References of "Foidart, Jean-Michel"
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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, 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 detailUse of Estetrol with other Steroids for Attenuation of Neonatal Hypoxic-Ischemic brain injury:to combine or not to combine?
Tskitishvili, Ekaterine ULg; Pequeux, Christel ULg; Munaut, Carine ULg et al

in Oncotarget (2016)

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 ... [more ▼]

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. [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 ▲]

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See detailNeonatal Hypoxic-Ischemic Encephalopathy: a new view of an old problem
Tskitishvili, Ekaterine ULg; VIELLEVOYE, Renaud ULg; Gérard, Céline et al

in Références en Gynécologie Obstétrique (2016), 17(1-1),

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a challenge of perinatal medicine. It is an important cause of long term morbidity, including motor and behavioral deficits, mental retardation ... [more ▼]

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a challenge of perinatal medicine. It is an important cause of long term morbidity, including motor and behavioral deficits, mental retardation, seizures and cerebral palsy, and mortality in newborns. This paper reviews the pathophysiology and current concepts of the management of neonatal HIE as well as the future potential neuroprotective strategies for attenuation of this disease. [less ▲]

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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 ▲]

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See detailImpact of estetrol on breast cancer development, metastatic dissemination and angiogenesis
Gallez, Anne ULg; Gérard, Céline ULg; BLACHER, Silvia ULg et al

Poster (2016)

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 breast cancer development when it is used at concentrations effective for menopause symptom relief. Treatment of estrogen receptor (ER)-positive breast cancer-developing mice (MMTV-PyMT) with several concentrations of E4 has shown that 0.3 mg/kg/day E4 did not increase tumor development and metastasis dissemination. 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. In an in vivo model of ER-negative tumors, we observed that 3mg/kg/day E4 improved tumor growth by increasing angiogenesis, and subsequently decreasing necrosis and tumor hypoxia. In contrast, 0.3 mg/kg/day E4 did not induce any of these effects on ER-negative tumors and tumor microenvironment. In conclusion, we have shown that 0.3 mg/kg/day E4, already reported to prevent menopause symptoms, does not increase breast tumor growth, metastasis dissemination, and angiogenesis. However, similarly to E2, higher concentrations of E4 are pro-tumorous. These results support that E4, if it is used in strictly controlled clinical applications, could have no or only limited impact on breast cancer. [less ▲]

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See detailQuantitative assessment of mouse mammary gland morphology using automated digital image processing and TEB detection.
Blacher, Silvia ULg; Gérard, Céline ULg; Gallez, Anne ULg et al

in Endocrinology (2016)

The assessment of rodent mammary gland morphology is largely used to study the molecular mechanisms driving breast development and to analyze the impact of various endocrine disruptors with putative ... [more ▼]

The assessment of rodent mammary gland morphology is largely used to study the molecular mechanisms driving breast development and to analyze the impact of various endocrine disruptors with putative pathological implications. In this work, we propose a methodology relying on fully automated digital image analysis methods including image processing and quantification of the whole ductal tree and of the terminal end buds (TEB) as well. It allows to accurately and objectively measure both growth parameters and fine morphological glandular structures. Mammary gland elongation was characterized by two parameters: the length and the epithelial area of the ductal tree. Ductal tree fine structures were characterized by: 1) branch end-point density, 2) branching density and 3) branch length distribution. The proposed methodology was compared to quantification methods classically used in the literature. This procedure can be transposed to several software and thus largely used by scientists studying rodent mammary gland morphology. [less ▲]

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See detailElastin density: Link between histological and biomechanical properties of vaginal tissue in women with pelvic organ prolapse?
DE LANDSHEERE, Laurent ULg; Brieu, Mathias; Blacher, Silvia ULg et al

in International Urogynecology Journal & Pelvic Floor Dysfunction (2016)

INTRODUCTION AND HYPOTHESIS: The aim of the study was to correlate histological and biomechanical characteristics of the vaginal wall in women with pelvic organ prolapse (POP). METHODS: Tissue samples ... [more ▼]

INTRODUCTION AND HYPOTHESIS: The aim of the study was to correlate histological and biomechanical characteristics of the vaginal wall in women with pelvic organ prolapse (POP). METHODS: Tissue samples were collected from the anterior [point Ba; POP Questionnaire (POP-Q)] and/or posterior (point Bp; POP-Q) vaginal wall of 15 women who underwent vaginal surgery for POP. Both histological and biomechanical assessments were performed from the same tissue samples in 14 of 15 patients. For histological assessment, the density of collagen and elastin fibers was determined by combining high-resolution virtual imaging and computer-assisted digital image analysis. For biomechanical testing, uniaxial tension tests were performed to evaluate vaginal tissue stiffness at low (C0) and high (C1) deformation rates. RESULTS: Biomechanical testing highlights the hyperelastic behavior of the vaginal wall. At low strains (C0), vaginal tissue appeared stiffer when elastin density was low. We found a statistically significant inverse relationship between C0 and the elastin/collagen ratio (p = 0.048) in the lamina propria. However, at large strain levels (C1), no clear relationship was observed between elastin density or elastin/collagen ratio and stiffness, likely reflecting the large dispersion of the mechanical behavior of the tissue samples. CONCLUSION: Histological and biomechanical properties of the vaginal wall vary from patient to patient. This study suggests that elastin density deserves consideration as a relevant factor of vaginal stiffness in women with POP. [less ▲]

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See detailSupplementation of transport and freezing media with anti-apoptotic drugs improves ovarian cortex survival
HENRY, Laurie ULg; Fransolet, Maïté ULg; LABIED, Soraya ULg et al

in Journal of Ovarian Research (2016)

Background: Ovarian tissue preservation is proposed to patients at risk of premature ovarian failure, but this procedure still needs to be optimized. To limit injury during ovarian tissue cryopreservation ... [more ▼]

Background: Ovarian tissue preservation is proposed to patients at risk of premature ovarian failure, but this procedure still needs to be optimized. To limit injury during ovarian tissue cryopreservation, anti-apoptotic drugs were added to the transport and freezing media of ovarian cortex tissue. Methods: Sheep ovaries were transported, prepared and frozen in solutions containing vehicle or anti-apoptotic drugs (Z-VAD-FMK, a pan-caspase inhibitor, or sphingosine-1-phosphate (S1P), a bioactive lipid). After the tissue was thawed, the ovarian cortex was cultured for 2 or 6 days. Follicular quantification and morphological and proliferation analyses were performed on histological sections. Results: After 2 days of culture, S1P improved the quality of primordial follicles; higher densities of morphologically normal and proliferative primordial follicles were found. Z-VAD-FMK displayed similar effects by preserving global primordial follicular density, but this effect was evident after 6 days of culture. This drug also improved cell proliferation after 2 and 6 days of culture. Conclusions: Our results showed that the addition of S1P or Z-VAD-FMK to the transport and freezing media prior to ovarian tissue cryopreservation improves primordial follicular quality and therefore improves global tissue survival. This should ultimately lead to improved fertility restoration after auto-transplantation. [less ▲]

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See detailG-CSF as a non-invasive predictive marker for embryo implantation
Munaut, Carine ULg; NOEL, Laure ULg; Lédée, N et al

Scientific conference (2015, December 07)

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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 detailIn vitro evaluation of an anti-apoptotic drug, Z-VAD-FMK, for further use in ovarian tissue transplantation
Fransolet, Maïté ULg; HENRY, Laurie ULg; LABIED, Soraya ULg et al

Poster (2015, June 14)

Study question: In a model reproducing early ischemia after ovarian tissue transplantation, does the pan-caspase inhibitor Z-VAD-FMK could prevent granulosa cell apoptosis? Summary answer: Results ... [more ▼]

Study question: In a model reproducing early ischemia after ovarian tissue transplantation, does the pan-caspase inhibitor Z-VAD-FMK could prevent granulosa cell apoptosis? Summary answer: Results obtained with HGL5 granulosa cell line suggest that Z-VAD-FMK is efficient to protect granulosa cells from etoposide or CoCl2 induced apoptosis. What is known already: Removal, cryopreservation and subsequent graft of ovarian strips after cancer treatment have been successfully used to re-establish female fertility. However, the pregnancy rate after autografting of cryopreserved tissue is about 30%. Indeed, the major problem after transplantation is follicular loss due to ischemic reperfusion injury. Study design, size, duration: Three human granulosa cell lines (GC1a, HGL5 and COV434) were cultured during 48h with Z-VAD-FMK with or without etoposide to induce apoptosis. To reproduce the ischemic phase of the graft, cells were cultured without serum under reduced O2 (1%) or with CoCl2 (chemical hypoxia). Participants/materials, setting, methods: Granulosa cells were used as a model since they are essential for oocyte survival. Metabolic cell activity was evaluated by the WST-1 assay. Cell apoptosis was analyzed by flow cytometry after annexin V-FITC and propidium iodide double staining. The mRNA levels and protein expression of apoptotic markers were evaluated using RT-qPCR and western blot analysis. Main results and the role of chance: Flow cytometry showed that cells co-treated with etoposide and Z-VAD-FMK displayed a higher percentage of viable cells as compared to etoposide alone. When in vivo ischemic stage was mimicked (1% O2), no beneficial effect of the Z-VAD-FMK was detected. However, a significant decrease of the number of early apoptotic cells was evidenced by flow cytometry for HGL5 cells treated with Z-VAD-FMK. RT-qPCR and western blot analysis revealed that apoptotic molecules were not modulated. Metabolic activity of the 3 cell lines was reduced by CoCl2. For HGL5 cells, this decrease was partially reversed by Z-VAD-FMK. The number of viable cells was reduced by CoCl2 in HGL5 cells but Z-VAD-FMK allowed to preserve a similar number of viable and apoptotic cells than in control condition. Limitations, reasons for caution: In this study we used 3 different cell lines but granulosa cells represent only a part of the cell types present in ovarian tissue biopsies. Experiences on the effect of Z-VAD-FMK on primary culture of granulosa cells have not yet been realized. Wider implications of the findings: This study suggests that the use of an antiapoptotic drug could be efficient to improve ovarian tissue transplantation outcomes. Ovarian tissue grafting studies using our xenograft murine model will be performed to test the potential efficacy of this drug to improve tissue viability and primordial follicles preservation after transplantation. [less ▲]

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See detailCombined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms
Gérard, Céline ULg; Mestdagt, Mélanie; Tskitishvili, Ekaterine ULg et al

in Oncotarget (2015)

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 ... [more ▼]

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. [less ▲]

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See detailLIPOSOME CONTAINING ESTETROL FOR THE TREATMENT OF ISCHEMIA DISEASES IN PREMATURE BABIES
Palazzo, Claudio ULg; Karim, Reatul ULg; Mawet, Marie et al

Poster (2015, April 14)

Detailed reference viewed: 54 (14 ULg)