Higher androgen bioactivity is associated with excessive erythrocytosis and chronic mountain sickness in Andean Highlanders: a review

Populations living at high altitudes (HA), particularly in the Peruvian Central Andes, are characterised by presenting subjects with erythrocytosis and others with excessive erythrocytosis (EE)(Hb>21 g dl−1). EE is associated with chronic mountain sickness (CMS), or lack of adaptation to HA. Testosterone is an erythropoietic hormone and it may play a role on EE at HA. The objective of the present review was to summarise findings on role of serum T levels on adaptation at HA and genes acting on this process. Men at HA without EE have higher androstenedione levels and low ratio androstenedione/testosterone than men with EE, suggesting low activity of 17beta‐hydroxysteroid dehydrogenase (17beta‐HSD), and this could be a mechanism of adaptation to HA. Higher conversion of dehydroepiandrosterone to testosterone in men with EE suggests nigher 17beta‐HSD activity. Men with CMS at Peruvian Central Andes have two genes SENP1, and ANP32D with higher transcriptional response to hypoxia relative to those without. SUMO‐specific protease 1 (SENP1) is an erythropoiesis regulator, which is essential for the stability and activity of hypoxia‐inducible factor 1 (HIF‐1α) under hypoxia. SENP1 reverses the hormone‐augmented SUMOylation of androgen receptor (AR) increasing the transcription activity of AR.In conclusion, increased androgen activity is related with CMS.

[1]  Pauline C Ng,et al.  Whole genome sequencing. , 2010, Methods in molecular biology.

[2]  G. Gonzales,et al.  High serum testosterone levels are associated with excessive erythrocytosis of chronic mountain sickness in men. , 2009, American journal of physiology. Endocrinology and metabolism.

[3]  R. Naeije,et al.  Pulmonary hypertension and chronic mountain sickness. , 2013, High altitude medicine & biology.

[4]  S. Jakob,et al.  The role of androgens on hypoxia‐inducible factor (HIF)‐1α‐induced angiogenesis and on the survival of ischemically challenged skin flaps in a rat model , 2012, Microsurgery.

[5]  Jennifer L. Kirby,et al.  Hypoxia-inducible factor-1alpha is constitutively expressed in murine Leydig cells and regulates 3beta-hydroxysteroid dehydrogenase type 1 promoter activity. , 2008, Journal of andrology.

[6]  W. G. Murphy,et al.  Why do women have similar erythropoietin levels to men but lower hemoglobin levels? , 2010, Blood.

[7]  K. Kubo,et al.  Adaptation to High Altitude in Sherpas: Association with the Insertion/Deletion Polymorphism in the Angiotensin-Converting Enzyme Gene , 2008, Wilderness & environmental medicine.

[8]  I. Georgiou,et al.  Evidence for association of sex hormone‐binding globulin and androgen receptor genes with semen quality , 2008, Andrologia.

[9]  K. Kidd,et al.  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. , 2010, High altitude medicine & biology.

[10]  G. Gonzales.  Serum testosterone levels and excessive erythrocytosis during the process of adaptation to high altitudes. , 2013, Asian journal of andrology.

[11]  D. Kiel,et al.  Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms , 2011, PLoS genetics.

[12]  D. Carmelli,et al.  Heritability of plasma sex hormones and hormone binding globulin in adult male twins. , 2005, The Journal of clinical endocrinology and metabolism.

[13]  S. Chen,et al.  Effects of hypoxia on testosterone release in rat Leydig cells. , 2009, American journal of physiology. Endocrinology and metabolism.

[14]  D. Moon,et al.  Effect of testosterone undecanoate on hematological profiles, blood lipid and viscosity and plasma testosterone level in castrated rabbits. , 2013, Canadian Urological Association journal = Journal de l'Association des urologues du Canada.

[15]  T. Ganz,et al.  Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin , 2014, Hepatology.

[16]  G. Gonzales.  [Hemoglobin and testosterone: importance on high altitude acclimatization and adaptation]. , 2011, Revista peruana de medicina experimental y salud publica.

[17]  C. Beall,et al.  Salivary testosterone concentration of Aymara men native to 3600 m. , 1992, Annals of human biology.

[18]  Yu-Jun Chang,et al.  Simvastatin downregulates the expression of hepcidin and erythropoietin in HepG2 cells , 2013, Hemodialysis international. International Symposium on Home Hemodialysis.

[19]  G. Zamaratskaia,et al.  Regulation of 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase: A Review , 2013, International journal of molecular sciences.

[20]  Ye Yin,et al.  Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes , 2014, Genome Biology.

[21]  J. Palvimo,et al.  Analysis of androgen receptor SUMOylation. , 2011, Methods in molecular biology.

[22]  G. Gonzales,et al.  Low pulse oxygen saturation in post‐menopausal women at high altitude is related to a high serum testosterone/estradiol ratio , 2000, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[23]  A. Kurkar,et al.  Effects of opioid (tramadol) treatment on testicular functions in adult male rats: The role of nitric oxide and oxidative stress , 2014, Clinical and experimental pharmacology & physiology.

[24]  C. Qualls,et al.  Gene expression, autonomic function and chronic hypoxia:lessons from the Andes , 2006, Clinical Autonomic Research.

[25]  J. Arias-Stella,et al.  The Heart and Pulmonary Circulation at High Altitudes: Healthy Highlanders and Chronic Mountain Sickness , 2007, Circulation.

[26]  G. Gonzales,et al.  Prevention of high altitude-induced testicular disturbances by previous treatment with cyproheptadine in male rats. , 1990, Archives of andrology.

[27]  T. Toki,et al.  Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages. , 2011, Archives of biochemistry and biophysics.

[28]  I. Shimada,et al.  Mitochondrial DNA analysis of ancient Peruvian highlanders. , 2006, American journal of physical anthropology.

[29]  Yiseul Kim,et al.  Hypoxia enhances ligand-occupied androgen receptor activity. , 2012, Biochemical and biophysical research communications.

[30]  R. Feinn,et al.  Evidence for low androgenicity among Indian (South Asian) men , 2014, The aging male : the official journal of the International Society for the Study of the Aging Male.

[31]  C. Ohlsson,et al.  DHEA and mortality: What is the nature of the association? , 2015, The Journal of Steroid Biochemistry and Molecular Biology.

[32]  Ville Paakinaho,et al.  Dynamic SUMOylation Is Linked to the Activity Cycles of Androgen Receptor in the Cell Nucleus , 2012, Molecular and Cellular Biology.

[33]  J. Macdougall,et al.  Androgen insensitivity syndrome , 2012, The Lancet.

[34]  J. Carrero,et al.  Endogenous testosterone, muscle strength, and fat-free mass in men with chronic kidney disease. , 2013, Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation.

[35]  M. H. Angelis,et al.  Androgen metabolism via 17beta-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme. , 2005, Journal of molecular endocrinology.

[36]  Kui Li,et al.  AKT3, ANGPTL4, eNOS3, and VEGFA associations with high altitude sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau , 2012, International Journal of Hematology.

[37]  L. Fu,et al.  Testosterone replacement therapy promotes angiogenesis after acute myocardial infarction by enhancing expression of cytokines HIF-1a, SDF-1a and VEGF. , 2012, European journal of pharmacology.

[38]  J. Prchal,et al.  Hypoxia. 5. Hypoxia and hematopoiesis. , 2011, American journal of physiology. Cell physiology.

[39]  G. Semenza,et al.  Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. , 2012, Physiological reviews.

[40]  Z. Karim,et al.  Iron metabolism: State of the art. , 2017, Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine.

[41]  O. Cussenot,et al.  Serum sex steroids measured in middle-aged European and African-Caribbean men by gas chromatography-mass spectrometry. , 2011, European journal of endocrinology.

[42]  J. Beilby,et al.  Differential associations of testosterone, dihydrotestosterone and oestradiol with physical, metabolic and health‐related factors in community‐dwelling men aged 17–97 years from the Busselton Health Survey , 2014, Clinical endocrinology.

[43]  S. Kelly,et al.  Cytochrome b(5) modulation of 17{alpha} hydroxylase and 17-20 lyase (CYP17) activities in steroidogenesis. , 2005, The Journal of endocrinology.

[44]  F. Léon-Velarde,et al.  Pulmonary pressure and cardiac function in chronic mountain sickness patients. , 2009, Chest.

[45]  G. Gonzales,et al.  Adrenopause or decline of serum adrenal androgens with age in women living at sea level or at high altitude. , 2002, The Journal of endocrinology.

[46]  E. Messing,et al.  Localization of androgen receptor expression in human bone marrow , 2001, The Journal of pathology.

[47]  Jinke Cheng,et al.  SUMO-Specific Protease 1 Is Essential for Stabilization of HIF1α during Hypoxia , 2007, Cell.

[48]  F. Léon-Velarde,et al.  Genetic association analysis of chronic mountain sickness in an Andean high-altitude population. , 2005, Haematologica.

[49]  J. Palvimo,et al.  Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1). , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[50]  A. Di Rienzo,et al.  Plasma hepcidin of Ethiopian highlanders with steady-state hypoxia. , 2013, Blood.

[51]  G. Gonzales,et al.  Aromatase Activity After a Short-course of Letrozole Administration in Adult Men at Sea Level and at High Altitude (with or without Excessive Erythrocytosis) , 2012, Hormone and Metabolic Research.

[52]  Wang Min,et al.  SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis , 2010, The Journal of experimental medicine.

[53]  Sang-Ah Lee,et al.  Association between CAG repeat polymorphisms and the risk of prostate cancer: a meta-analysis by race, study design and the number of (CAG)n repeat polymorphisms. , 2013, International journal of molecular medicine.

[54]  M. Aldenderfer.  Peopling the Tibetan plateau: insights from archaeology. , 2011, High altitude medicine & biology.

[55]  E. Yeh,et al.  SUMO-specific protease 1 promotes prostate cancer progression and metastasis , 2013, Oncogene.

[56]  C. Vorkas,et al.  Testosterone replacement therapy and polycythemia in HIV-infected patients , 2012, AIDS.

[57]  Zhengxin Wang,et al.  SENP1 Enhances Androgen Receptor-Dependent Transcription through Desumoylation of Histone Deacetylase 1 , 2004, Molecular and Cellular Biology.

[58]  Jinke Cheng,et al.  SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. , 2007, Cell.

[59]  J. Jacobson,et al.  Effects of prenatal alcohol exposure on testosterone and pubertal development. , 2014, Alcoholism, clinical and experimental research.

[60]  Diane M. Robins,et al.  Length of the human androgen receptor glutamine tract determines androgen sensitivity in vivo , 2011, Molecular and Cellular Endocrinology.

[61]  F. Léon-Velarde,et al.  Pathophysiology and Epidemiology of Chronic Mountain Sickness , 1992, International journal of sports medicine.

[62]  G. Gonzales.  Hemoglobina y testosterona: importancia en la aclimatación y adaptación a la altura , 2011 .

[63]  W. Murphy.  The sex difference in haemoglobin levels in adults - mechanisms, causes, and consequences. , 2014, Blood reviews.

[64]  M. McMullin.  Diagnosis and management of congenital and idiopathic erythrocytosis , 2012, Therapeutic advances in hematology.

[65]  N. Chamberlain,et al.  The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. , 1994, Nucleic acids research.

[66]  P. Swart,et al.  Cytochrome b5: Novel roles in steroidogenesis , 2013, Molecular and Cellular Endocrinology.

[67]  S. Bhasin,et al.  Testosterone supplementation improves anemia in aging male mice. , 2014, The journals of gerontology. Series A, Biological sciences and medical sciences.

[68]  C. Sultan,et al.  Molecular action of androgens , 2002, Molecular and Cellular Endocrinology.

[69]  D. Meldrum,et al.  Sex Steroids and Stem Cell Function , 2008, Molecular medicine.

[70]  R. Ekart,et al.  Testosterone and hemoglobin in hemodialysis male and female patients. , 2014, Artificial organs.

[71]  Jinke Cheng,et al.  Induction of the SUMO-specific Protease 1 Transcription by the Androgen Receptor in Prostate Cancer Cells* , 2007, Journal of Biological Chemistry.

[72]  C. Ohlsson,et al.  Genome-wide association studies on serum sex steroid levels , 2014, Molecular and Cellular Endocrinology.

[73]  K. Kubo,et al.  Genetic contribution of the endothelial nitric oxide synthase gene to high altitude adaptation in sherpas. , 2006, High altitude medicine & biology.

[74]  C. Beall,et al.  An Ethiopian pattern of human adaptation to high-altitude hypoxia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[75]  G. Gonzales,et al.  Serum testosterone levels and score of chronic mountain sickness in Peruvian men natives at 4340 m , 2011, Andrologia.

[76]  L. Jorde,et al.  Shared and Unique Signals of High-Altitude Adaptation in Geographically Distinct Tibetan Populations , 2014, PloS one.

[77]  R. Auchus,et al.  Human cytochrome b5 requires residues E48 and E49 to stimulate the 17,20-lyase activity of cytochrome P450c17. , 2006, Biochemistry.

[78]  J. Kaufman,et al.  Genetic Variations in the Androgen Receptor Are Associated with Steroid Concentrations and Anthropometrics but Not with Muscle Mass in Healthy Young Men , 2014, PloS one.

[79]  G. Gonzales,et al.  Birth weight at high altitudes in Peru , 2006, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[80]  R. Tuder,et al.  Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α. , 2013, Cell metabolism.

[81]  Megan J. Wilson,et al.  Andean and Tibetan patterns of adaptation to high altitude , 2013, American journal of human biology : the official journal of the Human Biology Council.

[82]  Yu Wang,et al.  Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders. , 2013, American journal of human genetics.

[83]  Yu-qi Gao,et al.  Regulation of bone marrow hematopoietic stem cell is involved in high-altitude erythrocytosis. , 2011, Experimental hematology.

[84]  Y. Shang,et al.  Formation of the androgen receptor transcription complex. , 2002, Molecular cell.

[85]  Thomas G. Smith,et al.  Regulation of hepcidin expression at high altitude. , 2012, Blood.

[86]  K. Kubo,et al.  Genetic Variants in EPAS1 Contribute to Adaptation to High-Altitude Hypoxia in Sherpas , 2012, PloS one.

[87]  Peter O'Hare,et al.  Characterization of the Localization and Proteolytic Activity of the SUMO-specific Protease, SENP1* , 2004, Journal of Biological Chemistry.

[88]  J. Rubio,et al.  High serum zinc and serum testosterone levels were associated with excessive erythrocytosis in men at high altitudes , 2011, Endocrine.

[89]  A. Conley,et al.  Colocalization of P450c17 and Cytochrome b5 in Androgen-Synthesizing Tissues of the Human1 , 2004, Biology of reproduction.

[90]  A. Agarwal,et al.  Have androgen receptor gene CAG and GGC repeat polymorphisms an effect on sperm motility in infertile men? , 2014, Andrologia.

[91]  D. Delev,et al.  Effect of Testosterone Propionate on Erythropoiesis after Experimental Orchiectomy , 2013, Folia medica.

[92]  A. Daar,et al.  Prostate Cancer Risk: The Significance of Differences in Age Related Changes in Serum Conjugated and Unconjugated Steroid Hormone Concentrations Between Arab and Caucasian Men , 2006, International Urology and Nephrology.

[93]  A. Bigham,et al.  Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing* , 2014, The Journal of Biological Chemistry.

[94]  J. Palvimo,et al.  SUMO-specific protease 1 (SENP1) reverses the hormone-augmented SUMOylation of androgen receptor and modulates gene responses in prostate cancer cells. , 2009, Molecular endocrinology.

[95]  P. Swart,et al.  Allosteric interaction between 3β‐hydroxysteroid dehydrogenase/Δ5‐Δ4 isomerase and cytochrome b5 influences cofactor binding , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[96]  R. Naeije,et al.  Exercise pathophysiology in patients with chronic mountain sickness exercise in chronic mountain sickness. , 2012, Chest.

[97]  A. Arnaiz-Villena,et al.  Origin of Bolivian Quechua Amerindians: their relationship with other American Indians and Asians according to HLA genes. , 2006, European journal of medical genetics.

[98]  T. Travison,et al.  Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. , 2014, The journals of gerontology. Series A, Biological sciences and medical sciences.

[99]  E. Fung,et al.  Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. , 2012, Cell metabolism.

[100]  J. Carrero,et al.  Testosterone deficiency is a cause of anaemia and reduced responsiveness to erythropoiesis-stimulating agents in men with chronic kidney disease. , 2012, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[101]  R. Conradie,et al.  Cytochrome b5 augments 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase activity , 2011, The Journal of Steroid Biochemistry and Molecular Biology.

[102]  L. Ferrucci,et al.  Is the haematopoietic effect of testosterone mediated by erythropoietin? The results of a clinical trial in older men , 2013, Andrology.

[103]  T. Travison,et al.  Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells , 2013, Aging cell.

[104]  M. Gassmann,et al.  Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2α. , 2011, High altitude medicine & biology.

[105]  M. Hentze,et al.  The Molecular Circuitry Regulating the Switch between Iron Deficiency and Overload in Mice* , 2006, Journal of Biological Chemistry.

[106]  S. Elliott,et al.  Progress in detecting cell-surface protein receptors: the erythropoietin receptor example , 2013, Annals of Hematology.

[107]  E. Nemeth,et al.  Molecular liaisons between erythropoiesis and iron metabolism. , 2014, Blood.

[108]  J. Kaufman,et al.  Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle‐aged and elderly men , 2009, Clinical endocrinology.

[109]  C. Sartori,et al.  RV contractility and exercise-induced pulmonary hypertension in chronic mountain sickness: a stress echocardiographic and tissue Doppler imaging study. , 2013, JACC. Cardiovascular imaging.

[110]  H. Broxmeyer.  Erythropoietin: multiple targets, actions, and modifying influences for biological and clinical consideration , 2013, The Journal of experimental medicine.

[111]  W. Jelkmann.  Physiology and Pharmacology of Erythropoietin , 2013, Transfusion Medicine and Hemotherapy.

[112]  M. Yanagita,et al.  Renal anemia: from incurable to curable. , 2013, American journal of physiology. Renal physiology.

[113]  L. Eapen,et al.  Effects of radiation and total androgen blockade on serum hemoglobin, testosterone, and erythropoietin in patients with localized prostate cancer. , 2012, Current oncology.

[114]  P. W. Hochachka,et al.  Genetic approaches to understanding human adaptation to altitude in the Andes. , 2001, The Journal of experimental biology.

[115]  C. Giordano,et al.  DAX-1, as an androgen-target gene, inhibits aromatase expression: a novel mechanism blocking estrogen-dependent breast cancer cell proliferation , 2013, Cell Death and Disease.

[116]  C. Beaumont,et al.  Actualité du métabolisme du fer , 2012 .

[117]  A. Silman,et al.  Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats. , 2009, The Journal of clinical endocrinology and metabolism.

[118]  M. Hentze,et al.  The IRP1-HIF-2α axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. , 2013, Cell metabolism.

[119]  S. Bandinelli,et al.  Low testosterone levels and the risk of anemia in older men and women. , 2006, Archives of internal medicine.

[120]  F. Léon-Velarde,et al.  Relationship of ovarian hormones to hypoxemia in women residents of 4,300 m. , 2001, American journal of physiology. Regulatory, integrative and comparative physiology.

[121]  H. Escobar-Morreale,et al.  Role of decreased circulating hepcidin concentrations in the iron excess of women with the polycystic ovary syndrome. , 2011, The Journal of clinical endocrinology and metabolism.

[122]  H. Morita,et al.  Effect of royal jelly ingestion for six months on healthy volunteers , 2012, Nutrition Journal.

[123]  F. Léon-Velarde,et al.  Increasing prevalence of excessive erythrocytosis with age among healthy high-altitude miners. , 1989, The New England journal of medicine.

[124]  F. Léon-Velarde,et al.  Gene expression in chronic high altitude diseases. , 2008, High altitude medicine & biology.

[125]  E. Barrett-Connor,et al.  High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. , 2011, Journal of the American College of Cardiology.

[126]  Takahiro Matsumoto,et al.  Androgen Receptor Promotes Sex-Independent Angiogenesis in Response to Ischemia and Is Required for Activation of Vascular Endothelial Growth Factor Receptor Signaling , 2013, Circulation.

[127]  M. Maggio,et al.  Androgens and erythropoiesis: Past and present , 2009, Journal of endocrinological investigation.

[128]  Jinchuan Xing,et al.  Genetic Evidence for High-Altitude Adaptation in Tibet , 2010, Science.

[129]  Ge-dong,et al.  Hemoglobin levels in Qinghai-Tibet: different effects of gender for Tibetans vs. Han. , 2005, Journal of applied physiology.

[130]  R. Staroń,et al.  [Heme metabolism as an integral part of iron homeostasis]. , 2014, Postepy higieny i medycyny doswiadczalnej.

[131]  J. Adamson,et al.  Modern aspects of the pathophysiology of renal anemia. , 1988, Contributions to nephrology.

[132]  Su-Jin Park,et al.  Direct and Indirect Effects of Androgens on Survival of Hematopoietic Progenitor Cells In Vitro , 2005, Journal of Korean medical science.

[133]  C. Beall.  Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. , 2006, Integrative and comparative biology.

[134]  C. Sartori,et al.  Systemic vascular dysfunction in patients with chronic mountain sickness. , 2012, Chest.

[135]  Michael C. Gregory,et al.  Active site proton delivery and the lyase activity of human CYP17A1. , 2014, Biochemical and Biophysical Research Communications - BBRC.

[136]  R. Voutilainen,et al.  Blood erythrocyte and hemoglobin concentrations in premature adrenarche. , 2013, The Journal of clinical endocrinology and metabolism.

[137]  D. Kiel,et al.  Genetic Determinants of Serum Testosterone Concentrations in Men , 2011, PLoS genetics.

[138]  K. Taylor,et al.  Genome-Wide Association , 2007, Diabetes.

[139]  I. Georgiou,et al.  Semen quality is influenced by androgen receptor and aromatase gene synergism. , 2012, Human reproduction.

[140]  A. Boveris,et al.  Heart mitochondrial nitric oxide synthase is upregulated in male rats exposed to high altitude (4,340 m). , 2005, American journal of physiology. Heart and circulatory physiology.

[141]  L. Huicho,et al.  Adaptation and Mal-Adaptation to Ambient Hypoxia; Andean, Ethiopian and Himalayan Patterns , 2008, PloS one.

[142]  R. Means.  Hepcidin and Iron Regulation in Health and Disease , 2013, The American journal of the medical sciences.

[143]  R. Mclachlan,et al.  Proteomic Changes in Rat Spermatogenesis in Response to In Vivo Androgen Manipulation; Impact on Meiotic Cells , 2012, PloS one.

[144]  T. Whayne.  Cardiovascular Medicine at High Altitude , 2014, Angiology.

[145]  Mingyao Liu,et al.  Induction of SENP1 in Endothelial Cells Contributes to Hypoxia-driven VEGF Expression and Angiogenesis* , 2010, The Journal of Biological Chemistry.

[146]  Association of androgen receptor CAG repeat polymorphism with VO₂max response to hypoxic training in North China Han men. , 2010, International journal of andrology.

[147]  D. Porubek.  CYP17A1: a biochemistry, chemistry, and clinical review. , 2013, Current topics in medicinal chemistry.

[148]  Jin Cheng.  [SUMO-specific protease 1 and cancer]. , 2008, Ai zheng = Aizheng = Chinese journal of cancer.