Title:The Critical Period for Neuroprotection by Estrogen Replacement Therapy and the Potential Underlying Mechanisms
Volume: 18
Issue: 6
Author(s): Hang Guo, Min Liu, Lixia Zhang, Long Wang, Wugang Hou, Yaqun Ma*Yulong Ma*
Affiliation:
- Department of Anesthesiology, The Seventh Medical Center to Chinese PLA General Hospital, Beijing 100700,China
- Anesthesia and Operation Center, The First Medical Center to Chinese PLA General Hospital, Beijing 100853,China
Keywords:
Estrogen, neuroprotection, ischemic stroke, alzheimer's disease, parkinson's disease, menopause, critical period,
hormone therapy.
Abstract: 17β-Estradiol (estradiol or E2) is a steroid hormone that has been broadly applied as a
neuroprotective therapy for a variety of neurodegenerative and cerebrovascular disorders such as
ischemic stroke, Alzheimer's disease, and Parkinson's disease. Several laboratory and clinical studies
have reported that Estrogen Replacement Therapy (ERT) had no effect against these diseases in
elderly postmenopausal women, and at worst, increased their risk of onset and mortality. This review
focuses on the growing body of data from in vitro and animal models characterizing the potential
underlying mechanisms and signaling pathways that govern successful neuroprotection by ERT,
including the roles of E2 receptors in mediating neuroprotection, E2 genomic regulation of apoptosis-
related pathways, membrane-bound receptor-mediated non-genomic signaling pathways, and the
antioxidant mechanisms of E2. Also discussed is the current evidence for a critical period of effective
treatment with estrogen following natural or surgical menopause and the outcomes of E2
administration within an advantageous time period. The known mechanisms governing the duration
of the critical period include depletion of E2 receptors, the switch to a ketogenic metabolic profile
by neuronal mitochondria, and a decrease in acetylcholine that accompanies E2 deficiency. Also the
major clinical trials and observational studies concerning postmenopausal Hormone Therapy (HT)
are summarized to compare their outcomes with respect to neurological disease and discuss their
relevance to the critical period hypothesis. Finally, potential controversies and future directions for
this field are discussed throughout the review.