Testosterone Therapy for Men with Alzheimer Disease?

For years, postmenopausal women have agonized over the risks and benefits of estrogen replacement therapy. Now comes a hint that elderly men, particularly those with Alzheimer disease (AD), might benefit from a testosterone top up. A study reported in yesterday’s Archives of Neurology online concludes that the male hormone, applied daily as a cream, can lead to improved quality of life in men with mild to moderate forms of the disease.

The pilot study was led by Jeffrey Cummings and colleagues at the University of California Los Angeles, and also at Irvine and San Francisco. At total of 38 elderly men (22 healthy controls and 16 with AD) received the daily testosterone balm, or a placebo, for 24 weeks, during which first author Po Lu and colleagues gathered quality-of-life data. Then, at the end of the study, the researchers tested participants for serum hormones, cognitive ability, and neuropsychiatric symptoms.

Lu and colleagues reported that caregivers found AD patients did better when given the hormone. Assessments revealed a small, though statistically significant, increase in quality of life at week 24 of the trial compared to week 12. Unfortunately, the patients did not seem to notice this improvement because self-assessment scores were no different between subjects in the hormone and placebo groups. Likewise, doctors failed to detect any benefit for the patient, as judged by a test called the Clinician’s Interview-Based Impression of Change. It is unclear why only caregivers noticed the change, but the trial was double-blinded to ensure that they did not know which patients were receiving the hormone. In healthy men, self-assessments did indicate that the topical testosterone increased quality of life; however, this trend was not statistically significant.

Cognitive and neuropsychiatric outcomes were disappointing. Though serum testosterone and dihydrotestosterone increased markedly in the treatment groups, subjects taking the hormone cream performed no better in cognitive tasks than did those on placebo. This finding should be considered in the context of results from another recent study led by Suzanne Craft and colleagues at the University of Washington, Seattle. That small pilot trial suggested that the hormone can improve spatial memory in men with mild cognitive impairment or AD (see Cherrier et al., 2005).

Cummings and colleagues also failed to find any neuropsychiatric improvement in AD patients on testosterone. But the steroid did seem to maintain (or slightly improve) visual motor skills—patients on placebo scored poorer in such tasks at the end of the trial. This result suggests that testosterone may protect against loss of visual-spatial function (see also the recent report by Tan et al., 2003).

The authors caution that the present results are preliminary and do not warrant routine treatment of AD and healthy control men with testosterone. Future studies with larger sample sizes will be needed, they stress. In this regard, it is worth noting the “on again, off again” recommendations about estrogen replacement therapy for women. These accompanied each new estrogen replacement trial, starting in the 1970s and culminating when the estrogen-only arm of the Women’s Health Initiative trial was prematurely halted because of safety concerns (see related National Institutes of Health information). Public concern over safety was an issue in this testosterone trial, as well. Lu and colleagues report that “subject recruitment was more difficult than anticipated due to the strict inclusion and exclusion criteria and the caregivers’ fear of adverse events associated with testosterone.” Researchers who wish to recruit large numbers of AD patients for testosterone trials may have some heavy lifting to do.—Tom Fagan

Comments

  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:

    Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM. Free testosterone and risk for Alzheimer disease in older men. Neurology. 2004 Jan 27;62(2):188-93. PubMed.

    Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD. Serum total testosterone is lower in men with Alzheimer's disease. Neuro Endocrinol Lett. 2001 Jun;22(3):163-8. PubMed.

    Janowsky JS, Oviatt SK, Orwoll ES. Testosterone influences spatial cognition in older men. Behav Neurosci. 1994 Apr;108(2):325-32. PubMed.

    Barrett-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab. 1999 Oct;84(10):3681-5. PubMed.

    Janowsky JS, Chavez B, Orwoll E. Sex steroids modify working memory. J Cogn Neurosci. 2000 May;12(3):407-14. PubMed.

    Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, Raskind MA, Brodkin K, Bremner W, Petrova A, Latendresse S, Craft S. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology. 2001 Jul 10;57(1):80-8. PubMed.

    Vermeulen A. Androgen replacement therapy in the aging male--a critical evaluation. J Clin Endocrinol Metab. 2001 Jun;86(6):2380-90. PubMed.

    Kenny AM, Bellantonio S, Gruman CA, Acosta RD, Prestwood KM. Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. 2002 May;57(5):M321-5. PubMed.

    Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci. 2002 Feb;57(2):M76-99. PubMed.

    Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM. Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab. 2002 Nov;87(11):5001-7. PubMed.

    Yaffe K, Lui LY, Zmuda J, Cauley J. Sex hormones and cognitive function in older men. J Am Geriatr Soc. 2002 Apr;50(4):707-12. PubMed.

    Yaffe K, Edwards ER, Lui LY, Zmuda JM, Ferrell RE, Cauley JA. Androgen receptor CAG repeat polymorphism is associated with cognitive function in older men. Biol Psychiatry. 2003 Nov 1;54(9):943-6. PubMed.

    Cherrier MM, Matsumoto AM, Amory JK, Ahmed S, Bremner W, Peskind ER, Raskind MA, Johnson M, Craft S. The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology. 2005 Jan 25;64(2):290-6. PubMed.

    Raber J, Bongers G, LeFevour A, Buttini M, Mucke L. Androgens protect against apolipoprotein E4-induced cognitive deficits. J Neurosci. 2002 Jun 15;22(12):5204-9. PubMed.

    View all comments by Jacob Raber

  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:

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

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

    View all comments by Christopher Gregory

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References

Paper Citations

  1. Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, Peskind ER, Raskind MA, Craft S. Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology. 2005 Jun 28;64(12):2063-8. PubMed.
  2. Tan RS, Pu SJ. A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer's disease. Aging Male. 2003 Mar;6(1):13-7. PubMed.

External Citations

  1. National Institutes of Health

Further Reading

Papers

  1. Hogervorst E, Bandelow S, Moffat SD. Increasing testosterone levels and effects on cognitive functions in elderly men and women: a review. Curr Drug Targets CNS Neurol Disord. 2005 Oct;4(5):531-40. PubMed.
  2. Pennanen C, Laakso MP, Kivipelto M, Ramberg J, Soininen H. Serum testosterone levels in males with Alzheimer's disease. J Neuroendocrinol. 2004 Feb;16(2):95-8. PubMed.

Primary Papers

  1. Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, Reback E, Porter V, Swerdloff R, Cummings JL. 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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