Bone and body composition response to testosterone therapy vary according to polymorphisms in the CYP19A1 gene
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.
KeywordsCYP19A1 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.
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.
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 was obtained from all individual participants included in the study.
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