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Effects of Long-Term Hormone Therapy on Cholinergic Synaptic Concentrations in Healthy Postmenopausal Women¹

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology (Y.R.S.); Department of Radiology, Division of Nuclear Medicine (S.M., D.E.K., J.K.Z.); and Department of Psychiatry and Mental Health Research Institute (J.K.Z.), University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Dr. Yolanda R. Smith, Department of Obstetrics and Gynecology, Room L4224, Women’s Hospital, University of Michigan Health Systems, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0276. E-mail: ysmith{at}umich.edu

Experimental evidence suggests that gonadal steroids regulate brain neurochemical systems associated with cognitive function, such as the cholinergic system. This study examines the effect of long-term postmenopausal hormone therapy on the brain concentrations of cholinergic synaptic terminals in women using single photon emission computed tomography and the radiotracer [¹²³I]iodobenzovesamicol ([¹²³I]IBVM). [¹²³I]IBVM labels the vesicular acetylcholine transporter (VAChT) located in the presynaptic terminals of these neurons. Sixteen healthy women treated with hormone therapy since the menopause and 12 women not treated with hormones were studied. There were no significant differences in regional IBVM binding indexes between the 2 groups. The length of hormone replacement therapy correlated positively with VAChT binding indexes in multiple cortical areas (P < 0.05): frontal cortex (Spearman rank correlation: = 0.79), parietal cortex ( = 0.62), temporal cortex ( = 0.80), anterior cingulate ( = 0.71), and posterior cingulate ( = 0.63), but not in the basal ganglia ( = 0.35; P = 0.2). An earlier onset of menopause in hormone-treated women was associated with higher VAChT indexes in the anterior cingulate ( = -0.56; P = 0.02) and posterior cingulate ( = -0.63; P = 0.01). The opposite was found in the posterior cingulate of women not treated with hormones ( = 0.58; P = 0.04). Women treated with estrogen alone also showed higher VAChT indexes than women treated with estrogen and progestin in the posterior cingulate cortex (by Mann-Whitney U test: z = 2.42; P = 0.015). Although an overall effect of postmenopausal hormone therapy was not found, associations between an index of cortical cholinergic terminal concentrations and the length of hormonal replacement suggest that hormone therapy may influence the survival or plasticity of these cells in postmenopausal women. The data also suggest possible differential effects of estrogen and estrogen with progestin treatments in brain areas critical for cognitive processing.

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