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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 106098
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 01.10.2004 - 30.09.2007
Approved amount 377'000.00
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Keywords (12)

hormone therapy; menopause; estrogen; metabolism; women's health; heart disease; cardiovascular; smooth muscle cells; methoxyestradiol; cancer; cardioprotection; neuroprotection

Lay Summary (English)

Lead
Lay summary
Aim : To investigate the hypothesis that, estradiol metabolites, rather than estradiol per se, are responsible for the cardiovascular protective actions of estradiol (E2). Using selective inhibitors and antisense we have previously shown that the protective actions of estradiol are mediated via its sequential metabolism to methoxyestradiols, by specific Cytochorme P-450s (CYP450) and Catechol-O-Demethyltransferase (COMT), respectively. Because progestins are also substrates for CYP450s, we hypothesized that MPA may abrogate the vasoprotective effects of E2 by competing for CYP450s and inhibiting the formation of HEs and MEs. Here we demonstrated that in SMCs, the inhibitory effects of E2 on cell number, DNA synthesis, collagen synthesis and SMC migration were significantly abrogated by MPA. The abrogatory effects of MPA were also evident in SMCs cultured from ER-alpha/beta knockout mice. In microsomal preparations and SMCs, MPA inhibited the conversion of E2 to 2-HE and 2-ME. Our findings suggest that the inhibitory actions of MPA on the metabolism of E to HEs and MEs may play a critical role in abrogating the cardioprotective actions of estradiol in women receiving HT (E2 + MPA). Moreover, use of MPA in the WHI and HERS trial may be responsible for the lack or protective actions of estrogens in these studies. Apart, from MPA, the protective effects of E2 can also be abrogated by lifestyle factors. Because, resveratrol, a red wine constituent, can block the metabolism of E2 by CYP450, we hypothesized and demonstrated that the antimitogenic effects of estradiol on SMCs can be blocked by resveratrol and that these effects were due to its inhibitory effects on the conversion of E2 to HEs and MEs. This suggests that factors interfering with E2 metabolism to HE and ME can abrogate the protective actions of hormone therapy. ME is anticarcinogenic, hence, the abrogatory effects of MPA on its production could also contribute to increased incidence of breast cancer in women taking E + MPA, but not in women taking E alone. Using molecular and pharmacological approach, we demonstrated that conversion of E to ME couteracts the mitogenic effects of E in breast cancer cells and lack of ME formation is associated with enhanced proliferation of cancer cells (See PhD thesis work of Mara Foletti). Also, based on our previous finding that E2 may induce its protective actions via cAMP-adenosine pathway, we now show that this pathway is responsible for the in-vivo generation of adenosine. Because, adenosine is a SMC growth inhibitor, the antimitogenic effects of E may be mediated via this mechanism. Moreover, we show that this pathway is active in the hepatopancreatic system.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
117998 Role of estradiol metabolism in the pathophysiology and pharmacology of estrogen therapy 01.10.2007 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)

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