Clinical applications for estetrol

Visser, Maartje De; Bennink, Herjan J.T. Coelingh

doi:10.1016/j.jsbmb.2008.12.013

Cited by 38 publications

(31 citation statements)

References 24 publications

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“…E 4 was unable to increase cyclin D1 expression, an ERa-inducible gene that governs E 2 -dependent epithelial cell growth in mammary gland (Liu et al 2002, Casimiro et al 2013. At these concentrations, E 4 has been reported to significantly prevent osteoporosis and hot flushes in preclinical rat models (Visser & Coelingh Bennink 2009). Altogether, these results highlight that E 4 could be suitable to control reproduction, osteoporosis, and vasomotor symptoms with limited impact on breast proliferation.…”

Section: Discussionmentioning

confidence: 99%

Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation

Gérard¹,

Blacher²,

Communal³

et al. 2014

Journal of Endocrinology

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Estetrol (E 4 ) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol and estradiol (E 2 ), E 4 has a minimal impact on liver cell activity and could provide a better safety profile in contraception or hormone therapy. The aim of this study was to delineate if E 4 exhibits an activity profile distinct from that of E 2 on mammary gland. Compared with E 2 , E 4 acted as a low-affinity estrogen in both human in vitro and murine in vivo models. E 4 was 100 times less potent than E 2 to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary gland in vitro and in vivo respectively. This effect was prevented by fulvestrant and tamoxifen, supporting the notion that ERa (ESR1) is the main mediator of the estrogenic effect of E 4 on the breast. Interestingly, when E 4 was administered along with E 2 , it significantly antagonized the strong stimulatory effect of E 2 on HBE cell proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E 4 on mammary gland. Our results highlight that E 4 is less potent than E 2 and exhibits antagonistic properties toward the proliferative effect of E 2 on breast epithelial cells. These data support E 4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation.

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Section: Discussionmentioning

confidence: 99%

Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation

Gérard¹,

Blacher²,

Communal³

et al. 2014

Journal of Endocrinology

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“…This seems to be the case of the breast, where E4 was found to reduce the growth of breast cancers induced with a chemical carcinogen in rats, similar to tamoxifen (14). This raises the hypothesis that E4 may be a naturally occurring selective estrogen receptor (ER) modulator.…”

Section: Introductionmentioning

confidence: 96%

Effects of Estetrol on Migration and Invasion in T47-D Breast Cancer Cells through the Actin Cytoskeleton

et al. 2014

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Estetrol (E4) is a natural human estrogen present at high concentrations during pregnancy. Due to its high oral bioavailability and long plasma half-life, E4 is particularly suitable for therapeutic applications. E4 acts as a selective estrogen receptor (ER) modulator, exerting estrogenic actions on the endometrium or the central nervous system, while antagonizing the actions of estradiol in the breast. We tested the effects of E4 on its own or in the presence of 17β-estradiol (E2) on T47-D ER+ breast cancer cell migration and invasion of three-dimensional matrices. E4 administration to T47-D cells weakly stimulated migration and invasion. However, E4 decreased the extent of movement and invasion induced by E2. Breast cancer cell movement requires a remodeling of the actin cytoskeleton. During exposure to E4, a weak, concentration-dependent, re-distribution of actin fibers toward the cell membrane was observed. However, when E4 was added to E2, an inhibition of actin remodeling induced by E2 was seen. Estrogens stimulate ER+ breast cancer cell movement through the ezrin–radixin–moesin family of actin regulatory proteins, inducing actin and cell membrane remodeling. E4 was a weak inducer of moesin phosphorylation on Thr558, which accounts for its functional activation. In co-treatment with E2, E4 blocked the activation of this actin controller in a concentration-related fashion. These effects were obtained through recruitment of estrogen receptor-α. In conclusion, E4 acted as a weak estrogen on breast cancer cell cytoskeleton remodeling and movement. However, when E2 was present, E4 counteracted the stimulatory actions of E2. This contributes to the emerging hypothesis that E4 may be a naturally occurring ER modulator in the breast.

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“…As a result of these favorable metabolic and protein binding properties, E 4 has excellent oral potency despite its low-to-moderate affinity for ERs. E 4 has been studied in many validated models and has been shown to behave as a full ER agonist, similar to E 2 , in most of these (Coelingh Bennink et al 2008b, Heegaard et al 2008, Visser & Coelingh Bennink 2009). However, important differences between E 4 and E 2 were noted.…”

Section: Introductionmentioning

confidence: 99%

Vasorelaxing effects of estetrol in rat arteries

Hilgers¹,

Oparil²,

Wouters³

et al. 2012

Journal of Endocrinology

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This study compared ex vivo relaxing responses to the naturally occurring human hormone estetrol (E 4 ) vs 17b-estradiol (E 2 ) in eight different vascular beds. Arteries were mounted in a myograph, contracted with either phenylephrine or serotonin, and cumulative concentrationresponse curves (CRCs) to E 4 and E 2 (0 . 1-100 mmol/l) were constructed. In all arteries tested, E 4 had lower potency than E 2 , although the differential effect was less in larger than smaller arteries. In uterine arteries, the nonselective estrogen receptor (ER) blocker ICI 182 780 (1 mmol/l) caused a significant rightward shift in the CRC to both E 4 and E 2 , indicating that the relaxation responses were ER dependent. Pharmacological blockade of nitric oxide (NO) synthases by N u -nitro-L-arginine methyl ester (L-NAME) blunted E 2 -mediated but not E 4 -mediated relaxing responses, while inhibition of prostaglandins and endothelium-dependent hyperpolarization did not alter relaxation to either E 4 or E 2 in uterine arteries. Combined blockade of NO release and action with L-NAME and the soluble guanylate cyclase (sGC) inhibitor ODQ resulted in greater inhibition of the relaxation response to E 4 compared with E 2 in uterine arteries. Endothelium denudation inhibited responses to both E 4 and E 2 , while E 4 and E 2 concentration-dependently blocked smooth muscle cell Ca 2C entry in K C -depolarized and Ca 2C -depleted uterine arteries. In conclusion, E 4 relaxes precontracted rat arteries in an artery-specific fashion. In uterine arteries, E 4 -induced relaxations are partially mediated via an endothelium-dependent mechanism involving ERs, sGC, and inhibition of smooth muscle cell Ca 2C entry, but not NO synthases or endothelium-dependent hyperpolarization.

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Clinical applications for estetrol

Cited by 38 publications

References 24 publications

Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation

Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation

Effects of Estetrol on Migration and Invasion in T47-D Breast Cancer Cells through the Actin Cytoskeleton

Vasorelaxing effects of estetrol in rat arteries

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