Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats

Ilpo T. Huhtaniemi, Stephen R. Pye, Kate L. Limer, Wendy Thomson, Terence W. O'Neill, Hazel Platt, Debbie Payne, Sally L. John, Min Jiang, Steven Boonen, Herman Borghs, Dirk Vanderschueren, Judith E. Adams, Kate A. Ward, G. Bártfai, Felipe Casanueva, Joseph D. Finn, Gianni Forti, Aleksander Giwercman, Thang S. Han & 24 others Krzysztof Kula, Michael E J Lean, Neil Pendleton, Margus Punab, Alan J. Silman, Frederick C W Wu, Luisa Petrone, Antonio Cilotti, Jolanta Slowikowska-Hilczer, Renata Walczak-Jedrzejowska, Ilpo Huhtaniemi, Frederick Wu, Alan Silman, Terence O'Neill, Joseph Finn, Philip Steer, Abdelouahid Tajar, David Lee, Stephen Pye, Marta Ocampo, Mary Lage, I. Földesi, I. Fejes, Paul Korrovitz

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

Context: The individual variability in the waning androgenic-anabolic functions of aging men may be influenced by the CAG repeat polymorphism in exon 1 of the androgen receptor (AR), affecting androgen sensitivity. However, findings on its phenotypic effects are inconclusive. Objective: The aim was to investigate the relationships between health status, various reproductive hormones, and the AR CAG repeat length. Design: We conducted a multinational prospective cohort observational study with cross-sectional baseline data. Setting: This was a population survey of community-dwelling men. Participants: Men (40-79 yr old; n = 3369) were randomly recruited from centers in eight European countries; CAG repeat analysis was performed in 2878 men. Main Outcome Measures: We measured the correlations of the CAG repeat length with selected endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action. Results: Only minor differences were found in CAG repeat lengths between the eight European countries. They showed significant positive association with total, free, and bioavailable levels of testosterone (T) and estradiol. FSH but not LH correlated inversely with CAG repeat length. Significant associations were found with bone ultrasound parameters at the calcaneus. Negative correlation was found with triglycerides, but not with other blood lipids or with anthropometry, blood pressure, hemoglobin, insulin sensitivity, or sexual and prostatic functions. Conclusions: The AR CAG repeat length correlates significantly with serum T and estradiol of aging men. Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or nearly totally compensated for by higher T levels. The residual phenotypic correlations may reflect differences in estrogen levels/actions after aromatization of the higher T levels.

Original languageEnglish
Pages (from-to)277-284
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume94
Issue number1
DOIs
Publication statusPublished - Jan 2009

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Androgen Receptors
Androgens
Estrogens
Aging of materials
Estradiol
Anthropometry
Aromatization
Blood pressure
Gonadal Steroid Hormones
Independent Living
Polymorphism
Calcaneus
Testosterone
Exons
Bone
Hemoglobins
Triglycerides
Blood
Ultrasonics
Health Status

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Huhtaniemi, I. T., Pye, S. R., Limer, K. L., Thomson, W., O'Neill, T. W., Platt, H., ... Korrovitz, P. (2009). Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats. Journal of Clinical Endocrinology and Metabolism, 94(1), 277-284. https://doi.org/10.1210/jc.2008-0848

Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats. / Huhtaniemi, Ilpo T.; Pye, Stephen R.; Limer, Kate L.; Thomson, Wendy; O'Neill, Terence W.; Platt, Hazel; Payne, Debbie; John, Sally L.; Jiang, Min; Boonen, Steven; Borghs, Herman; Vanderschueren, Dirk; Adams, Judith E.; Ward, Kate A.; Bártfai, G.; Casanueva, Felipe; Finn, Joseph D.; Forti, Gianni; Giwercman, Aleksander; Han, Thang S.; Kula, Krzysztof; Lean, Michael E J; Pendleton, Neil; Punab, Margus; Silman, Alan J.; Wu, Frederick C W; Petrone, Luisa; Cilotti, Antonio; Slowikowska-Hilczer, Jolanta; Walczak-Jedrzejowska, Renata; Huhtaniemi, Ilpo; Wu, Frederick; Silman, Alan; O'Neill, Terence; Finn, Joseph; Steer, Philip; Tajar, Abdelouahid; Lee, David; Pye, Stephen; Ocampo, Marta; Lage, Mary; Földesi, I.; Fejes, I.; Korrovitz, Paul.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 94, No. 1, 01.2009, p. 277-284.

Research output: Contribution to journalArticle

Huhtaniemi, IT, Pye, SR, Limer, KL, Thomson, W, O'Neill, TW, Platt, H, Payne, D, John, SL, Jiang, M, Boonen, S, Borghs, H, Vanderschueren, D, Adams, JE, Ward, KA, Bártfai, G, Casanueva, F, Finn, JD, Forti, G, Giwercman, A, Han, TS, Kula, K, Lean, MEJ, Pendleton, N, Punab, M, Silman, AJ, Wu, FCW, Petrone, L, Cilotti, A, Slowikowska-Hilczer, J, Walczak-Jedrzejowska, R, Huhtaniemi, I, Wu, F, Silman, A, O'Neill, T, Finn, J, Steer, P, Tajar, A, Lee, D, Pye, S, Ocampo, M, Lage, M, Földesi, I, Fejes, I & Korrovitz, P 2009, 'Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats', Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 1, pp. 277-284. https://doi.org/10.1210/jc.2008-0848
Huhtaniemi, Ilpo T. ; Pye, Stephen R. ; Limer, Kate L. ; Thomson, Wendy ; O'Neill, Terence W. ; Platt, Hazel ; Payne, Debbie ; John, Sally L. ; Jiang, Min ; Boonen, Steven ; Borghs, Herman ; Vanderschueren, Dirk ; Adams, Judith E. ; Ward, Kate A. ; Bártfai, G. ; Casanueva, Felipe ; Finn, Joseph D. ; Forti, Gianni ; Giwercman, Aleksander ; Han, Thang S. ; Kula, Krzysztof ; Lean, Michael E J ; Pendleton, Neil ; Punab, Margus ; Silman, Alan J. ; Wu, Frederick C W ; Petrone, Luisa ; Cilotti, Antonio ; Slowikowska-Hilczer, Jolanta ; Walczak-Jedrzejowska, Renata ; Huhtaniemi, Ilpo ; Wu, Frederick ; Silman, Alan ; O'Neill, Terence ; Finn, Joseph ; Steer, Philip ; Tajar, Abdelouahid ; Lee, David ; Pye, Stephen ; Ocampo, Marta ; Lage, Mary ; Földesi, I. ; Fejes, I. ; Korrovitz, Paul. / Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats. In: Journal of Clinical Endocrinology and Metabolism. 2009 ; Vol. 94, No. 1. pp. 277-284.
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abstract = "Context: The individual variability in the waning androgenic-anabolic functions of aging men may be influenced by the CAG repeat polymorphism in exon 1 of the androgen receptor (AR), affecting androgen sensitivity. However, findings on its phenotypic effects are inconclusive. Objective: The aim was to investigate the relationships between health status, various reproductive hormones, and the AR CAG repeat length. Design: We conducted a multinational prospective cohort observational study with cross-sectional baseline data. Setting: This was a population survey of community-dwelling men. Participants: Men (40-79 yr old; n = 3369) were randomly recruited from centers in eight European countries; CAG repeat analysis was performed in 2878 men. Main Outcome Measures: We measured the correlations of the CAG repeat length with selected endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action. Results: Only minor differences were found in CAG repeat lengths between the eight European countries. They showed significant positive association with total, free, and bioavailable levels of testosterone (T) and estradiol. FSH but not LH correlated inversely with CAG repeat length. Significant associations were found with bone ultrasound parameters at the calcaneus. Negative correlation was found with triglycerides, but not with other blood lipids or with anthropometry, blood pressure, hemoglobin, insulin sensitivity, or sexual and prostatic functions. Conclusions: The AR CAG repeat length correlates significantly with serum T and estradiol of aging men. Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or nearly totally compensated for by higher T levels. The residual phenotypic correlations may reflect differences in estrogen levels/actions after aromatization of the higher T levels.",
author = "Huhtaniemi, {Ilpo T.} and Pye, {Stephen R.} and Limer, {Kate L.} and Wendy Thomson and O'Neill, {Terence W.} and Hazel Platt and Debbie Payne and John, {Sally L.} and Min Jiang and Steven Boonen and Herman Borghs and Dirk Vanderschueren and Adams, {Judith E.} and Ward, {Kate A.} and G. B{\'a}rtfai and Felipe Casanueva and Finn, {Joseph D.} and Gianni Forti and Aleksander Giwercman and Han, {Thang S.} and Krzysztof Kula and Lean, {Michael E J} and Neil Pendleton and Margus Punab and Silman, {Alan J.} and Wu, {Frederick C W} and Luisa Petrone and Antonio Cilotti and Jolanta Slowikowska-Hilczer and Renata Walczak-Jedrzejowska and Ilpo Huhtaniemi and Frederick Wu and Alan Silman and Terence O'Neill and Joseph Finn and Philip Steer and Abdelouahid Tajar and David Lee and Stephen Pye and Marta Ocampo and Mary Lage and I. F{\"o}ldesi and I. Fejes and Paul Korrovitz",
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AU - Huhtaniemi, Ilpo T.

AU - Pye, Stephen R.

AU - Limer, Kate L.

AU - Thomson, Wendy

AU - O'Neill, Terence W.

AU - Platt, Hazel

AU - Payne, Debbie

AU - John, Sally L.

AU - Jiang, Min

AU - Boonen, Steven

AU - Borghs, Herman

AU - Vanderschueren, Dirk

AU - Adams, Judith E.

AU - Ward, Kate A.

AU - Bártfai, G.

AU - Casanueva, Felipe

AU - Finn, Joseph D.

AU - Forti, Gianni

AU - Giwercman, Aleksander

AU - Han, Thang S.

AU - Kula, Krzysztof

AU - Lean, Michael E J

AU - Pendleton, Neil

AU - Punab, Margus

AU - Silman, Alan J.

AU - Wu, Frederick C W

AU - Petrone, Luisa

AU - Cilotti, Antonio

AU - Slowikowska-Hilczer, Jolanta

AU - Walczak-Jedrzejowska, Renata

AU - Huhtaniemi, Ilpo

AU - Wu, Frederick

AU - Silman, Alan

AU - O'Neill, Terence

AU - Finn, Joseph

AU - Steer, Philip

AU - Tajar, Abdelouahid

AU - Lee, David

AU - Pye, Stephen

AU - Ocampo, Marta

AU - Lage, Mary

AU - Földesi, I.

AU - Fejes, I.

AU - Korrovitz, Paul

PY - 2009/1

Y1 - 2009/1

N2 - Context: The individual variability in the waning androgenic-anabolic functions of aging men may be influenced by the CAG repeat polymorphism in exon 1 of the androgen receptor (AR), affecting androgen sensitivity. However, findings on its phenotypic effects are inconclusive. Objective: The aim was to investigate the relationships between health status, various reproductive hormones, and the AR CAG repeat length. Design: We conducted a multinational prospective cohort observational study with cross-sectional baseline data. Setting: This was a population survey of community-dwelling men. Participants: Men (40-79 yr old; n = 3369) were randomly recruited from centers in eight European countries; CAG repeat analysis was performed in 2878 men. Main Outcome Measures: We measured the correlations of the CAG repeat length with selected endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action. Results: Only minor differences were found in CAG repeat lengths between the eight European countries. They showed significant positive association with total, free, and bioavailable levels of testosterone (T) and estradiol. FSH but not LH correlated inversely with CAG repeat length. Significant associations were found with bone ultrasound parameters at the calcaneus. Negative correlation was found with triglycerides, but not with other blood lipids or with anthropometry, blood pressure, hemoglobin, insulin sensitivity, or sexual and prostatic functions. Conclusions: The AR CAG repeat length correlates significantly with serum T and estradiol of aging men. Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or nearly totally compensated for by higher T levels. The residual phenotypic correlations may reflect differences in estrogen levels/actions after aromatization of the higher T levels.

AB - Context: The individual variability in the waning androgenic-anabolic functions of aging men may be influenced by the CAG repeat polymorphism in exon 1 of the androgen receptor (AR), affecting androgen sensitivity. However, findings on its phenotypic effects are inconclusive. Objective: The aim was to investigate the relationships between health status, various reproductive hormones, and the AR CAG repeat length. Design: We conducted a multinational prospective cohort observational study with cross-sectional baseline data. Setting: This was a population survey of community-dwelling men. Participants: Men (40-79 yr old; n = 3369) were randomly recruited from centers in eight European countries; CAG repeat analysis was performed in 2878 men. Main Outcome Measures: We measured the correlations of the CAG repeat length with selected endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action. Results: Only minor differences were found in CAG repeat lengths between the eight European countries. They showed significant positive association with total, free, and bioavailable levels of testosterone (T) and estradiol. FSH but not LH correlated inversely with CAG repeat length. Significant associations were found with bone ultrasound parameters at the calcaneus. Negative correlation was found with triglycerides, but not with other blood lipids or with anthropometry, blood pressure, hemoglobin, insulin sensitivity, or sexual and prostatic functions. Conclusions: The AR CAG repeat length correlates significantly with serum T and estradiol of aging men. Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or nearly totally compensated for by higher T levels. The residual phenotypic correlations may reflect differences in estrogen levels/actions after aromatization of the higher T levels.

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