Estrogen deprivation leads to the death of dopamine cells in the brain, a finding by Yale researchers that could have implications for post-menopausal women. The cells can be regenerated if estrogen is administered within 10 days, but by 30 days, the cells appear to be permanently lost, said D. Eugene Redmond, Jr., professor of psychiatry and neurosurgery at Yale School of Medicine and director of the Neural Transplantation and Regeneration Program. Redmond is co-investigator and spokesperson about the study published in the December issue of The Journal of Neuroscience.
The principal investigator was Csaba Leranth, M.D., professor of obstetrics and gynecology and neurobiology.
"Without estrogen, more than 30 percent of all the dopamine neurons disappeared in a major area of the brain that produces the neurotransmitter, dopamine," Redmond said. "This finding is consistent with a lot of observations for which there has been, until now, no explanation. The results of the study shed light on why men, who have less estrogen in their bodies and more androgen to antagonize it, are more likely to develop Parkinson's Disease than pre-menopausal women, and why post menopausal women are more likely then to develop the disease."
The discovery was made after the researchers removed the ovaries of female monkeys, thereby depleting their bodies of estrogen and other gonadal hormones. Within 10 days, key neurons in the brain that protect against Parkinson's Disease disappeared. Redmond said monkeys were used in the study because, unlike usual laboratory animals, they have real menstrual cycles and many other close similarities to humans.
The researchers were interested in sexual differences in dopamine neurons in the substantia nigra area of the midbrain, whose destruction is associated with Parkinson's Disease and dementia. The researchers first sought to determine whether circulating estrogen might have long term effects by altering the number of dopamine neurons. The density of dopamine neurons was calculated in the substantia nigra of intact male and female primates; in female primates whose ovaries had been removed; and in female primates whose ovaries had been removed but were receiving estrogen replacement therapy.
"After both 10 and 30 days of estrogen deprivation, apparently 30 percent of the total number of substantia nigra dopamine cells are lost," Redmond said. "Furthermore, the density calculations showed that brief estrogen replacement restores the density of the total number of neurons in that area of the brain 10 days after the ovaries have been removed, but not 30 days later."
"These observations show the essential role of estrogen in maintaining the integrity of the nigral dopamine system involved in muscle control and higher brain functions. It suggests a new prevention or treatment strategy for patients at risk of Parkinson's disease and certain forms of memory-impairing disorders," he said.
"This also provides another rationale for estrogen replacement therapy for postmenopausal women. Thirty percent is a very significant number of cells in this system. Maintenance, restoration, or loss of that many cells could make the difference between severe parkinsonism and having no symptoms at all." But Redmond cautioned that women should not use the results to make a decision about estrogen replacement therapy until further studies look at the effects on dopamine cells of much longer periods of estrogen deprivation.
Redmond said the researchers also want to see if much larger doses of estrogen or other hormones administered at 30 days and beyond of estrogen deprivation would resuscitate the cells. All of this must be in the context of possible side effects of hormone replacement that women should take into account in consultation with their doctors.
Other investigators were Robert Roth, professor of psychiatry and pharmacology; John Elsworth, senior research scientist, psychiatry; Frederick Naftolin, M.D., professor of obstetrics and gynecology and of molecular, cellular and developmental biology, and Tamas Horvath, associate professor of obstetrics and gynecology and neurobiology.
The study was carried out at the St. Kitts Biomedical Research Foundation in the West Indies.
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