, Volume 65, Issue 3, pp 692–706 | Cite as

Bone and body composition response to testosterone therapy vary according to polymorphisms in the CYP19A1 gene

  • Lina E. Aguirre
  • Georgia Colleluori
  • David Robbins
  • Richard Dorin
  • Vallabh O. Shah
  • Rui Chen
  • Irum Zeb Jan
  • Clifford Qualls
  • Dennis T. Villareal
  • Reina Armamento-VillarealEmail author
Original Article



To evaluate the influence of single nucleotide polymorphisms (SNPs) of CYP19A1 on the response and susceptibility to side effects from testosterone therapy. This is a prospective, single-arm study of men with low-morning serum testosterone (<10.68 nmol/l) administered testosterone cypionate 200 mg intramuscularly every 2 weeks for 18 months.


We measured areal bone mineral density (aBMD) and body composition by dual energy X-ray absorptiometry, tibial volumetric BMD and geometry by peripheral quantitative computer tomography, bone turnover markers by enzyme-linked immunosorbent assay, testosterone, and estradiol by liquid-chromatography/mass-spectroscopy, genotyping by microarray, CYP19A1 expression by quantitative polymerase chain reaction, hematocrit and prostate-specific antigen (PSA).


We enrolled 105 men (40–74-years-old). SNPs rs1062033 and rs700518 were associated with significant differences in outcomes at 18 months. The GG genotype in rs1062033 had significant increase in whole body aBMD, but had significant decrease in tibial bone size compared to the CG and CC genotypes. Body composition analysis showed that the CC genotype of rs1062033, and the AA genotype of rs700518, had significant increase in total lean and appendicular lean mass compared to CG and GG, and AG and GG, respectively. The GG genotype of rs700518 had significant increase in PSA (GG = 105.8 ± 23.3% vs. AG + AA = 53.4 ± 11.3%, p = 0.046) while hematocrit changes were comparable among genotypes. CYP19A1 expression was highest in GG genotype in both SNPs.


For the first time, we demonstrated that CYP19A1 SNPs influence response to testosterone therapy in hypogonadal men, highlighting the importance of genetic profiling in therapeutics even for common clinical conditions.


CYP19A1 Aromatase Testosterone Bone mineral density Body composition 



This study was supported by the resources at the New Mexico VA Health Care System in Albuquerque, NM, USA; the Biomedical Research of New Mexico, Albuquerque, NM, USA; the Michael E. DeBakey VA Medical Center, Houston, TX, USA and the Center for Translational Research in Inflammatory Diseases at the Michael E. DeBakey VA Medical Center, Houston, TX, Alkek Foundation, Houston, TX.

Author contributions

R.A.-V. designed the study. G.C., L.E.A., I.Z.J., D.R., R.D., D.T.V., R.A.-V. conducted the study and collected the data. G.C., C.Q., D.T.V., R.A.-V. analyzed and interpreted the data. G.C., R.C., V.O.S., D.T.V., R.A.-V. drafted the paper. All the authors take responsibility for the paper content, the integrity of the data analysis and approval of the final version of the paper.


This study was funded by VA Merit Review (5101 CX00042403) and 1 R01 HD093047-01.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12020_2019_2008_MOESM1_ESM.docx (21 kb)
Supplementary Tables


  1. 1.
    N. Bassil, S. Alkaade, J.E. Morley, The benefits and risks of testosterone replacement therapy: a review. Ther. Clin. Risk Manag. 5(3), 427–448 (2009).Google Scholar
  2. 2.
    P.J. Snyder, S. Bhasin, G.R. Cunningham, A.M. Matsumoto, A.J. Stephens-Shields, J.A. Cauley, T.M. Gill, E. Barrett-Connor, R.S. Swerdloff, C. Wang, K.E. Ensrud, C.E. Lewis, J.T. Farrar, D. Cella, R.C. Rosen, M. Pahor, J.P. Crandall, M.E. Molitch, D. Cifelli, D. Dougar, L. Fluharty, S.M. Resnick, T.W. Storer, S. Anton, S. Basaria, S.J. Diem, X. Hou, E.R. Mohler III, J.K. Parsons, N.K. Wenger, B. Zeldow, J.R. Landis, S.S. Ellenberg, Effects of testosterone treatment in older men. N. Engl. J. Med. 374(7), 611–624 (2016)CrossRefGoogle Scholar
  3. 3.
    S. Basaria, A.S. Dobs, Hypogonadism and androgen replacement therapy in elderly men. Am. J. Med. 110(7), 563–572 (2001)CrossRefGoogle Scholar
  4. 4.
    P.J. Snyder, H. Peachey, P. Hannoush, J.A. Berlin, L. Loh, J.H. Holmes, A. Dlewati, J. Staley, J. Santanna, S.C. Kapoor, M.F. Attie, J.G. Haddad Jr., B.L. Strom, Effect of testosterone treatment on bone mineral density in men over 65 years of age. J. Clin. Endocrinol. Metab. 84(6), 1966–1972 (1999)Google Scholar
  5. 5.
    J.A. Riancho, C. Sanudo, C. Valero, C. Pipaon, J.M. Olmos, V. Mijares, J.L. Fernandez-Luna, M.T. Zarrabeitia, Association of the aromatase gene alleles with BMD: epidemiological and functional evidence. J. Bone Miner. Res. 24(10), 1709–1718 (2009)CrossRefGoogle Scholar
  6. 6.
    N. Napoli, D.T. Villareal, S. Mumm, L. Halstead, S. Sheikh, M. Cagaanan, G.B. Rini, R. rmamento-Villareal, Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density. J. Bone Miner. Res. 20(2), 232–239 (2005)CrossRefGoogle Scholar
  7. 7.
    S. Khosla, L.J. Melton III, E.J. Atkinson, W.M. O’Fallon, Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J. Clin. Endocrinol. Metab. 86(8), 3555–3561 (2001)CrossRefGoogle Scholar
  8. 8.
    J.S. Finkelstein, H. Lee, B.Z. Leder, S.A. Burnett-Bowie, D.W. Goldstein, C.W. Hahn, S.C. Hirsch, A. Linker, N. Perros, A.B. Servais, A.P. Taylor, M.L. Webb, J.M. Youngner, E.W. Yu, Gonadal steroid-dependent effects on bone turnover and bone mineral density in men. J. Clin. Invest 126(3), 1114–1125 (2016)CrossRefGoogle Scholar
  9. 9.
    C. Carani, K. Qin, M. Simoni, M. Faustini-Fustini, S. Serpente, J. Boyd, K.S. Korach, E.R. Simpson, Effect of testosterone and estradiol in a man with aromatase deficiency. N. Engl. J. Med. 337(2), 91–95 (1997)CrossRefGoogle Scholar
  10. 10.
    E. Barrett-Connor, J.E. Mueller, D.G. von Muhlen, G.A. Laughlin, D.L. Schneider, D.J. Sartoris, Low levels of estradiol are associated with vertebral fractures in older men, but not women: the Rancho Bernardo Study. J. Clin. Endocrinol. Metab. 85(1), 219–223 (2000)Google Scholar
  11. 11.
    L. Gennari, L. Masi, D. Merlotti, L. Picariello, A. Falchetti, A. Tanini, C. Mavilia, M.F. Del, S. Gonnelli, B. Lucani, C. Gennari, M.L. Brandi, A polymorphic CYP19 TTTA repeat influences aromatase activity and estrogen levels in elderly men: effects on bone metabolism. J. Clin. Endocrinol. Metab. 89(6), 2803–2810 (2004)CrossRefGoogle Scholar
  12. 12.
    J. Somner, S. McLellan, J. Cheung, Y.T. Mak, M.L. Frost, K.M. Knapp, A.S. Wierzbicki, M. Wheeler, I. Fogelman, S.H. Ralston, G.N. Hampson, Polymorphisms in the P450c17 (17-hydroxylase/17,20-Lyase) and P450 c19 (aromatase) genes: association with serum sex steroid concentrations and bone mineral density in postmenopausal women. J. Clin. Endocrinol. Metab. 89(1), 344–351 (2004)CrossRefGoogle Scholar
  13. 13.
    J.A. Riancho, C. Valero, A. Naranjo, D.J. Morales, C. Sanudo, M.T. Zarrabeitia, Identification of an aromatase haplotype that is associated with gene expression and postmenopausal osteoporosis. J. Clin. Endocrinol. Metab. 92(2), 660–665 (2007)CrossRefGoogle Scholar
  14. 14.
    C.L. Tofteng, A. Kindmark, H. Brandstrom, B. Abrahamsen, S. Petersen, F. Stiger, L.S. Stilgren, J.E. Jensen, P. Vestergaard, B.L. Langdahl, L. Mosekilde, Polymorphisms in the CYP19 and AR genes-relation to bone mass and longitudinal bone changes in postmenopausal women with or without hormone replacement therapy: The Danish Osteoporosis Prevention Study. Calcif. Tissue Int. 74(1), 25–34 (2004)CrossRefGoogle Scholar
  15. 15.
    S. Bhasin, G.R. Cunningham, F.J. Hayes, A.M. Matsumoto, P.J. Snyder, R.S. Swerdloff, V.M. Montori, Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 95(6), 2536–2559 (2010)CrossRefGoogle Scholar
  16. 16.
    J.C.C. Kwong, Y. Krakowsky, E. Grober, Testosterone deficiency: a review and comparison of current guidelines. J. Sex. Med 16(6), 812–820 (2019). CrossRefGoogle Scholar
  17. 17.
    J.P. Mulhall, L.W. Trost, R.E. Brannigan, E.G. Kurtz, J.B. Redmon, K.A. Chiles, D.J. Lightner, M.M. Miner, M.H. Murad, C.J. Nelson, E.A. Platz, L.V. Ramanathan, R.W. Lewis, Evaluation and management of testosterone deficiency: AUA Guideline. J. Urol. 200(2), 423–432 (2018). CrossRefGoogle Scholar
  18. 18.
    G. Defeudis, R. Mazzilli, D. Gianfrilli, A. Lenzi, A.M. Isidori, The CATCH checklist to investigate adult-onset hypogonadism. Andrology 6(5), 665–679 (2018). CrossRefGoogle Scholar
  19. 19.
    L.E. Aguirre, G. Colleluori, K.E. Fowler, I.Z. Jan, K. Villareal, C. Qualls, D. Robbins, D.T. Villareal, R. Armamento-Villareal, High aromatase activity in hypogonadal men is associated with higher spine bone mineral density, increased truncal fat and reduced lean mass. Eur. J. Endocrinol. 173(2), 167–174 (2015)CrossRefGoogle Scholar
  20. 20.
    L.E. Aguirre, G. Colleluori, R. Dorin, D. Robbins, R. Chen, B. Jiang, C. Qualls, D.T. Villareal, R. Armamento-Villareal, Hypogonadal men with higher bodymass index have higher bone density and better bone quality but reduced muscle density. Calcif. Tissue Int. 101(6), 602–611 (2017).CrossRefGoogle Scholar
  21. 21.
    S. Vandewalle, Y. Taes, T. Fiers, K. Toye, C.E. Van, I. Roggen, S.J. De, J.M. Kaufman, Associations of sex steroids with bone maturation, bone mineral density, bone geometry, and body composition: a cross-sectional study in healthy male adolescents. J. Clin. Endocrinol. Metab. 99(7), E1272–E1282 (2014)CrossRefGoogle Scholar
  22. 22.
    H. Haapasalo, S. Kontulainen, H. Sievanen, P. Kannus, M. Jarvinen, I. Vuori, Exercise-induced bone gain is due to enlargement in bone size without a change in volumetric bone density: a peripheral quantitative computed tomography study of the upper arms of male tennis players. Bone 27(3), 351–357 (2000)CrossRefGoogle Scholar
  23. 23.
    R. Armamento-Villareal, V.O. Shah, L.E. Aguirre, A.L. Meisner, C. Qualls, M.E. Royce, The rs4646 and rs12592697 polymorphisms in CYP19A1 are associated with disease progression among patients with breast cancer from different racial/ethnic backgrounds. Front Genet 7, 211 (2016). CrossRefGoogle Scholar
  24. 24.
    N. Napoli, A. Rastelli, C. Ma, J. Yarramaneni, S. Vattikutti, G. Moskowitz, T. Giri, C. Mueller, V. Kulkarny, C. Qualls, M. Ellis, R. Armamento-Villareal, Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER+breast cancer. Bone 55(2), 309–314 (2013)CrossRefGoogle Scholar
  25. 25.
    A.L. Eriksson, M. Lorentzon, L. Vandenput, F. Labrie, M. Lindersson, A.C. Syvanen, E.S. Orwoll, S.R. Cummings, J.M. Zmuda, O. Ljunggren, M.K. Karlsson, D. Mellstrom, C. Ohlsson, Genetic variations in sex steroid-related genes as predictors of serum estrogen levels in men. J. Clin. Endocrinol. Metab. 94(3), 1033–1041 (2009)CrossRefGoogle Scholar
  26. 26.
    J.K. Amory, N.B. Watts, K.A. Easley, P.R. Sutton, B.D. Anawalt, A.M. Matsumoto, W.J. Bremner, J.L. Tenover, Exogenous testosterone or testosterone withfinasteride increases bone mineral density in older men with low serum testosterone. J. Clin. Endocrinol. Metab. 89(2), 503–510 (2004).CrossRefGoogle Scholar
  27. 27.
    B. Devlin, N. Risch, A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 29, 311–322 (1995).CrossRefGoogle Scholar
  28. 28.
    R.C. Lewontin, On measures of gametic disequilibrium. Genetics 120, 849–852 (1988).Google Scholar
  29. 29.
    R. Colomer, M. Monzo, I. Tusquets, J. Rifa, J.M. Baena, A. Barnadas, L. Calvo, F. Carabantes, C. Crespo, M. Munoz, A. Llombart, A. Plazaola, R. Artells, M. Gilabert, B. Lloveras, E. Alba, A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma. Clin. Cancer Res. 14(3), 811–816 (2008)CrossRefGoogle Scholar
  30. 30.
    N. Napoli, A. Rastelli, C. Ma, G. Colleluori, S. Vattikuti, R. Armamento-Villareal, Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with body composition changes in women on aromatase inhibitors for ER (+) breast cancer. Pharm. Genom. 25(8), 377–381 (2015). CrossRefGoogle Scholar
  31. 31.
    J.S. Finkelstein, E.W. Yu, S.A. Burnett-Bowie, Gonadal steroids and body composition, strength, and sexual function in men. N. Engl. J. Med. 369(25), 2457 (2013)CrossRefGoogle Scholar
  32. 32.
    R. Armamento-Villareal, L. Aguirre, N. Napoli, K. Shah, T. Hilton, D.R. Sinacore, C. Qualls, D.T. Villareal, Changes in thigh muscle volume predict bone mineral density response to lifestyle therapy in frail, obese older adults. Osteoporos. Int. 25(2), 551–558 (2014)Google Scholar
  33. 33.
    T.G. Travison, S. Basaria, T.W. Storer, A.M. Jette, R. Miciek, W.R. Farwell, K. Choong, K. Lakshman, N.A. Mazer, A.D. Coviello, P.E. Knapp, J. Ulloor, A. Zhang, B. Brooks, A.H. Nguyen, R. Eder, N. LeBrasseur, A. Elmi, E. Appleman, L. Hede-Brierley, G. Bhasin, A. Bhatia, A. Lazzari, S. Davis, P. Ni, L. Collins, S. Bhasin, Clinical meaningfulness of the changes in muscle performance and physical function associated with testosterone administration in older men with mobility limitation. J. Gerontol. A Biol. Sci. Med. Sci. 66(10), 1090–1099 (2011)CrossRefGoogle Scholar
  34. 34.
    G.K. Dimitriadis, H.S. Randeva, S. Aftab, A. Ali, J.G. Hattersley, S. Pandey, D.K. Grammatopoulos, G. Valsamakis, G. Mastorakos, T.H. Jones, T.M. Barber, Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy. Endocrine 60(1), 175–184 (2018). CrossRefGoogle Scholar
  35. 35.
    C.J. Gruber, W. Tschugguel, C. Schneeberger, J.C. Huber, Production and actions of estrogens. N. Engl. J. Med 346(5), 340–352 (2002). CrossRefGoogle Scholar
  36. 36.
    M. Shozu, E.R. Simpson, Aromatase expression of human osteoblast-like cells. Mol. Cell Endocrinol. 139(1-2), 117–129 (1998)CrossRefGoogle Scholar
  37. 37.
    A. Vottero, V. Rochira, M. Capelletti, I. Viani, L. Zirilli, T.M. Neri, C. Carani, S. Bernasconi, L. Ghizzoni, Aromatase is differentially expressed in peripheral blood leukocytes from children, and adult female and male subjects. Eur. J. Endocrinol. 154(3), 425–431 (2006). CrossRefGoogle Scholar
  38. 38.
    Y. He, C.L. Wang, Effects of testosterone on PPARgamma and P450arom expression in polycystic ovary syndrome patients and related mechanisms. Eur. Rev. Med Pharm. Sci. 22(6), 1549–1553 (2018). Google Scholar
  39. 39.
    S.J. Ellem, J.F. Schmitt, J.S. Pedersen, M. Frydenberg, G.P. Risbridger, Local aromatase expression in human prostate is altered in malignancy. J. Clin. Endocrinol. Metab. 89(5), 2434–2441 (2004)CrossRefGoogle Scholar
  40. 40.
    S.J. Ellem, H. Wang, M. Poutanen, G.P. Risbridger, Increased endogenous estrogen synthesis leads to the sequential induction of prostatic inflammation (prostatitis) and prostatic pre-malignancy. Am. J. Pathol. 175(3), 1187–1199 (2009)CrossRefGoogle Scholar
  41. 41.
    O. Cussenot, A.R. Azzouzi, N. Nicolaiew, G. Fromont, P. Mangin, L. Cormier, G. Fournier, A. Valeri, S. Larre, F. Thibault, J.P. Giordanella, M. Pouchard, Y. Zheng, F.C. Hamdy, A. Cox, G. Cancel-Tassin, Combination of polymorphisms from genes related to estrogen metabolism and risk of prostate cancers: the hidden face of estrogens. J. Clin. Oncol. 25(24), 3596–3602 (2007)CrossRefGoogle Scholar
  42. 42.
    J. Beuten, J.A. Gelfond, J.L. Franke, K.S. Weldon, A.C. Crandall, T.L. Johnson-Pais, I.M. Thompson, R.J. Leach, Single and multigenic analysis of the association between variants in 12 steroid hormone metabolism genes and risk of prostate cancer. Cancer Epidemiol. Biomark. Prev. 18(6), 1869–1880 (2009)CrossRefGoogle Scholar
  43. 43.
    L. Tang, M.E. Platek, S. Yao, C. Till, P.J. Goodman, C.M. Tangen, Y. Wu, E.A. Platz, M.L. Neuhouser, F.Z. Stanczyk, J.K.V. Reichardt, R.M. Santella, A. Hsing, W.D. Figg, S.M. Lippman, I.M. Thompson, C.B. Ambrosone, Associations between polymorphisms in genes related to estrogen metabolism and function and prostate cancer risk: results from the Prostate Cancer Prevention Trial. Carcinogenesis 39(2), 125–133 (2018). CrossRefGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019

Authors and Affiliations

  • Lina E. Aguirre
    • 1
    • 2
  • Georgia Colleluori
    • 3
    • 4
  • David Robbins
    • 1
    • 2
  • Richard Dorin
    • 1
    • 2
  • Vallabh O. Shah
    • 1
    • 2
  • Rui Chen
    • 3
    • 4
  • Irum Zeb Jan
    • 1
  • Clifford Qualls
    • 1
    • 2
    • 5
  • Dennis T. Villareal
    • 3
    • 4
  • Reina Armamento-Villareal
    • 3
    • 4
    Email author
  1. 1.New Mexico VA Health Care SystemAlbuquerqueUSA
  2. 2.University of New Mexico School of MedicineAlbuquerqueUSA
  3. 3.Baylor College of MedicineHoustonUSA
  4. 4.Michael E. DeBakey VA Medical CenterHoustonUSA
  5. 5.Biomedical Research Institute of New MexicoAlbuquerqueUSA

Personalised recommendations