This review has two aims. First, to examine whether or not sex and gender may influence the
brain cholinergic system in animals and in humans. Second, to examine the available evidence of sexually
dimorphic response to the therapeutic and toxic effects of cholinesterase inhibitors. Animal research
reveals no marked difference in the general morphology of the brain cholinergic system but subtle functional
gender differences have been reported. In humans, gender differences in nucleus basalis of
Meynert (NBM) exist. In animals, some cholinergic neurons express estrogen alpha receptors in females
and androgens in males. It is known that sex hormones exert trophic effects on the cholinergic system.
Females show higher frontal cortex cholinergic activity whereas males have higher activity in the hippocampus.
Gender differences in the pharmacological effects result in higher sensitivity to the toxic effects
of organophosphate cholinesterase inhibitors in males. A stronger and more selective benefit of ChEI
treatment in AD has been reported in men by several authors. Sex and estrogen receptor phenotype may
both influence the response to donepezil and rivastigmine. Hence, aged male and female individuals
might respond differently to ChEI due to either sex-specific differences in structures and function of the
cholinergic system, pharmacokinetics, memory function or in the way aging or AD affects these processes.
Keywords: Acetylcholine, aging, estrogens, nerve growth factor, nucleus basalis magnocellularis, cholinesterase inhibitors,
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