High serum zinc and serum testosterone levels were associated with excessive erythrocytosis in men at high altitudes


Chronic mountain sickness (CMS), a lack of adaptation to altitude characterized by excessive erythrocytosis (EE), is a health problem associated with life at high altitude. The erythropoietic process is regulated by both erythropoietin and testosterone. Zinc (Zn) is known to be related with testosterone and hemoglobin levels; meanwhile, nitric oxide was also associated with adaptation to high altitude. The aim of this study was to determine the relationship of hemoglobin and CMS score with serum levels of zinc, total testosterone (TT), calculated free testosterone (cFT), bioavailable testosterone (BAT), hemoglobin, and nitric oxide in men at high altitude with or without EE. Men residing in Lima (150 m) and Cerro de Pasco (4,340 m), Peru, were divided into three groups: (1) low altitude, (2) high altitude without EE (hemoglobin < 21 g/dl), and (3) high altitude with EE (hemoglobin ≥ 21 g/dl). Adjusted multivariable regression models showed that serum testosterone (total or free) and Zn levels were independently correlated with increased hemoglobin levels. Similarly, hemoglobin was positively related with signs/symptoms of CMS; however, both increased the serum Zn and the nitric oxide levels correlated with reduced risk for signs/symptoms of CMS. In conclusion, higher serum testosterone levels and Zn levels were associated with EE, and low scores of signs/symptoms of CMS were associated with higher Zn and nitric oxide levels.

This is a preview of subscription content, access via your institution.



Body mass index


High altitude


Low altitude




Excessive erythrocytosis


Chronic mountain sickness


Total testosterone


Calculated free testosterone


Bioavailable testosterone




Nitric oxide




Delta-aminolevulinic acid dehydratase


Hypoxia-inducible factor


  1. 1.

    M.C. Monge, Chronic mountain sickness. Physiol. Rev. 23, 166–184 (1943)

    CAS  Google Scholar 

  2. 2.

    G. Xing, C. Qualls, L. Huicho, M. Rivera-Ch, T. Stobdan, M. Slessarev, E. Prisman, S. Ito, H. Wu, A. Norboo, D. Dolma, M. Kunzang, T. Norboo, J.L. Gamboa, V.E. Claydon, J. Fisher, G. Zenebe, A. Gebremedhin, R. Hainsworth, A. Verma, O. Appenzeller, Adaptation and mal-adaptation to ambient hypoxia; Andean, Ethiopian and Himalayan patterns. PLoS ONE 3, e2342 (2008)

    PubMed  Article  Google Scholar 

  3. 3.

    J.T. Reeves, F. Leon-Velarde, Chronic mountain sickness: recent studies of the relationship between hemoglobin concentration and oxygen transport. High Alt. Med. Biol. 5, 147–155 (2004)

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    D. Peñaloza, J. Arias-Stella, The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation 115, 1132–1146 (2007)

    PubMed  Article  Google Scholar 

  5. 5.

    M.A. Pasha, J.H. Newman, High-altitude disorders: pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest 137, 13S–19S (2010)

    PubMed  Article  Google Scholar 

  6. 6.

    C.C. Monge, A. Arregui, F. León-Velarde, Pathophysiology and epidemiology of chronic mountain sickness. Int. J. Sports Med 13, S79–S81 (1992)

    Article  Google Scholar 

  7. 7.

    F. León-Velarde, M.A. Ramos, J.A. Hernandez, De Idiaquez, D., Munoz, L.S., Gaffo, A., Cordova, S., Durand, D., Monge, C.: The role of menopause in the development of chronic mountain sickness. Am. J. Physiol. 272, R90–R94 (1997)

    PubMed  Google Scholar 

  8. 8.

    K. Okuyima, R. Sakamoto, Y. Kimura, M. Ishine, Y. Kosaka, T. Wada, C. Wada, M. Naktsuka, Y. Ishimoto, M. Hirosaki, Y. Kasahara, A. Konno, W. Chen, M. Fujisawa, K. Otsuka, M. Nakashima, H. Wang, Q. Dai, A. Yang, H. Qiao, H. Gao, Z. Li, Y. Zhang, R.L. Ge, K. Matsubayashi, Comprehensive geriatric assessment of elderly highlanders in Qinghai, China II: the association of polycythemia with lifestyle-related diseases among the three ethnicities. Geriatr. Gerontol. Int. 9, 342–351 (2009)

    Article  Google Scholar 

  9. 9.

    F. León-Velarde, M. Maggiorini, J.T. Reeves, A. Aldashev, I. Asmus, L. Bernardi, R.L. Ge, P. Hackett, T. Kobayashi, L.G. Moore, D. Penaloza, J.P. Richalet, R. Roach, T. Wu, E. Vargas, G. Zubieta-Castillo, G. Zubieta-Calleja, Consensus statement on chronic and subacute high altitude diseases. High Alt. Med. Biol. 6, 147–157 (2005)

    PubMed  Article  Google Scholar 

  10. 10.

    T.D. Richmond, M. Chohan, D.L. Barberm, Turning cells red: signal transduction mediated by erythropoietin. Trends Cell Biol. 15, 146–155 (2005)

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    M. Zitsmann, Effects of testosterone replacement and its pharmacogenetics on physical performance and metabolism. Asian J. Androl. 10, 364–372 (2008)

    Article  Google Scholar 

  12. 12.

    R. Favier, H. Spielvogel, E. Caceres, A. Rodriguez, B. Sempore, J. Pequignot, Differential effects of ventilatory stimulation by sex hormones and almitrine on hypoxic erythrocytosis. Pflugers Arch 434, 97–103 (1996)

    Article  Google Scholar 

  13. 13.

    A.D. Coviello, B. Kaplan, K.M. Lakshman, T. Chen, A.B. Singh, S. Bhasin, Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J. Clin. Endocrinol. Metab. 93, 914–919 (2008)

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    G.F. Gonzales, M. Gasco, V. Tapia, C. Gonzales-Castañeda, High serum testosterone levels are associated with excessive erythrocytosis of chronic mountain sickness in men. Am. J. Physiol. Endocrinol. Metab. 296, E1319–E1325 (2009)

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    S. Banudevi, P. Elumalai, R. Arunkumar, K. Senthilkumar, D.N. Gunadharini, G. Sharmilla, J. Arunakaran, Chemoprotective effect of zinc on prostate carcinogenesis induced by N-methyl-N-nitrosourea and testosterone in adult male Sprague-Dawley rats. J. Cancer Res. Clin. Oncol. 137, 677–686 (2010)

    PubMed  Article  Google Scholar 

  16. 16.

    A.K. Baltaci, K. Ozyurek, R. Mogulkoc, E. Kurtoglu, E. Oztekin, A. Kul, Effects of zinc deficiency and supplementation on some hematologic parameters of rats performing acute swimming exercise. Acta Physiol. Hung. 90, 125–132 (2003)

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    A.S. Prasad, C.S. Mantzoros, F.W. Beck, J.W. Hess, G.J. Brewer, Zinc status and serum testosterone levels of healthy adults. Nutrition 12, 344–348 (1996)

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    O. Kaya, K. Gokdemir, M. Kilic, A.K. Baltaci, Zinc supplementation in rats subjected to acute swimming exercise: its effect on testosterone levels and relation with lactate. Neuro. Endocrinol. Lett. 27, 267–270 (2006)

    PubMed  CAS  Google Scholar 

  19. 19.

    S.C. Erzurum, S. Ghosh, A.J. Janocha, W. Xu, S. Bauer, N.S. Bryan, J. Tejero, C. Hemann, R. Hille, D.J. Stuehr, M. Feelisch, C.M. Beall, Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans. Proc. Natl. Acad. Sci. USA 104, 17593–17598 (2007)

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    J.Y. Li, X.Y. Li, M. Li, G.K. Zhang, F.L. Ma, Z.M. Liu, N.Y. Zhang, P. Meng, Decline of serum levels of free testosterone in aging healthy Chinese men. Aging Male 8, 203–206 (2005)

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    A. Vermeulen, L. Verdonck, J.M. Kaufman, A critical evaluation of simple methods for the estimation of free testosterone in serum. J. Clin. Endocrinol. Metab. 84, 3666–3672 (1999)

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    J. Sun, X. Zhang, M. Broderick, H. Fein, Measurement of nitric oxide production in biological systems by using Griess reaction assay. Sensors 3, 276–284 (2003)

    Article  CAS  Google Scholar 

  23. 23.

    G.F. Gonzales, Peruvian contributions to the study on human reproduction at altitude: from the chronicles of the Spanish conquest to the present. Respir. Physiol. Neurobiol. 158, 172–179 (2007)

    PubMed  Article  Google Scholar 

  24. 24.

    T.Y. Wu, Chronic mountain sickness on the Qinghai-Tibetan plateau. Chin. Med. J. 118, 161–168 (2005)

    PubMed  Google Scholar 

  25. 25.

    L. Rice, W. Ruiz, T. Driscoll, C.E. Whitley, R. Tapia, D.L. Hachey, G.F. Gonzales, C.P. Alfrey, Neocytolysis on descent from altitude: a newly recognized mechanism for the control of red cell mass. Ann. Intern. Med. 134, 652–656 (2001)

    PubMed  CAS  Google Scholar 

  26. 26.

    F. León-Velarde, C. Monge, A. Vidal, M. Carcagno, M. Criscuolo, C.E. Bozzini, Serum immunoreactive erythropoietin in high altitude natives with and without excessive erythrocytosis. Exp. Hematol. 19, 257–260 (1991)

    PubMed  Google Scholar 

  27. 27.

    O.M. Mejía, J.T. Prchal, F. León-Velarde, A. Hurtado, D.W. Stockton, Genetic association analysis of chronic mountain sickness in an Andean high-altitude population. Haematologica 90, 13–19 (2005)

    PubMed  Google Scholar 

  28. 28.

    G.S. Hwang, S.W. Wang, W.M. Tseng, C.H. Yu, P.S. Wang, Effect of hypoxia on the release of vascular endothelial growth factor and testosterone in mouse TM3 Leydig cells. Am. J. Physiol. Endocrinol. Metab. 292, E1763–E1769 (2007)

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    N.P. Goncharov, G.V. Katsya, N.A. Chagina, L.J. Gooren, Testosterone and obesity in men under the age of 40 years. Andrologia 41, 76–83 (2009)

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    B.B. Yeap, O.P. Almeida, Z. Hyde, P.E. Norman, S.A. Chubb, K. Jamrozik, L. Flicker, In men older than 70 years, total testosterone remains stable while free testosterone declines with age. The health in men study. Eur. J. Endocrinol. 156, 585–594 (2007)

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    C.M. Beall, C.M. Worthman, J. Stallings, K.P. Strohl, G.M. Brittenham, M. Barragan, Salivary testosterone concentration of Aymara men native to 3,600 m. Ann. Hum. Biol. 19, 67–78 (1992)

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    H.G. Li, Y.M. Ren, S.C. Guo, L. Cheng, D.P. Wang, J. Yang, Z.J. Chang, X.Q. Zhao, The protein level of hypoxia-inducible factor-1alpha is increased in the plateau pika (Ochotona curzoniae) inhabiting high altitudes. J. Exp. Zool. 311, 134–141 (2009)

    Article  Google Scholar 

  33. 33.

    T.G. Smith, P.A. Robbins, P.J. Ratcliffe, The human side of hypoxia-inducible factor. Br. J. Haematol. 141, 325–334 (2008)

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    S.H. Li, J.H. Ryu, S.E. Park, Y.S. Cho, J.W. Park, W.J. Lee, Y.S. Chun, Vitamin C supplementation prevents testosterone-induced hyperplasia of rat prostate by down-regulating HIF-1alpha. J. Nutr. Biochem. 21, 801–808 (2010)

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    M. Idei, K. Miyake, Y. Horiuchi, Y. Tabe, N. Miyake, N. Ikeda, T. Miida, Serum zinc concentration decreases with age and is associated with anemia in middle-aged and elderly people. Rinsho Byori 58, 205–210 (2010). (in Japanese)

    PubMed  CAS  Google Scholar 

  36. 36.

    D. Mafra, L. Cuppari, D.I. Fávaro, S.M. Cozzolino, Zinc levels after iron supplementation in patients with chronic kidney disease. J. Ren. Nutr. 14, 164–169 (2004)

    PubMed  Article  Google Scholar 

  37. 37.

    J.A. Jefferson, E. Escudero, M.E. Hurtado, J. Pando, R. Tapia, E.R. Swenson, J. Prchal, G.F. Schreiner, R.B. Schoene, A. Hurtado, R.J. Johnson, Excessive erythrocytosis, chronic mountain sickness, and serum cobalt levels. Lancet 359, 407–408 (2002)

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    K.H. Astrin, D.F. Bishop, J.G. Wetmur, B. Kaul, B. Davidow, R.J. Desnick, Delta-Aminolevulinic acid dehydratase isozymes and lead toxicity. Ann. N.Y. Acad. Sci. 514, 23–29 (1987)

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    F. Scinicariello, H.E. Murray, D.B. Moffett, H.G. Abadin, M.J. Sexton, B.A. Fowler, Lead and delta-aminolevulinic acid dehydratase polymorphism: where does it lead? A meta-analysis. Environ. Health Perspect. 115, 35–41 (2007)

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    A.S. Prasad, Antioxidant effect of zinc in human. Free Radic. Biol. Med. 37, 1182–1190 (2004)

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    J.A. Jefferson, J. Simoni, E. Escudero, M.E. Hurtado, E.R. Swenson, D.E. Wesson, G.F. Schreiner, R.B. Schoene, R.J. Johnson, A. Hurtado, Increased oxidative stress following acute and chronic high altitude exposure. High Alt. Med. Biol. 5, 61–69 (2004)

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    I. Kim, C.H. Kim, G.H. Seo, H.S. Kim, J. Lee, D.G. Kim, Y.S. Ahn, Inhibitory effect of zinc on hypoxic HIF-1 activation in astrocytes. Neuroreport 19, 1063–1066 (2008)

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    M. McMahon, D.J. Lamont, K.A. Beattie, J.D. Hayes, Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. Proc. Natl. Acad. Sci. USA 107, 18838–188343 (2010)

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    A. Tomat, R. Elesgaray, V. Zago, H. Fasoli, A. Fellet, A.M. Balaszczuk, L. Schreier, M.A. Costa, C. Arranz, Exposure to zinc deficiency in fetal and postnatal life determines nitric oxide system activity and arterial blood pressure levels in adult rats. Br. J. Nutr. 104, 382–389 (2010)

    PubMed  Article  CAS  Google Scholar 

Download references


This study was supported by a Grant from the Fogarty Program of The National Institutes of Health of the United States (NIH Research Grant # 5-D43TW005746-04 funded by the Fogarty International Center, National Institutes on Environmental Health Services, National Institute for Occupational Safety and Health, and the Agency for Toxic Substances and Disease Registry).

Conflict of interest

The authors have no conflicts of interest or financial ties to disclose.

Author information



Corresponding author

Correspondence to Gustavo F. Gonzales.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gonzales, G.F., Tapia, V., Gasco, M. et al. High serum zinc and serum testosterone levels were associated with excessive erythrocytosis in men at high altitudes. Endocrine 40, 472–480 (2011). https://doi.org/10.1007/s12020-011-9482-1

Download citation


  • Testosterone
  • Zinc
  • Nitric oxide
  • High altitude
  • Chronic mountain sickness signs/symptoms
  • Excessive erythrocytosis