Project

Back to overview

Role of estradiol metabolism in the pathophysiology and pharmacology of estrogen therapy

English title Role of estradiol metabolism in the pathophysiology and pharmacology of estrogen therapy
Applicant Dubey Raghvendra K.
Number 117998
Funding scheme Project funding (Div. I-III)
Research institution Klinik für Reproduktions-Endokrinologie Departement Frauenheilkunde Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Gynaecology
Start/End 01.10.2007 - 31.12.2011
Approved amount 480'101.00
Show all

Keywords (6)

estradiol; estradiol metabolites; metabolic disorder; hormone therapy; menopause; ageing

Lay Summary (English)

Lead
Lay summary
Hormone therapy (HT) with estrogen alleviates multiple postmenopausal disorders. With increase in life expectancy, the number of PMW in developed countries, including Switzerland, is expected to increase and result in increased prescriptions for HT. Epidemiological/observational studies provide strong evidence the estrogens protect women against cardiovascular disease1, however, results from two randomized clinical trials with conjugated equine estrogens (HERS2 and WHI3 study) showed no primary or secondary cardiovascular protective effects. However, another trial using estradiol (EPAT4) demonstrated cardiovascular protective effects. The differences in the outcome of these studies remain controversial. Because the mechanisms by which estrogens induce their cardiovascular protective and/or deleterious effects are unclear and several different types of estrogens are used clinically,1,5 it is hard to explain the reasons for these differential effects and underscores the need to explore basic mechanisms of cardiovascular protection by estrogens. Ongoing studies from our laboratory demonstrate that the major metabolites of 17ß-estradiol, namely 2-hydroxyestradiol, 2-methoxyestradiol (2ME), 4-hydroxyestradiol, and 4-methoxyestradiol, which have little or no binding affinity for estrogen receptors, are more potent than 17ß-estradiol in inhibiting vascular smooth muscle cell (SMC) and cardiac fibroblast (CF) growth. These observations, together with the findings that 17 -estradiol inhibits injury-induced neointima formation in mice lacking the functional ER- , ER- , or both ER-? and ER-?, led us to hypothesize that estradiol metabolites, rather than estradiol per se, are responsible for the cardiovascular protection afforded by estrogen therapy and that variable metabolism of estrogen(s) explains the inconsistent clinical response to HRT. In this context using molecular (siRNA; knock out mice) and pharmacological approaches we previously demonstrated that ER-independent anti-proliferative effects of 17 -estradiol is mediated via its sequential conversion to methoxyestradiols. Because, 2-methoxyestradiol is anticarcinogenic it may serve as a safer alternative for hormone therapy. Hence using cellular, molecular (gene silencing, microarrays) and biochemical (proteonomics) approaches, the objective of this proposal is to investigate the mechanisms by which 2-methoxyestradiol and estradiol-derived 2-methoxestradiol influences key mechanisms associated with the pathophysiology of vascular remodeling process in coronary artery disease and atherosclerosis.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
2-Methoxyestradiol: A 17β-Estradiol Metabolite With Gender-Independent Therapeutic Potential
Dubey Raghvendra (2017), 2-Methoxyestradiol: A 17β-Estradiol Metabolite With Gender-Independent Therapeutic Potential, in Hypertension, 69, 1014-1016.
2-Methoxyestradiol, an endogenous 17-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism
Schaufelberger Sara, Rosselli Marinella, Barchiesi Federica, Gillespie D, Jackson E, Dubey RK., 2-Methoxyestradiol, an endogenous 17-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism, in Am J Physiol Endocrinol Metab, 310, E313-E322.
Candidate Genes and Mechanisms for 2-Methoxyestradiol- Mediated Vasoproection
Barchiesi Federica, Candidate Genes and Mechanisms for 2-Methoxyestradiol- Mediated Vasoproection, in Hypertension, 56, 964-972.
Estrogen Receptor But No or GPER inhibits High Glucose-Induced Human VSMC Proliferation: Potential Role of ROS and ERK
Ortmann Jana, Estrogen Receptor But No or GPER inhibits High Glucose-Induced Human VSMC Proliferation: Potential Role of ROS and ERK, in J Clin Endocrinol Metab, 96(1), 220-228.
Expression of the 2,3-cAMP-adenosine pathway in asterocytes and microglia
Verrier Jonathan D., Expression of the 2,3-cAMP-adenosine pathway in asterocytes and microglia, in Journal of Neurochemistry, (118), 979-987.
Extracellular 2.3. Cyclic Adenosine 5 ...
Jackson Edwin K., Extracellular 2.3. Cyclic Adenosine 5 ..., in Hypertension, 56, 151-158.
Receptor for Activated Protein Kinase C1 REgulates Cell Proliferation by Modulating Calcium Signaling
Cheng Dongmei, Receptor for Activated Protein Kinase C1 REgulates Cell Proliferation by Modulating Calcium Signaling, in Hypertension, (58), 689-695.
Sex Hormones
Dubey Raghvendra, Sex Hormones, InTech, Croatia.

Collaboration

Group / person Country
Types of collaboration
Dr. Juergen Fingerle/Hoffmann La Roche Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Edwin K. Jackson/University of Pittsburgh United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
106098 Role of Estradiol Metabolism in the Pathophysiology and Pharmacology of Estrogen Therapy 01.10.2004 Project funding (Div. I-III)
138067 Role of Estradiol Metabolism in the Pathophysiology and Pharmacology of Estrogen Therapy 01.01.2012 Project funding (Div. I-III)

-