Effects of gonadal hormones on cognitive behaviour in elderly men and women.

Over the last four decades, animal and cell culture studies have shown that sex steroids can have protective effects on the ageing brain. Limited short-term positive effects (2-4 months) of oestrogen treatment were found in women without (as well as with) dementia. By contrast to these initial promising findings, several large treatment studies showed that longer-term oestrogen treatment, particularly when given in combination with progesterone, could exert negative effects on cognitive function in women aged over 65 years. Several observational studies of older women and men also suggest that longer exposure to higher endogenous oestrogen levels at an older age might confer risk for accelerated cognitive decline and dementia. However, health of participants may modify this association and, in women closer to the age at the onset of menopause, positive associations of oestrogens with cognition were also found. The 'healthy cell bias' theory suggests that oestrogens have protective effects in healthy neurones, although cells undergoing pathological change show acceleration in their demise when exposed to oestrogens. In older men, most studies reported higher bioavailable testosterone levels to be associated with better cognitive function. Other studies have reported optimal testosterone levels for better global cognitive function and a reduced risk of cognitive decline. Variation in health status over time and the use of (in)sensitive cognitive tests and hormone assays may explain why this was not always found. In older women, this association (of testosterone with cognition) is less clear. Small studies reported some benefits of testosterone treatment in combination with oestrogen on cognition, although these were of short duration. Several observational studies, on the other hand, found negative associations between high testosterone levels and worse cognitive function in older women. Age, health status, duration of treatment and sex may thus modify effects of longer-term elevated sex steroid levels on brain function.