5 October 2001. 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.
Reference:Hammond J, Le Q, Goodyer C, Gelfand M, Trifiro M, LeBlanc A. Testosterone-mediated neuroprotection through the androgen
receptor in human primary neurons. J Neurochem 2001;(77):1319-26. Abstract
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.
Benedetti MD, Maraganore DM, Bower JH, McDonnell SK, Peterson BJ, Ahlskog JE, Schaid DJ, Rocca WA. Hysterectomy, menopause, and estrogen use preceding Parkinson's disease: an exploratory case-control study. Mov Disord. 2001 Sep;16(5):830-7. Abstract