Genetics of androgen disposition : implications for doping tests
Author: Jakobsson Schulze, Jenny
Date: 2007-11-23
Location: Hörsal 4U, Alfred Nobels Allé 8, plan 4, Karolinska Universitetssjukhuset, Huddinge
Time: 09.00
Department: Institutionen för laboratoriemedicin / Department of Laboratory Medicine
View/ Open:
thesis.pdf (1.441Mb)
Abstract
Anabolic androgenic steroids (AAS) are derivatives of testosterone.
Doping with AAS is a severe challenge to the vision, moral and ethics in
sports and has also become an increasing problem in society.
Testosterone abuse is conventionally assessed by the urinary testosterone glucuronide/ epitestosterone glucuronide (T/E) ratio, levels above 4.0 being considered suspicious. However, there is a large inter-individual variation in testosterone glucuronide and epitestosterone glucuronide excretion, which challenges the accuracy of the test.
There are reasons to believe that genetic variation is the single most important cause of variation in disposition of many androgenic compounds. Twin studies in men have demonstrated heritability estimates of 85% and 96% for production rates of testosterone and dihydrotestosterone, respectively. The primary aim of this thesis was to investigate the contribution of genetic components to inter-individual variation in androgen disposition.
We found that a deletion polymorphism in the UGT2B17 gene was strongly associated with the urinary testosterone glucuronide levels. All individuals homozygous for the deletion had negligible amounts of urinary testosterone glucuronide. It is a common polymorphism with an allele frequency of 29 % in Swedes and 78 % in Koreans.
After a single dose of 360 mg testosterone, 40 % of the subjects homozygous for the UGT2B17 deletion never reached the T/E cut off ratio of 4.0. We showed that the sensitivity and specificity of the T/E test could be markedly improved by using genotype-based cut off ratios.
A CYP17 T>C promoter polymorphism was associated with urinary epitestosterone glucuronide levels and consequently the T/E ratio. High natural T/E ratios due to low urinary levels of epitestosterone glucuronide may be partly explained by this polymorphism. Considering only individuals with a functional UGT2B17 enzyme, carriers of the CYP17 TT genotype exhibited 64 % higher T/E ratios than men with one or two C-alleles. The frequency of the TT genotype was 35 % in Caucasians.
Another polymorphism (E77G) in 17b-hydroxysteroid dehydrogenase type 5 (HSD17B5), an enzyme that catalyses the step between androstenedione and testosterone, was associated with serum testosterone levels in Caucasian men. Considering only individuals with a functional UGT2B17 enzyme, this polymorphism was also associated with urinary testosterone glucuronide levels. The polymorphism had an allele frequency of 4.8 % in Swedes but was completely absent in Koreans. We also found a novel functional promoter polymorphism in the CYP7B1 gene, which was associated with significantly higher promoter activity and had an allele frequency of 4 % in Swedes and 0.65 % in Koreans.
In summary, genetic variation has a large impact on androgen disposition. This variation is of the utmost importance for the interpretation of doping test results. The role of this variation for diseases in steroid target organs or for endocrine adverse reactions to drugs remains to be elucidated.
Testosterone abuse is conventionally assessed by the urinary testosterone glucuronide/ epitestosterone glucuronide (T/E) ratio, levels above 4.0 being considered suspicious. However, there is a large inter-individual variation in testosterone glucuronide and epitestosterone glucuronide excretion, which challenges the accuracy of the test.
There are reasons to believe that genetic variation is the single most important cause of variation in disposition of many androgenic compounds. Twin studies in men have demonstrated heritability estimates of 85% and 96% for production rates of testosterone and dihydrotestosterone, respectively. The primary aim of this thesis was to investigate the contribution of genetic components to inter-individual variation in androgen disposition.
We found that a deletion polymorphism in the UGT2B17 gene was strongly associated with the urinary testosterone glucuronide levels. All individuals homozygous for the deletion had negligible amounts of urinary testosterone glucuronide. It is a common polymorphism with an allele frequency of 29 % in Swedes and 78 % in Koreans.
After a single dose of 360 mg testosterone, 40 % of the subjects homozygous for the UGT2B17 deletion never reached the T/E cut off ratio of 4.0. We showed that the sensitivity and specificity of the T/E test could be markedly improved by using genotype-based cut off ratios.
A CYP17 T>C promoter polymorphism was associated with urinary epitestosterone glucuronide levels and consequently the T/E ratio. High natural T/E ratios due to low urinary levels of epitestosterone glucuronide may be partly explained by this polymorphism. Considering only individuals with a functional UGT2B17 enzyme, carriers of the CYP17 TT genotype exhibited 64 % higher T/E ratios than men with one or two C-alleles. The frequency of the TT genotype was 35 % in Caucasians.
Another polymorphism (E77G) in 17b-hydroxysteroid dehydrogenase type 5 (HSD17B5), an enzyme that catalyses the step between androstenedione and testosterone, was associated with serum testosterone levels in Caucasian men. Considering only individuals with a functional UGT2B17 enzyme, this polymorphism was also associated with urinary testosterone glucuronide levels. The polymorphism had an allele frequency of 4.8 % in Swedes but was completely absent in Koreans. We also found a novel functional promoter polymorphism in the CYP7B1 gene, which was associated with significantly higher promoter activity and had an allele frequency of 4 % in Swedes and 0.65 % in Koreans.
In summary, genetic variation has a large impact on androgen disposition. This variation is of the utmost importance for the interpretation of doping test results. The role of this variation for diseases in steroid target organs or for endocrine adverse reactions to drugs remains to be elucidated.
List of papers:
I. Jakobsson J, Karypidis H, Johansson JE, Roh HK, Rane A, Ekström L (2004). "A functional C-G polymorphism in the CYP7B1 promoter region and its different distribution in Orientals and Caucasians." Pharmacogenomics J 4(4): 245-50
Pubmed
II. Jakobsson J, Palonek E, Lorentzon M, Ohlsson C, Rane A, Ekström L (2007). "A novel polymorphism in the 17beta-hydroxysteroid dehydrogenase type 5 (aldo-keto reductase 1C3) gene is associated with lower serum testosterone levels in caucasian men." Pharmacogenomics J 7(4): 282-9. Epub 2006 Sep 19
Pubmed
III. Jakobsson J, Ekström L, Inotsume N, Garle M, Lorentzon M, Ohlsson C, Roh HK, Carlström K, Rane A (2006). "Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-glucuronosyl transferase 2B17 polymorphism." J Clin Endocrinol Metab 91(2): 687-93. Epub 2005 Dec 6
Pubmed
IV. Jakobsson Schulze J, Lundmark J, Garle M, Skilving I, Ekström L, Rane A (2007). "Doping test results dependent on the major enzyme (UGT2B17) for testosterone glucuronidation." J Clin Endocrinol Metab (Submitted)
V. Jakobsson Schulze J, Lorentzon M, Ohlsson C, Lundmark J, Roh H. K, Rane A, Ekström L (2007). "Genetic aspects of epitestosterone formation and androgen disposition; Influence of polymorphisms in CYP17 and UGT2B enzymes." Pharmacogenetics and Genomics (Submitted)
I. Jakobsson J, Karypidis H, Johansson JE, Roh HK, Rane A, Ekström L (2004). "A functional C-G polymorphism in the CYP7B1 promoter region and its different distribution in Orientals and Caucasians." Pharmacogenomics J 4(4): 245-50
Pubmed
II. Jakobsson J, Palonek E, Lorentzon M, Ohlsson C, Rane A, Ekström L (2007). "A novel polymorphism in the 17beta-hydroxysteroid dehydrogenase type 5 (aldo-keto reductase 1C3) gene is associated with lower serum testosterone levels in caucasian men." Pharmacogenomics J 7(4): 282-9. Epub 2006 Sep 19
Pubmed
III. Jakobsson J, Ekström L, Inotsume N, Garle M, Lorentzon M, Ohlsson C, Roh HK, Carlström K, Rane A (2006). "Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-glucuronosyl transferase 2B17 polymorphism." J Clin Endocrinol Metab 91(2): 687-93. Epub 2005 Dec 6
Pubmed
IV. Jakobsson Schulze J, Lundmark J, Garle M, Skilving I, Ekström L, Rane A (2007). "Doping test results dependent on the major enzyme (UGT2B17) for testosterone glucuronidation." J Clin Endocrinol Metab (Submitted)
V. Jakobsson Schulze J, Lorentzon M, Ohlsson C, Lundmark J, Roh H. K, Rane A, Ekström L (2007). "Genetic aspects of epitestosterone formation and androgen disposition; Influence of polymorphisms in CYP17 and UGT2B enzymes." Pharmacogenetics and Genomics (Submitted)
Issue date: 2007-11-02
Rights:
Publication year: 2007
ISBN: 978-91-7357-397-9
Statistics
Total Visits
Views | |
---|---|
Genetics ...(legacy) | 1248 |
Genetics ... | 282 |
Total Visits Per Month
February 2024 | March 2024 | April 2024 | May 2024 | June 2024 | July 2024 | August 2024 | |
---|---|---|---|---|---|---|---|
Genetics ... | 5 | 1 | 6 | 4 | 9 | 7 | 5 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 702 |
thesis.pdf | 632 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 618 |
Sweden | 149 |
Germany | 92 |
China | 82 |
United Kingdom | 37 |
South Korea | 21 |
Finland | 20 |
France | 16 |
Denmark | 15 |
Russia | 15 |
Top cities views
Views | |
---|---|
Sunnyvale | 85 |
Romeo | 42 |
Beijing | 40 |
Stockholm | 33 |
Kiez | 29 |
London | 26 |
Seattle | 26 |
Ashburn | 20 |
Seoul | 16 |
Helsinki | 12 |