BACKGROUND: Estrogens mediate various effects in the brain not only via classical estrogen receptors (ERs) but also through their splice variants. We showed earlier that the ERα splice variant TADDI is abundantly expressed in the human hypothalamic supraoptic nucleus (SON). METHODS: In the present study we aimed at determining a possible effect of TADDI on human SON neuronal morphometric parameters in 58 control patients from 20 to 94 years old and in 26 patients with Alzheimer's disease (AD) aged 54-94 years old. The size of neuronal nuclear and perikaryal profiles was determined as measure of the neuronal metabolic activity in relation to the intensity of TADDI immunocytochemical staining. The size of SON neuronal nuclei and perikarya were also measured with respect to the wild type (wt) ERα nuclear staining in the group of 11 elderly patients. RESULTS: Independently of gender, age or AD status SON neuronal nuclei and perikarya were significantly smaller in neurons with moderate and strong TADDI staining than in neurons that did not express this ERα splice variant. On the contrary, neuronal nuclei and perikarya were considerably larger in SON neurons with moderate and strong nuclear staining for wt ERα as compared to neurons that showed an absence of the classic receptor. It is noteworthy that TADDI immunoreactivity was increased in control patients with pneumonia and/or respiratory insufficiency. CONCLUSIONS: We showed for the first time the association of the ERα splice variant TADDI with neuronal morphometric parameters in the human postmortem brain tissue.