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Jeanmichel Foidart - One of the best experts on this subject based on the ideXlab platform.

  • Estetrol and Mammary Gland: Friends or Foes?
    Springer Science and Business Media LLC, 2021
    Co-Authors: Anne Gallez, Jeanmichel Foidart, Isabelle Dias Da Silva, Vincent Wuidar, Christel Péqueux
    Abstract:

    AbstractEstrogens have pleiotropic effects on many reproductive and non-reproductive tissues and organs including the mammary gland, uterus, ovaries, vagina, and endothelium. Estrogen receptor α functions as the principal mediator of estrogenic action in most of these tissues. Estetrol (E4) is a native fetal estrogen with selective tissue actions that is currently approved for use as the estrogen component in a combined oral contraceptive and is being developed as a menopause hormone therapy (MHT, also known as hormone replacement therapy). However, exogenous hormonal treatments, in particular MHTs, have been shown to promote the growth of preexisting breast cancers and are associated with a variable risk of breast cancer depending on the treatment modality. Therefore, evaluating the safety of E4-based formulations on the breast forms a crucial part of the clinical development process. This review highlights preclinical and clinical studies that have assessed the effects of E4 and E4-progestogen combinations on the mammary gland and breast cancer, focusing in particular on the estrogenic and anti-estrogenic properties of E4. We discuss the potential advantages of E4 over current available estrogen-formulations as a contraceptive and for the treatment of symptoms due to menopause. We also consider the potential of E4 for the treatment of endocrine-resistant breast cancer.

  • Estetrol drospirenone combination oral contraceptive north american phase 3 efficacy and safety results
    Contraception, 2021
    Co-Authors: Mitchell D Creinin, Jeanmichel Foidart, Carolyn Westhoff, Celine Bouchard, Melissa J Chen, Jeffrey T Jensen, Andrew M Kaunitz, Sharon L Achilles, David F Archer
    Abstract:

    Abstract Objective To assess efficacy, cycle control, and safety of an oral contraceptive containing Estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. Study design Women aged 16 to 50 years with a body mass index ≤35 kg/m2 enrolled in this multicenter, open-label, 13-cycle, phase 3 trial evaluating E4/DRSP in a 24-active/4-placebo regimen. Follow-up was scheduled at Cycles 2, 4, 7, and 10 and within 3 weeks of completing Cycle 13. Participants used daily diaries to record pill use and vaginal bleeding. We evaluated efficacy outcomes in women 16 to 35 years and bleeding patterns and safety (adverse events [AEs]) in all participants. We assessed overall and method-failure pregnancy rates using the Pearl index (PI) and life-table analysis. Scheduled bleeding included spotting or bleeding starting during the 4-day placebo period or first 3 days of the next cycle. Results We enrolled 1864 women of whom 1674 were 16 to 35 years. Women 16 to 35 years had a PI of 2.65 (95% CI 1.73–3.88), method-failure PI of 1.43 (95% CI 0.7–2.39) and 13-cycle life-table pregnancy rate of 2.1%. Scheduled bleeding occurred in 82.9% to 87.0% of women per cycle; median duration was 4.5 days. Unscheduled bleeding decreased from 30.3% in Cycle 1 to 21.3% to 22.1% during Cycles 2 to 4 and remained stable (15.5% to 19.2%) thereafter. The most frequently reported AEs were headache (5.0%) and metrorrhagia (4.6%). One-hundred thirty-two (7.1%) women discontinued the study early for an AE, most commonly for metrorrhagia (0.9%) and menorrhagia (0.8%). No thromboembolic events occurred. Conclusion E4/DRSP is an effective oral contraceptive with a predictable bleeding pattern for most women and low AE rates. Implications statement A new oral contraceptive with a novel estrogen, Estetrol, combined with drospirenone has efficacy and safety within the range of other available oral contraceptives. Large phase 4 studies will be needed to confirm if this combination is associated with an improved adverse event profile or lower thrombosis risk.

  • endocrine and metabolic effects of an oral contraceptive containing Estetrol and drospirenone
    Contraception, 2021
    Co-Authors: Christine Klipping, Ingrid Duijkers, Marie Mawet, Catherine Maillard, Maud Jost, Adriana Bastidas, Jeanmichel Foidart
    Abstract:

    Abstract Objectives To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing Estetrol (E4) and drospirenone (DRSP). Study design Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism. Results At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] −7.5%) compared to EE/LNG (FSH −84.0%, LH −92.0%) and EE/DRSP (FSH −64.0%, LH −90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism. Conclusions E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products. Implications statement Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.

  • effects of an oral contraceptive containing Estetrol and drospirenone on ovarian function
    Contraception, 2021
    Co-Authors: Ingrid Duijkers, Christine Klipping, Maud Jost, Virginie Kinet, Adriana Bastidas, Jeanmichel Foidart
    Abstract:

    Abstract Objective To evaluate the effects of Estetrol 15 mg/drospirenone 3 mg on ovarian function. Study design Single-center, randomized, open-label, parallel study in healthy young women with proven ovulatory cycles. Participants received either Estetrol 15 mg/drospirenone 3 mg (E4/DRSP) (n = 41) or ethinylestradiol 20 µg/drospirenone 3 mg (EE/DRSP) (n = 41) in a 24/4-day regimen for 3 consecutive cycles. Follicular size and endometrial thickness were measured by transvaginal ultrasound every 3 days in cycles 1 and 3. Blood was sampled for hormone analysis. Ovarian function expressed as Hoogland score was based on follicular size, serum estradiol (E2) and progesterone (P) concentrations. Ovulation was defined as a ruptured follicle-like structure >13 mm with serum E2 concentrations >100 pmol/L and serum P concentrations >5 nmol/L. We assessed return of ovulation after treatment cessation, and safety throughout the study. Results None of the participants ovulated with E4/DRSP use, while one participant ovulated once and one participant ovulated twice during EE/DRSP treatment. Most participants had a Hoogland score of 1 (no ovarian activity) in cycle 1 (85.0% and 82.9% of participants on E4/DRSP and EE/DRSP, respectively) and in cycle 3 (65.8% and 83.8%, respectively). E4/DRSP suppressed follicle-stimulating hormone and luteinizing hormone to a lesser extent than EE/DRSP, whereas both treatments comparably suppressed E2 and P and endometrial thickness. Return of ovulation occurred, on average, 15.5 days after E4/DRSP treatment discontinuation. E4/DRSP was safe and well-tolerated. Conclusions E4 15 mg/DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, comparable to a marketed combined oral contraceptive containing EE/DRSP. Implications statement Treatment with E4 15 mg/DRSP 3 mg showed complete ovulation inhibition, despite less suppression of follicle-stimulating hormone and luteinizing hormone compared to EE/DRSP. If it becomes commercially available, E4/DRSP, containing a naturally occurring estrogen, should be as effective as EE/DRSP.

  • Estetrol prevents western diet induced obesity and atheroma independently of hepatic estrogen receptor α
    American Journal of Physiology-endocrinology and Metabolism, 2021
    Co-Authors: Melissa Buscato, Rana Zahreddine, Jeanmichel Foidart, Marine Adlanmerini, Morgane Davezac, Raphael Metivier, Marianne Fillet, Gael Cobraiville, Cedric Moro, Francoise Lenfant
    Abstract:

    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 with 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 estrogen receptor (ER) α in the preventive effect of E4 against obesity and associated disorders such as atherosclerosis and steatosis, mice harboring 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.NEW & NOTEWORTHY Estetrol prevents obesity, steatosis, and atherosclerosis in mice fed a Western diet. Hepatic ERα is necessary for the prevention of steatosis, but not of obesity and atherosclerosis.

Herjan Coelingh J T Bennink - One of the best experts on this subject based on the ideXlab platform.

  • Estetrol cotreatment of androgen deprivation therapy in infiltrating or metastatic castration sensitive prostate cancer a randomized double blind phase ii trial pcombi
    European urology open science, 2021
    Co-Authors: Herjan Coelingh J T Bennink, Yacov Reisman, Jeroen Van Moorselaar, David E Crawford, Erik P M Roos, Diederik M Somford, Ton A Roeleveld, Tjard D De Haan, Harm H E Van Melick, Yvette Zimmerman
    Abstract:

    Background Androgen deprivation therapy (ADT) for prostate cancer with luteinizing hormone-releasing hormone (LHRH) agonists can be improved. Objective To assess safety, the frequency and severity of hot flushes (HFs), bone health, and antitumor effects of high-dose Estetrol (HDE4) when combined with ADT. Design setting and participants A phase II, double-blind, randomized, placebo-controlled study was conducted in advanced prostate cancer patients requiring ADT (the PCombi study). Intervention Patients receiving LHRH agonist treatment were randomized 2:1 to 40 mg HDE4 (n = 41) or placebo (n = 21) cotreatment for 24 wk. Outcome measurements and statistical analysis Coprimary endpoints were frequency/severity of HFs and levels of total and free testosterone (T). Secondary endpoints included assessments of bone metabolism (osteocalcin and type I collagen telopeptide [CTX1]), prostate-specific antigen (PSA), and follicle-stimulating hormone (FSH). Efficacy analysis was based on the selected per-protocol (PP) population. Results and limitations Of 62 patients included in the study, 57 were suitable for a PP analysis (37 HDE4; 20 placebo). No E4-related serious cardiovascular adverse events occurred at 24 wk. Weekly HFs were reported by 13.5% of patients with HDE4 and 60.0% with placebo (p < 0.001). Daily HFs occurred in 5.9% versus 55%. Bone turnover parameters decreased significantly with HDE4 (p < 0.0001). Total and free T decreased earlier (p < 0.05), and free T was suppressed further (p < 0.05). PSA suppression was more profound and earlier (p < 0.005). FSH levels were suppressed by 98% versus 57% (p < 0.0001). Estrogenic side effects were nipple sensitivity (34%) and gynecomastia (17%). Conclusions HDE4 cotreatment of ADT patients with advanced prostate cancer was well tolerated, and no treatment-related cardiovascular adverse events were observed at 24 wk. HFs and bone turnover were substantially reduced. Suppression of free T, PSA, and FSH was more rapid and profound, suggesting enhanced disease control by HDE4 cotreatment. Larger and longer-lasting studies are needed to confirm the results of the study reported here. Patient summary Cotreatment of androgen deprivation therapy with high-dose Estetrol in advanced prostate cancer patients results in fewer occurrences of hot flushes, bone protection, and other antitumor benefits. Nipple sensitivity and gynecomastia may occur as side effects.

  • tumor suppression dose limiting toxicity and wellbeing with the fetal estrogen Estetrol in patients with advanced breast cancer
    Journal of Cancer Research and Clinical Oncology, 2020
    Co-Authors: Marcus Schmidt, Yvette Zimmerman, Hans Lenhard, Arnd Hoenig, Jan Krijgh, Monique Jansen, Herjan Coelingh J T Bennink
    Abstract:

    The aim of this study (the ABCE4 study) was to assess dose-limiting toxicity (DLT), safety, tolerability and preliminary efficacy of high doses of the fetal estrogen Estetrol (E4) in postmenopausal patients with heavily pretreated, locally advanced and/or metastatic ER+/HER2−breast cancer, resistant to anti-estrogens. This was a multicenter, open-label, phase IB/IIA, dose-escalation study with a 3 + 3 cohort design, whereby successive cohorts of three patients received 20 mg, 40 mg or 60 mg E4 per day for 12 weeks by oral administration. DLTs, safety and wellbeing were evaluated after 4, 8 and 12 weeks of treatment. Anti-tumor effects were investigated by computer tomography scanning and evaluated according to RECIST criteria before and after 12 weeks of treatment. Wellbeing was judged weekly by the investigator and by quality-of-life questionnaires by the patients. In view of the small number of patients, no statistical testing was performed. All 12 patients enrolled had progressive, heavily pre-treated advanced breast cancer. No treatment-related serious adverse events or DLTs occurred during the first 4 weeks of E4 treatment allowing the investigation of all three doses. Five of nine patients completing 12 weeks of E4 treatment showed objective anti-tumor effects and six of nine patients reported improved wellbeing. High doses of Estetrol seem to be safe and are well tolerated during 12 weeks of treatment without dose-limiting toxicity and with anti-tumor effects in five of nine heavily treated patients with progressive, anti-estrogen resistant, advanced breast cancer.

  • a multicenter randomized study to select the minimum effective dose of Estetrol e4 in postmenopausal women e4relief part 1 vasomotor symptoms and overall safety
    Menopause, 2020
    Co-Authors: U Gaspard, Marie Mawet, Herjan Coelingh J T Bennink, Melanie Taziaux, Maud Jost, Valerie Gordenne, Rogerio A Lobo, Wulf H Utian, Jeanmichel Foidart
    Abstract:

    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:http://links.lww.com/MENO/A591.

  • abstract p5 11 15 Estetrol for treatment of advanced er her2 breast cancer
    Cancer Research, 2020
    Co-Authors: Marcus Schmidt, Yvette Zimmerman, Carole Verhoeven, Hans Lenhard, Jan Krijgh, A Honig, K Almstedt, Marco Johannes Battista, Herjan Coelingh J T Bennink
    Abstract:

    Introduction: A high dose of the fetal estrogen Estetrol (E4) is anticipated to have anti-tumor effects in patients with advanced, anti-estrogen resistant, ER+/HER2- breast cancer (BC). It will most likely also improve patient’s quality of life by reducing symptoms of estrogen deficiency such as hot flushes, arthralgia, sleep disturbances, vaginal dryness, mood changes and depression, bone loss and fractures and cognition. The ABCE4 study is performed in Germany in this patient population. The main objectives of the study are to assess safety and tolerability of three doses of E4, to determine anti-tumor response and to evaluate estrogen deficiency symptoms. Study design: This is a multi-center, open-label, phase IB/IIA, dose-escalation study with a 3 + 3 cohort design, whereby successive cohorts of 3 patients receive 20 mg, 40 mg and 60 mg E4 per day by oral administration. Dose limiting toxicity (DLT), safety and wellbeing are evaluated after 4, 8 and 12 weeks of treatment. Occurrence of DLT at completion of phase IB after 4 weeks treatment determines escalation to the next higher dose. Objective anti-tumor effects are assessed by computer tomography scanning and evaluated according to RECIST criteria before and after 12 weeks of treatment. Thereafter treatment may continue based on an evaluation of the patient and her treating physician. In view of the small numbers required for this study design no statistical testing was performed. Results: A total of 12 postmenopausal women with progressive, heavily pre-treated advanced BC have been enrolled. Nine patients completed Phase IB. One patient in the 20 mg group discontinued the study during Phase IIA due to disease progression after 9,5 weeks of E4 treatment. She died 3 weeks later. Eight patients completed both the Phase IB and IIA part of the study. None of the patients experienced a DLT. All three E4 doses were well tolerated by all patients. In total 38 adverse events were reported. Adverse events were mainly of mild or moderate intensity. The following 8 events were considered possibly related to E4 treatment: increased endometrial thickness, spotting (2 patients), dry skin, pruritus, edema, fatigue (2 patients), alopecia and acid regurgitation. Seven events fulfilled the criteria of seriousness from which one was considered to be related to E4 treatment. This patient experienced moderate vaginal bleeding after 36 weeks treatment with 20 mg E4 and was hospitalized for hysteroscopy and endometrial ablation with full recovery thereafter. Importantly five of the eight patients who completed treatment with E4 reported subjective improvement and “felt much better” than before the start of E4 treatment. This was described by one of the patients as: ‘”feeling less down and exhausted; instead feeling much more optimistic, powerful and positive when taking E4”. Five patients completing 12 weeks E4 treatment showed objective anti-tumor effects with stable disease (n=4) and one remission. All five continued E4 treatment. Tumor assessment after 24 weeks of E4 treatment showed again stable disease in 4 patients. Conclusion: We conclude that daily doses of 20 mg, 40 mg and 60 mg E4 are well tolerated without DLTs. The majority of patients experienced favorable subjective effects and four patients treated for 24 weeks or longer showed stable disease and tumor remission respectively. Treatment with E4 meets the criteria for further investigation and development of E4 as a new drug for the treatment of anti-estrogen resistant advanced breast cancer. Final dose selection of E4 will take place in September 2019. Citation Format: Marcus Schmidt, Arnd Honig, Yvette Zimmerman, Carole Verhoeven, Katrin Almstedt, Marco Battista, Hans Georg Lenhard, Jan Krijgh, Herjan Coelingh Bennink. Estetrol for treatment of advanced ER+/HER2- breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-15.

  • a dose escalating study with the fetal estrogen Estetrol in healthy men
    The Journal of Clinical Endocrinology and Metabolism, 2018
    Co-Authors: Herjan Coelingh J T Bennink, Cornelis Kluft, Yvette Zimmerman, Carole Verhoeven, Alice E Dutman, Tjeert Mensinga, Yacov Reisman, F M J Debruyne
    Abstract:

    Context Luteinizing hormone-releasing hormone (LHRH) agonists have replaced estrogens for endocrine treatment of advanced prostate cancer (PC) because of cardiovascular side effects. The fetal estrogen Estetrol (E4) may be safer for PC treatment and is expected to decrease testosterone (T) and prevent estrogen deficiency. Objective To investigate the safety and T-suppressive effect of E4 in healthy men. Design Double-blind, randomized, placebo-controlled, dose-escalating study. Setting The study was conducted at a phase I clinical unit (QPS, Netherlands). Participants Healthy male volunteers aged 40 to 70 years. Intervention(s) Three treatment cohorts of 15 volunteers with placebo (n = 5) and E4 (n = 10). Estetrol doses tested were 20, 40, and 60 mg/d. Subjects were treated for 4 weeks. Main Outcome Measures Subjective side effects, pharmacodynamic effects on hemostatic variables, lipids, glucose, bone parameters, and endocrine parameters related to T metabolism. Results Total and free T decreased dose-dependently and significantly. Nipple tenderness occurred in 40% and decrease of libido occurred in 30% of E4-treated men. The unwanted estrogenic effects on hemostasis were small, dose dependent, and in some cases significant. Lipid and bone parameters showed a favorable trend. Conclusion The effect of E4 on testosterone levels is insufficient for standalone PC treatment. Taking all clinical and pharmacodynamic variables into consideration, a daily dose of 40 mg E4 seems safe for further evaluation of endocrine PC treatment in combination with LHRH analogs.

H Coelingh J T Bennink - One of the best experts on this subject based on the ideXlab platform.

  • fetal Estetrol e4 inhibits growth hormone gh signal transduction in breast cancer cell lines
    Austin Journal of Obstetrics and Gynecology, 2018
    Co-Authors: Carole Verhoeven, H Coelingh J T Bennink, E P M Sprang, J S Liu, Ana Gracanin, J A Mol
    Abstract:

    Objective: Inhibition of GH signaling has been associated with increased longevity and cancer resistance. As the fetal estrogen Estetrol was also linked to longevity and cancer resistance, we hypothesized that these effects of Estetrol are mediated by inhibition of GH activity. Design: The CNMm-6TR mammary cell line, stably transfected with doxycycline (DOX)-inducible GHR (CNMm-cGHR cells), HEK293 cell line transfected with rGHR and the human T47D cell line were used to assess effects of Estetrol on GH signal transduction. Proliferation was measured using the colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay (MTT). Spi-luciferase reporter activity, responsive to phosphorylated Stat5, was used to assess GH signaling. GHR mRNA expression was normalized to a reference gene. Results: Treatment of CNMm-cGHR cells with GH resulted in decreased proliferation rates. No effect was seen by the co-inhibition with Estetrol. Using the spi-luc reporter activity, it was shown that GH activates the GHR/Jak2/ Stat5 pathway. Estetrol partially inhibited this activation. In the HEK-rGHR cells, Estetrol was able to inhibit the GH induced activation of the spi-luc reporter, but only in the presence of an ERα expression plasmid. Effects of Estetrol on the expression of GHR mRNA was assessed in T47D cells, a cell-line expressing ER, PR and GHR under natural promoters. After incubation with Estetrol, a mean 4-fold inhibition of GHR mRNA expression was observed. Conclusion: Using different cell systems, it was shown that Estetrol is able to inhibit GH signaling, a process dependent on the presence of the Estrogen Receptor (ER). Estetrol may therefore be used to inhibit GH-induced effects on breast cancer proliferation.

  • pharmacokinetics of the fetal estrogen Estetrol in a multiple rising dose study in postmenopausal women
    Climacteric, 2017
    Co-Authors: H Coelingh J T Bennink, Yvette Zimmerman, Carole Verhoeven, M Visser, J B Foidart, Kristina Gemzelldanielsson
    Abstract:

    Objectives: Estetrol (E4) is a natural fetal estrogen. In this open-label, multiple-rising-dose study, the pharmacokinetic effects of E4 in postmenopausal women were investigated as a secondary obj...

  • antiestrogenic effects of the natural fetal estrogen Estetrol e4 in women with estrogen receptor positive early breast cancer
    Journal of Clinical Oncology, 2011
    Co-Authors: C F Singer, C Natter, Stefan Steurer, Farid Moinfar, M Visser, Nicole Appels, E Kubista, H Coelingh J T Bennink
    Abstract:

    280 Background: Estetrol (E4) is a fetal estrogen which exerts estrogenic effects on vaginal epithelium, hot flushes and bone, but has estrogen-antagonistic effects on breast cancer cell lines in vitro and in the rat DMBA model. Therefore E4 may be suitable for Hormone Replacement Therapy (HRT) in women with breast cancer including women treated with aromatase inhibitors. Methods: We have investigated the effect of 14 days pre-operative treatment with 20 mg E4 per day on proliferation, apoptosis, ER-receptors and sex steroid levels in a prospective, randomised, double-blind, placebo-controlled, neo-adjuvant study in 15 pre- and 15 postmenopausal women with estrogen-receptor positive early breast cancer. Results: Estetrol induced a significant increase of SHBG, a significant decrease of FSH in postmenopausal women and no increase of gonadotrophins in premenopausal women. Estetrol had no effect on Ki67 expression and on apoptosis-related Bax and Bcl-2, but the apoptosis index in tumor tissue increased signi...

  • preventive effect of oral Estetrol in a menopausal hot flush model
    Climacteric, 2008
    Co-Authors: Christian Franz Holinka, Mark Brincat, H Coelingh J T Bennink
    Abstract:

    Objective To evaluate the efficacy of Estetrol (E4) in alleviating hot flushes in an experimental animal model considered representative for menopausal vasomotor symptoms.Methods Recording of the thermal responses in the tail skin of morphine-dependent ovariectomized rats after morphine withdrawal by administration of naloxone. Six groups of rats were treated orally for 8 days as follows: vehicle (negative) control; E4: 0.1, 0.3, 1.0 and 3.0 mg/kg/day; and, as active (positive) control, ethinylestradiol 0.3 mg/kg/day. On day 8, tail skin temperature was recorded at baseline and for 60 min at 5-min intervals following naloxone administration.Results In control animals, tail skin temperature increased sharply by about 4.5°C after naloxone treatment and reverted to baseline by 60 min. Estetrol suppressed the tail skin temperature increase in a dose-dependent fashion. The highest dose of E4 tested (3 mg/kg/day) was equipotent to a 10-fold lower dose of ethinylestradiol. Both fully suppressed tail skin tempera...

  • maternal and fetal Estetrol levels during pregnancy
    Climacteric, 2008
    Co-Authors: Coelingh F Bennink, Christian Franz Holinka, M Visser, H Coelingh J T Bennink
    Abstract:

    This Appendix summarizes available data of maternal and fetal Estetrol (E4) levels reported in the literature and obtained in a recent clinical study. The literature data were published mainly in t...

Carole Verhoeven - One of the best experts on this subject based on the ideXlab platform.

  • abstract p5 11 15 Estetrol for treatment of advanced er her2 breast cancer
    Cancer Research, 2020
    Co-Authors: Marcus Schmidt, Yvette Zimmerman, Carole Verhoeven, Hans Lenhard, Jan Krijgh, A Honig, K Almstedt, Marco Johannes Battista, Herjan Coelingh J T Bennink
    Abstract:

    Introduction: A high dose of the fetal estrogen Estetrol (E4) is anticipated to have anti-tumor effects in patients with advanced, anti-estrogen resistant, ER+/HER2- breast cancer (BC). It will most likely also improve patient’s quality of life by reducing symptoms of estrogen deficiency such as hot flushes, arthralgia, sleep disturbances, vaginal dryness, mood changes and depression, bone loss and fractures and cognition. The ABCE4 study is performed in Germany in this patient population. The main objectives of the study are to assess safety and tolerability of three doses of E4, to determine anti-tumor response and to evaluate estrogen deficiency symptoms. Study design: This is a multi-center, open-label, phase IB/IIA, dose-escalation study with a 3 + 3 cohort design, whereby successive cohorts of 3 patients receive 20 mg, 40 mg and 60 mg E4 per day by oral administration. Dose limiting toxicity (DLT), safety and wellbeing are evaluated after 4, 8 and 12 weeks of treatment. Occurrence of DLT at completion of phase IB after 4 weeks treatment determines escalation to the next higher dose. Objective anti-tumor effects are assessed by computer tomography scanning and evaluated according to RECIST criteria before and after 12 weeks of treatment. Thereafter treatment may continue based on an evaluation of the patient and her treating physician. In view of the small numbers required for this study design no statistical testing was performed. Results: A total of 12 postmenopausal women with progressive, heavily pre-treated advanced BC have been enrolled. Nine patients completed Phase IB. One patient in the 20 mg group discontinued the study during Phase IIA due to disease progression after 9,5 weeks of E4 treatment. She died 3 weeks later. Eight patients completed both the Phase IB and IIA part of the study. None of the patients experienced a DLT. All three E4 doses were well tolerated by all patients. In total 38 adverse events were reported. Adverse events were mainly of mild or moderate intensity. The following 8 events were considered possibly related to E4 treatment: increased endometrial thickness, spotting (2 patients), dry skin, pruritus, edema, fatigue (2 patients), alopecia and acid regurgitation. Seven events fulfilled the criteria of seriousness from which one was considered to be related to E4 treatment. This patient experienced moderate vaginal bleeding after 36 weeks treatment with 20 mg E4 and was hospitalized for hysteroscopy and endometrial ablation with full recovery thereafter. Importantly five of the eight patients who completed treatment with E4 reported subjective improvement and “felt much better” than before the start of E4 treatment. This was described by one of the patients as: ‘”feeling less down and exhausted; instead feeling much more optimistic, powerful and positive when taking E4”. Five patients completing 12 weeks E4 treatment showed objective anti-tumor effects with stable disease (n=4) and one remission. All five continued E4 treatment. Tumor assessment after 24 weeks of E4 treatment showed again stable disease in 4 patients. Conclusion: We conclude that daily doses of 20 mg, 40 mg and 60 mg E4 are well tolerated without DLTs. The majority of patients experienced favorable subjective effects and four patients treated for 24 weeks or longer showed stable disease and tumor remission respectively. Treatment with E4 meets the criteria for further investigation and development of E4 as a new drug for the treatment of anti-estrogen resistant advanced breast cancer. Final dose selection of E4 will take place in September 2019. Citation Format: Marcus Schmidt, Arnd Honig, Yvette Zimmerman, Carole Verhoeven, Katrin Almstedt, Marco Battista, Hans Georg Lenhard, Jan Krijgh, Herjan Coelingh Bennink. Estetrol for treatment of advanced ER+/HER2- breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-15.

  • abstract p4 13 12 Estetrol for treatment of advanced er breast cancer
    Cancer Research, 2019
    Co-Authors: M Schmidt, Carole Verhoeven, Hans Lenhard, Jan Krijgh, A Honig, K Almstedt, Marco Johannes Battista, Coelingh H Bennink
    Abstract:

    Introduction: Currently, a multi-center, open-label, phase I/IIA, dose-escalation study with the fetal estrogen Estetrol (E4) is ongoing in Germany in postmenopausal patients with advanced breast cancer (ABCE4 study). The objective of the study is to assess safety and tolerability of different doses of E4 (range 20-60 mg per day). In addition initial anti-tumor response will be determined. Study design: Patients are treated for 12 weeks with E4; 4 weeks in Phase I and thereafter 8 weeks in Phase IIA. Phase I of the study will follow the traditional 3 + 3 design to determine the optimal dose in patients with advanced breast cancer. Patients are treated in cohorts of three all receiving the same dose. Occurrence of dose limiting toxicity (DLT) at completion of phase I (4 weeks treatment) will determine escalation to the next higher dose in the study. After completion of Phase I, patients will continue treatment for 8 weeks to assess preliminary anti-tumor response in Phase IIA. Treatment may continue beyond 12 weeks based on evaluation of the patient and her treating physician. Results: Phase I of the first treatment cohort with 20 mg E4 per day has been completed. A total of six postmenopausal women with advanced breast cancer has been included in the first cohort. One patient withdrew consent before treatment with E4 started. She was replaced. Two patients discontinued the study before completion of Phase I for reasons other than DLTs. These patients were unevaluable for toxicity and were also replaced. Three patients completed Phase I. One patient discontinued the study during Phase IIA due to disease progression after 9,5 weeks of E4 treatment. One patient completed both the Phase I and IIA part of the study. She had stable disease at study completion and wanted to continue E4 treatment because of improved well-being. Tumor assessment after 24 weeks of E4 treatment showed again stable disease. One patient is presently in Phase IIA of the study. None of the patients experienced a DLT. The 20 mg E4 dose was well tolerated by all patients. In total 17 adverse events were reported. Adverse events were mainly of mild or moderate intensity. Five of 17 events fulfilled criteria of seriousness; none of these events were considered to be related to the E4 treatment. Four events were considered to be possibly related to the E4 treatment. These events were increased endometrial thickness, dry skin, pruritus and fatigue, all of mild intensity. A remarkable finding was that three of the five patients treated with E4 reported to the investigator to “feel better” than before the start of E4 treatment. This 9”feeling better” was described by one of the patients as: 9”feeling less down and exhausted; instead feeling much more optimistic, powerful and positive when taking E4”. So far anti-tumor response could be estimated in one patient. This patient, who started the study with progressive disease, had stable disease as shown by tumor assessments after 12 weeks and 24 weeks of E4 treatment. Conclusion: Based on these results, we conclude that a daily dose of 20 mg E4 is well tolerated. The majority of patients experienced favorable subjective effects on wellbeing. The data obtained with the 20 mg dose E4 allow dose escalation to the next higher dose of 40 mg E4 per day. Citation Format: Schmidt M, Honig A, Verhoeven C, Almstedt K, Battista M, Lenhard HG, Krijgh J, Coelingh Bennink H. Estetrol for treatment of advanced ER+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-12.

  • Pro-Apoptotic Effects of Estetrol on Long-Term Estrogen-Deprived Breast Cancer Cells and at Low Doses on Hormone-Sensitive Cells
    SAGE Publishing, 2019
    Co-Authors: Wei Yue, Carole Verhoeven, Herjan Coelingh Bernnink, Ji-ping Wang, Richard J Santen
    Abstract:

    Purpose: Postmenopausal women with estrogen receptor-positive breast cancers often respond initially to tamoxifen or aromatase inhibitor therapy. Resistance to these treatments usually develops within 12 to 18 months. Clinical studies have demonstrated that high-dose estrogen can induce regression of these endocrine-resistant tumors. However, side-effects of high-dose estradiol (E 2 ) or diethylstilbestrol (DES) limit their usage. Estetrol (E 4 ) is the most abundant estrogen during pregnancy and has a long half-life and a low potential for side-effects. Estetrol might then provide benefits similar to DES on tumor regression but with lesser toxicity. Methods: In this study, we systematically evaluated the effects of E 4 on cell proliferation and apoptosis in wild-type MCF-7 and long-term estrogen-deprived (LTED) MCF-7 cells and compared its effects with E 2 and estriol (E 3 ). Results: Estetrol induced apoptosis in LTED cells but stimulated growth of MCF-7 cells at concentrations from 10 −11 to 10 −8 M. These effects of E 4 are similar to those of E 2 but require much higher doses. Differing from E 2 , E 4 at 10 −12 M induced apoptosis in MCF-7 cells and another pregnancy estrogen, E 3 , acted similarly. No antagonistic effect of E 4 or E 3 against E 2 occurred when they were combined. Conclusions: The pro-apoptotic effects of E 4 and E 3 on LTED cells and at low doses on MCF-7 cells indicate that these steroids could be used as therapeutic agents for endocrine-resistant or sensitive breast cancer

  • E4_paper_suppl_figs_xyz1348068aa41d3_(1) – Supplemental material for Pro-Apoptotic Effects of Estetrol on Long-Term Estrogen-Deprived Breast Cancer Cells and at Low Doses on Hormone-Sensitive Cells
    2019
    Co-Authors: Wei Yue, Carole Verhoeven, Herjan Coelingh Bernnink, Ji-ping Wang, Richard J Santen
    Abstract:

    Supplemental material, E4_paper_suppl_figs_xyz1348068aa41d3_(1) for Pro-Apoptotic Effects of Estetrol on Long-Term Estrogen-Deprived Breast Cancer Cells and at Low Doses on Hormone-Sensitive Cells by Wei Yue, Carole Verhoeven, Herjan Coelingh Bernnink, Ji-ping Wang and Richard J Santen in Breast Cancer: Basic and Clinical Research

  • fetal Estetrol e4 inhibits growth hormone gh signal transduction in breast cancer cell lines
    Austin Journal of Obstetrics and Gynecology, 2018
    Co-Authors: Carole Verhoeven, H Coelingh J T Bennink, E P M Sprang, J S Liu, Ana Gracanin, J A Mol
    Abstract:

    Objective: Inhibition of GH signaling has been associated with increased longevity and cancer resistance. As the fetal estrogen Estetrol was also linked to longevity and cancer resistance, we hypothesized that these effects of Estetrol are mediated by inhibition of GH activity. Design: The CNMm-6TR mammary cell line, stably transfected with doxycycline (DOX)-inducible GHR (CNMm-cGHR cells), HEK293 cell line transfected with rGHR and the human T47D cell line were used to assess effects of Estetrol on GH signal transduction. Proliferation was measured using the colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay (MTT). Spi-luciferase reporter activity, responsive to phosphorylated Stat5, was used to assess GH signaling. GHR mRNA expression was normalized to a reference gene. Results: Treatment of CNMm-cGHR cells with GH resulted in decreased proliferation rates. No effect was seen by the co-inhibition with Estetrol. Using the spi-luc reporter activity, it was shown that GH activates the GHR/Jak2/ Stat5 pathway. Estetrol partially inhibited this activation. In the HEK-rGHR cells, Estetrol was able to inhibit the GH induced activation of the spi-luc reporter, but only in the presence of an ERα expression plasmid. Effects of Estetrol on the expression of GHR mRNA was assessed in T47D cells, a cell-line expressing ER, PR and GHR under natural promoters. After incubation with Estetrol, a mean 4-fold inhibition of GHR mRNA expression was observed. Conclusion: Using different cell systems, it was shown that Estetrol is able to inhibit GH signaling, a process dependent on the presence of the Estrogen Receptor (ER). Estetrol may therefore be used to inhibit GH-induced effects on breast cancer proliferation.

Ekaterine Tskitishvili - One of the best experts on this subject based on the ideXlab platform.

  • Estetrol and its effects on the damaged brain
    2019
    Co-Authors: Ekaterine Tskitishvili, Jeanmichel Foidart
    Abstract:

    Estrogens play an important role not only in the reproductive system but in the central nervous system as well. Major events of ontogenesis that occur earlier in pregnancy are connected to the formation of estrogen receptors and expression of estrogens leading to the normal physiological development of the central nervous system, though development of the brain by itself is a complex process and lasts during the whole pregnancy. Estetrol (E4) is a recently described natural estrogen with four hydroxyl groups that is synthesized exclusively during pregnancy by the human fetal liver. Its role in the central nervous system is not fully understood. Our studies showed for the first time and proved impressive antioxidative effects of E4 in vitro and proved its tremendous neuroprotective, promyelinating, neurogenic, and cerebro-angiogenic properties in vivo. E4 decreases brain damage markers (S100B and GFAP) in blood assuming that E4 attenuates neonatal hypoxic-ischemic encephalopathy in vivo. We have also shown that the combined use of E4 with other steroids does not have any priority over the single use of E4. E4’s antioxidative actions mostly depend on ERα and ERβ, whereas neurogenesis and possibly promyelinating activities might be realized through ERβ. Taken together our studies suggest importance of E4 treatment possibly not only in neonates but in adults with different neurological diseases like that opening new directions for the use of E4 in clinical practice in neurological diseases.

  • unique vascular benefits of Estetrol a native fetal estrogen with specific actions in tissues nest
    2019
    Co-Authors: Jeanmichel Foidart, Pierre Gourdy, Anne Gallez, Christel Péqueux, Ekaterine Tskitishvili, U Gaspard, Maud Jost, Valerie Gordenne, Mariec Valera, Coralie Fontaine
    Abstract:

    Estrogens (E), in oral contraceptives (COCs) and hormone replacement therapy (HRT) drugs used for the relief of climacteric symptoms of menopause, increase the synthesis of clotting factors, decrease the levels of coagulation inhibitors, and increase the risk of venous thromboembolic events (VTE). Ischemic stroke incidence in postmenopausal women during HRT use is also increased and is probably due to a thrombotic event. This suggests that a safer estrogen may reduce stroke and VTE incidence, with lower impact on hemostasis.

  • estrogen receptors and Estetrol dependent neuroprotective actions a pilot study
    Journal of Endocrinology, 2017
    Co-Authors: Ekaterine Tskitishvili, Christel Péqueux, Michelle Nisolle, Carine Munaut, Agnes Noel, Renaud Viellevoye, Jeanmichel Foidart
    Abstract:

    Estetrol (E4) has strong antioxidative, neurogenic and angiogenic effects in neural system resulting in the attenuation of neonatal hypoxic-ischemic encephalopathy. We aimed to define the role of estrogen receptors in E4-dependent actions in neuronal cell cultures and prove the promyelinating effect of E4. In vitro the antioxidative and cell survival/proliferating effects of E4 on H2O2-induced oxidative stress in primary hippocampal cell cultures were studied using different combinations of specific inhibitors for ERα (MPP dihydrochloride), ERβ (PHTTP), GPR30 (G15) and palmytoilation (2-BR). LDH activity and cell survival assays were performed. In vivo the promyelinating role of different concentrations of E4 (1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 50 mg/kg/day) was investigated using the hypoxic-ischemic brain damage model in the 7-day-old immature rats before/after the induction of hypoxic-ischemic insult. Myelin basic protein (MBP) immunostaining was performed on brain coronal sections. Our results show that LDH activity is significantly upregulated in cell cultures where the E4's effect was completely blocked by concomitant treatment either with ERα and ERβ inhibitors (MPP and PHTPP, respectively), or ERα and ERβ inhibitors combined with 2-BR. Cell survival is significantly downregulated in cell cultures where the effect of E4 was blocked by ERβ inhibitor (PHTTP) alone. The blockage of GRP30 receptor did affect neither LDH activity nor cell survival. MBP immunostaining is significantly upregulated in E4-pretreated groups at a concentration of 5 mg/kg/day and 50 mg/kg/day E4, whereas the MBP-positive area OD ratio is significantly increased in all the E4-treated groups. E4's antioxidative actions mostly depend on ERα and ERβ, whereas neurogenesis and possibly promyelinating activities might be realized through ERβ.

  • use of Estetrol with other steroids for attenuation of neonatal hypoxic ischemic brain injury to combine or not to combine
    Oncotarget, 2016
    Co-Authors: Ekaterine Tskitishvili, Christel Péqueux, Michelle Nisolle, Carine Munaut, Agnes Noel, Renaud Viellevoye, Jeanmichel Foidart
    Abstract:

    // Ekaterine Tskitishvili 1 , Christel Pequeux 1 , Carine Munaut 1 , Renaud Viellevoye 2 , Michelle Nisolle 3 , Agnes Noel 1 and Jean-Michel Foidart 1 1 Laboratory of Development Biology and Tumor, GIGA-Cancer, Department of Obstetrics and Gynecology/Department of Clinical Sciences, University of Liege, Liege 1, Belgium 2 Neonatal Intensive Care Unit, Department of Pediatrics, University of Liege, Liege 1, Belgium 3 Department of Obstetrics and Gynecology, University of Liege, Liege1, Belgium Correspondence to: Ekaterine Tskitishvili, email: // Keywords : neonatal hypoxic-ischemic encephalopathy, hippocampus, cortex, Estetrol, estradiol, Pathology Section Received : March 16, 2016 Accepted : May 17, 2016 Published : May 25, 2016 Abstract Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal hypoxic-ischemic encephalopathy (HIE). In vitro the effect of E4 combined with other steroids on oxidative stress and the cell viability in primary hippocampal cultures was evaluated by lactate dehydrogenase and cell survival assays. In vivo neuroprotective and therapeutic efficacy of E4 combined with other steroids was studied in HIE model of immature rats. The rat pups rectal temperature, body and brain weights were evaluated.The hippocampus and the cortex were investigated by histo/immunohistochemistry: intact cell number counting, expressions of markers for early gray matter lose, neuro- and angiogenesis were studied. Glial fibrillary acidic protein was evaluated by ELISA in blood samples. In vitro E4 and combinations of high doses of E4 with P4 and/or E2 significantly diminished the LDH activity and upregulated the cell survival. In vivo pretreatment or treatment by different combinations of E4 with other steroids had unalike effects on body and brain weight, neuro- and angiogenesis, and GFAP expression in blood. The combined use of E4 with other steroids has no benefit over the single use of E4.

  • combined estrogenic and anti estrogenic properties of Estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms
    Oncotarget, 2015
    Co-Authors: Celine Gerard, Francoise Lenfant, Jean-françois Arnal, Ekaterine Tskitishvili, Agnes Noel, Melanie Mestdagt, Laudine Communal, Anne Gompel, Elisabete Silva, Jeanmichel Foidart
    Abstract:

    // Celine Gerard 1 , Melanie Mestdagt 1 , Ekaterine Tskitishvili 1 , Laudine Communal 2 , Anne Gompel 2,3 , Elisabete Silva 4 , Jean-Francois Arnal 5 , Francoise Lenfant 5 , Agnes Noel 1 , Jean-Michel Foidart 1 and Christel Pequeux 1 1 Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liege, Liege, Belgium 2 Gynaecological Endocrinology Unit, Paris Descartes University, Hopitaux Universitaires, Paris, France 3 INSERM U 938, UPMC, Paris 4 Institute of Environment, Health and Societies, Brunel University London, UB83PH Uxbridge, United Kingdom 5 INSERM U1048, Institut des Maladies Metaboliques et Cardiovasculaires, University of Toulouse, UPS, Toulouse, France Correspondence to: Christel Pequeux, email: // Keywords : Estetrol, menopause, breast cancer, estrogen receptor, SERM Received : March 03, 2015 Accepted : May 02, 2015 Published : May 19, 2015 Abstract Increased risk of breast cancer is a critical side effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a promising compound for clinical use in MHT. However, its impact on breast cancer is controversial and poorly defined. In this preclinical study, we show that E4 acts as a weak estrogen by stimulating the growth of hormone-dependent breast cancer only at concentrations exceeding menopausal therapeutic needs. E4 presents also an antitumor activity by decreasing the strong proliferative effect of estradiol (E2). While estrogen receptor alpha (ERα) is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extra-nuclear signaling pathway are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. Altogether, our results highlight that E4 has a limited impact on breast cancer and may offer a safe therapeutic window for the treatment of menopausal symptoms.