References of "FOIDART, Jean-Michel"
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See detailInhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study
Duijkers, I. J. M.; Klipping, C.; Zimmerman, Y. et al

in European Journal of Contraception & Reproductive Health Care (2015), 20(6), 476-489

Objectives The aim of the study was to evaluate the efficacy of different dosages of estetrol (E<inf>4</inf>) combined with one of two progestins in suppressing the pituitary-ovarian axis and ovulation in ... [more ▼]

Objectives The aim of the study was to evaluate the efficacy of different dosages of estetrol (E<inf>4</inf>) combined with one of two progestins in suppressing the pituitary-ovarian axis and ovulation in healthy premenopausal women.Methods This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E<inf>4</inf>/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E<inf>4</inf>/150 g levonorgestrel; or 20 g ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary-ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication.Results A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E<inf>4</inf> dosage: the highest suppression was observed in the 20 mg E<inf>4</inf> group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe.Conclusions Combined with a progestin, E<inf>4</inf> adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day. © 2015 The European Society of Contraception and Reproductive Health. [less ▲]

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See detailThe activation function-1 of estrogen receptor alpha prevents arterial neointima development through a direct effect on smooth muscle cells
Smirnova, N. F.; Fontaine, C.; Buscato, M. et al

in Circulation Research (2015), 117(9), 770-777

Rationale: 17β-Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor (ER) via 2 activation functions, AF1 and AF2, and ... [more ▼]

Rationale: 17β-Estradiol (E2) exerts numerous beneficial effects in vascular disease. It regulates gene transcription through nuclear estrogen receptor (ER) via 2 activation functions, AF1 and AF2, and can also activate membrane ER. The role of E2 on the endothelium relies on membrane ER activation, but the molecular mechanisms of its action on vascular smooth muscle cells (VSMCs) are not fully understood. Objective: The aim of this study was to determine which cellular target and which ER subfunction are involved in the preventive action of E2 on neointimal hyperplasia. Methods and Results: To trigger neointimal hyperplasia of VSMC, we used a mouse model of femoral arterial injury. Cre-Lox models were used to distinguish between the endothelial- and the VSMC-specific actions of E2. The molecular mechanisms underlying the role of E2 were further characterized using both selective ER agonists and transgenic mice in which the ER AF1 function had been specifically invalidated. We found that (1) the selective inactivation of ER in VSMC abrogates the neointimal hyperplasia protection induced by E2, whereas inactivation of endothelial and hematopoietic ER has no effect; (2) the selective activation of membrane ER does not prevent neointimal hyperplasia; and (3) ER AF1 is necessary and sufficient to inhibit postinjury VSMC proliferation. Conclusions: Altogether, ER AF1-mediated nuclear action is both necessary and sufficient to inhibit postinjury arterial VSMC proliferation, whereas membrane ER largely regulates the endothelial functions of E2. This highlights the exquisite cell/tissue-specific actions of the ER subfunctions and helps to delineate the spectrum of action of selective ER modulators. © 2015 American Heart Association, Inc. [less ▲]

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See detailUnique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives
Mawet, M.; Maillard, C.; Klipping, C. et al

in European Journal of Contraception & Reproductive Health Care (2015), 20(6), 463-475

Objectives Estetrol (E<inf>4</inf>) is a natural estrogen produced by the human fetal liver. In combination with drospirenone (DRSP) or levonorgestrel (LNG), E<inf>4</inf> blocks ovulation and has less ... [more ▼]

Objectives Estetrol (E<inf>4</inf>) is a natural estrogen produced by the human fetal liver. In combination with drospirenone (DRSP) or levonorgestrel (LNG), E<inf>4</inf> blocks ovulation and has less effect on haemostatic biomarkers in comparison with ethinylestradiol (EE) combined with DRSP. This study evaluates the impact of several doses of E<inf>4</inf>/DRSP and E<inf>4</inf>/LNG on safety parameters such as liver function, lipid metabolism, bone markers and growth endocrine parameters.Methods This was a dose-finding, single-centre, controlled study performed in healthy women aged 18 to 35 years with a documented pretreatment ovulatory cycle. Participants received 5 mg or 10 mg E<inf>4</inf>/3 mg DRSP; 5 mg, 10 mg or 20 mg E<inf>4</inf>/150 g LNG; or 20 g EE/3 mg DRSP as a comparator for three consecutive cycles in a 24/4-day regimen. Changes from baseline to end of treatment in liver parameters, lipid metabolism, bone markers and growth endocrinology were evaluated.Results A total of 109 women were included in the study. Carrier proteins were minimally affected in the E<inf>4</inf>/DRSP and E<inf>4</inf>/LNG groups, in comparison with the EE/DRSP group, where a significant increase in sex hormone-binding globulin was observed. Similarly, minor effects on lipoproteins were observed in the E<inf>4</inf> groups, and the effects on triglycerides elicited by the E<inf>4</inf> groups were significantly lower than those in the EE/DRSP group. No imbalances in bone markers were observed in any groups. No alterations in insulin-like growth factor were observed in the E<inf>4</inf> groups.Conclusions E<inf>4</inf>-containing combinations have a limited effect on liver function, lipid metabolism, and bone and growth endocrine parameters. © 2015 The European Society of Contraception and Reproductive Health. [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 detailHypoxic-Ischemic Encephalopathy and Premature Babies Brain Damage: Impact of Estetrol
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

in The 11th Congress of the European Society of Gynecology, Prague 21-24 October, 2015 (2015)

Neonatal hypoxic-ischemic brain injury remains a main problem of perinatal medicine. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities ... [more ▼]

Neonatal hypoxic-ischemic brain injury remains a main problem of perinatal medicine. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities mostly in the form of motor and cognitive delays. The nature of the deficits is dependent on the gestational age and severity of the insult, though it is s seldom reported in preterm infants. No medical treatment provides important neuroprotection against HIE. 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. In this study, we defined the antioxidative effect of E4 in primary hippocampal cell cultures taken from newborn rat pups (in vitro) and evaluated its neuroprotective and therapeutic potency in neonatal HIE model of the immature newborn rat (in vivo). Lactate Dehydrogenase (LDH) and cell survival (MTS) assays were performed on primary neuronal cell cultures. 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 two markers of brain damage (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Our results demonstrate that E4 has a significant neuroprotective and therapeutic dose-dependent effects. Estetrol has powerful antioxidative and cell survival effects 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, Estetrol might become an important safe and physiological substance to treat neonatal HIE. [less ▲]

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See detailThe Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts.
Kuchnio, Anna; Moens, Stijn; Bruning, Ulrike et al

in Cell Reports (2015), 12(6), 992-1005

Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model ... [more ▼]

Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model. Here, we show that global PHD2 haplodeficiency reduced metastasis without affecting tumor growth. Second, it is unknown whether PHD2 regulates cancer by affecting cancer-associated fibroblasts (CAFs). We show that PHD2 haplodeficiency reduced metastasis via two mechanisms: (1) by decreasing CAF activation, matrix production, and contraction by CAFs, an effect that surprisingly relied on PHD2 deletion in cancer cells, but not in CAFs; and (2) by improving tumor vessel normalization. Third, the effect of concomitant PHD2 inhibition in malignant and stromal cells (mimicking PHD2 inhibitor treatment) is unknown. We show that global PHD2 haplodeficiency, induced not only before but also after tumor onset, impaired metastasis. These findings warrant investigation of PHD2's therapeutic potential. [less ▲]

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See detailSoluble factors regulated by epithelial-mesenchymal transition mediate tumour angiogenesis and myeloid cell recruitment.
Suarez-Carmona, Meggy ULg; Bourcy, Morgane ULg; LESAGE, J et al

in Journal of Pathology (The) (2015)

Epithelial-to-mesenchymal transition (EMT) programs provide cancer cells with invasive and survival capacities that might favor metastatic dissemination. Whilst signaling cascades triggering EMT have been ... [more ▼]

Epithelial-to-mesenchymal transition (EMT) programs provide cancer cells with invasive and survival capacities that might favor metastatic dissemination. Whilst signaling cascades triggering EMT have been extensively studied, the impact of EMT on the crosstalk between tumor cells and the tumor microenvironment remains elusive. We aimed to identify EMT-regulated soluble factors that facilitate the recruitment of host cells in the tumor. Our findings indicate that EMT phenotypes relate to the induction of a panel of secreted mediators, namely IL-8, IL-6, sICAM-1, PAI-1 and GM-CSF, and implicate the EMT-transcription factor Snail as a regulator of this process. We further show that EMT-derived soluble factors are pro-angiogenic in vivo (in the mouse ear sponge assay), ex vivo (in the rat aortic ring assay) and in vitro (in a chemotaxis assay). Additionally, conditioned medium from EMT-positive cells stimulates the recruitment of myeloid cells. In a bank of 40 triple-negative breast cancers, tumors presenting features of EMT were significantly more angiogenic and infiltrated by a higher quantity of myeloid cells compared to tumors with little or no EMT. Taken together, our results show that EMT programs trigger the expression of soluble mediators in cancer cells that stimulate angiogenesis and recruit myeloid cells in vivo, which might in turn favor cancer spread. [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 detailInfluence of mouse strain on ovarian tissue recovery after engraftment with angiogenic factor.
Fransolet, Maïté ULg; Henry, Laurie ULg; Labied, Soraya et al

in Journal of Ovarian Research (2015), 8(1), 14

BACKGROUND: For women facing gonadotoxic treatment, cryopreservation of ovarian tissue with subsequent retransplantation during remission is a promising technique for fertility preservation. However ... [more ▼]

BACKGROUND: For women facing gonadotoxic treatment, cryopreservation of ovarian tissue with subsequent retransplantation during remission is a promising technique for fertility preservation. However, follicle loss within grafted ovarian tissue can be caused by ischemia and progressive revascularization. Several xenograft models using different immunodeficient rodent lines are suitable for studying ovarian tissue survival and follicular viability after frozen-thawed ovarian cortex transplantation. SCID mice, which are deficient for functional B and T cells, are the most commonly used mice for ovarian xenograft studies. However, due to incomplete immunosuppression, NOD-SCID mice displaying low NK cell function and an absence of circulating complement might be more appropriate. The present study aims to define the most appropriate immunodeficient mouse strain for ovarian tissue xenotransplantation by comparing ovarian graft recovery in SCID and NOD-SCID mice following engraftment in the presence of isoform 111 of vascular endothelial growth factor. METHODS: Sheep ovarian cortex fragments were embedded in a collagen matrix, with or without VEGF111, before being stitched onto the ovaries of SCID and NOD-SCID mice. Transplants were recovered after 3 days to study early revascularization or after 3 weeks to evaluate follicle preservation and tissue fibrosis through histological analyses. RESULTS: At day 3, vessels were largely reorganized in the ovarian grafts of both mouse strains. After 3 weeks, the cortical tissue was clearly identifiable in SCID mice but not in NOD-SCID mice. Upon VEGF111 treatment, vascularization was significantly improved 3 days after transplantation in SCID mice. This increase in vessel density was correlated with better follicular preservation in SCID mice 3 weeks after transplantation. Fibrosis was not decreased by VEGF treatment in either mouse strain. CONCLUSIONS: Tissue architecture and follicular morphology were better preserved in ovarian tissues grafted in SCID mice in comparison with NOD-SCID mice. Moreover, tissue revascularization was improved in SCID mice by VEGF111 graft treatment. Thus, we consider SCID mice to be the best murine model for studying ovarian tissue xenografts. [less ▲]

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See detailIsoform 165 of vascular endothelial growth factor in collagen matrix improves ovine cryopreserved ovarian tissue revascularisation after xenotransplantation in mice.
Henry, Laurie ULg; LABIED, Soraya ULg; Fransolet, Maïté ULg et al

in Reproductive biology and endocrinology (2015), 13(1), 15

BACKGROUND: Aggressive anti-cancer treatments can result in ovarian failure. Ovarian cryopreservation has been developed to preserve the fertility of young women, but early graft revascularisation still ... [more ▼]

BACKGROUND: Aggressive anti-cancer treatments can result in ovarian failure. Ovarian cryopreservation has been developed to preserve the fertility of young women, but early graft revascularisation still requires improvement. METHODS: Frozen/thawed sheep ovarian cortical biopsies were embedded in collagen matrix with or without isoform 165 of vascular endothelial growth factor (VEGF165) and transplanted into ovaries of immunodeficient mice. Ovaries were chosen as transplantation sites to more closely resemble clinical conditions in which orthotopic transplantation has previously allowed several spontaneous pregnancies. RESULTS: We found that VEGF165 significantly increased the number of Dextran-FITC positive functional vessels 3 days after grafting. Dextran- fluorescein isothiocyanate (FITC) positive vessels were detectable in 53% and 29% of the mice in the VEGF-treated and control groups, respectively. Among these positive fragments, 50% in the treated group displayed mature smooth-muscle-actin-alpha (alpha-SMA) positive functional vessels compared with 0% in the control group. CD31 positive murine blood vessels were observed in 40% of the VEGF165 transplants compared with 21% of the controls. After 3 weeks, the density of murine vessels was significantly higher in the VEGF165 group. CONCLUSION: The encapsulation of ovarian tissue in collagen matrix in the presence of VEGF165 before grafting has a positive effect on functional blood vessel recruitment. It can be considered as a useful technique to be improved and further developed before human clinical applications in female cancer patients in the context of fertility preservation. [less ▲]

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See detailA Membrane-Type-1 Matrix Metalloproteinase (MT1-MMP) - Discoidin Domain Receptor 1 Axis Regulates Collagen-Induced Apoptosis in Breast Cancer Cells.
Assent, Delphine; Bourgot, Isabelle ULg; Hennuy, Benoît ULg et al

in PloS one (2015), 10(3), 0116006

During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and pro-apoptotic properties. To ... [more ▼]

During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and pro-apoptotic properties. To develop metastatic capabilities, tumour cells must acquire the capacity to cope with this novel microenvironment. How cells interact with and respond to their microenvironment during cancer dissemination remains poorly understood. To address the impact of type I collagen on the fate of tumour cells, human breast carcinoma MCF-7 cells were cultured within three-dimensional type I collagen gels (3D COL1). Using this experimental model, we have previously demonstrated that membrane type-1 matrix metalloproteinase (MT1-MMP), a proteinase overexpressed in many aggressive tumours, promotes tumour progression by circumventing the collagen-induced up-regulation of BIK, a pro-apoptotic tumour suppressor, and hence apoptosis. Here we performed a transcriptomic analysis to decipher the molecular mechanisms regulating 3D COL1-induced apoptosis in human breast cancer cells. Control and MT1-MMP expressing MCF-7 cells were cultured on two-dimensional plastic plates or within 3D COL1 and a global transcriptional time-course analysis was performed. Shifting the cells from plastic plates to 3D COL1 activated a complex reprogramming of genes implicated in various biological processes. Bioinformatic analysis revealed a 3D COL1-mediated alteration of key cellular functions including apoptosis, cell proliferation, RNA processing and cytoskeleton remodelling. By using a panel of pharmacological inhibitors, we identified discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase specifically activated by collagen, as the initiator of 3D COL1-induced apoptosis. Our data support the concept that MT1-MMP contributes to the inactivation of the DDR1-BIK signalling axis through the cleavage of collagen fibres and/or the alteration of DDR1 receptor signalling unit, without triggering a drastic remodelling of the transcriptome of MCF-7 cells. [less ▲]

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See detailRestoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: II. Clinical effects.
Zimmerman, Y.; Foidart, Jean-Michel ULg; Pintiaux, Axelle ULg et al

in Contraception (2015), 91(2), 134-42

OBJECTIVES: Combined oral contraceptives (COCs) decrease androgen levels, including testosterone (T), which may be associated with sexual dysfunction and mood complaints in some women. We have shown that ... [more ▼]

OBJECTIVES: Combined oral contraceptives (COCs) decrease androgen levels, including testosterone (T), which may be associated with sexual dysfunction and mood complaints in some women. We have shown that 'co-administration' of dehydroepiandrosterone (DHEA) to a drospirenone (DRSP)-containing COC restored total T levels to baseline and free T levels by 47%. Here we describe the effects on sexual function, mood and quality of life of such an intervention. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled study in 99 healthy COC starters. A COC containing 30mcg ethinylestradiol (EE) and 3mg DRSP was used for three cycles, followed by six cycles of the same COC combined with 50mg/day DHEA or placebo. Subjects completed the Moos Menstrual Distress Questionnaire (MDQ), the McCoy Female Sexuality Questionnaire and the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Safety and tolerability, including effects on skin, were evaluated. RESULTS: The addition of DHEA induced small but significant improvements compared to placebo in the MDQ score for autonomic reactions during the menstrual (-2.0 vs. 0.71; p=0.05) and the premenstrual phase (-3.1 vs. 2.9; p=0.01) and for behavior during the intermenstrual phase (-1.4 vs. 3.6; p=0.02). A significant difference was found in the MDQ score for arousal during the premenstrual phase in favor of placebo (-5.0 vs. 1.0; p=0.01). There were no statistically significant differences between groups for the MSFQ and Q-LES-Q scores. DHEA 'co-administration' resulted in an acceptable safety profile. DHEA negated the beneficial effect of the COC on acne according to the subjects' self-assessment. CONCLUSIONS: 'Co-administration' with DHEA did not result in consistent improvements in sexual function, mood and quality of life indicators in women taking EE/DRSP. Retrospectively, the 50 mg dose of DHEA may be too low for this COC. IMPLICATIONS: A well-balanced judgment of the clinical consequences of normalizing androgens during COC use may require complete normalization of free T. [less ▲]

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See detailRestoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: I. Endocrine effects.
Zimmerman, Y.; Foidart, Jean-Michel ULg; Pintiaux, Axelle ULg et al

in Contraception (2015), 91(2), 127-33

OBJECTIVES: Combined oral contraceptives (COCs) decrease testosterone (T) levels. This study investigated restoration of T and other androgen concentrations during COC use by 'co-administration' of ... [more ▼]

OBJECTIVES: Combined oral contraceptives (COCs) decrease testosterone (T) levels. This study investigated restoration of T and other androgen concentrations during COC use by 'co-administration' of dehydroepiandrosterone (DHEA). STUDY DESIGN: In this randomized, double-blind, placebo-controlled study in 99 new COC starters (18-35 years old with body mass index range 18-34kg/m(2)), a COC containing 30mcg ethinylestradiol (EE) and 3mg drospirenone (DRSP) was used for 3cycles, followed by 6cycles of the same COC combined with either 50mg/day DHEA or placebo. Total T, albumin, sex hormone-binding globulin (SHBG), DHEA-sulfate (DHEA-S), Delta4-androstenedione (AD), 3alpha-androstanediol glucuronide (ADG) and estradiol (E2) were measured, whereas free T and the free T index (FTI) were calculated. Assessments took place at baseline (no COC use), after the run-in period (COC use alone) and during the treatment period (DHEA or placebo). RESULTS: During COC use alone, androgen levels decreased, especially total T by 62% and free T by 86%, and SHBG increased by 243%. Total T increased with DHEA compared to placebo (change from end of run-in period to end of treatment period - 1.3+/-1.2nmol/L vs. 0.0+/-0.4nmol/L; p<.0001) - and was restored to baseline levels. Free T and the FTI increased significantly (p<.0001), but the free T level was still 53% below baseline levels. DHEA-S, AD and ADG increased significantly to levels above baseline (p<.0001 for each). DHEA had no effect on SHBG, albumin and E2. CONCLUSIONS: An EE/DRSP containing COC strongly suppressed endogenous androgen concentrations in all users. The addition of 50mg DHEA to a COC regimen containing EE/DRSP restored total T to baseline levels, but free T levels were restored by only 47% as most of the T remains bound to SHBG. IMPLICATIONS: When using a COC that increases SHBG considerably, a daily dose of 50mg DHEA is insufficient to normalize free T levels completely. [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 detailEGFR activation and signaling in cancer cells are enhanced by the membrane-bound metalloprotease MT4-MMP.
Paye, Alexandra ULg; Truong, Alice ULg; Yip, Cassandre ULg et al

in Cancer Research (2014), 74(23), 6758-70

MT4-MMP (MMP-17) is a GPI-anchored matrix metalloprotease expressed on the surface of cancer cells which promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of ... [more ▼]

MT4-MMP (MMP-17) is a GPI-anchored matrix metalloprotease expressed on the surface of cancer cells which promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein (Rb) inactivation. We also determine a functional link between MT4-MMP and the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4-MMP and its positive effects on EGFR phosphorylation in response to TGF- and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expression were correlated in human triple negative breast cancer specimens. Altogether our results identify MT4-MMP as a positive modifier of EGFR outside-in signaling that acts to cooperatively drive cancer cell proliferation. [less ▲]

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See detailExpression et localisation immunohistochimique de KISS1 et de son récepteur GPR54 : étude du tissu thyroïdien non tumoral et d'une série de patients opérés d'un cancer thyroïdien papillaire
VALDES SOCIN, Hernan Gonzalo ULg; Munaut, Carine ULg; SCAGNOL, Irène ULg et al

in Abstract book - Annales d'Endocrinologie : 31ème Congrès de la Société Française d'Endocrinologie, Lyon 5-8 novembre 2014 (2014, October)

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