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Anne Orbo - One of the best experts on this subject based on the ideXlab platform.
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bcl 2 bax and apoptosis in endometrial hyperplasia after high dose Gestagen therapy a comparison of responses in patients treated with intrauterine levonorgestrel and systemic medroxyprogesterone
Gynecologic Oncology, 2005Co-Authors: Anne Beate Vereide, Turid Kaino, Georg Sager, Anne OrboAbstract:Abstract Objectives. The aim of the study was to investigate apoptosis as a growth regulatory mechanism of Gestagen in endometrial precancers and to compare differences in the apoptotic cascade after high and low dose Gestagen regimens. Method. Pre- and post-treatment paraffin-embedded endometrial hyperplasia specimens from women treated with levonorgestrel intrauterine device ( n = 26) and women treated with 10 mg medroxyprogesterone for 10 days per cycle ( n = 31) were examined for changes in the expression of Bcl-2 and BAX and the extent of apoptosis after 3 months of treatment. Immunohistochemical expression in tissue specimens for Bcl-2 and BAX was evaluated by H-score. Average number of apoptotic cells per hundred cells within ten different high power field (40×) was evaluated for each section after in situ apoptosis detection (TUNEL method). A second group of patients with endometrial hyperplasia was examined after 1 week treatment with levonorgestrel IUD ( n = 6) or medroxyprogesterone ( n = 5) to determine early effects on expression of Bcl-2 and BAX and the extent of apoptosis. Results. All the patients in the IUD group ( n = 31) but only about half of the patients in per oral group (16 of 26) responded to treatment. The glandular reduction in Bcl-2 expression was markedly greater for the IUD patients than for the patients who received oral Gestagen. The decrease in BAX expression after IUD treatment was less than the reduction of Bcl-2. Decrease in glandular Bcl-2 after 3 months of treatment was coincident with a significant increase in the measurable amount of apoptosis. In stromal cells, the increase in expression of Bcl-2 and BAX was found after Gestagen treatment, the response being much more marked for the IUD group. The non- responders to per oral Gestagen had no Bcl-2 expression in stroma after 3 months of therapy whereas an increase was observed for the responders. After 1 week, glandular Bcl-2 expression was significantly reduced after treatment in the IUD group. As for the rest, no changes were detected in either of the groups. Conclusion. Our results indicate that proteins in the apoptotic cascade are regulated by Gestagen therapy in human endometrial precancers. Expression of these proteins is shown to be dependent on administration form and/or type of Gestagen. Stromal Bcl-2 expression appears to be a potential biomarker which can separate responders of Gestagen treatment from non-responders after oral administration.
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nuclear morphometric changes and therapy monitoring in patients with endometrial hyperplasia a study comparing effects of intrauterine levonorgestrel and systemic medroxyprogesterone
Gynecologic Oncology, 2003Co-Authors: Anne Beate Vereide, Marit Arnes, Bjorn Straume, J M Maltau, Anne OrboAbstract:Abstract Objectives To show that local application of the levonorgestrel intrauterine device was a better therapy for endometrial hyperplasia (EH) compared to per-oral Gestagen treatment based on subjective (WHO criteria) and objective (prognostic data-based morphometric and stereological method/ D score, predicting the risk of cancer development for each single patient) evaluation. Method Women between 30 and 70 years with EH and D score > 0 were treated with levonorgestrel intrauterine device ( n = 26) and the results compared to a historic group of women treated with per-oral Gestagen ( n = 31). In both treatment groups only patients with low risk ( D score > 1) and uncertain risk ( D score=0–1) of cancer development were included. Endometrial specimens were investigated prior to treatment and after 3 months of therapy. The endometrial samples from the two groups were examined by light microscopy and objective data-based morphometry to assess tissue characteristics and to evaluate nuclear size variation. Results After 3 months all patients treated with levonorgestrel intrauterine device showed regression of hyperplasia, whereas 14 of 31 patients in the per-oral group still had persisting disease. The objective morphometric analysis showed reduction in nuclear size for both treatment groups, including the D score > 1 as well as the D score 0–1 patients. However, the reduction was most obvious for the levonorgestrel intrauterine device-treated patients with initial D score of 0–1. Conclusion The present study indicates that levonorgestrel intrauterine device is a superior alternative to per oral treatment of endometrial hyperplasia. By using objective morphometric treatment monitoring we have shown that the hyperplasia patients with the highest malignant potential ( D score=0–1) were those taking most benefit from local high-dose levonorgestrel therapy.
Edward F Orlando - One of the best experts on this subject based on the ideXlab platform.
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environmental Gestagens activate fathead minnow pimephales promelas nuclear progesterone and androgen receptors in vitro
Environmental Science & Technology, 2014Co-Authors: Laura E Ellestad, Daniel L Villeneuve, Vickie S Wilson, Mary C Cardon, Phillip C Hartig, Ian G Chambers, Jennifer L Farmer, Kyle Stevens, Edward F OrlandoAbstract:Gestagen is a collective term for endogenous and synthetic progesterone receptor (PR) ligands. In teleost fishes, 17α,20β-dihydroxy-4-pregnen-3-one (DHP) and 17α,20β,21-trihydroxy-4-pregnen-3-one (20β-S) are the predominant progestogens, whereas in other vertebrates the major progestogen is progesterone (P4). Progestins are components of human contraceptives and hormone replacement pharmaceuticals and, with P4, can enter the environment and alter fish and amphibian reproductive health. In this study, our primary objectives were to clone the fathead minnow (FHM) nuclear PR (nPR), to develop an in vitro assay for FHM nPR transactivation, and to screen eight Gestagens for their ability to transactivate FHM nPR. We also investigated the ability of these Gestagens to transactivate FHM androgen receptor (AR). Fish progestogens activated FHM nPR, with DHP being more potent than 20β-S. The progestin drospirenone and P4 transactivated the FHM nPR, whereas five progestins and P4 transactivated FHM AR, all at enviro...
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Environmental Gestagens Activate Fathead Minnow (Pimephales promelas) Nuclear Progesterone and Androgen Receptors in Vitro
2014Co-Authors: Laura E Ellestad, Daniel L Villeneuve, Ian G Chambers, Jennifer L Farmer, Kyle Stevens, Mary Cardon, Phillip Hartig, Vickie Wilson, Edward F OrlandoAbstract:Gestagen is a collective term for endogenous and synthetic progesterone receptor (PR) ligands. In teleost fishes, 17α,20β-dihydroxy-4-pregnen-3-one (DHP) and 17α,20β,21-trihydroxy-4-pregnen-3-one (20β-S) are the predominant progestogens, whereas in other vertebrates the major progestogen is progesterone (P4). Progestins are components of human contraceptives and hormone replacement pharmaceuticals and, with P4, can enter the environment and alter fish and amphibian reproductive health. In this study, our primary objectives were to clone the fathead minnow (FHM) nuclear PR (nPR), to develop an in vitro assay for FHM nPR transactivation, and to screen eight Gestagens for their ability to transactivate FHM nPR. We also investigated the ability of these Gestagens to transactivate FHM androgen receptor (AR). Fish progestogens activated FHM nPR, with DHP being more potent than 20β-S. The progestin drospirenone and P4 transactivated the FHM nPR, whereas five progestins and P4 transactivated FHM AR, all at environmentally relevant concentrations. Progestins are designed to activate human PR, but older generation progestins have unwanted androgenic side effects in humans. In FHMs, several progestins proved to be strong agonists of AR. Here, we present the first mechanistic evidence that environmental Gestagens can activate FHM nPR and AR, suggesting that Gestagens may affect phenotype through nPR- and AR-mediated pathways
Anne Beate Vereide - One of the best experts on this subject based on the ideXlab platform.
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bcl 2 bax and apoptosis in endometrial hyperplasia after high dose Gestagen therapy a comparison of responses in patients treated with intrauterine levonorgestrel and systemic medroxyprogesterone
Gynecologic Oncology, 2005Co-Authors: Anne Beate Vereide, Turid Kaino, Georg Sager, Anne OrboAbstract:Abstract Objectives. The aim of the study was to investigate apoptosis as a growth regulatory mechanism of Gestagen in endometrial precancers and to compare differences in the apoptotic cascade after high and low dose Gestagen regimens. Method. Pre- and post-treatment paraffin-embedded endometrial hyperplasia specimens from women treated with levonorgestrel intrauterine device ( n = 26) and women treated with 10 mg medroxyprogesterone for 10 days per cycle ( n = 31) were examined for changes in the expression of Bcl-2 and BAX and the extent of apoptosis after 3 months of treatment. Immunohistochemical expression in tissue specimens for Bcl-2 and BAX was evaluated by H-score. Average number of apoptotic cells per hundred cells within ten different high power field (40×) was evaluated for each section after in situ apoptosis detection (TUNEL method). A second group of patients with endometrial hyperplasia was examined after 1 week treatment with levonorgestrel IUD ( n = 6) or medroxyprogesterone ( n = 5) to determine early effects on expression of Bcl-2 and BAX and the extent of apoptosis. Results. All the patients in the IUD group ( n = 31) but only about half of the patients in per oral group (16 of 26) responded to treatment. The glandular reduction in Bcl-2 expression was markedly greater for the IUD patients than for the patients who received oral Gestagen. The decrease in BAX expression after IUD treatment was less than the reduction of Bcl-2. Decrease in glandular Bcl-2 after 3 months of treatment was coincident with a significant increase in the measurable amount of apoptosis. In stromal cells, the increase in expression of Bcl-2 and BAX was found after Gestagen treatment, the response being much more marked for the IUD group. The non- responders to per oral Gestagen had no Bcl-2 expression in stroma after 3 months of therapy whereas an increase was observed for the responders. After 1 week, glandular Bcl-2 expression was significantly reduced after treatment in the IUD group. As for the rest, no changes were detected in either of the groups. Conclusion. Our results indicate that proteins in the apoptotic cascade are regulated by Gestagen therapy in human endometrial precancers. Expression of these proteins is shown to be dependent on administration form and/or type of Gestagen. Stromal Bcl-2 expression appears to be a potential biomarker which can separate responders of Gestagen treatment from non-responders after oral administration.
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nuclear morphometric changes and therapy monitoring in patients with endometrial hyperplasia a study comparing effects of intrauterine levonorgestrel and systemic medroxyprogesterone
Gynecologic Oncology, 2003Co-Authors: Anne Beate Vereide, Marit Arnes, Bjorn Straume, J M Maltau, Anne OrboAbstract:Abstract Objectives To show that local application of the levonorgestrel intrauterine device was a better therapy for endometrial hyperplasia (EH) compared to per-oral Gestagen treatment based on subjective (WHO criteria) and objective (prognostic data-based morphometric and stereological method/ D score, predicting the risk of cancer development for each single patient) evaluation. Method Women between 30 and 70 years with EH and D score > 0 were treated with levonorgestrel intrauterine device ( n = 26) and the results compared to a historic group of women treated with per-oral Gestagen ( n = 31). In both treatment groups only patients with low risk ( D score > 1) and uncertain risk ( D score=0–1) of cancer development were included. Endometrial specimens were investigated prior to treatment and after 3 months of therapy. The endometrial samples from the two groups were examined by light microscopy and objective data-based morphometry to assess tissue characteristics and to evaluate nuclear size variation. Results After 3 months all patients treated with levonorgestrel intrauterine device showed regression of hyperplasia, whereas 14 of 31 patients in the per-oral group still had persisting disease. The objective morphometric analysis showed reduction in nuclear size for both treatment groups, including the D score > 1 as well as the D score 0–1 patients. However, the reduction was most obvious for the levonorgestrel intrauterine device-treated patients with initial D score of 0–1. Conclusion The present study indicates that levonorgestrel intrauterine device is a superior alternative to per oral treatment of endometrial hyperplasia. By using objective morphometric treatment monitoring we have shown that the hyperplasia patients with the highest malignant potential ( D score=0–1) were those taking most benefit from local high-dose levonorgestrel therapy.
Rabe T - One of the best experts on this subject based on the ideXlab platform.
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Schwangerschaften während der Anwendung kontrazeptiver Methoden - Eine Stellungnahme der Deutschen Gesellschaft für Gynäkologische Endokrinologie und Fortpflanzungsmedizin (DGGEF) e.V. und des Berufsverbands der Frauenärzte (BVF) e.V.
Krause & Pachernegg GmbH, 2013Co-Authors: Rabe T, Goeckenjan M, Dikow N, Schaefer C, Merkle E, Merki G, Egarter C, König KAbstract:Alle kontrazeptiven Methoden bei der Frau weisen keine 100%ig zuverlässige Verhütungssicherheit auf. Eine Schwangerschaft während der Anwendung kontrazeptiver Methoden tritt unvorbereitet, unerwartet und gelegentlich auch über längere Zeit unerkannt auf. Innerhalb kurzer Zeit müssen das Risiko für die Schwangerschaft und ggf. für die Schwangere abgeschätzt und mögliche weitere Schädigungen des Embryos vermieden werden. Die Beratung wird durch die unzureichende Datenlage zu Schwangerschaften während der Anwendung kontrazeptiver Maßnahmen erschwert. Der Artikel gibt zunächst eine Übersicht über grundsätzliche Aspekte zur Teratogenität von Medikamenten und beschreibt anschließend die besonderen Risiken, die mit der unbeabsichtigten Anwendung kontrazeptiver Maßnahmen in der Schwangerschaft verbunden sind. Für hormonelle kombinierte Kontrazeption (oral, vaginal, transdermal) wird aktuell kein erhöhtes teratogenes Risiko bei der Anwendung in der Frühschwangerschaft angenommen. Hingegen wird für einige Gestagene bei therapeutisch hochdosierter Einnahme in der Frühschwangerschaft ein erhöhtes teratogenes Risiko diskutiert. Die Anwendung einer postkoitalen Kontrazeption mit reinen Gestagenen oder selektiven Progesteronrezeptor-Modulatoren scheint nach aktueller Datenlage nicht mit einem Risiko für den Embryo einherzugehen. Risiken für die Schwangerschaft bei liegendem Kupfer-haltigen IUP bestehen insbesondere in einer erhöhten Rate an Infektionen, Extrauteringraviditäten sowie Fehl- und Frühgeburten. Schwangerschaften unter einem korrekt liegenden Gestagen-freisetzenden Intrauterin-System sind zu selten, um eine klare Aussage zur möglichen Teratogenität des lokal wirksamen Gestagens zu treffen. Ziel dieser Übersicht ist es, neben der Beschreibung von Studien und Daten zur Wirkung von Kontrazeptiva auf eine Schwangerschaft, konkrete Vorgehensweisen, obligate Aspekte der Beratung und spezialisierte Beratungsstellen vorzustellen, die eine individuelle Risikobewertung für die einzelnen Methoden ermöglichen. Risikosituationen, wie bspw. Arzneimittelinteraktionen, die zu ungewollten Schwangerschaften während der Anwendung verschiedener hormonaler Kontrazeptiva führen, werden dargestellt. Diese Stellungnahme soll zur Orientierung bei der Beratung und Betreuung von Frauen im reproduktiven Alter dienen. Die meisten Schwangerschaften, die während der Nutzung kontrazeptiver Methoden eintreten, verlaufen ohne Komplikationen und die Schwangere kann diesbezüglich beruhigt werden; für komplexere Fragestellungen werden Handlungsvorschläge und Kontaktadressen vorgestellt
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Kontrazeption & Thrombophilie - Eine Stellungnahme der Deutschen Gesellschaft für Gynäkologische Endokrinologie und Fortpflanzungsmedizin (DGGEF) e. V. und des Berufsverbands für Frauenärzte (BVF) e.V.
Krause & Pachernegg GmbH, 2012Co-Authors: Rabe T, Luxembourg B, Ludwig M, Bauersachs R, Rott H, Albring CAbstract:Mehr als eine halbe Million Menschen sterben jährlich in der EU an venösen Thromboembolien (VTE), meist in höherem Alter oder im Zusammenhang mit Operationen, aber auch junge Frauen im reproduktiven Alter unter Anwendung hormonaler Kontrazeptiva. In einigen Teilen der Bevölkerung sind angeborene Störungen im Gerinnungssystem (Faktor-V-Leiden, Prothrombin-Mutation G20210A, Protein C-, Protein S- und Antithrombin-Mangel) für ein erhöhtes VTE-Risiko verantwortlich. Das VTE-Risiko wird durch folgende Faktoren beeinflusst: Langstreckenreisen, Immobilisierung, Lebensalter, Zigarettenrauchen, hoher Body Mass Index, Operationen, Krebserkrankungen, Flüssigkeitsverlust, Schwangerschaft, orale hormonale Kontrazeptiva, Hormonersatztherapie. Ein generelles Laborscreening für Thrombophilie vor Verordnung oraler Kontrazeptiva (OC) wird nicht empfohlen. Es sollte nur bei positiver Familienanamnese und/oder Eigenanamnese hinsichtlich VTE oder kardiovaskulärer Verschlusserkrankungen durchgeführt werden. Faktor-V-Leiden-Mutation ist die häufigste kongenitale Thrombophilie. Eine heterozygote Faktor-V-Leiden-Mutation (VTE-Risiko ca. 5-fach erhöht) findet man bei 313 %, eine homozygote (VTE-Risiko ca. 10-fach erhöht) bei 0,21 % der europäischen Bevölkerung. Prothrombin-Mutation G20210A: Autosomal dominant vererbte Mutation (ca. 2 % der Europäer) führt zu einem ca. 3-fachen Anstieg des VTE-Risikos. Das VTE-Risiko ist deutlich erhöht, wenn einer oder mehrere zusätzliche Risikofaktoren, wie Faktor- V-Leiden, Protein C-, Protein S- und Antithrombin- Mangel, vorliegen. Protein-C- und Protein-S-Mangel: Das Risiko venöser Thrombosen wird durch einen Protein C- oder Protein S-Mangel erhöht (Odds Ratio 315 bzw. 511). Antithrombin-Mangel führt in Abhängigkeit vom Typ des Antithrombin-Mangels zu einem 450-fach erhöhten VTE-Risiko. Orale hormonale Kontrazeptiva für Frauen enthalten meist Gestagene in Kombination mit oder ohne synthetische Östrogene (meist Ethinylestradiol [EE]), bzw. seit 2008 auch natürliche Östrogene (Estradiol bzw. ein Derivat Estradiolvalerat). Sie beeinflussen die Inzidenz von VTE bei gesunden Frauen (VTEFälle pro 10.000 Frauenjahre) wie folgt, vgl. Tab. 1: Kombinierte hormonale Kontrazeptiva (KOK): Kein methodenbedingter Risikoanstieg [34] (VTE-Fälle pro 10.000 Frauenjahre): Nicht hormonale Kontrazeptiva (z. B. Tubensterilisation, Kondome, Spermizide, Verhaltensmethoden, Kupfer-IUDs). Kein oder nur leicht erhöhtes Risiko [34]: Levonorgestrel-IUS, klassische Minipille, östrogenfreie Ovulationshemmer. Leicht erhöhtes Risiko [310]: KOK mit 50 µg EE und als Gestagen Norethisteron, Norethisteronazetat, Levonorgestrel, Norgestimat, Chlormadinonazetat und Dienogest, OCs mit Estradiolvalerat und Dienogest, kombinierter östrogen-/Gestagenhaltiger Vaginalring und DepotGestagene. Mäßig erhöhtes Risiko [614]: KOK mit 50 µg EE und als Gestagen Desogestrel, Gestoden, Cyproteronacetat, Drospirenon sowie kombiniertes östrogen-/Gestagenhaltiges Pflaster. Eine Vorauswahl von Frauen mit einem erhöhten VTE-Risiko anhand einer Familien- und Eigenanamnese ist vor jeder hormonalen Therapie absolut notwendig. Ein generelles Thrombophilie-Screening wird nicht empfohlen. Zusätzliche individuelle Risikofaktoren müssen berücksichtigt werden. Jede Patientin, die orale Kontrazeptiva einnimmt, sollte über die Risiken und deren Frühsymptome vaskulärer Verschlusserkrankungen beraten werden. Bei Patienten mit erhöhtem Thromboserisiko ist eine Risiko-Nutzen-Analyse erforderlich, unter Berücksichtigung nicht hormonaler Kontrazeptionsmethoden sowie nicht kontrazeptiver Vorteile einer Hormonbehandlung (KOK: z. B. Zyklusnormalisierung, weniger Dysmenorrhoe, Verbesserung der Akne). Eine gemeinsame Therapieentscheidung (shared decision making und informed consent) wird dringend empfohlen
Ralph Ruhl - One of the best experts on this subject based on the ideXlab platform.
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regulation of expression of the retinoic acid metabolizing enzyme cyp26a1 in uteri of ovariectomized mice after treatment with ovarian steroid hormones
Molecular Reproduction and Development, 2007Co-Authors: Pascal Dolle, Britta Fritzsche, Julien Vermot, Ulrike Neumann, Anja Schmidt, Florian J Schweigert, Ralph RuhlAbstract:The retinoic acid (RA) synthesizing enzymes, retinaldehyde dehydrogenases (RALDH), are expressed in specific spatial and temporal patterns in uterine tissues during estrous cycle and early pregnancy in mice. Expression of RALDH1 and 2 has been shown to be induced by estrogen treatment within the uterus. In this study, we determined the influence of progesterone and 17-s-estradiol on the uterine expression of the RA-metabolizing enzyme CYP26A1 after specific time intervals (1, 4, 24, and 48 hr after treatment of ovariectomized mice). In a following experiment, we investigated the influence of Gestagen (promegestone 0.3 mg/kg body weight), estrogen (estradiol 3 µg/kg), their combination, as well as the antagonizing anti-progesterone hormone (RU 486 10 mg/kg) on the uterine expression of CYP26A1. Expression of CYP26A1 was localized using in situ hybridization and quantified using RT-PCR. CYP26A1 mRNA expression was strongly—although transiently—induced in uterine endometrial epithelial and glandular cells after administration of Gestagen or the combination of Gestagen + estrogen, but not by estrogen alone. These observations were confirmed by semi-quantitative RT-PCR experiments on whole uteri. Thus, we show that the expression of CYP26A1 in endometrial epithelial cells is regulated by progesterone and not significantly influenced by co-administration of estrogen. These data indicate an additional level of hormonal control of endogenous RA levels in the mouse uterus, where its synthesis would rely on estrogen-dependent expression of RALDH enzymes, whereas its active metabolism would be triggered by progesterone-induced CYP26A1 expression. Mol. Reprod. Dev. © 2006 Wiley-Liss, Inc.
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Regulation of expression of the retinoic acid-synthesising enzymes retinaldehyde dehydrogenases in the uteri of ovariectomised mice after treatment with oestrogen, Gestagen and their combination.
Reproduction Fertility and Development, 2006Co-Authors: Ralph Ruhl, Britta Fritzsche, Julien Vermot, Ulrike Neumann, Anja Schmidt, Florian J Schweigert, Karen Niederreither, Pascal DolleAbstract:The active metabolite of vitamin A, retinoic acid (RA), plays an important role in the female reproductive system. The synthesis of RA is tightly regulated by the activity of retinaldehyde dehydrogenases (Raldh). Among these, Raldh1 and Raldh2 exhibit specific temporal and spatial expression patterns in the mouse uterus, both during the oestrous cycle and early pregnancy. In the present study, we have assessed whether oestradiol and progesterone directly influence the uterine expression of Raldh1 and Raldh2 in ovariectomised mice. We investigated the effect of Gestagen (promegestone 0.3 mg kg(-1) bodyweight), oestrogen (oestradiol 3 microg kg(-1) bodyweight) and their combination on the uterine expression of Raldh2. Expression was analysed using in situ hybridisation and quantified using real-time detection reverse transcription-polymerase chain reaction. The results show that the expression of Raldh2 is rapidly (within 1-4 h) induced in stromal cells by oestrogen, but not by Gestagen, treatment, whereas combined oestrogen + Gestagen treatment leads to a more prolonged (48 h) response. In contrast, oestrogen, but not progesterone, treatment downregulates (within 4-24 h) Raldh1 expression in the uterine glandular epithelium. We conclude that the uterine RA concentrations are regulated by oestrogens via an effect on the expression of the Raldh synthesising enzymes. Such a regulation is consistent with the natural fluctuations of Raldh expression during the oestrous cycle, early pregnancy and blastocyst implantation.