Lifelong endocrine fluctuations and related cognitive disorders.

The aim of this review is to examine the relationship between endocrine fluctuation and cognitive functioning. A plethora of in vitro and in vivo studies has demonstrated the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented post-menopausal women suggest a temporary positive effect (notably on verbal memory), and four recent meta-analyses converge to suggest a possible protective effect in relation to Alzheimer's disease (reducing risk by 29 to 44%). However, data from the only large randomised controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Several methodological differences between observation studies and controlled trials with regard to patient group, type, timing and duration of HRT, cognitive measures and analyses, are discussed to explain these discrepancies. The association between hormonal serum level and cognitive functioning remains controversial suggesting high inter-individual vulnerability in risk. Moreover, research on the impact of endocrine functioning on cognition during the female reproductive cycle suggests life-long fluctuations in vulnerability. Etiological models taking into account the interaction of clinical, reproductive, and menstrual events throughout life may provide a more valid approach in understanding the effects of steroids on the brain and in determining sub-groups at heightened risk. Cognitive disorders in the elderly are more likely be related to cumulated lifelong exposure to steroids, rather than to a specific exposure to a given steroid. Multifactorial models based on an exhaustive view of all hormonal events throughout reproductive life together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.