits ventilation. It could therefore, be associated to the adaptation to high altitudes. Excessive erythrocytosis, which in turn will develop chronic mountain sickness is caused by low arterial oxygen saturation and ventilatory inefficiency and blunted ventilatory response to hypoxia. Testosterone is elevated in natives at high altitude with excessive erythrocytosis (>21 g /dl hemoglobin in men and >19 g/dl in women). Natives from the Peruvian central Andes with chronic mountain sickness express gene SENP1 that enhances the activity of the androgen receptor. Results of the current investigations suggest that increase in serum testosterone and hemoglobin is not adequate for adaptation to high altitude.
References
Aghazadeh, M.; Pastuszak, A. W.; Johnson, W. G.; McIntyre, M. G.; Hsieh, T. M. & Lipshultz, L. I. Elevated Dihydrotestosterone is Associated with Testosterone Induced Erythrocytosis. J. Urol., 194(1):160-5, 2015.
Bachman, E.; Feng, R.; Travison, T.; Li, M.; Olbina, G.; Ostland, V.; Ulloor, J.; Zhang, A.; Basaria, S.; Ganz, T.; Westerman, M. & Bhasin, S. Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis. J. Clin. Endocrinol. Metab., 95(10):4743-7, 2010.
Bachman, E.; Travison, T. G.; Basaria, S.; Davda, M. N.; Guo, W.; Li, M.; Connor Westfall, J.; Bae, H.; Gordeuk, V. & Bhasin, S. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J. Gerontol. A Biol. Sci. Med. Sci., 69(6):725-35, 2014.
Beall, C. M.; Decker, M. J.; Brittenham, G. M.; Kushner, I.; Gebremedhin, A. & Strohl, K. P. An Ethiopian pattern of human adaptation to highaltitude hypoxia. Proc. Natl. Acad. Sci. U. S. A., 99(26):17215-8, 2002.
Beall, C. M.; Worthman, C. M.; Stallings, J.; Strohl, K. P.; Brittenham, G. M. & Barragan, M. Salivary testosterone concentration of Aymara men native to 3600 m. Ann. Hum. Biol., 19(1):67-78, 1992.
Castillo, R. L.; Zepeda, A. B.; Short, S. E.; Figueroa, E.; Bustos-Obregon, E. & Farías, J. G. Protective effects of polyunsatutared fatty acids supplementation against testicular damage induced by intermittent hypobarichypoxia in rats. J. Biomed. Sci., 22:8, 2015.
Chowdhuri, S.; Bascom, A.; Mohan, D.; Diamond, M. P. & Badr, M. S. Testosterone conversion blockade increases breathing stability in healthy men during NREM sleep. Sleep. 36(12):1793-8, 2013.
Cikutovic, M.; Fuentes, N. & Bustos-Obregón, E. Effect of intermittent hypoxia on the reproduction of rats exposed to high altitude in the Chilean Altiplano. High Alt. Med. Biol., 10(4):357-63,2009.
Cole, A. M.; Petousi, N.; Cavalleri, G. L. & Robbins, P. A. Genetic variation in SENP1 and ANP32D as predictors of chronic mountain sickness. High Alt. Med. Biol., 15(4):497-9, 2014.
Coviello, A. D.; Kaplan, B.; Lakshman, K. M.; Chen, T.; Singh, A. B. & Bhasin, S. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J. Clin. Endocrinol. Metab., 93(3):914-9, 2008.
Coyotupa, J. Maduración sexual en Cerro de Pasco (4340 m) y Lima (150 m). Tesis Doctoral. Lima, Universidad Peruana Cayetano Heredia, 1986.
Delev, D. P.; Davcheva, D. P.; Kostadinov, I. D. & Kostadinova, I. I. Effect of testosterone propionate on erythropoiesis after experimental orchiectomy. Folia Med. (Plovdiv), 55(2):51-7, 2013.
Droma, Y.; Hanaoka, M.; Basnyat, B.; Arjyal, A.; Naupane, P.; Pandit, A.; Sharma, D.; Miwa, N.; Ito, M.; Katsuyama, Y.; Ota, M. & Kubo, K. Genetic contribution of the endothelial nitric oxide synthase gene to high altitude adaptation in sherpas. High Alt. Med. Biol., 7(3):209-20, 2006.
Droma, Y.; Hanaoka, M.; Basnyat B.; Arjyal, A.; Neupane, P.; Pandit, A.; Sharma, D.; Ito, M.; Miwa, N.; Katsuyama, Y.; Ota, M. & Kubo, K. Adaptation to high altitude in Sherpas: association with the insertion/deletion polymorphism in the Angiotensinconverting enzyme gene. Wilderness Environ. Med., 19(1):22-9, 2008.
Ekart, R.; Taskovska, M.; Hojs, N.; Bevc, S. & Hojs, R. Testosterone and hemoglobin in hemodialysis male and female patients. Artif. Organs, 38(7):598-603, 2014.
Farias, J. G.; Bustos-Obregón, E.; Orellana, R.; Bucarey, J. L.; Quiroz, E. & Reyes, J. G. Effects of chronic hypobaric hypoxia on testis histology and round spermatid oxidative metabolism. Andrologia, 37(1):47-52, 2005.
Garmendia, F.; Valdivia, H.; Castillo, O.; Ugarte, N. & Garmendia, A. Función endocrina en el hombre normal de mediana altitud. Resumen. La Oroya, I Jornada de Medicina y Cirugía de Altura, 1978.
Gonzales, G. F. Hematocrit values in women at high altitude and its relationship with sex hormone levels. J. Qinghai Med. Coll., 25:267-72, 2004.
Gonzales, G. F. Peruvian contributions to the study on human reproduction at high altitude: from the chronicles of the Spanish conquest to the present. Respir. Physiol. Neurobiol., 158(2-3):172-9, 2007.
Gonzales, G. F. Fisiología reproductiva en la altura. En: Gonzales, G. F. (Ed.). Reproducción Humana en la Altura. Lima, Ediciones IIA, 1993. pp.3-24.
Gonzales, G. F. Hemoglobina y testosterona: importancia en la aclimatación y adaptación a la altura. Rev. Peru. Med. Exp. Salud Publica, 28(1):92-100, 2011.
Gonzales, G. F. Serum testosterone levels and excessive erythrocytosis during the process of adaptation to high altitudes. Asian J. Androl., 15(3):368-74, 2013.
Gonzales, G. F. & Reynafarje, C. Cambios del hematocrito con la pubertad. Diagn. (Lima), 9:161-78, 1982.
Gonzales, G. F. & Chaupis, D. Higher androgen bioactivity is associated with excessive erythrocytosis and chronic mountain sickness in Andean Highlanders: a review. Andrologia, 47(7):729-43, 2015.
Gonzales, G. F. & Villena, A. Low pulse oxygen saturation in post-menopausal women at high altitude is related to a high serum testosterone/ estradiol ratio. Int. J. Gynaecol. Obstet., 71(2):147-54, 2000.
Gonzales, G. F.; Tapia, V.; Gasco, M. & GonzalesCastañeda, C. Serum testosterone levels and score of chronic mountain sickness in Peruvian men natives at 4340 m. Andrologia, 43(3):189-95, 2011.
Gonzales, G. F.; Gasco, M.; Tapia, V. & GonzalesCastañeda, C. High serum testosterone levels are associated with excessive erythrocytosis of chronic mountain sickness in men. Am. J. Physiol. Endocrinol. Metab., 296(6):E1319-25, 2009.
Gonzales, G. F.; Tapia, V.; Gasco, M. & GonzalesCastañeda, C. Aromatase activity after a shortcourse of letrozole administration in adult men at sea level and at high altitude (with or without excessive erythrocytosis). Horm. Metab. Res., 44(2):140-5, 2012.
Gonzales, G. F.; Lozano-Hernández, R.; Gasco, M.; Gonzales-Castañeda, C. & Tapia, V. Resistance of sperm motility to serum testosterone in men with excessive erythrocytosis at high altitude. Horm. Metab. Res., 44(13):987-92, 2012.
Gonzales, G. F.; Tapia, V.; Gasco, M. & GonzalesCastañeda, C. Serum testosterone levels and score of chronic mountain sickness in Peruvian men natives at 4340 m. Andrologia, 43(3):189-95, 2011.
Gonzales, G. F.; Rodriguez, L.; Valera, J.; Sandoval, E. & Garcia-Hijarles, M. Prevention of high altitudeinduced testicular disturbances by previous treatment with cyproheptadine in male rats. Arch. Androl., 24(2):201-5, 1990.
Gonzales, G. F.; Tapia, V.; Gasco, M.; Rubio, J. & Gonzales-Castañeda, C. High serum zinc and serum testosterone levels were associated with excessive erythrocytosis in men at high altitudes. Endocrine, 40(3):472-80, 2011.
Gonzales, G. F.; Villena, A.; Llaque, W.; Kaneku, L.; Coyotupa, J. & Guerra-García, R. Función endócrina testicular en la exposición aguda a la altura y en el nativo andino. Rev. Per. Endocrin. Metab., 3:62-76, 1997.
Gonzales, G. F.; Chung, F. A.; Miranda, S.; Valdez, L. B.; Zaobornyj, T.; Bustamante, J. & Boveris, A. Heart mitochondrial nitric oxide synthase is upregulated in male rats exposed to high altitude (4,340 m). Am. J. Physiol. Heart Circ. Physiol., 288(6):H2568-73, 2005.
Grote Beverborg, N.; Verweij, N.; Klip, I. T.; van der Wal, H. H.; Voors, A. A.; van Veldhuisen, D. J.; Gansevoort, R. T.; Bakker, S. J.; van der Harst, P. & van der Meer, P. Erythropoietin in the general population: reference ranges and clinical, biochemical and genetic correlates. PLoS One, 10(4):e0125215, 2015.
Guo, W.; Bachman, E.; Li, M.; Roy, C. N.; Blusztajn, J.; Wong, S.; Chan, S. Y.; Serra, C.; Jasuja, R.; Travison, T. G.; Muckenthaler, M. U.; Nemeth, E. & Bhasin, S. Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging Cell, 12(2):280-91, 2013.
Hartinger, S.; Tapia, V.; Carrillo, C.; Bejarano, L. & Gonzales, G. F. Birth weight at high altitudes in Peru. Int. J. Gynaecol. Obstet., 93(3):275-81, 2006.
Jelkmann, W. Physiology and pharmacology of erythropoietin. Transfus. Med. Hemother., 40(5):302-9, 2013.
Kaneku, L. Respuesta testicular a la hCG en varones jóvenes y ancianos a nivel del mar y en la altura. Tesis de Maestría. Lima, Universidad Peruana Cayetano Heredia, 1989.
Killick, R.; Wang, D.; Hoyos, C. M.; Yee, B. J.; Grunstein, R. R. & Liu, P. Y. The effects of testosterone on ventilatory responses in men with obstructive sleep apnea: a randomised, placebocontrolled trial. J. Sleep Res., 22(3):331-6, 2013.
Kobayashi, H.; Abe, M.; Okada, K.; Tei, R.; Maruyama, N.; Kikuchi, F.; Higuchi, T. & Soma, M. Oral zinc supplementation reduces the erythropoietin responsiveness index in patients on hemodialysis. Nutrients, 7(5):3783-95, 2015.
Kuhrt, D. & Wojchowski, D. M. Emerging EPO and EPO receptor regulators and signal transducers. Blood, 125(23):3536-41, 2015.
León-Velarde, F. Evolución de las ideas sobre la policitemia como mecanismo adaptativo a la altura. Bull. Inst. Fr. Etudes Andines, 19(2):443-53, 1990.
León-Velarde, F.; Monge, C. C.; Vidal, A.; Carcagno, M.; Criscuolo, M. & Bozzini, C. E. Serum immunoreactive erythropoietin in high altitude natives with and without excessive erythrocytosis. Exp. Hematol., 19(4):257-60, 1991.
León-Velarde, F.; Ramos, M. A.; Hernández, J. A.; De Idiáquez, D.; Muñoz, L. S.; Gaffo, A.; Córdova, S.; Durand, D. & Monge, C. The role of menopause in the development of chronic mountain sickness. Am. J. Physiol., 272(1 Pt.2):R90-4, 1997.
León-Velarde, F.; Gamboa, A.; Chuquiza, J. A.; Esteba, W. A.; Rivera-Chira, M. & Monge, C. C. Hematological parameters in high altitude residents living at 4,355, 4,660, and 5,500 meters above sea level. High Alt. Med. Biol., 1(2):97- 104, 2000.
Li, S.; Liu, Y.; Wang, Y.; Qi, P. & Wang, D. The role of serum hepcidin and ferroportin1 in placenta on iron transfer from mother to fetus. Zhonghua XueYe Xue Za Zhi, 36(4):307-11, 2015.
Llaque, W. Estudio del eje hipotálamo-hipofisiariogonadal en hombres normales a nivel del mar y en la altura. Tesis Doctoral. Lima, Universidad Peruana Cayetano Heredia, 1974.
Maggio, M.; Snyder, P. J.; Ceda, G. P.; Milaneschi, Y.; Luci, M.; Cattabiani, C.; Masoni, S.; Vignali, A.; Volpi, R.; Lauretani, F.; Peachey, H.; Valenti, G.; Cappola, A. R.; Longo, D. & Ferrucci, L. Is the haematopoietic effect of testosterone mediated by erythropoietin? The results of a clinical trial in older men. Andrology, 1(1):24-8, 2013.
Miseta, A.; Nagy, J.; Nagy, T.; Poór, V. S.; Fekete, Z. & Sipos, K. Hepcidin and its potential clinical utility. Cell Biol. Int., 39(11):1191-202, 2015.
Murphy, W. G. The sex difference in haemoglobin levels in adults — Mechanisms, causes, and consequences. Blood Rev., 28(2):41-7, 2014.
Painschab, M. S.; Malpartida, G. E.; Dávila-Roman, V. G.; Gilman, R. H.; Kolb, T. M.; León-Velarde, F.; Miranda, J. J. & Checkley, W. Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude peru. High Alt. Med. Biol., 16(1):26-33, 2015.
Pasha, M. A. & Newman, J. H. High-altitude disorders: pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest, 137(6 Suppl.):13S-19S, 2010.
Peñaloza, D. & Arias-Stella, J. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation, 115(9):1132-46, 2007.
Schmidt, P. J. Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation. J. Biol. Chem., 290(31):18975-83, 2015.
Shahani, S.; Braga-Basaria, M.; Maggio, M. & Basaria, S. Androgens and erythropoiesis: past and present. J. Endocrinol. Invest., 32(8):704-16, 2009.
Simonson, T. S.; Yang, Y.; Huff, C. D.; Yun, H.; Qin, G.; Witherspoon, D. J.; Bai, Z.; Lorenzo, F. R.; Xing, J.; Jorde, L. B.; Prchal, J. T. & Ge, R. Genetic evidence for high-altitude adaptation in Tibet. Science, 329(5987):72-5, 2010.
Souma, T.; Suzuki, N. & Yamamoto, M. Renal erythropoietin-producing cells in health and disease. Front Physiol., 6:167, 2015.
Sutinen, P.; Rahkama, V.; Rytinki, M. & Palvimo, J. J. Nuclear mobility and activity of FOXA1 with androgen receptor are regulated by SUMOylation. Mol. Endocrinol., 28(10):1719-28, 2014.
Talbot, N. P.; Lakhal, S.; Smith, T. G.; Privat, C.; Nickol, A. H.; Rivera-Ch, M.; León-Velarde, F.; Dorrington, K. L.; Mole, D. R. & Robbins, P. A. Regulation of hepcidin expression at high altitude. Blood, 119(3):857-60, 2012.
Udpa, N.; Ronen, R.; Zhou, D.; Liang, J.; Stobdan, T.; Appenzeller, O.; Yin, Y.; Du, Y.; Guo, L.; Cao, R.; Wang, Y.; Jin, X.; Huang, C.; Jia, W.; Cao, D.; Guo, G.; Claydon, V. E.; Hainsworth, R.; Gamboa, J. L.; Zibenigus, M.; Zenebe, G.; Xue, J.; Liu, S.; Frazer, K. A.; Li, Y.; Bafna, V. & Haddad, G. G. Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes. Genome Biol., 15(2):R36, 2014.
Utriainen, P.; Jääskeläinen, J. & Voutilainen, R. Blood erythrocyte and hemoglobin concentrations in premature adrenarche. J. Clin. Endocrinol. Metab., 98(1):E87-91, 2013.
Vargas, A.; Bustos-Obregón, E. & Hartley, R. Effects of hypoxia on epididymal sperm parameters and protective role of ibuprofen and melatonin. Biol. Res., 44(2):161-7, 2011.
Viault, F. G. Sur l'augmentation considérable du nombre des globules rouges dans le sang chez les habitants des hauts plateaux de l'Amérique du Sud. C. R. Acad. Sci. Paris, 111:917-8, 1890.
Villafuerte, F. C.; Macarlupú, J. L.; Anza-Ramírez, C.; Corrales-Melgar, D.; Vizcardo-Galindo, G.; Corante, N. & León-Velarde, F. Decreased plasma soluble erythropoietin receptor in high-altitude excessive erythrocytosis and Chronic Mountain Sickness. J. Appl. Physiol. (1985), 117(11):1356-62, 2014.
Wang, H. Y.; Hu, Y.; Wang, S. H.; Shan, Q. L.; Li, Y. C.; Nie, J.; Yi, L. Y.; Bao, D. P.; Xu, C. Y. & He, Z. H. Association of androgen receptor CAG repeat polymorphism with VO?max response to hypoxic training in North China Han men. Int. J. Androl., 33(6):794-9, 2010a.
Wang, P.; Ha, A. Y.; Kidd, K. K.; Koehle, M. S. & Rupert, J. L. A variant of the endothelial nitric oxide synthase gene (NOS3) associated with AMS susceptibility is less common in the Quechua, a high altitude Native population. High Alt. Med. Biol., 11(1):27-30,2010b.
Whittembury, J. & Monge, C. C. High altitude, haematocrit and age. Nature, 238(5362):278-9, 1972.
Winslow, R. M. & Monge, C. C. Hypoxia, polycythemia and chronic mountain sickness. Baltimore, John Hopkins University Press, 1987.
Wu, R.; Cui, Y.; Yuan, X.; Yuan, H.; Wang, Y.; He, J.; Zhao, J. & Peng, S. SUMO-specific protease 1 modulates cadmium-augmented transcriptional activity of androgen receptor (AR) by reversing AR SUMOylation. Toxicol. Lett., 229(2):405-13, 2014.
Wu, T.; Wang, X.; Wei, C.; Cheng, H.; Wang, X.; Li, Y.; Ge-Dong; Zhao, H.; Young, P.; Li, G. & Wang, Z. Hemoglobin levels in Qinghai-Tibet: different effects of gender for Tibetans vs. Han. J. Appl. Physiol. (1985), 98(2):598-604, 2005.
Wuren, T.; Simonson, T. S.; Qin, G.; Xing, J.; Huff, C. D.; Witherspoon, D. J.; Jorde, L. B. & Ge, R. L. Shared and unique signals of high-altitude adaptation in geographically distinct Tibetan populations. PLoS One, 9(3):e88252, 2014.
Zhou, D.; Udpa, N.; Ronen, R.; Stobdan, T.; Liang, J.; Appenzeller, O.; Zhao, H. W.; Yin, Y.; Du, Y.; Guo, L.; Cao, R.; Wang, Y.; Jin, X.; Huang, C.; Jia, W.; Cao, D.; Guo, G.; Gamboa, J. L.; Villafuerte, F.; Callacondo, D.; Xue, J.; Liu, S.; Frazer, K. A.; Li, Y.; Bafna, V. & Haddad, G. G. Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders. Am. J. Hum. Genet., 93(3):452-62, 2013.