Estrogen is essential for maintaining nigrostriatal dopamine neurons in primates: implications for Parkinson's disease and memory

Abstract

There are sexual differences in several parameters of the nigrostriatal dopamine neurons, as well as in the progression of diseases associated with this system, e.g., Parkinson's disease and dementia. These differences, as well as direct experimental data in rodents, suggest that gonadal hormones play a role in modulating this system. 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 compact zone of the substantia nigra of male and intact female short- (10 d) and longer-term (30 d) ovariectomized and short- and longer-term ovariectomized but estrogen-replaced nonhuman primates (African green monkeys). Furthermore, the number of tyrosine hydroxylase-expressing neurons, the total number of all types of neurons, and the volume of the compact zone of the substantia nigra were calculated in 30 d ovariectomized and in 30 d ovariectomized and estrogen-replaced monkeys. Unbiased stereological analyses demonstrated that a 30 d estrogen deprivation results in an apparently permanent loss of >30% of the total number of substantia nigra dopamine cells. Furthermore, the density calculations showed that brief estrogen replacement restores the density of tyrosine hydroxylase-immunoreactive cells after a 10 d, but not after a 30 d, ovariectomy. Moreover, the density of dopamine cells is higher in females than in males. These observations show the essential role of estrogen in maintaining the integrity of the nigral dopamine system, suggest a new treatment strategy for patients with Parkinson's disease and with certain forms of memory-impairing disorders, and provide another rationale for estrogen replacement therapy for postmenopausal women.

Fig. 1.

Light micrographs show TH-immunoreactive neurons in the substantia nigra of female and male monkeys.a, Intact female. b, Ten day OVX plus 2 d estrogen-treated female. c, Ten day OVX female.d, Male. Note the higher density of TH-immunopositive neurons in the intact female, male, and estrogen-treated OVX animals compared with the OVX monkey. Scale bar, 500 μm.

Fig. 2.

Light micrographs taken from the substantia nigra of an intact female and a 10 d OVX monkey. a, In the intact female, all of the TH-immunoreactive neurons have long, heavily immunostained dendrites. b, In the OVX animal, the TH-containing cells appear to be smaller, and many of them do not exhibit immunostained dendrites (arrows). Scale bar, 20 μm.