Two very different reports suggest that testosterone may be important in protecting neurons from Aβ, the peptide suspected of killing neurons in Alzheimer's disease. The first, from Andrea LeBlanc, Morrie Gelfand, and colleagues at McGill University in Montreal, examines testosterone's potential to protect neurons in culture from programmed cell death, or apoptosis. The second, from Sam Gandy, Ralph Martins, and their colleagues at New University and the University of Western Australia, examines whether therapeutic testosterone reduction in men with prostate cancer affects levels of Aβ in the brain.

Epidemiological studies have made a strong case for estrogen decline as a risk factor for Alzheimer's. In addition, some studies have found that hormone replacement therapy in postmenopausal women can reduce the Alzheimer's risk, although other studies challenge this claim. At the cellular level, a number of studies have shown that estrogen protects neurons. How it might do so is unclear, in part because estrogen has multiple effects both at the level of gene transcription and in post-transcriptional molecular interactions.

LeBlanc and colleagues wondered if the male sex hormone, testosterone, might also be neuroprotective. They report in the Journal of Neurochemistry that physiological concentrations of testosterone protect cultured human neurons from apoptosis induced by serum deprivation, and did so to the same extent as estrogen. They further demonstrated that the neuroprotective effect is mediated by the androgen receptor and that testosterone does not first have to be converted into estrogen to protect the cells.

In the second report, presented this week at the annual meeting of the American Neurological Association, Gandy and colleagues followed up previous work showing that brain concentrations of Aβ40 and 42 increased significantly in female guinea pigs whose ovaries had been removed. When the animals received hormone replacement therapy, their levels of brain amyloid dropped. The researchers realized that a natural experiment could be conducted with men whose testosterone levels are suppressed as part of their prostate cancer treatment. "In each of six men, when testosterone levels were suppressed, plasma amyloid [Aβ40] levels roughly doubled over the six-month duration of the study," Gandy said.

LeBlanc et al. caution, however, that androgen receptors are lost as a normal part of aging. Thus, unless one could artificially maintain or increase the number of receptors, there may only be a limited time window for any sex hormone to be therapeutically effective against Alzheimer's.

In a related story, Mayo Clinic researchers report the first link between hysterectomy and an increased risk of developing Parkinson's disease. Their results, published in the journal Movement Disorders, were based on a review of the medical records of 72 female Parkinson's patients and 72 age-matched controls. They found that hysterectomy conferred a threefold increased risk of Parkinson's. Although the data support the hypothesis that low endogenous estrogen is a risk factor for Parkinson's, the authors point to the methodological limitations of their study and caution that the results must be confirmed in a larger study.—Hakon Heimer

No authors listed. 126th Annual meeting of the American Neurological Association. Neurology Outcomes Research: Current Science and Future Directions. September 30-October 3, 2001. Chicago, Illinois, USA. Abstracts. Ann Neurol 2001 Sept;50(3)(suppl 1):S8-79.

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  1. We published a paper recently which might be interesting given the topic: Serum testosterone levels in males with Alzheimer's disease.

    References:

    . Serum testosterone levels in males with Alzheimer's disease. J Neuroendocrinol. 2004 Feb;16(2):95-8. PubMed.

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Primary Papers

  1. . Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons. J Neurochem. 2001 Jun;77(5):1319-26. PubMed.
  2. . Hysterectomy, menopause, and estrogen use preceding Parkinson's disease: an exploratory case-control study. Mov Disord. 2001 Sep;16(5):830-7. PubMed.