Fetal Estrogen Estetrol Research Articles

Estetrol Inhibits the Prostate Cancer Tumor Stimulators FSH and IGF-1

Background: The co-treatment of androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) with the fetal estrogen estetrol (E4) may further inhibit endocrine PCa tumor stimulators. We previously reported the suppression of follicle-stimulating hormone (FSH), total and free testosterone, and prostate-specific antigen by ADT+E4. Here, we provide more detailed data on FSH suppression by E4 and present new findings on the effect of ADT+E4 on insulin-like growth factor-1 (IGF-1). Methods: A Phase II, double-blind, randomized, placebo-controlled study (the PCombi study) was conducted in advanced PCa patients treated with ADT. The study assessed the effect of E4 co-treatment with LHRH agonist ADT on tumor stimulators, including FSH and IGF-1. Patients starting ADT were randomized 2:1 to receive either 40 mg E4 (n = 41) or placebo (n = 21) for 24 weeks. Non-parametric analyses were performed on the per-protocol population (PP) and individual changes were visualized. Results: The PP included 57 patients (37 ADT+E4; 20 ADT+placebo). ADT+E4 almost completely suppressed FSH in all patients (98% versus 37%; p < 0.0001). IGF-1 levels decreased by 41% with ADT+E4 versus an increase of 10% with ADT+placebo (p < 0.0001). Conclusions: The almost complete suppression of the tumor stimulator FSH using ADT plus E4 observed in all individual patients in this study, along with the augmented suppression of IGF-1 versus an increase by ADT only, may be clinically relevant and suggest the enhanced anti-cancer treatment efficacy of E4 in addition to the previously reported additional suppression of total and free T and PSA.

The Loss of Estradiol by Androgen Deprivation in Prostate Cancer Patients Shows the Importance of Estrogens in Males.

The role of estradiol (E2; an estrogen) in men needs to be more appreciated. In this review, we address the clinical situations that allow the study of the clinical consequences of E2 deficiency in men and discuss the effects of restoration of levels of this reproductive steroid hormone. In men with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT), E2 is suppressed along with testosterone, leading to side effects affecting the quality of life. These include hot flashes, arthralgia, fatigue, mood changes, cognition problems, weight gain, bone loss, and increased risk of cardiovascular disease. Transdermal E2 alone for ADT has shown equivalent testosterone suppression compared to gonadotropin-releasing hormone (GnRH) agonists while also preventing estrogen-deficiency side effects, including hot flashes and bone loss. Co-treatment of ADT with fetal estrogen estetrol (E4) has shown significant improvements of estrogen-deficiency symptoms. These observations emphasize the need to raise awareness of the importance of estrogens in men among clinicians and the lay public.

Estetrol Prevents Hot Flushes and Improves Quality of Life in Patients with Advanced Prostate Cancer Treated with Androgen Deprivation Therapy: The PCombi Study

BackgroundAndrogen deprivation therapy (ADT) for prostate cancer (PCa) is accompanied by side effects affecting health-related quality of life (HRQL). ObjectiveTo assess the effects of the fetal estrogen estetrol (E4) on symptoms related to estrogen and androgen deficiency, and on HRQL measured using the validated Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Design, setting, and participantsThis was a phase 2, double-blind, randomized, placebo-controlled study in patients with advanced PCa. InterventionPatients receiving ADT were randomly assigned at a 2:1 ratio to daily treatment with a high dose of E4 (HDE4; n = 41) or placebo (n = 21) for 24 wk. Outcome measurements and statistical analysisThe primary outcome was the effect of HDE4 cotreatment on hot flushes (HFs). Secondary outcomes were the Q-Man questionnaire for evaluation of the effect on estrogen and androgen deficiency symptoms, and the FACT-P questionnaire for evaluating HRQL. Results and limitationsAt 24 wk, the number of patients experiencing HFs was significantly lower in the HDE4 group than in the placebo group (14.3% vs 60.0%; p < 0.001). HDE4 treatment was associated with lower incidence of night sweats, arthralgia, and fatigue, but more nipple tenderness and gynecomastia. At 24 wk, the mean HRQL score favored HDE4 over placebo for the FACT-P total score (122.2 ± 12.3 vs 118.7 ± 19.7) and for several other FACT subscales. ConclusionsDaily HDE4 coadministration almost completely prevented HFs in patients with advanced PCa treated with ADT. HDE4 also had positive effects on HRQL and counteracted other estrogen deficiency symptoms caused by ADT. These data support the dual efficacy concept of ADT and HDE4 to improve HRQL and increase the antitumor effect of ADT. Patient summaryFor patients on androgen deprivation therapy for advanced prostate cancer, cotreatment with a high dose of estetrol almost completely prevents the occurrence of hot flushes and improves quality of life and well-being, but nipple sensitivity and an increase in breast size may occur.

Tumor suppression, dose-limiting toxicity and wellbeing with the fetal estrogen estetrol in patients with advanced breast cancer

PurposeThe 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.MethodsThis 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.ResultsAll 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.ConclusionHigh 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.

Abstract P5-11-15: Estetrol for treatment of advanced ER+/HER2- breast cancer

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 Hönig, 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

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 '”feeling better” was described by one of the patients as: '”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, Hönig 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.

Fetal Estetrol (E4) Inhibits Growth Hormone (GH) Signal Transduction in Breast Cancer Cell Lines

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.

Abstract OT1-04-01: Estetrol for treatment of advanced ER+ breast cancer

Abstract Background information Estrogen therapy was the endocrine treatment of choice in postmenopausal women with advanced breast cancer for several decades since 1944. In the 1970s, estrogen therapy was replaced by tamoxifen. Tamoxifen showed similar regression rates but less toxicity as compared to estrogen therapy and was therefore considered preferred. Recently, estrogen therapy has gained new interest as several clinical studies showed clinical benefit in heavily pre-treated patients with advanced breast cancer after long-term estrogen deprivation. Estrogen therapy is an effective treatment for breast cancer but it has a negative safety reputation, especially related to the cardiovascular (CV) system. The fetal estrogen estetrol (E4) might be a new treatment option for patients with advanced breast cancer. It has less interference with liver function and is expected to be less harmful for the CV system compared to other estrogens whereas data from non-clinical and clinical studies suggest anti-tumor effects of E4 in breast tumors. Hypothesis The fetal estrogen E4 may have anti-tumor effects in patients with advanced ER+ breast cancer. It will most likely also reduce symptoms and signs of estrogen deficiency such as hot flushes, arthralgia, sleep disturbances, bone loss and cognition and improve patient's quality of life. Trial design and methods This is a multi-center, open-label, phase I/IIa, dose-escalation study with a 3 + 3 cohort design to determine the recommended dose of E4 for the treatment of patients with advanced breast cancer. Cohorts of at least 3 patients will receive doses of 20 mg, 40 mg and 60 mg E4 respectively, until the non-tolerable dose is determined or the maximum dose of 60 mg is reached. Patients will be treated once daily by oral administration for 12 weeks. In total 9-18 patients with advanced ER+ breast cancer will be enrolled at three centers in Germany. Objectives The main objectives of this study are to evaluate the safety, the effects on estrogen deficiency symptoms and the preliminary anti-tumor activity of E4 in patients with advanced breast cancer. Eligibility criteria Women who are more than 5 years postmenopausal, with ER+ and HER2-negative locally advanced and/or metastatic breast cancer are eligible for inclusion. In addition, patients should have failed on anti-estrogen treatment with tamoxifen and aromatase inhibitors. Patients with a history of venous or arterial thromboembolic disease or a known defect in the blood coagulation system will be excluded as well as patients who have used treatment with fulvestrant within 6 months prior to start of E4 treatment. Statistical methods Statistical tests used in this study are exploratory only. No confirmatory statistical test procedure is envisaged. Contact information For further information regarding the study, please contact Dr Carole Verhoeven (cv@pantarheibio.com). Citation Format: Verhoeven C, Schmidt M, Hönig A, Dünnebacke J, Dutman E, Krijgh J, Coelingh Bennink H. Estetrol for treatment of advanced ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-04-01.

Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study

Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated. This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2 V) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40 mg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers. Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2 V control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent. In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10 mg estetrol were similar to the study comparator 2 mg estradiol valerate.

210 - The effects of the human fetal estrogen estetrol (E4) in healthy men to estimate its potential use for the treatment of prostate cancer

210 - The effects of the human fetal estrogen estetrol (E4) in healthy men to estimate its potential use for the treatment of prostate cancer

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

ObjectiveEstetrol (E4) is a natural fetal estrogen. The safety of increasing doses of E4 and its preliminary effects on the vagina, endometrium and menopausal vasomotor symptoms were investigated. Study designThis was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Subjects with an intact uterus were randomized to receive either 2mg E4 or 2mg estradiol-valerate (E2V) for 28days. Subsequent dose-escalation groups (non-randomized) were: 10mg E4 (intact uterus and ≥35 hot flushes/week); and 20mg and 40mg E4 (hysterectomized subjects). Main outcome measureAdverse events (AEs) and vaginal cytology were evaluated in all treatment groups; hot flushes/sweating and endometrial proliferation were analyzed with 2 and 10mg E4 and 2mg E2V. ResultsEstetrol appeared to be safe, without serious drug-related AEs. In all the groups there was a clear shift from parabasal to superficial vaginal cells, indicating an estrogenic effect and a potential for the treatment of vulvovaginal atrophy. The endometrial thickness remained stable in the 2mg E4 group and increased with E2V and 10mg E4. A decrease in the mean number of hot flushes and sweating was seen with 2 and 10mg E4 and 2mg E2V. ConclusionsEstetrol in a dose range of 2–40mg per day improved vaginal cytology and vasomotor symptoms in postmenopausal women. Endometrial proliferation occurred with the 10mg dose. Estetrol seems a safe and suitable candidate to develop further for hormone therapy.

Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer.

Estetrol (E4) is a fetal estrogen with estrogenic effects on reproductive organs and bone in preclinical models and in postmenopausal women. However, E4 exerts antiestrogenic effects on breast cancer (BC) cell growth in vitro and in vivo. We have investigated the effect of 14 days preoperative treatment with 20mg E4 per day on tumor proliferation markers, sex steroid receptor expression and endocrine parameters in a prospective, randomized, placebo-controlled, preoperative window trial in 30 pre- and post-menopausal women with estrogen-receptor positive early BC. E4 had a significant pro-apoptotic effect on tumor tissue, whereas Ki67 expression remained unchanged in both pre- and post-menopausal women. E4 increased sex-hormone-binding globulin significantly thereby reducing the concentrations of bioavailable estradiol. Follicle-stimulating hormone levels decreased in postmenopausal women only and luteinizing hormone levels remained unchanged. Systemic insulin growth factor-1 levels decreased significantly. Intratumoral epithelial ERα expression decreased significantly and a trend was found towards an increased expression of ERβ. This clinical data support the preclinical findings that E4 has antiestrogenic effects on BC cells, whereas earlier studies have shown that E4 has estrogenic effects on reproductive tissues and bone. Further clinical studies seem acceptable and are needed to confirm the safety and efficacy of E4 for the breast in hormone replacement therapy, including hormone replacement therapy in women who have or have had BC, especially in those BC patients treated with aromatase inhibitors and suffering from serious complaints due to estrogen deficiency.

297 Efficacy and Safety of Fetal Human Estrogen Estetrol (E4) in Women with Estrogen-receptor Positive Early Breast Cancer

297 Efficacy and Safety of Fetal Human Estrogen Estetrol (E4) in Women with Estrogen-receptor Positive Early Breast Cancer

P4-02-02: The Natural Fetal Estrogen Estetrol (E4), Causes Anti-Estrogenic Effects in Women with Endocrine-Responsive Positive Early Breast Cancer.

Abstract Background: Estetrol (E4) is a natural fetal estrogen which exerts estrogenic effects on reproductive organs and on the bone, and effectively reduces menopausal smyptoms. In contrast to other estrogens, however, E4 has estrogen-antagonistic effects on breast cancer cell lines in vitro and in the rat DMBA model, which would make it a suitable Hormone Replacement Therapy (HRT) in breast cancer patients, particularly in women who are being treated with aromatase inhibitors. Patients and Methods: We have investigated the effect of 14 days preoperative treatment with 20 mg E4 per day on tumor proliferation, apoptosis, ER-receptors, PgR receptor and several endocrine parameters in a prospective, randomised, double-blind, placebo-controlled, neo-adjuvant study in 15 pre- and 14 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 significantly. Systemic IGF-1 levels decreased significantly. Surprisingly the intratumoral epithelial ER-alpha expression decreased significantly, whereas the ER-beta expression showed a trend to increase. Conclusion: Our data suggest that E4 may be suitable and safe for HRT in women with spontaneous or induced menopausal symptoms, since apoptosis increases, IGF-1 decreases and no unfavourable effects are observed on Ki67, Bax and Bcl-2. The decrease of ER-alpha and the increase of ER-beta suggest a mechanism of action, explaining why the natural fetal estrogen E4 has estrogen-antagonistic effects on breast cancer tissue. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-02.

Clinical applications for estetrol

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 symptoms), contraception, osteoporosis and breast cancer.