Department of Molecular Pharmacology and Toxicology, School of Pharmacy, Program in Neuroscience, and Department of Biomedical Engineering, Pharmaceutical Sciences Center, University of Southern California, Los Angeles, California 90089-9121, USA
Address for correspondence: Roberta Diaz Brinton, Ph.D., Department of Molecular Pharmacology and Toxicology, Norris Foundation Laboratory for Neuroscience Research, Pharmaceutical Sciences Center, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90089-9121. Voice: 323-442-1430; fax: 323-442-1489. rbrinton{at}hsc.usc.edu
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 (Psychoneuroendocrinology13: 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.
