In order to determine the role of peripheral sex hormone levels in the expression of corticotropin-releasing hormone (CRH) neurons, we investigated by means of immunocytochemistry the number of CRH neurons in the hypothalamic paraventricular nucleus (PVN) in postmortem material of young and old subjects with normal and abnormal sex hormone conditions. Clinical data and nuclear androgen receptor (AR) immunoreactivity (ir) in the hypothalamic medial mamillary nucleus (MMN) were used as an estimate for changes in circulating sex hormone levels. It was confirmed that nuclear AR-ir staining in the MMN is a good estimate for abnormal peripheral androgen levels and that the CRH neurons in the hypothalamic PVN are activated with age in male subjects. Male subjects with lower testosterone levels due to castration showed significantly fewer CRH neurons than age-matched male controls. Castrated male-to-female (MF) transsexuals with estrogen replacement showed normal numbers of CRH neurons, while one male case, which had high estrogen levels due to an estrogen-producing tumor, even showed a high number of CRH neurons in the PVN. Results of the present study suggested that the activation of CRH neurons during aging in male subjects results from factors other than changes in endogenous peripheral sex hormone levels. Since estrogens can prevent the drop of CRH cell number following castration in MF transsexuals, and more CRH neurons were found in the case of an estrogen-producing tumor, estrogen seems to play a stimulating role in the activity of CRH neurons in the PVN. The stimulatory effect of androgens on CRH neurons seems to occur via an indirect effect following aromatization into estrogens.