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An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
The assessment of non-feminizing estrogens for use in neuroprotection
Kun Don Yi1, Evelyn Perez, Shaohua Yang
1Institute for Aging and Alzheimer's Disease Research, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Abstract:
Menopause is associated with a precipitous decline in circulating estrogens and a resulting loss of the neuroprotective actions of this steroid hormone. In view of the results of the Women's Health Initiative and the preceding knowledge that orally administered estrogens has a variety of adverse side effects, likely through actions on peripheral estrogen receptor alpha (ERα), we initiated a program of research to synthesis and assess a group of non-feminizing estrogens that lack ability to interact with ERs but retain much of the neuroprotective action of feminizing estrogens. This program of research is aimed at the identification of compounds which do not stimulate ERs but are potentially neuroprotective in vitro and in animal models of neuronal cell death. We discovered that the most effective non-feminizing estrogens were those with large bulky groups in the 2 and/or 4 carbon of the phenolic A ring of the steroid. These compounds were 8- to 114-fold more potent than 17 β-estradiol (βE2), but lacked ER binding capacity in vitro and feminizing effects in vivo. The success of this program of research suggests that strategies to optimize non-feminizing estrogens for use in postmenopausal women can be successful.
Insights
Researchers developed novel non-feminizing estrogens that protect neurons without estrogen receptor binding. These compounds show promise for postmenopausal women, offering neuroprotection with fewer side effects than traditional estrogens.
Area of Science:
- Neuroscience
- Endocrinology
- Pharmacology
Background:
- Menopause causes estrogen decline, leading to loss of neuroprotection.
- Oral estrogens have adverse effects via estrogen receptor alpha (ERα).
- Need for neuroprotective agents without feminizing side effects.
Purpose of the Study:
- Synthesize and assess non-feminizing estrogens.
- Identify compounds retaining neuroprotection but lacking ER binding.
- Develop safer alternatives for postmenopausal women.
Main Methods:
- Chemical synthesis of novel estrogen analogs.
- In vitro assays for ER binding capacity.
- In vivo studies in animal models for feminizing effects.
- Evaluation of neuroprotective potential in neuronal cell death models.
Main Results:
- Identified potent non-feminizing estrogens with bulky groups on the phenolic A ring.
- Compounds were 8- to 114-fold more potent than 17 β-estradiol (βE2).
- These novel estrogens lacked ER binding and in vivo feminizing effects.
Conclusions:
- Successful development of non-feminizing estrogens with retained neuroprotective actions.
- Demonstrated potential for optimizing these compounds for postmenopausal therapy.
- Suggests a viable strategy for mitigating menopausal neuroprotection loss.
