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ABSTRACT: To elucidate the mode of action of chlormadinone acetate (CMA) in reducing dysmenorrheic pain by studying the effects of CMA and dexamethasone (DEX) on messenger RNA (mRNA) abundance of cyclo-oxygenase-2 (COX-2), annexin-1 (ANXA1), glucocorticoid receptor (GR), progesterone receptor (PR), and concentrations of prostaglandin F(2α) (PGF(2α)) and leukotrienes B(4) (LTB(4)) and C(4) (LTC(4)) in human endometrial explants.
Ex vivo study.
University hospital.
Fifteen premenopausal patients undergoing surgery for benign gynecologic disorders.
Endometrial explants were obtained by aspiration curettage and stimulated ex vivo with interleukin-1β before exposure to CMA or DEX; mRNA levels were determined via reverse transcription-quantitative real-time polymerase chain reaction, and concentrations of arachidonic acid metabolites by enzyme immunoassays.
Messenger RNA levels of COX-2, ANXA1, PR, and GR; concentrations of PGF(2α), LTB(4), and LTC(4) in endometrial explants treated with CMA or DEX.
In IL-1β-treated explants COX-2 mRNA and PGF(2α), concentrations were significantly down-regulated by CMA but not by DEX. Chlormadinone acetate did not affect mRNA abundance of ANXA1, PR, and GR.
Our data suggest that CMA is a suppressor of COX-2 expression. Comparison with DEX revealed that progestin-specific activity of CMA may mainly be responsible for suppression of prostaglandin biosynthesis in human endometrium.
Fertility and sterility 07/2012; 98(4):1017-22. · 3.97 Impact Factor
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Wolfgang R Schäfer,
Lara Fischer,
Katrin Roth,
Antonia K Jüllig,
Johanna E Stuckenschneider,
Peter Schwartz,
Marc Weimer,
Marzenna Orlowska-Volk, Aida Hanjalic-Beck,
Iris Kranz,
Wolfgang R Deppert,
Hans P Zahradnik
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ABSTRACT: The human endometrium is unique among adult tissues. Its functions are modulated by numerous hormones and mediators. The aim of this study was to evaluate the suitability of human endometrial explants for studying functional effects of chemicals and drugs on gene expression biomarkers. Endometrial tissues were obtained by aspiration curettage and cultivated for up to 24 h. Relative mRNA concentrations were determined by reverse transcription quantitative real-time PCR. Viability was assessed by light microscopy, lactate dehydrogenase assay and scanning electron microscopy. It was acceptable after 6 h of culture but reduced after 24 h. Culture-induced alterations of mRNA levels were found for progesterone receptor, estrogen receptor(α), leukemia inhibitory factor and cyclooxygenase-2 in tissues from all cycle stages. The suitability of the model to detect chemical effects was demonstrated by the down-regulation of cyclooxygenase-2 mRNA by chlormadinone acetate in proliferative and secretory endometrium. The model is mainly restricted by interindividual variations and varying tissue quality. An advantage is the preservation of tissue composition. We conclude that human endometrial explants are a complex model due to limited viability, difficult standardization and intrinsic alterations during culture. Experiments with this model should be performed over a limited time period under strictly controlled conditions.
Molecular Human Reproduction 11/2010; 17(4):255-65. · 3.85 Impact Factor
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ABSTRACT: The objective of this study was to investigate the effect of metformin versus acarbose in terms of ovulation rate, their impact on hormonal and metabolic status and tolerability of both drugs in patients with polycystic ovary syndrome (PCOS). Seventy-five patients with PCOS were included in this prospective randomised controlled double-blinded clinical study. According to randomisation, patients were allocated to receive either metformin 2550 mg/day (n = 37) or acarbose 300 mg/day (n = 38) for 12 weeks. Primary study outcomes were ovulation rate, restoration of a regular menstrual cycle and the incidence of side effects. Secondary outcomes included treatment-related hormonal and metabolic changes. Comparable high rates of regular menstrual cycles as well as ovulation could be achieved in both groups (70% and 73% for metformin vs. 78% and 59% for acarbose, p = 0.330 and p = 0.185, respectively). In contrast, only in patients treated with metformin a statistically significant decrease in fasting insulin and cholesterol levels as well as BMI was observed. However, comparing both groups at the end of treatment, no significant differences in metabolic and/or hormonal parameters could be detected. Regarding side effects, the rate of flatulence and/or diarrhoea was significantly lower for acarbose compared to metformin (38% vs. 80%, p < 0.001).
Gynecological Endocrinology 09/2010; 26(9):690-7. · 1.58 Impact Factor
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ABSTRACT: This article is a comprehensive overview of dysmenorrhea and a systematic review of the available literature on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and hormonal contraceptives for the therapy and management of dysmenorrhea.
A comprehensive search of the PubMed database for clinical trials and observational studies of dysmenorrhea treatments from 2004 onwards.
Eighteen publications were identified. Ten randomized controlled trials (RCTs) assessing NSAIDs for treating primary dysmenorrhea demonstrated superior pain relief compared with placebo, but no superiority was established among different NSAIDS. Two RCTs and six nonrandomized observational or prospective studies assessing the effect of hormonal contraceptives on dysmenorrhea strongly suggest a beneficial effect for dysmenorrheic pain relief and were conducted mainly in larger populations (N=41-6169) than those in the NSAID trials (N=10-337). Ethinylestradiol/chlormadinone acetate was the only formulation that provided a more pronounced relief of dysmenorrheic pain compared with a parallel alternative or previously used hormonal contraceptive. Methodological inconsistencies were widespread between the hormonal contraceptive studies.
The findings of this review support the use of NSAIDs as a first-line therapy for pain relief from dysmenorrhea in women without wish for contraception. For women who wish contraception, combined oral contraceptives (COCs) are the preferential therapy for pain relief from dysmenorrhea as the additional noncontraceptive benefit of pain relief from dysmenorrhea is not linked to additional risks, eliminates the risks associated with taking NSAIDs and is a more suitable long-term option. Recommendations are made to strengthen the impact of future trials through improved methodology.
Contraception 03/2010; 81(3):185-96. · 2.72 Impact Factor
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ABSTRACT: The aim of this study was to investigate whether sphingosine-1-phosphate (S1P), an apoptosis-inhibitor would be able to protect ovarian follicles from hypoxia-induced cell death in ovarian transplantation.
In four sheep, both ovaries were removed and immediately transplanted back into the abdominal wall. In two of them, one ovary was treated with S1P locally by injection and incubation after dissecting the ovarian cortex. The contra lateral ovary of both sheep and both ovaries of the remaining sheep served as controls. After 2 weeks, all grafts were evaluated histologically.
Although the mean number of apoptotic cells were increased after grafting compared with fresh tissue, we were not able to demonstrate a significant difference regarding the follicular density in tissue with S1P treatment (mean number of follicles per field of view: 0.21 vs. 0.23, p = 0.909).
Apoptosis seems to play a role in follicular loss during ovarian transplantation; however, local application of S1P does not prevent primordial/primary follicles from hypoxia-induced cell death in cortical grafts in our study.
Gynecological Endocrinology 01/2009; 25(12):839-43. · 1.58 Impact Factor
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ABSTRACT: This open-label, noncontrolled study assessed the long-term efficacy and tolerability of the monophasic combined low-dose oral contraceptive (OC) ethinyl estradiol (EE) 30 mcg+chlormadinone acetate (CMA) 2 mg (Belara).
In total, 781 women who had already taken EE 30 mcg+CMA 2 mg for 24 cycles in a previous Phase III study were assessed for up to 45 cycles.
Over 23,033 cycles, the Pearl Index was 0.16 (95% confidence interval, 0.04-0.42). Approximately 86% of women had regular withdrawal bleeding in each cycle, while incidence of intracyclic bleedings (1.6-6.4%) and proportion of women with amenorrhea (4%) were low. The incidence of acne decreased from 13.8% to 5.7%, while rates of hirsutism, alopecia and seborrhea remained low (< or =4%) throughout this study. The most frequent adverse events were consistent with OC treatment, and no unexpected events occurred. No changes in mean blood pressure and pulse rate were observed during the study, and there were no clinically relevant changes in liver or hematological parameters, hemostasis or carbohydrate metabolism. The incidence of pathological findings in gynecological examination was low and decreased over time.
EE 30 mcg+CMA 2 mg was an effective and well-tolerated OC, with beneficial effects on cycle stability, intracyclic bleeding, amenorrhea and signs of androgenization that were maintained during long-term treatment for up to 5 years. There was no evidence of an increased risk of thromboembolic events, atherogenic disease or cervical cancer, suggesting that 30 EE mcg+CMA 2 mg is highly suitable for long-term use.
Contraception 05/2008; 77(5):337-43. · 2.72 Impact Factor
