Metformin versus acarbose therapy in patients with polycystic ovary syndrome (PCOS): a prospective randomised double-blind study.

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).

Effects of different progestins on prostaglandin biosynthesis in human endometrial explants.

OBJECTIVE: To compare the effects of chlormadinone acetate (CMA), dienogest (DNG) and drospirenone (DRSP) on prostaglandin biosynthesis in a human endometrial explants model. STUDY DESIGN: Human endometrial explants obtained by aspiration curettage and human endometrial YHES cells were stimulated with interleukin-1ß (IL-1ß) and exposed to CMA, DNG, DRSP or dexamethasone (DEX; YHES cells). Cellular messenger RNA (mRNA) levels of cyclooxygenase-2 (COX-2) were analyzed by reverse-transcription quantitative real-time polymerase chain reaction. Concentrations of prostaglandin F2α (PGF2α) in culture supernatants were measured by enzyme-linked immunosorbent assay. RESULTS: CMA exerted after IL-1ß stimulation a stronger down-regulation of COX-2 mRNA compared to DNG and DRSP in human explants (-55% vs. -40% and 46%, respectively). The effect of CMA on COX-2 mRNA was significantly stronger (p=.025) than that of DNG. Moreover, the effect of CMA was independent from cycle phase or presence of endometriosis. In order to evaluate the impact of the investigated progestins on effector molecules, PGF2α release was determined in supernatants. Again, CMA reduced the PGF2α release significantly by an average of -60% (p<.01). In contrast, no significant reduction was found for DNG and DRSP. In YHES cells, only DEX but not the progestins under study exerted a significant down-regulating effect (-79%, p<.01) on COX-2 mRNA after IL-1ß stimulation. CONCLUSION: Among the tested progestins, CMA displayed the most consistent suppression of prostaglandin biosynthesis in human endometrial explants. IMPLICATION: Among three tested progestins, chlormadinone acetate had the most consistent suppressive effect on prostaglandins in endometrial explants. These findings support clinical observations about the efficacy of chlormadinone acetate in dysmenorrhea treatment.

Efficacy, safety and sustainability of treatment continuation and results of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg chlormadinone acetate, in long-term usage (up to 45 cycles)--an open-label, prospective, noncontrolled, office-based Phase III study.

BACKGROUND: 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). STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Nitric oxide detection by DAF (diaminofluorescein) fluorescence in human myometrial tissue.

Nitric oxide (NO) is considered to be involved in the modulation of uterine contractility. In the present pilot study, the direct detection of intracellular NO in pregnant human myometrial tissues has been investigated by using the fluorescent indicator 4,5-diaminofluorescein-2 diacetate (DAF-2DA). Pregnant myometrial tissue samples were obtained during Cesarean sections between week 34 and 40 of gestation before the onset of labor. Living explants were loaded with 10 microM DAF-2DA, stimulated with 1 mM arginine, subsequently fixed with glutaraldehyde and examined by fluorescence microscopy. The presence of NO synthases (NOS) was studied by immunohistochemistry. After application of DAF-2DA, DAF fluorescence was located primarily in blood vessels and to a minor extent in myometrial cells. By immunohistochemistry, strong endothelial NOS (eNOS) staining was found in vessel walls. In myometrial cells weak staining of eNOS and inducible NOS was observed. We conclude that the direct NO detection by DAF-2DA provides a new and independent method to identify sites of NO production in myometrium and other heterogeneous tissues.

Effect of a weight loss intervention on anthropometric measures and metabolic risk factors in pre- versus postmenopausal women.

BACKGROUND: The present study examines changes in body weight, fat mass, metabolic and hormonal parameters in overweight and obese pre- and postmenopausal women who participated in a weight loss intervention. METHODS: Seventy-two subjects were included in the analysis of this single arm study (premenopausal: 22 women, age 43.7 +/- 6.4 years, BMI 31.0 +/- 2.4 kg/m2; postmenopausal: 50 women, age 58.2 +/- 5.1 years, BMI 32.9 +/- 3.7 kg/m2). Weight reduction was achieved by the use of a meal replacement and fat-reduced diet. In addition, from week 6 to 24 participants attended a guided exercise program. Body composition was analyzed with the Bod Pod(R). Blood pressures were taken at every visit and blood was collected at baseline and closeout of the study to evaluate lipids, insulin, cortisol and leptin levels. RESULTS: BMI, fat mass, waist circumference, systolic blood pressure, triglycerides, glucose, leptin and cortisol were higher in the postmenopausal women at baseline. Both groups achieved a substantial and comparable weight loss (pre- vs. postmenopausal: 6.7 +/- 4.9 vs 6.7 +/- 4.4 kg; n.s.). However, in contrast to premenopausal women, weight loss in postmenopausal women was exclusively due to a reduction of fat mass (-5.3 +/- 5.1 vs -6.6 +/- 4.1 kg; p < 0.01). In premenopausal women 21% of weight loss was attributed to a reduction in lean body mass. Blood pressure, triglycerides, HDL-cholesterol, and glucose improved significantly only in postmenopausal women whereas total cholesterol and LDL-cholesterol were lowered significantly in both groups. CONCLUSION: Both groups showed comparable weight loss and in postmenopausal women weight loss was associated with a pronounced improvement in metabolic risk factors thereby reducing the prevalence of metabolic syndrome.

Triglyceride-rich lipoproteins are associated with hypertension in preeclampsia.

Disorders of the lipoprotein metabolism are a major cause of endothelial dysfunction that may result in hypertension and proteinuria, clinical hallmarks of preeclampsia (PE). Lipoproteins and low-density lipoprotein (LDL) subfractions were investigated in 15 women with severe PE and compared with 23 women with a normal course of pregnancy. Compared with normal pregnancy, in PE apolipoprotein (apo)B in very low-density lipoprotein was increased by 76% (P = 0.008), and the triglyceride content of intermediate dense lipoproteins (IDL) was increased by 51% (P < 0.001); cholesterol and apoB in LDL were decreased by 26% (P = 0.005) and 23% (P = 0.016), respectively. Although not significant, the LDL profile was dominated by the most buoyant LDL-1. ApoB in the most dense LDL (dLDL), namely LDL-5 and LDL-6, was significantly decreased by 49% (P < 0.001) and 55% (P < 0.001), respectively. Diastolic blood pressure was positively correlated with the triglyceride content of IDL (r = 6.31; P < 0.001 and r = 0.352; P = 0.033 by partial correlation controlling for the presence or absence of PE) and negatively correlated with the concentration of apoB in dLDL (r = -0.500; P = 0.002). In addition, IDL triglycerides correlated negatively with infant birth weight percentile (r = -0.373; P = 0.027) and positively with proteinuria (r = 0.430; P = 0.014). Low birth weight was associated with high IDL triglycerides and low rather than high concentrations of dLDL. Triglyceride-rich remnants are known to cause endothelial dysfunction. Because the triglyceride content of IDL was positively correlated with elevated blood pressure and proteinuria, triglyceride-rich remnant lipoproteins might contribute to the pathophysiology of PE.

Transient remnant removal disease in acute fatty liver of pregnancy.

OBJECTIVE: To elucidate the potential role of an altered lipid metabolism in the pathophysiology of acute fatty liver of pregnancy (AFLP). CASE REPORT: We report on two otherwise healthy women in the 34th gestational week who presented with symptoms of AFLP. Besides characteristic symptoms like nausea, abdominal pain, highly elevated serum amino transferase levels, and increased creatinine concentrations, the patients' clotting system showed consumption and/or decreased synthesis of coagulation factors. Pregnancies were terminated by elective cesarean section because of worsening symptoms. Blood tests normalized quickly and both the mothers and their baby boys could be dismissed in healthy condition. STUDY DESIGN: Blood samples were collected shortly before delivery and 5, 15, 70, and 110 days afterwards. Lipids and apolipoproteins (apo) were analyzed in whole plasma as well as in very low density, intermediate density, low density (LDL), and high density lipoprotein. Total LDL was further separated into 6 LDL subfractions by equilibrium density ultracentrifugation. RESULTS: Before delivery, the LDL subfraction pattern was characterized by the virtual absence of intermediate and most dense LDL. Lipoprotein electrophoresis showed the presence of beta-migrating VLDL. Within days after delivery, the distribution of apoB-containing lipoproteins returned to normal. Genetic variations of apoE, lipoprotein lipases, and the long-chain 3-hydroxyacyl-coenzyme A dehydrogenase were not detected in any of the patients. CONCLUSIONS: The lipoprotein metabolism in the acute phase of AFLP was reminiscent of hepatic lipase deficiency, a disorder characterized by impaired removal of lipoprotein remnants. As these triglyceride-rich particles cause endothelial dysfunction, they may contribute to the pathophysiology of AFLP.

Nonsteroidal anti-inflammatory drugs and hormonal contraceptives for pain relief from dysmenorrhea: a review.

BACKGROUND: 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. STUDY DESIGN: A comprehensive search of the PubMed database for clinical trials and observational studies of dysmenorrhea treatments from 2004 onwards. RESULTS: 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. CONCLUSIONS: 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.

Beneficios no anticonceptivos de 0, 02 mg de etinilestradiol/2 mg de acetato de clormadinona administrados en un régimen de 24+4 días / Non-contraceptive benefits of 0.02 mg ethinylestradiol /2 mg chlormadinone acetate in a 24 +4 days intake regimen

Objetivo: Demostrar la influencia sobre las molestias emocionales y físicas (beneficios no anticonceptivos) experimentadas durante el primer año de uso de un anticonceptivo oral combinado (AOC) que contiene 0,02 mg de etinilestradiol (EE) y 2 mg de acetato de clormadinona (ACM) administrado en un régimen de 24 + 4 días de placebo. Diseño del estudio: Análisis adicional de las sensaciones subjetivas registradas en los diarios de 1665 participantes de un estudio de Fase III multicéntrico, no controlado, de administración múltiple, después de 13 ciclos de EE/ACM en un régimen de administración de 24 + 4 días, publicado previamente. Resultados: Se informó de menor frecuencia de molestias emocionales y físicas en el ciclo de medicación 13 en comparación con los datos en la admisión y en el ciclo 1. La incidencia de ánimo depresivo se redujo en 84,5 por ciento y 72,2 por ciento respectivamente, y la irritabilidad en 87,3 por ciento y 66,0 por ciento. Las cefaleas se redujeron en 75,5 por ciento y 74,7 por ciento, las molestias mamarias en 77,1 por ciento y 66,1 por ciento, y la dismenorrea preexistente en 77,9 por ciento y 67,6 por ciento respectivamente. El abandono prematuro del estudio a causa de las molestias fue marginal, y el perfil del sangrado fue aceptable. Conclusiones: Un AOC de baja dosis que contiene 0,02 mg de EE + 2 mg de ACM, administrado en un régimen de 24 + 4 días, reduce significativamente la mayor parte de las molestias emocionales y físicas que se presentan durante los ciclos espontáneos de las mujeres, y se combina con un adecuado perfil de sangrado.

Objective: To demonstrate the influence on physical and psychological complaints during the first year of intake of the combined oral contraceptive (COC) 0.02 mg ethinylestradiol (EE)/2 mg chlormadinone acetate (CMA), administered in a regimen of 24 days of CMA/EE intake followed by 4 days of placebo intake. Study design: The subjective feelings of non-contraceptive benefits registered in women's diaries of 1,665 subjects participating in a multicentre, uncontrolled, multiadministration, Phase III trial, published elsewhere, were analyzed post-hoc after 13 cycles intake of EE/CMA in a 24 +4 days intake regimen. Results: Emotional complaints were reported less frequently at medication cycle 13 compared with admission and cycle 1. Depressive mood was reduced by 84.5 percent and 72.2 percent, irritability by 87.3 percent and 66.0 percent; physical complaints were also reduced: headaches by 75.5 percent and 74.7 percent, breast discomfort by 77.1 percent and 66.1 percent; pre-existing dysmenorrhea by 77.9 percent and 67.6 percent. Premature termination due to complaints was only marginal, the bleeding profile was accepted. Conclusions: The low-dose COC, 0.02 mg EE/2 mg CMA, administered in a 24 +4 day regimen, reduces significantly most of the emotional and physical complaints occurring during spontaneous cycles of women, combined with an adequate bleeding profile.

Evaluation of different strategies for real-time RT-PCR expression analysis of corticotropin-releasing hormone and related proteins in human gestational tissues.

In this article real-time quantitative RT-PCR strategies for investigation of mRNA distribution in stress-related corticotropin-releasing hormone (CRH), CRH-binding protein (CRH-BP), and CRH receptors (CRH-R1, CRH-R2) in human gestational tissues are described. The effect of sample and RNA preparation, reverse transcription, and the quantitation strategy were investigated. Both thawing of the sample before homogenization and the RT reaction were identified as critical steps. In contrast, the time-lag from the biopsy until snap-freezing and the homogenization procedure had little effect. The "housekeeping" gene cyclophilin was found to be differently expressed in gestational tissues, compromising its use as internal reference. For relative quantitation of mRNA levels by TaqMan PCR the standard curve method and the comparative C (T) method (DeltaDeltaC (T) or DeltaC (T)' method) were compared. Both calculation strategies delivered similar relative mRNA amounts in identifying the placenta as the main source of CRH and CRH-BP mRNA compared with myometrium and decidua. Consistent results were also obtained for CRH-R1 and CRH-R2 by both methods of calculation. We conclude that the simpler comparative C (T) method is adequate for assessing the mRNA levels of CRH, CRH-BP, and CRH receptors in human gestational tissues.