Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women

Bennink, Herjan J.T. Coelingh; Verhoeven, Carole; Zimmerman, Yvette; Visser, Maartje De; Jm, Foidart; Gemzell‐Danielsson, Kristina

doi:10.1080/13697137.2017.1291608

Cited by 18 publications

(8 citation statements)

References 12 publications

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“…Moreover, in contrast to E2, E4 is not metabolized to other active estrogen metabolites. 14 , 15 In a multiple rising dose study in postmenopausal women, 2 to 40 mg E4 once-daily improved vaginal cytology and VMS (only evaluated at 2 and 10 mg E4), and a dose-dependent estrogenic effect was observed on endocrine parameters, bone turnover markers, lipids, and lipoproteins, together with only a small increase in triglycerides and almost neutral for hemostatic parameters. 16 , 17 …”

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confidence: 99%

A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety

et al. 2020

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Objective: The aim of this study was to select the minimum effective dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women. Methods: This was a multicenter, randomized, double-blind, placebo-controlled study. Postmenopausal women ( n = 257, of whom 32 were hysterectomized) aged 40 to 65 years, with ≥7 moderate to severe hot flushes (HFs) per day, or 50 or more moderate to severe HFs weekly, received 2.5, 5, 10, or 15 mg E4, or placebo once-daily for a period of 12 weeks. Efficacy was assessed by recording the frequency and severity of HFs. Overall safety was assessed by recording adverse events, measuring endometrial thickness, and monitoring bleeding patterns. Treatment groups were compared using analysis of covariance. Results: The frequency of moderate to severe HFs decreased with all E4 doses. The difference in the percentage change of weekly HF frequency was significant for 15 mg E4 versus placebo at both W4 (−66% vs −49%, P = 0.032) and W12 (−82% vs −65%, P = 0.022). The decrease in severity of HFs was significantly more pronounced for 15 mg E4 than for placebo at both W4 (−0.59 vs −0.33, P = 0.049) and W12 (−1.04 vs −0.66, P = 0.049); the other doses failed to achieve statistical significance. In nonhysterectomized women, endometrial thickness increased during treatment and normalized following progestin treatment at study completion. No endometrial hyperplasia was observed. Conclusions: Estetrol 15 mg is considered to be the minimum effective daily oral dose for treatment of vasomotor symptoms. Its current seemingly favorable safety profile is further to be confirmed in phase 3 clinical development. Video Summary: .

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confidence: 99%

A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety

et al. 2020

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“…We demonstrate that E4, administered continuously to mimic the steady-state plasma concentrations observed in women, affects neither breast cancer growth nor metastatic dissemination to the lung when used at 0.3 mg/kg/day. This dose is within the range of E4 levels circulating in the blood when administered orally at 2-20 mg/day, corresponding to the dose used in clinical trials [38]. Treatment of post-menopausal women with 15 mg E4/day reduces hot flushes [8] and the combination of 15 mg E4/3 mg DRSP has shown contraceptive efficacy [17,18].…”

Section: Discussionmentioning

confidence: 98%

“…E2 has been chosen as a reference treatment since it is recognized as the most widely used for MHT [1]. E4 was used at two doses: (i) 0.3 mg/kg/day, which falls into the range of the plasma concentration of the E4 therapeutic dose (15 mg/day) for COC or MHT in women [8,17,18,38];…”

Section: Therapeutic Dose Of E4 Stimulates Endometrial Proliferationmentioning

confidence: 99%

Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer

Gallez

Blacher

Maquoi

et al. 2021

Cancers

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Given the unequivocal benefits of menopause hormone therapies (MHT) and combined oral contraceptives (COC), there is a clinical need for new formulations devoid of any risk of breast cancer promotion. Accumulating data from preclinical and clinical studies support that estetrol (E4) is a promising natural estrogen for MHT and COC. Nevertheless, we report here that E4 remains active on the endometrium, even under a dose that is neutral on breast cancer growth and lung metastasis dissemination. This implies that a progestogen should be combined with E4 to protect the endometrium of non-hysterectomized women from hyperplasia and cancer. Through in vivo observations and transcriptomic analyses, our work provides evidence that combining a progestogen to E4 is neutral on breast cancer growth and dissemination, with very limited transcriptional impact. The assessment of breast cancer risk in patients during the development of new MHT or COC is not possible given the requirement of long-term studies in large populations. This translational preclinical research provides new evidence that a therapeutic dose of E4 for MHT or COC, combined with progesterone or drospirenone, may provide a better benefit/risk profile towards breast cancer risk compared to hormonal treatments currently available for patients.

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“…In this therapeutic indication, phase III development is ongoing but phase II clinical investigations already provided positive results (18). Indeed, in a multiple-rising-dose study involving postmenopausal women, E4 improved vasomotor symptoms and vaginal cytology, and a dose-dependent estrogenic effect was observed on endocrine parameters, bone turnover markers, lipids and lipoproteins, along with only a small effect on haemostatic parameters (10,11). However, although this is an important issue to consider for HT, the ability of E4 to prevent postmenopausal metabolic disorders was still unknown.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…E4 used in clinical studies is synthesized from estrone contained in soy and is identical to the natural hormone with over 99% purity. E4 is currently evaluated in phase III clinical studies for HT and a recent multiple-rising-dose study showed that it had beneficial effects on vasomotor symptoms, bone metabolism and genito-urinary syndrome in menopausal women (10,11).…”

Section: Introductionmentioning

confidence: 99%

Estetrol prevents Western diet–induced obesity and atheroma independently of hepatic estrogen receptor α

Buscato

Davezac

Zahreddine

et al. 2021

American Journal of Physiology-Endocrinology and Metabolism

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Estetrol (E4), a natural estrogen synthesized by the human fetal liver, is currently evaluated in phase III clinical studies as a new menopause hormone therapy. Indeed, E4 significantly improves vasomotor and genito-urinary menopausal symptoms and prevents bone demineralization. Compared to other estrogens, E4 was found to have limited effects on coagulation factors in the liver of women allowing to expect less thrombotic events. To fully delineate its clinical potential, the aim of this study was to assess the effect of E4 on metabolic disorders. Here, we studied the pathophysiological consequences of a western diet (42% kcal fat, 0.2% cholesterol) in ovariectomized female mice under chronic E4 treatment. We showed that E4 reduces body weight gain and improves glucose tolerance in both C57Bl/6 and LDLR-/- mice. To evaluate the role of hepatic ERα in the preventive effect of E4 against obesity and associated disorders such as atherosclerosis and steatosis, mice harbouring a hepatocyte-specific ERα deletion (LERKO) were crossed with LDLR-/- mice. Our results demonstrated that, whereas liver ERα is dispensable for the E4 beneficial actions on obesity and atheroma, it is necessary to prevent steatosis in mice. Overall, these findings suggest that E4 could prevent metabolic, hepatic and vascular disorders occurring at menopause, extending the potential medical interest of this natural estrogen as a new hormonal treatment.

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Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women

Abstract: The pharmacokinetic profile of estetrol is characterized by a very fast absorption phase, followed by an initial rapid decline, and a slow terminal elimination phase. Based on its kinetic properties, estetrol seems suitable for use as a once-daily oral drug.

Cited by 18 publications

References 12 publications

A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety

A multicenter, randomized study to select the minimum effective dose of estetrol (E4) in postmenopausal women (E4Relief): part 1. Vasomotor symptoms and overall safety

Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer

Estetrol prevents Western diet–induced obesity and atheroma independently of hepatic estrogen receptor α

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