Research Article| Volume 50, ISSUE 5, P371-376, September 01, 2001

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Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men

  • Stuart N Seidman
    Address reprint requests to Stuart N. Seidman, MD, College of Physicians & Surgeons of Columbia University, Department of Psychiatry, 1051 Riverside Drive, Unit 98, New York, NY 10032
    Department of Clinical Psychopharmacology at the New York State Psychiatric Institute, College of Physicians & Surgeons of Columbia University, New York, New York, USA (SNS, SPR)
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  • Andre B Araujo
    New England Research Institutes (ABA, JBM), Watertown, MA, USA
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  • Steven P Roose
    Department of Clinical Psychopharmacology at the New York State Psychiatric Institute, College of Physicians & Surgeons of Columbia University, New York, New York, USA (SNS, SPR)
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  • John B McKinlay
    New England Research Institutes (ABA, JBM), Watertown, MA, USA
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      Background: Testosterone (T) level declines progressively with age. Psychiatric symptoms of T deficiency (e.g., dysphoria, fatigue, irritability, low libido) are also symptoms of depression, and appear to be variably expressed.
      Methods: We assessed independent measures of hypothalamic-pituitary-gonadal axis functioning, i.e., total T level and androgen receptor (AR) CAG repeat length (CAG RL), a genetic trait marker associated with AR function; and depression (diagnosed by above-threshold score on the Center for Epidemiologic Studies-Depression Scale [CES-D]) in 1000 men (mean age = 62.6 years; SD = 8.3) who participated in the Massachusetts Male Aging Study.
      Results: There were 110 (11%) men with “depression” (CES-D score ≥ 16) in the analysis sample. Neither total T level nor CAG RL was associated with depression in bivariate analyses. Among men with shorter CAG RLs, the percentage of men with depression was 21.6% in the lowest subgroup of total T (defined by quintiles) and 4.2% in the highest subgroup of total T. This was confirmed in simple logistic regression models with depression as the dependent variable and continuous total T as the predictor, run separately within the three CAG RL subgroups: depression was significantly and inversely associated with total T in men with shorter CAG RLs but not in men with moderate and longer CAG RLs.
      Conclusions: CAG isotype, a genetic trait marker of androgen receptor function, may mediate the expression of the central nervous system effects of T deficiency in men.


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        • Araujo A.B
        • Durante R
        • Feldman H.A
        • et al.
        The relationship between depressive symptoms and male erectile dysfunction.
        Psychosom Med. 1998; 60: 458-465
        • Barrett-Connor E
        • Von Muhlen D.G
        • Kritz-Silverstein D
        Bioavailable testosterone and depressed mood in older men.
        J Clin Endocrinol Metab. 1999; 84: 573-577
        • Booth A
        • Johnson D.R
        • Granger D.A
        Testosterone and men’s depression.
        J Health Soc Behav. 1999; 40: 130-140
        • Brambilla D.J
        • McKinlay S.M
        • McKinlay J.B
        • et al.
        Does collecting repeated blood samples from each subject improve the precision of estimated steroid hormone levels?.
        J Clin Epidemiol. 1996; 49: 345-350
        • Bratt O
        • Borg A
        • Kristoffersson U
        • et al.
        CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk.
        Br J Cancer. 1999; 8: 672-676
        • Chamberlain N.L
        • Driver E.D
        • Miesfeld R.L
        The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function.
        Nucleic Acids Res. 1994; 22: 3181-3186
        • Edwards A
        • Hammond H.A
        • Jin L
        • et al.
        Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups.
        Genomics. 1992; 12: 241-253
        • Field A.E
        • Colditz G.A
        • Willett W.C
        • et al.
        The relation of smoking, age, relative weight, and dietary intake to serum adrenal steroids, sex hormones, and sex hormone-binding globulin in middle-aged men.
        J Clin Endocrinol Metab. 1994; 79: 1310-1316
        • Krithivas K
        • Yurgalevitch S.M
        • Mohr B.A
        • 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.
        J Endocrinol. 1999; 162: 137-142
        • Lubahn D.B
        • Joseph D.R
        • Sullivan P.M
        • et al.
        Cloning of human androgen receptor complementary DNA and localization to the X chromosome.
        Science. 1988; 240: 327-330
        • McKinlay J.B
        • Longcope C
        • Gray A
        The questionable physiologic and epidemiologic basis for a male climacteric syndrome.
        Maturitas. 1989; 11: 103-115
        • Morales A
        • Heaton J.P
        • Carson C.C
        J Urol. 2000; 163: 705-712
        • Myers J.K
        • Weissman M.M
        Use of a self-report symptom scale to detect depression in a community sample.
        Am J Psychiatry. 1980; 137: 1081-1084
        • Pope H.G.J
        • Katz D.L
        Psychiatric and medical effects of anabolic-androgenic steroid use. A controlled study of 160 athletes.
        Arch Gen Psychiatry. 1994; 51: 375-382
        • Pope H.G.J
        • Kouri E.M
        • Hudson J.I
        Effects of supraphysiologic doses of testosterone on mood and aggression in normal men. A randomized controlled trial.
        Arch Gen Psychiatry. 2000; 57: 133-140
        • Roberts R.E
        • Vernon S.W
        The Center for Epidemiologic Studies Depression Scale.
        Am J Psychiatry. 1983; 140: 41-46
        • Schmidt P.J
        • Bloch M
        • Roca C.A
        • et al.
        Estrogens and androgens.
        Neuropsychopharmacology. 2000; 23 (Abstract): S56-S56
        • Seidman S.N
        • Araujo A.B
        • Roose S.P
        • et al.
        Low testosterone levels in elderly men with dysthymic disorder.
        Neuropsychopharmacology. 2000; 23 (Abstract): S147
      1. Seidman SN, Spatz E, Roose SP (in press b): Testosterone replacement for depressed men: Randomized clinical trial. J Clin Psychiatry. 62.

        • Shores M.M
        • Sloan K
        • Moceri V
        • et al.
        The prevalence and incidence of depression in older hypogonadal men. Abstract presented at the American Association of Geriatric Psychiatry Annual Meeting. 2001
        • Simental J.A
        • Sar M
        • Lane M.V
        • et al.
        Transcriptional activation and nuclear targeting signals of the human androgen receptor.
        J Biol Chem. 1991; 266: 510-518
        • Simental J.A
        • Sar M
        • Wilson E.M
        Domain functions of the androgen receptor.
        J Steroid Biochem Mol Biol. 1992; 43: 37-41
        • Sternbach H
        Age-associated testosterone decline in men.
        Am J Psychiatry. 1998; 155: 1310-1318
        • Vermeulen A
        • Kaufman J.M
        Ageing of the hypothalamo-pituitary-testicular axis in men.
        Horm Res. 1995; 43: 25-28
        • Wang C
        • Alexander G
        • Berman N
        • et al.
        Testosterone replacement therapy improves mood in hypogonadal men—a clinical research center study.
        J Clin Endocrinol Metab. 1996; 81: 3578-3583
        • Yates W.R
        • Perry P
        • Macindoe J
        • et al.
        Psychosexual effects of three doses of testosterone in cycling and normal men.
        Biol Psychiatry. 1999; 45: 254-260