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See detailEsterification of vertebrate like steroids in molluscs: A target of endocrine disruptors?
Giusti, Arnaud ULg; Joaquim-Justo, Célia ULg

in Comparative Biochemistry and Physiology. C : Comparative Pharmacology and Toxicology (2013), 158(4), 187-198

Alterations of the reproductive organs of gastropod molluscs exposed to pollutants have been reported in natural populations for more than 40 years. In some cases these impacts have been linked to ... [more ▼]

Alterations of the reproductive organs of gastropod molluscs exposed to pollutants have been reported in natural populations for more than 40 years. In some cases these impacts have been linked to exposure to endocrine disrupting chemicals (EDCs), which are known to induce adverse impacts on vertebrates, mainly by direct binding to steroid receptors or by altering hormone synthesis. Investigations on the mechanisms of action of endocrine disruptors in molluscs show that EDCs induce modifications of endogenous titres of androgens (e.g., testosterone, androstenedione) and oestrogens (e.g., 17ß-oestradiol). Alterations of the activity of enzymes related to steroid metabolism (i.e., cytochrome P450 aromatase, acyltransferases) are also often observed. In bivalves and gastropods, fatty acid esterification of steroids might constitute the major regulation of androgen and oestrogen homeostasis. The present review indicates that metabolism of steroid hormones to fatty acid esters might be a target of synthetic EDCs. Alterations of this process would impact the concentrations of free, potentially bioactive, form of steroids. [less ▲]

Detailed reference viewed: 27 (4 ULg)
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See detailLes esters de l’acide 6-(acétoxyméthyl)-2-oxo-2H-1-benzopyrane-3-carboxylique en tant qu’agents antiinvasifs potentiels dans le traitement du cancer
Kempen, I.; Pochet, L.; Doucet, C. et al

Conference (2000, January 28)

Detailed reference viewed: 6 (2 ULg)
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See detailEstetrol : a new natural estrogen providing a safe therapeutic window for the treatment of menopause
Gérard, Céline ULg; Gallez, Anne ULg; Silva, Elisabete et al

Poster (2015, November 14)

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would ... [more ▼]

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would provide useful advances for patient care. Estetrol (E4) is a liver friendly promising candidate for HRT. In preclinical and/or clinical studies, E4 has been effective against the main symptoms of menopause from a starting dose of 0.3 mg/kg/day. The aim of this study was to define the impact of E4 on mammary gland and breast cancer development. Our preclinical data show that E4 is less efficient than estradiol (E2) to induce mammary gland growth. Treatment with several concentrations of E4 has shown that E4 did not increase tumor development, when it is used at 0.3 mg/kg/day. However, at 3 mg/kg/day, E4 increased tumor growth similarly to E2 (0.08 mg/kg/day). E4 presents also some anti-estrogenic effects on mammary gland and antitumor activity on breast cancer by decreasing the strong proliferative effect of E2. While 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 pathways 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. In conclusion, our results support that E4, if it is used in strictly controlled clinical applications, could have no or only limited impact on breast and breast cancer. [less ▲]

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See detailESTETROL AND ITS NEUROPROTECTIVE EFFECT IN NEONATAL HYPOXIC-ISCHEMIC ENCEPHALOPATHY
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

in The 12th World Congress of Perinatal Medicine, Madrid, 3-6 November 2015 (2015)

Perinatal hypoxic-ischemic encephalopathy (HIE) occurs in 1-8 cases per live 1000 births. Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes ... [more ▼]

Perinatal hypoxic-ischemic encephalopathy (HIE) occurs in 1-8 cases per live 1000 births. Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes of neonatal HIE accompanied by gray and white matter injuries occurring in neonates. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities. So far no medical treatment provides important neuroprotection against HIE. Studies of new neuroprotective agents in animal models of HIE may provide important information pertinent to the development of treatments for this pathological condition. Estetrol (E4) is a recently described estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. In this study, in vitro we defined antioxidative effect of E4 on primary hippocampal cell cultures, taken from newborn rat pups, before/after induction of oxidative stress. To examine oxidative stress and cell viability, lactate dehydrogenase (LDH) activity and cell survival (MTS) assays were performed on primary neuronal cell cultures. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal HIE model of 7-day-old newborn rat pups was used. Rat pups body temperatures were examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for neuronal cell viability (microtubule-associated protein-2 (MAP-2)), neurogenesis (doublecortin (DCX)) and angiogenesis (vascular-endothelial growth factor (VEGF)) were evaluated by histo- and immunohistochemistry. The serum levels of brain damage markers (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Our results demonstrate for the first time that E4 has a significant neuroprotective and therapeutic effects. Also, E4 has powerful antioxidative and cell survival properties in vitro. It decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo. Estetrol treatment has no effects on body weight, brain weight or body temperature. Taken together, E4 might become an important safe and physiological substance to treat neonatal HIE. [less ▲]

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See detailEstetrol and neuroprotection against perinatal ischemic insult
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

in Estetrol attenuates neonatal hypoxic-ischemic brain injury (2014)

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See detailEstetrol Attenuates Neonatal Hypoxic-Ischemic Encephalopathy: Preclinical Studies
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

Poster (2016, June 17)

Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes of neonatal hypoxic-ischemic encephalopathy (HIE) accompanied by gray and white matter ... [more ▼]

Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes of neonatal hypoxic-ischemic encephalopathy (HIE) accompanied by gray and white matter injuries occurring in neonates. Perinatal HIE still remains a challenge in perinatal medicine. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities. So far no medical treatment provides important neuroprotection against HIE. Studies of new neuroprotective agents in animal models of HIE may have importance for the development of new compounds and treatment strategies for this pathological condition. Estetrol (E4) is a recently described estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal HIE model of 7-day-old newborn rat pups was used. Rat pups body temperatures were examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for neuronal cell viability (microtubule-associated protein-2 (MAP-2)), neurogenesis (doublecortin (DCX)) and angiogenesis (vascular-endothelial growth factor (VEGF)) were evaluated by histo- and immunohistochemistry. The serum levels of brain damage markers (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Our results demonstrate for the first time that E4 has a significant neuroprotective and therapeutic effects. It decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo. Estetrol treatment has no effects on body weight, brain weight or body temperature. Taken together, E4 might become an important safe and physiological substance to treat neonatal HIE. [less ▲]

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See detailEstetrol attenuates neonatal hypoxic–ischemic brain injury
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Munaut, Carine ULg et al

in Experimental Neurology (2014), 261

Estetrol (E4) is a recently described natural estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. The aim ... [more ▼]

Estetrol (E4) is a recently described natural estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. The aim of the present study was to define the importance of E4 in the attenuation of neonatal hypoxic-ischemic encephalopathy. Antioxidative effect of 650μM, 3.25mM and 6.5mM E4 on primary hippocampal cell cultures was studied before/after H202-induced oxidative stress. To examine oxidative stress and cell viability, lactate dehydrogenase activity and cell proliferation colorimetric assays were performed. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal hypoxic-ischemic encephalopathy model of 7-day-old newborn rat pups was used. The neuroprotective and therapeutic effects of estetrol before/after hypoxic-ischemic insult was studied in 1mg/kg/day, 5mg/kg/day, 10mg/kg/day, 50mg/kg/day E4 pretreated/treated groups and compared with the sham and the vehicle treated groups. The body temperature of the rat pups was examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of microtubule-associated protein-2, doublecortin and vascular-endothelial growth factor were evaluated by histo- and immunohistochemistry. ELISAs were performed on blood samples to detect concentrations of S100B and glial fibrillary acidic protein as brain damage markers. This work reveals for the first time that E4 significantly decreases LDH activity and enhances cell proliferation in primary hippocampal neuronal cell cultures in vitro, and decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo. [less ▲]

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See detailEstetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation.
Gérard, Céline ULg; Blacher, Silvia ULg; Communal, Laudine et al

in Journal of Endocrinology (2015), 224(1), 86-95

Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol (EE) and estradiol (E2), E4 ... [more ▼]

Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol (EE) and estradiol (E2), E4 has a minimal impact on liver cells activity and could provide a better safety profile in contraception or hormone therapy. The aim of this study was to delineate if E4 exhibits an activity profile distinct from that of E2 on mammary gland. Compared to E2, E4 acted as a low affinity estrogen in both, human in vitro and murine in vivo, models. E4 was 100 times less potent than E2 to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary gland in vitro and in vivo, respectively. This effect was prevented by fulvestrant and by tamoxifen supporting the notion that ERalpha is the main mediator of the estrogenic effect of E4 on the breast. Interestingly, when E4 was administered along with E2, it significantly antagonized the strong stimulatory effect of E2 on HBE cells proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E4 on mammary gland. Our results highlight that E4 is less potent than E2 and exhibits antagonistic properties towards the proliferative effect of E2 on breast epithelial cells. These data support E4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation. [less ▲]

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See detailEstetrol, a natural SERM exhibiting combined estrogenic and anti-estrogenic properties on mammary gland and breast cancer
Gallez, Anne ULg; Gérard, Céline ULg; BLACHER, Silvia ULg et al

Poster (2016, May 30)

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would ... [more ▼]

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would provide useful advances for patient care. Estetrol (E4) is a liver friendly promising candidate for HRT. In preclinical and/or clinical studies, E4 has been effective against the main symptoms of menopause from a starting dose of 0.3 mg/kg/day. The aim of this study was to define the impact of E4 on mammary gland and breast cancer development. Our preclinical data show that E4 is less efficient than estradiol (E2) to induce mammary gland growth. Treatment with several concentrations of E4 has shown that E4 did not increase tumor development, when it is used at 0.3 mg/kg/day. However, at 3 mg/kg/day, E4 increased tumor growth similarly to E2 (0.08 mg/kg/day). E4 presents also some anti-estrogenic effects on mammary gland and antitumor activity on breast cancer by decreasing the strong proliferative effect of E2. While 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 pathways 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. In conclusion, our results support that E4, if it is used in strictly controlled clinical applications, could have no or only limited impact on breast and breast cancer. [less ▲]

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See detailEstetrol, a natural SERM exhibiting combined estrogenic and antiestrogenic properties on mammary gland and breast cancer
Gérard, Céline ULg; Gallez, Anne ULg; BLACHER, Silvia ULg et al

Conference (2016, May 09)

The increased risk of breast cancer and thromboembolism in women who take Hormone Replacement Therapy (HRT) currently is a major public health problem. The discovery of novel molecules with better safety ... [more ▼]

The increased risk of breast cancer and thromboembolism in women who take Hormone Replacement Therapy (HRT) currently is a major public health problem. The discovery of novel molecules with better safety profile would provide useful advances for patient care. Estretrol (E4) appears as a promising candidate for HRT. Indeed, in contrast to current treatment containing ethinyl estradiol or estradiol (E2), E4 has a minimal impact on liver cells activity supporting a decreased incidence on thromboembolic events. In preclinical studies, E4 has been effective against the main symptoms of menopause such as hot flushes, vaginal atrophy, and osteoporosis, from a starting dose of 0.3 mg/kg/day. The aim of this study was to define the impact of E4 on mammary gland and breast cancer development when it is used at concentrations effective for menopause symptom relief. We report preclinical data showing that E4 is less efficient than E2 to induce mammary gland growth. Treatment of estrogen receptor (ER)-positive breast cancer with several concentrations of E4 has shown that 0.3 mg/kg/day E4 did not increase tumor development. However, at 3mg/kg/day, E4 increased the growth of hormone-dependent tumors and their metastatic dissemination in ovariectomized and intact mice. This effect was similar to the one observed with E2 used at 0.08 mg/kg/day. E4 presents also some anti-estrogenic effects on mammary gland and antitumor activity on breast cancer by decreasing the strong proliferative effect of E2. While 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 extranuclear signaling pathways 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. In conclusion, our results support that E4, if it is used in strictly controlled clinical applications, could have no or only limited impact on breast and breast cancer. [less ▲]

Detailed reference viewed: 11 (0 ULg)
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See detailEstetrol: a new fetal estrogen with antioxidative and neuroprotective activity in the newborn
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

in Estetrol attenuates neonatal hypoxic-ischemic brain injury (2013)

Detailed reference viewed: 20 (1 ULg)
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See detailEstetrols’ Potential for Neuroprotection Following the injury to the Developing Brain: Preclinical Studies
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

in The 17th World Congress of Gynecological Endocrinology, Florence 2-5 March 2016 (2016, March)

Context: Hypoxic-Ischemic encephalopathy (HIE) remains a major cause of perinatal brain injury. The brain rapidly increases in size, shape and complexity during the second and third trimesters. A sentinel ... [more ▼]

Context: Hypoxic-Ischemic encephalopathy (HIE) remains a major cause of perinatal brain injury. The brain rapidly increases in size, shape and complexity during the second and third trimesters. A sentinel event in late pregnancy or the intrapartum period may have an acute profound effect on a previously neurologically intact fetus, leading to the development of (HIE). The nature of the deficits is dependent on the gestational age and severity of the insult, though it is seldom reported in preterm infants. Studies in animal models of HIE may provide important information for the development of treatment for this pathological condition. Estetrol (E4) is a recently described estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. Objective: In this study, we evaluated E4’s neuroprotective and therapeutic potency in neonatal (in vivo) HIE model of the immature 7-day-old newborn rat. Methods: Rat pups body temperatures were examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for neuronal early grey matter damage (microtubule-associated protein-2 (MAP-2)), neurogenesis (doublecortin (DCX)) and angiogenesis (vascular-endothelial growth factor (VEGF)) were evaluated by histo- and immunohistochemistry. The serum levels of two markers of brain damage (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Results: Our results demonstrate that E4 has a significant neuroprotective and therapeutic effects. Estetrol decreases the early gray matter loss, and promotes neuro- and angiogenesis in vivo. Estetrol treatment has no effects on body weight, brain weight or body temperature. Conclusion: Taken together, E4 might become an important safe and physiological substance to treat neonatal HIE. [less ▲]

Detailed reference viewed: 21 (2 ULg)
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See detailEsthésies. Conclusions
Ebert-Schifferer, Sybille; Von Hoffmann, Viktoria ULg

Conference (2015, May 29)

Detailed reference viewed: 13 (0 ULg)