Psychological implications

Testosterone substitution in hypogonadal men improves lethargic or depressive aspects of mood significantly (Burris etal. 1992). Studies exploring the relationship between gonadal function anddepressive episodes demonstrated testosterone levels to be markedly decreased in respective patients (Unden et al. 1988; Schweiger et al. 1999; Barrett-Connor etal. 1999). Accordingly, treatment with testosterone gel may improve symptoms in men with refractory depression (Pope etal. 2003). The age-dependent decline of testosterone levels is sometimes associated with symptoms of depression. It has been recently demonstrated in 1000 older men that this mood-dependency on androgen levels is modified by the CAG repeat polymorphism of the AR gene. Depression scores were significantly and inversely associated with testosterone levels in subjects with shorter CAG repeats, while this was not observed in men with moderate and longer polyglutamine stretches in the AR protein. Low versus high testosterone in such men was associated with a five-fold increased likelihood of depressive mood (Seidman et al. 2001). It can be speculated that the higher activation rate of the AR in this subgroup revealed effects of declining androgen levels more readily than in subgroups with longer CAG repeats.

In a sample of 172 Finnish men aged 41 to 70 years, the length of CAG repeats was significantly positively associated and independent from testosterone levels with symptom scores concerning 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) and also decreased beard growth (r = 0.49; p < 0.0001) (Harkonen etal. 2003).

Another aspect of psychological parameters is represented by the group of externalizing behaviours; these are predominantly found in males and have been associ-atedwith androgens (Zitzmann etal. 2001c; Diagnostic and Statistical Manual ofthe American Psychiatric Association 1994). Respective personality traits are attention deficit hyperactivity disorder (ADHD); conduct disorder (CD) and oppositional defiant disorder (ODD). A controlled study in 302 younger men concerning these disorders in relation to the CAG repeat of the AR gene demonstrated a significantly higher prevalance in genotypes with shorter repeat chains. The group also reported an association ofshort CAG repeats in the AR gene with novelty-seeking behaviour (drug abuse, pathological gambling) (Comings etal. 1999).

Similarly, in a sample of 183 healthy Swedish men aged 20-75 years, associations of CAG repeat length and scores in the Karolinska Scales of Personality were described. Tendencies indicated positive relationships between shorter CAG trinucleotide repeats and personality scales connected to dominance and aggression (low "Lack of Assertiveness", high "Verbal Aggression", high "Monotony Avoidance"). Longer polyglutamine tracts were associated with some neuroticism-related personality scales: high "Muscular Tension", high "Lack of Assertiveness" and high "Psychastenia" (Jonsson etal. 2001).

In addition, a case report of three Caucasian brothers describes mental retardation, especially demonstrating a delay in speech development, shy but sometimes aggressive behaviour, marfanoid habitus and relatively large testes in combination with abnormally short CAG repeats (8 triplets) (Kooy etal. 1999).

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