Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action.

The profound disparities between the largely positive basic science findings of gonadal steroid action in brain and the adverse outcomes of recent hormone therapy clinical trials in women who are either aged postmenopausal or postmenopausal with Alzheimer's disease have led to an intense reassessment of gonadal hormone action and the model systems used in basic and clinical science. The power of model systems is their predictive validity for a target population--in this case, menopausal women considering the health benefits and risks of hormone therapy. Analysis of the model systems used across the basic to clinical research continuum separate into two broad classes: those that use prevention interventions in healthy organisms and those that use hormone interventions in organisms with compromised neurological function. Basic science analyses that led to elucidation of the neurotrophic and neuroprotective effects of estrogen and the underlying mechanisms of action typically used a prevention-based experimental paradigm. This paradigm relies on healthy neurons/brains/animals/humans as the starting foundation followed by exposure to estrogen/hormone followed by exposure to neurodegenerative insult. The prevention paradigm in basic science analyses parallels the analyses of Sherwin and colleagues (Psychoneuroendocrinology 13: 345-357, 1988), who investigated the cognitive impact of estrogen therapy in women with surgical- or pharmacological-induced menopause. Observational retrospective and prospective studies are also consistent with the healthy cell bias of estrogen action and a prevention paradigm of estrogen or hormone therapy intervention. For the most part, the epidemiological observational data indicate reduction in the risk of Alzheimer's disease in women who began estrogen or hormone therapy at the time of the menopause. In contrast, studies that fall within the second class, hormone intervention in organisms with compromised neurological function--that is, a treatment paradigm--exhibit a mixed profile. In a randomized double-blind clinical trial of estrogen therapy in a cohort of women aged 72 or more years and diagnosed with Alzheimer's disease, estrogen therapy resulted in a modest benefit in the short term (2 months) and adverse progression of disease in the long term (12 months). In the Women's Health Initiative Memory Study (WHIMS) cohort of women 65 or more years of age, with no indicators of neurological disease but with variable health status, estrogen and hormone therapy for 5 years increased the risk of developing Alzheimer's disease. These data would suggest that as the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neurological function and survival. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. Based on these and other data, a hypothesis of a healthy cell bias of gonadal hormone action is put forth. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the domains of scientific inquiry and to access future applications of estrogen and hormone therapeutic interventions.