The polymorphic androgen receptor gene CAG repeat, pituitary-testicular function and andropausal symptoms in ageing men.

The activity of androgen receptor (AR) is modulated by a polymorphic CAG trinucleotide repeat in the AR gene. In the present study, we investigated hormonal changes among ageing men, and whether the number of AR CAG triplets is related to the appearance of these changes, as well as symptoms and diseases associated with ageing. A total of 213 41-70-year-old men donated blood for hormone analyses (LH, testosterone, oestradiol and SHBG) and answered questions concerning diseases and symptoms associated with ageing and/or androgen deficiency. Of these men, 172 donated blood for the measurement of the CAG repeat length of AR. The CAG repeat region of the AR gene was amplified by polymerase chain reaction (PCR) and the products were sized on polyacrylamide gels. The repeat number was analysed as a dichotomized variable divided according to cut-off limits of the lowest (< or =20 repeats) and the highest quartile (> or =23 repeats), and as a continuous variable. The proportion of men with serum LH in the uppermost quartile (>6.0 IU/L) with normal serum testosterone (>9.8 nmol/L, above the lowest 10%) increased significantly with age (p = 0.01). There were fewer men with this hormonal condition among those with CAG repeat number in the uppermost quartile (> or =23 repeats) (p = 0.03). These men also reported less decreased potency (p < 0.05). The repeat number was positively correlated with depression, as expressed by the wish to be dead (r = 0.45; p < 0.0001), depressed mood (r = 0.23; p = 0.003), anxiety (r = 0.15; p < 0.05), deterioration of general well-being (r = 0.22; p = 0.004), as well as decreased beard growth (r = 0.49; p < 0.0001). A hormonal condition where serum testosterone is normal but LH increased is a frequent finding in male ageing. Only certain types of age-related changes in ageing men were associated with the length of the AR gene CAG repeat, suggesting that this parameter may play a role in setting different thresholds for the array of androgen actions in the male.

[1]  I. Thompson,et al.  Androgen receptor length polymorphism associated with prostate cancer risk in Hispanic men. , 2002, The Journal of urology.

[2]  A. Araujo,et al.  Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men , 2001, Biological Psychiatry.

[3]  S. Roose,et al.  Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial. , 2001, The Journal of clinical psychiatry.

[4]  D. Lamb,et al.  Trinucleotide (CAG) repeat polymorphisms in the androgen receptor gene: molecular markers of risk for male infertility. , 2001, Fertility and sterility.

[5]  E. Rimm,et al.  Racial variation in prostate cancer incidence and in hormonal system markers among male health professionals. , 2000, Journal of the National Cancer Institute.

[6]  F. Comhaire,et al.  Andropause: Hormone Replacement Therapy in the Ageing Male , 2000, European Urology.

[7]  J. Kaprio,et al.  Self-reported life satisfaction and 20-year mortality in healthy Finnish adults. , 2000, American journal of epidemiology.

[8]  J. Benichou,et al.  Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China. , 2000, Cancer research.

[9]  I. Kanazawa,et al.  Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription , 2000, Nature Genetics.

[10]  R. Rosenfield,et al.  Role of hormones in pilosebaceous unit development. , 2000, Endocrine reviews.

[11]  P. Andersen,et al.  Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia , 2000, European Journal of Human Genetics.

[12]  J. Favaloro,et al.  Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. , 2000, Journal of molecular endocrinology.

[13]  H. Perry,et al.  Androgen deficiency in aging men: role of testosterone replacement therapy. , 2000, The Journal of laboratory and clinical medicine.

[14]  J. L. San Millán,et al.  The role of the CAG repeat polymorphism in the androgen receptor gene and of skewed X-chromosome inactivation, in the pathogenesis of hirsutism. , 2000, The Journal of clinical endocrinology and metabolism.

[15]  G. Coetzee,et al.  Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length. , 2000, Human molecular genetics.

[16]  M. Hüfner,et al.  Psychoendocrine sequelae of chronic testosterone deficiency. , 1999, Journal of psychiatric research.

[17]  A. Trounson,et al.  Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene , 1999, The Lancet.

[18]  Chawnshang Chang,et al.  The Linkage of Kennedy’s Neuron Disease to ARA24, the First Identified Androgen Receptor Polyglutamine Region-associated Coactivator* , 1999, The Journal of Biological Chemistry.

[19]  J B McKinlay,et al.  Evidence that the CAG repeat in the androgen receptor gene is associated with the age-related decline in serum androgen levels in men. , 1999, The Journal of endocrinology.

[20]  G. Chrousos,et al.  Androgen receptor-mediated hypersensitivity to androgens in women with nonhyperandrogenic hirsutism: skewing of X-chromosome inactivation. , 1999, The Journal of clinical endocrinology and metabolism.

[21]  E. Barrett-Connor,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1999 by The Endocrine Society Bioavailable Testosterone and Depressed Mood in Older Men: The Rancho Bernardo Study , 2022 .

[22]  A. Shalita,et al.  Androgen Receptor Polymorphisms (CAG Repeat Lengths) in Androgenetic Alopecia, Hirsutism, and Acne , 1998, Journal of cutaneous medicine and surgery.

[23]  J. Rabkin,et al.  Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression. , 1998, Journal of affective disorders.

[24]  F. Ghadessy,et al.  Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. , 1997, The Journal of clinical endocrinology and metabolism.

[25]  S. Piantadosi,et al.  Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  P J Garry,et al.  Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. , 1997, Metabolism: clinical and experimental.

[27]  P. Kantoff,et al.  The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  G. Coetzee,et al.  Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. , 1997, Journal of the National Cancer Institute.

[29]  H. Scher,et al.  Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. , 1996, The Journal of clinical endocrinology and metabolism.

[30]  H. Nakajima,et al.  Transcriptional activation by the androgen receptor in X-linked spinal and bulbar muscular atrophy , 1996, Journal of the Neurological Sciences.

[31]  L Pinsky,et al.  Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. , 1995, Human molecular genetics.

[32]  G. Jenster,et al.  Changes in the abundance of androgen receptor isotypes: effects of ligand treatment, glutamine-stretch variation, and mutation of putative phosphorylation sites. , 1994, Biochemistry.

[33]  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.

[34]  R. Legro,et al.  Size Polymorphisms of the Androgen Receptor Among Female Hispanics and Correlation With Androgenic Characteristics , 1994, Obstetrics and gynecology.

[35]  G. Rouleau,et al.  Reduced transcriptional regulatory competence of the androgen receptor in X–linked spinal and bulbar muscular atrophy , 1993, Nature genetics.

[36]  K. Tennekoon,et al.  Serum FSH, LH, and testosterone concentrations in presumably fertile men: effect of age. , 1993, International journal of fertility.

[37]  L. Jin,et al.  Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. , 1992, Genomics.

[38]  J. Mckinlay,et al.  Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. , 1991, The Journal of clinical endocrinology and metabolism.

[39]  K. Fischbeck,et al.  Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy , 1991, Nature.

[40]  J. Kaufman,et al.  Neuroendocrine regulation of pulsatile luteinizing hormone secretion in elderly men , 1990, The Journal of Steroid Biochemistry and Molecular Biology.

[41]  S. S. Davis,et al.  Secondary hypogonadism in older men: its relation to impotence. , 1990, The Journal of clinical endocrinology and metabolism.

[42]  T. Nagashima,et al.  Familial bulbo-spinal muscular atrophy associated with testicular atrophy and sensory neuropathy (Kennedy-Alter-Sung syndrome) Autopsy case report of two brothers , 1988, Journal of the Neurological Sciences.

[43]  S. S. Davis,et al.  Impotence and Aging: Clinical and Hormonal Factors , 1988, Journal of the American Geriatrics Society.

[44]  J. Yesavage,et al.  Plasma testosterone levels, depression, sexuality, and age , 1985, Biological Psychiatry.

[45]  J. Santamaria,et al.  A family with adult spinal and bulbar muscular atrophy, X-linked inheritance and associated testicular failure , 1983, Journal of the Neurological Sciences.

[46]  J. Wieland,et al.  Impaired Leydig cell reserve and altered serum androgen binding in the aging male. , 1976, Fertility and sterility.

[47]  A. Klibanski,et al.  Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. , 2000, The Journal of clinical endocrinology and metabolism.

[48]  P. Kantoff,et al.  The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia. , 1999, Urology.

[49]  T. Zimmermann,et al.  A new ‘aging males’ symptoms' rating scale , 1999 .

[50]  J. Deslypere,et al.  A new look to the andropause: altered function of the gonadotrophs. , 1989, Journal of steroid biochemistry.

[51]  J. Kaufman,et al.  Influence of age on pulsatile luteinizing hormone release and responsiveness of the gonadotrophs to sex hormone feedback in men. , 1987, The Journal of clinical endocrinology and metabolism.