Effective treatment of heavy and/or prolonged menstrual bleeding without organic cause: pooled analysis of two multinational, randomised, double-blind, placebo-controlled trials of oestradiol valerate and dienogest.

OBJECTIVES: To evaluate the efficacy of oestradiol valerate/dienogest (E2V/DNG) for the treatment of heavy and/or prolonged menstrual bleeding without organic pathology based on the analysis of data from two identically designed double-blind, randomised studies. METHODS: Women aged ≥ 18 years with heavy and/or prolonged menstrual bleeding were randomised to E2V/DNG (n = 269) or placebo (n = 152) for 196 days. Objective changes in menstrual blood loss (MBL) volume were assessed using the alkaline haematin method. RESULTS: After six months of treatment, median MBL decreased by 88% with E2V/DNG compared with 24% with placebo. The greatest reduction was achieved at the first withdrawal bleed after treatment initiation and it was sustained with no loss of effect throughout treatment. CONCLUSION: E2V/DNG was more effective than placebo in reducing MBL in women with heavy and/or prolonged menstrual bleeding without organic pathology. The reduction was largely achieved as early as the first withdrawal bleed, with further gradual improvement throughout treatment.

Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trial.

OBJECTIVE: To estimate the efficacy of a fixed estrogen step-down and progestin step-up 28-day estradiol (E2) valerate and dienogest oral contraceptive regimen in women with heavy menstrual bleeding, prolonged menstrual bleeding, or heavy and prolonged menstrual bleeding without organic pathology. METHODS: This double-blind, placebo-controlled study randomized women aged 18 years or older with prolonged, frequent, or heavy menstrual bleeding, objectively confirmed during a 90-day run-in phase, to treatment with E2 valerate and dienogest or placebo (2:1) for 196 days. Data from the last 90 days of treatment and the run-in phase were compared. The primary variable was the "complete response" rate (complete resolution of qualifying abnormal menstrual symptoms, including a 50% or greater reduction in pretreatment menstrual blood loss volume in women with heavy menstrual bleeding). Secondary variables included objective changes in menstrual blood loss volume (alkaline hematin methodology) and iron metabolism parameters. Overall, 180 women were needed to provide 90% power. RESULTS: There were no marked differences in the characteristics of E2 valerate and dienogest (n=120) and placebo (n=70) recipients. The proportion of "complete responders" in the evaluable group was significantly higher in E2 valerate and dienogest (35/80; 43.8%) compared with placebo (2/48, 4.2%, P<.001) recipients. The mean [standard deviation] reduction in menstrual blood loss with E2 valerate and dienogest from the run-in phase to the efficacy phase was substantial (-353 mL [309 mL]; mean -64.2%; median -70.6%) and significantly greater than that in placebo recipients (-130 mL [338 mL]; mean -7.8%; median -18.7%; P<.001). Significant improvements in hemoglobin, hematocrit, and ferritin were seen with E2 valerate and dienogest, but not with placebo. CONCLUSION: Oral E2 valerate and dienogest was highly effective compared with placebo in the treatment of women with heavy menstrual bleeding, prolonged menstrual bleeding, or heavy and prolonged menstrual bleeding without organic pathology. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00293059. LEVEL OF EVIDENCE: I.

Efficacy and safety of a novel oral contraceptive based on oestradiol (oestradiol valerate/dienogest): a Phase III trial.

OBJECTIVE: A novel oral contraceptive (OC) that contains oestradiol valerate (E2V; 1 mg of E2V is equivalent to 0.76 mg of 17beta-oestradiol) and dienogest (DNG) has been developed. The efficacy and safety of this formulation was assessed in the current study. STUDY DESIGN: This was a multicentre, open-label, non-comparative, 20-cycle study conducted in Germany, Austria and Spain in healthy women aged 18-50 years. E2V/DNG was administered using an oestrogen step-down and a progestin step-up approach over 26 days (E2V 3 mg on days 1 and 2, E2V 2 mg/DNG 2 mg on days 3-7, E2V 2 mg/DNG 3 mg on days 8-24, E2V 1 mg on days 25 and 26 and placebo on days 27 and 28). The primary outcome measure was the number of pregnancies during treatment in the whole study population and in the subgroup of women aged 18-35 years. Contraceptive efficacy was estimated by calculating the Pearl Index (number of pregnancies per 100 women-years of exposure). At a final examination, treatment satisfaction was assessed. RESULTS: In total, 1377 women received study treatment. During the study, thirteen pregnancies occurred (unadjusted Pearl Index: 0.73). Six of these were due to method failure (adjusted Pearl Index: 0.34). In the subgroup of 998 women aged 18-35 years, 12 pregnancies occurred (unadjusted Pearl Index: 0.94), five of which were due to method failure (adjusted Pearl Index: 0.40). The majority of women (79.5%) were satisfied or very satisfied with treatment. Treatment-related adverse events (considered at least possibly treatment-related) occurred in 19.8% of women. Overall, during 20 cycles of treatment, only 10.2% of women prematurely discontinued treatment due to an adverse event. CONCLUSIONS: A novel OC based on oestradiol provides highly effective and reliable contraception. This is achieved through the combination of oestradiol valerate (E2V) and dienogest (DNG) administered using an oestrogen step-down and a progestin step-up approach over 26 days of active treatment followed by 2 days of placebo. The preparation is well tolerated and is associated with a high degree of user satisfaction and a low discontinuation rate.

Adipocyte fatty acid-binding protein is associated with markers of obesity, but is an unlikely link between obesity, insulin resistance, and hyperandrogenism in polycystic ovary syndrome women.

OBJECTIVE: Many polycystic ovary syndrome (PCOS) women suffer from adiposity and insulin resistance (IR), which play an important role in the development and maintenance of PCOS. Adipocyte fatty acid-binding protein (A-FABP) is mainly expressed in adipocytes, and circulating A-FABP has been associated with markers of obesity and IR. Thus, as observed with other adipose tissue derived factors, secreted A-FABP might be involved in the pathogenesis of obesity-associated disorders such as PCOS. DESIGN: Plasma A-FABP concentrations were measured in 102 non-diabetic PCOS women, and associations with markers of obesity, IR, inflammation, and hyperandrogenism were investigated by correlation and multiple linear regression analyses. The effect of lifestyle intervention on A-FABP was studied in a second cohort of 17 obese PCOS women. RESULTS: A-FABP correlated with body mass index (BMI; R = 0.694, P < 0.001), dual-energy X-ray-absorptiometry (DEXA) fat mass (R = 0.729, P < 0.001), DEXA lean body mass (R = 0.399, P = 0.001), HOMA %S (R = -0.435, P < 0.001), hsCRP (R = 0.355, P = 0.001), and free testosterone (fT; R = 0.230, P = 0.02). Adjusted for age, smoking, and glucose metabolism the association of A-FABP with HOMA %S was still significant (P < 0.001), whereas the associations with fT (P = 0.09) and hsCRP (P = 0.25) were not. Inclusion of BMI into the model abolished the impact of A-FABP on HOMA %S. In BMI-matched PCOS women (n = 20 pairs), neither HOMA %S (P = 0.3) nor fT (P = 0.6) were different despite different A-FABP levels (P < 0.001), and in 17 obese PCOS women undergoing a lifestyle intervention, changes in IR were not paralleled by changes in A-FABP. CONCLUSIONS: Circulating A-FABP was correlated with markers of obesity, but had no major impact on IR, inflammation, or hyperandrogenemia in PCOS women.

Prenatal diagnosis of trisomy 1q21-qter: case report and review of literature.

We report on a midtrimester fetus with multiple malformations, who was prenatally found to have pure partial trisomy 1q with duplication 1q21-qter. Prenatal ultrasound at 23 gestational weeks demonstrated craniofacial dysmorphism, ventriculomegaly, hand anomalies, and multiple visceral anomalies including cardiac defect, duodenal atresia, omphalocele, and urethral obstruction in the fetus. After pregnancy termination, external morphologic examination confirmed the sonographic characteristics, but autopsy was refused. Cytogenetic analysis (GTG banding) and subtelomeric probes (FISH) demonstrated an aberrant karyotype 46,XY,der(1)(1qter --> 1q21::1p36.3 --> 1qter) in a total of 139 amniotic fluid cells. Trisomy of the long arm of chromosome 1 is a rare condition. Large duplications of almost the entire 1q had so far been described in five mosaic cases. The present case and review of the literature suggest that duplication 1q21-qter is a serious condition with pre- or perinatal demise of all reported cases. This case further delineates the phenotype in trisomy 1q.