Estrogenic uterovaginal effects of oral estetrol in the modified Allen–Doisy test

Heegaard, Anne‐Marie; Holinka, Christian F.; Kenemans, P.; Bennink, Herjan J.T. Coelingh

doi:10.1080/13697130701842490

Cited by 27 publications

(21 citation statements)

References 30 publications

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“…In well validated and predictive rat models E 4 behaves as an estrogen agonist in all tissues investigated, i. e. bone [16], vagina [21], myometrium [21], endometrium [21] and brain (hot flush [20] and ovulation inhibition [20 ,21]), except for breast tumor tissue where this steroid acts as an estrogen antagonist in the presence of E 2 [24].…”

Section: Discussionmentioning

confidence: 99%

“…The effect of E 4 on vaginal cornification and uterine weight was studied in OVX rats [21]. Six groups of rats were treated orally once daily for 7 days as follows: vehicle (negative) control; E 4 : 0.1, 0.3, 1.0 and 3.0 mg/(kg day) and EE 0.05 mg/(kg day) as active (positive) control.…”

Section: Vaginal Atrophymentioning

confidence: 99%

“…The onset of cornification with E 4 was dose-dependent. After 7 days treatment, the 2 highest E 4 doses (1.0 and 3.0 mg) induced statistically significantly higher uterine wet weight (myometrium) compared to vehicle [21]. Also a pharmacological study was performed to investigate the effect of E 4 on prevention of bone loss [16].…”

Section: Vaginal Atrophymentioning

confidence: 99%

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Clinical applications for estetrol

Visser

Bennink

2009

The Journal of Steroid Biochemistry and Molecular Biology

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In this paper the potential clinical applications for the human fetal estrogen estetrol (E 4 ) are presented based on recently obtained data in preclinical and clinical studies. In the past E 4 has been classified as a weak estrogen due to its rather low estrogen receptor affinity. However, recent research has demonstrated that due to its favorable pharmacokinetic properties, especially the slow elimination and long half-life, E 4 is an effective orally bioavailable estrogen agonist with estrogen antagonistic effects on the breast in the presence of estradiol. Based on the pharmacokinetic properties, the pharmacological profile and the safety and efficacy results in human studies, E 4 seems potentially suitable as a drug for human use in applications such as hormone replacement therapy (vaginal atrophy and vasomotor

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Section: Discussionmentioning

confidence: 99%

Section: Vaginal Atrophymentioning

confidence: 99%

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Clinical applications for estetrol

Visser

Bennink

2009

The Journal of Steroid Biochemistry and Molecular Biology

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“…In postmenopausal women, E4 was well tolerated and suppressed FSH and LH levels dosedependently after oral application [20] . When given to rats orally once daily, E4 displayed dose-dependent pharmacodynamic effects on preservation of bone mass and strength [19] , estrogenic responses in vaginal and uterine tissues [21] , alleviation of hot fl ushes [22] and inhibition of ovulation [23] with a rather consistent 10-20 times lower potency than ethinylestradiol (EE), a potent synthetic estrogen used in combined oral contraceptives (COCs).…”

Section: Introductionmentioning

confidence: 99%

Estetrol prevents and suppresses mammary tumors induced by DMBA in a rat model

Visser

Kloosterboer²,

Bennink

2012

Hormone Molecular Biology and Clinical Investigation

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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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Estrogenic uterovaginal effects of oral estetrol in the modified Allen–Doisy test

Abstract: Estetrol has estrogenic effects on the vagina and on the uterus of ovariectomized rats. The potency of E(4) is approximately 20-fold lower compared to ethinylestradiol.

Cited by 27 publications

References 30 publications

Clinical applications for estetrol

Clinical applications for estetrol

Estetrol prevents and suppresses mammary tumors induced by DMBA in a rat model

Vasorelaxing effects of estetrol in rat arteries

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