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. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol. 2006 Feb;63(2):177-85. PubMed.

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  1. This pilot study is important in determining the potential therapeutic effects of testosterone supplementation in healthy elderly men and those with mild AD. This study is very timely in light of accumulating prior evidence. (For a review of the interaction of testosterone with AD-related factors, see SAGE KE ARF Live Discussion .) Furthermore, data raising interest in such a trial include the association of low testosterone levels over time and increased risk of developing AD independent of health status, age, or education (Moffat et al., 2004), the lower serum testosterone levels in men with AD than in controls (Hogervorst et al., 2001), and the positive associations between testosterone levels and cognitive measures in elderly men with or without AD (Janowsky et al., 1994; Barrett-Connor et al., 1999; Janowsky et al., 2000; Cherrier et al., 2001; Vermeulen, 2001; Kenny et al., 2002; Matsumoto, 2002; Moffat et al., 2002; Yaffe et al., 2002; Yaffe et al., 2003; Cherrier et al., 2005).

    The results of this pilot study show that testosterone treatment improved scores on the caregiver version of the quality-of-life scale. No treatment effects were detected on cognitive scores, but in the testosterone-treated AD group greater improvement or less decline was observed on measures of visual-spatial functioning. In addition, in AD, but not control, significant positive relationships were observed between changes in hormone level (serum testosterone, free testosterone, dihydrotestosterone, and estradiol) and Judgement of Line Orientation (JOLO), which examines visual recognition and perception of angular relationships.

    With regard to the disappointing treatment effect on cognitive measures, it is important to note that eight of the 17 subjects in the testosterone treatment group (including both healthy controls and AD patients) showed no increase in serum testosterone at the end of the study. It would be of interest to know how these eight subjects were divided over the healthy control and AD groups.

    Baseline free testosterone levels were inversely correlated with visiospatial function in the current study, and in earlier studies testosterone treatment improved cognitive measures in hypogonadal men. Therefore, it is possible that the cognitive findings would have been more robust if low testosterone levels would have been used as an inclusion criterion, the authors also pointed out, so the proportion of subjects with low testosterone levels at baseline might contribute to the ability of a trial to detect significant effects of testosterone treatment on cognitive measures.

    Consistent with the concept, in a group of 27 community college students (mean age 29.1 ± 1.4 years) and 25 cognitively healthy elderly subjects (mean age 81.7 ± 2.2 years), salivary testosterone levels correlated with cognitive performance measures on a spatial navigation memory task. The correlations were not linear and showed an asymptotic profile, indicating that relatively low salivary testosterone levels contributed more to these correlations than relatively high salivary testosterone levels [Raber et al., abstract presented at the 2005 Society for Neuroscience Annual Meeting (92.1)].

    Besides testosterone levels at baseline, ApoE genotype might also be important in ability to detect effects of testosterone on cognitive measures. Studies with human ApoE transgenic mice showed that while ApoE4 transgenic female mice showed improved cognitive performance following testosterone treatment, female ApoE3 transgenic mice did not (Raber et al., 2002), and the ability of testosterone to improve cognitive performance in males might also be ApoE genotype-dependent.

    As the authors noted that caregivers’ fear of adverse events associated with testosterone contributed to a more difficult subject recruitment than anticipated, it might be warranted to develop and evaluate the therapeutic effects of Selective Androgen Receptor Modulators (SARMs). The compounds are tissue-selective and maintain the therapeutic effects of androgens but reduce their undesired side effects.

    References:

    . Free testosterone and risk for Alzheimer disease in older men. Neurology. 2004 Jan 27;62(2):188-93. PubMed.

    . Serum total testosterone is lower in men with Alzheimer's disease. Neuro Endocrinol Lett. 2001 Jun;22(3):163-8. PubMed.

    . Testosterone influences spatial cognition in older men. Behav Neurosci. 1994 Apr;108(2):325-32. PubMed.

    . Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab. 1999 Oct;84(10):3681-5. PubMed.

    . Sex steroids modify working memory. J Cogn Neurosci. 2000 May;12(3):407-14. PubMed.

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  2. In this manuscript, the authors present data from a pilot study that suggest that testosterone replacement therapy has beneficial effects on quality of life measures in patients with AD. However, only minimal effects on cognition were detected. While the sex steroids are indeed important for brain function, their regulation is maintained by a complex feedback loop consisting of gonadotropins (i.e., gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone). As serum concentrations of sex steroids decrease, serum concentrations of gonadotropins increase. It was previously reported that individuals with AD have elevated luteinizing hormone in neurons susceptible to AD pathology (1) and that men with a primary diagnosis of dementia have higher serum levels of luteinizing hormone and follicle-stimulating hormone compared to age-matched controls (2).

    In the current study by Lu et al., and in agreement with earlier findings, male AD patients had lower levels of serum testosterone, DHT, free testosterone, and estradiol compared to healthy control subjects. Conversely, male AD patients had higher levels of follicle-stimulating hormone and luteinizing hormone compared to healthy controls. In addition, testosterone replacement therapy in the AD patients was very effective at reducing serum follicle-stimulating hormone and luteinizing hormone levels (~10-fold reduction in both instances). The reduction in follicle-stimulating hormone and luteinizing hormone following administration of testosterone to healthy subjects was about 2.5- and twofold, respectively. Given that sex steroid regulation by gonadotropins is a complex feedback loop, the effects ascribed to testosterone could be explained by decreased levels of circulating gonadotropins. We hypothesize that if brain levels of gonadotropins are reduced sufficiently, cognitive function in AD patients would improve or stabilize, along with quality of life measures. Indeed, Voyager’s phase 2 clinical trial results, derived from a cohort of 108 women with mild to moderate AD, demonstrated a stabilizing effect on cognition and activities of daily living over 1 year of treatment with leuprolide acetate administered together with acetylcholinesterase inhibitors. Ongoing phase 3 clinical trials using leuprolide acetate to suppress luteinizing hormone in AD patients will provide further insight into this issue.

    References:

    . In situ GABAergic modulation of synchronous gonadotropin releasing hormone-1 neuronal activity. J Neurosci. 2002 Oct 15;22(20):8932-41. PubMed.

    . An association of elevated serum gonadotropin concentrations and Alzheimer disease?. J Neuroendocrinol. 2000 Apr;12(4):351-4. PubMed.

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