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Johannes Bitzer,1 Maria Jesusa Banal-Silao,2 Hans-Joachim Ahrendt,3 Jaime Restrepo,4 Marion Hardtke,5 Ulrike Wissinger-Graefenhahn,6 Dietmar Trummer7 1Department of Obstetrics and Gynecology, University Hospital of Basel, Basel, Switzerland; 2University of the Philippines College of Medicine, Manila, Philippines; 3Praxis für Frauenheilkunde, Klinische Forschung und Weiterbildung (Clinical Research and Further Education), Magdeburg, Germany; 4Centro de Investigación Clínica, Clinica Medellin Poblado, Medellin, Colombia; 5Global Clinical Development Operations, Bayer Pharma AG, Berlin, Germany; 6Global Medical Affairs Women’s Healthcare, Bayer Pharma AG, Berlin, Germany; 7Clinical Statistics Europe, Bayer Pharma AG, Berlin, Germany Objective: To assess whether the combined oral contraceptive (COC) ethinylestradiol (EE) 20 µg/drospirenone 3 mg taken in a 24/4-day regimen (ie, 4-day hormone-free interval) is more effective than an EE 20 µg/desogestrel (DSG) 150 µg COC taken in a 21/7-day regimen (ie, 7-day hormone-free interval) in reducing hormone withdrawal-associated symptoms (HWAS).Methods: This double-blind, randomized study (NLM identifier: NCT01076582) was conducted at 34 centers in 12 countries. Otherwise healthy women who experienced ≥2 HWAS of headache, pelvic pain, and/or bloating when using their current COCs in a 21/7-day regimen were recruited. Subjects rated the severity of their HWAS daily on a seven-point Likert scale during a baseline cycle and during four 28-day cycles with EE/drospirenone 24/4 (n=290) or EE/DSG 21/7 (n=304). The primary variable was the mean change from baseline to cycle 4 in the composite HWAS score (sum of scores for all three symptoms) during cycle days 22–28.Results: In the EE/drospirenone 24/4 group, the mean (standard deviation) composite HWAS score during cycle days 22–28 was reduced from 42.2 (24.8) at baseline to 12.8 (13.4) at cycle 4 (change from baseline: -30.3 [22.9]). In the EE/DSG 21/7 group, the corresponding value was reduced from 41.9 (25.8) to 14.3 (13.2) (change from baseline: -27.7 [24.8]), not significantly different versus EE/drospirenone 24/4. Bleeding pattern, treatment response, rescue medication use, compliance, quality of life, and tolerability were similar between treatments.Conclusion: Both EE/drospirenone 24/4 and EE/DSG 21/7 reduced the composite HWAS score from baseline to cycle 4 in otherwise healthy women. The differences between treatments were too small to be statistically significant.Keywords: combined oral contraceptives, ethinylestradiol, drospirenone, desogestrel, hormone withdrawal

Jeffrey T Jensen,1 Johannes Bitzer,2 Marco Serrani3 1Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA; 2Department of Social Medicine and Psychosomatics, Women’s Hospital, University Hospital of Basel, Basel, Switzerland; 3Global Medical Affairs, Women’s Healthcare, Bayer HealthCare Pharmaceuticals, Berlin, Germany Abstract: Three estradiol (E2)-containing oral contraceptives, estradiol valerate/cyproterone acetate (E2V/CPA, Femilar®), estradiol valerate/dienogest (E2V/DNG, Qlaira®/Natazia™), and estradiol/nomegestrol acetate (E2/NOMAC; Zoely®), have received approval for use in general practice. Only Finnish women currently have access to all three E2-based formulations. E2/NOMAC is currently approved only in Europe, while E2V/DNG is approved globally. To assist clinicians counseling women considering use of one of these formulations, we conducted a review of the published information about the current E2-containing oral contraceptives. A literature search was conducted using the Ovid interface and a combination of free search terms relevant to estradiol and oral contraception to identify suitable articles for inclusion in this review. The available data show that E2V/DNG, E2/NOMAC, and E2V/CPA are all effective oral contraceptives. While direct comparisons are lacking, indirect evidence suggests that E2V/DNG and E2/NOMAC may have better bleeding profiles than E2V/CPA. E2V/DNG is also approved for the treatment of heavy menstrual bleeding. Both E2V/DNG and E2/NOMAC have minimal influence on hemostatic, lipid, and carbohydrate metabolism parameters, or induce less change in these parameters relative to ethinylestradiol-based oral contraceptives. However, the predictive value of these surrogate parameters is a matter of debate, and whether these differences can be translated into meaningful clinical outcomes needs to be established in large-scale, post-marketing, prospective, Phase IV cohort studies. Future studies are required to determine whether E2-based oral contraceptives confer additional benefits compared with those of ethinylestradiol-based COCs. Keywords: estradiol valerate, dienogest, nomegestrol acetate, cyproterone acetate

Johannes Bitzer,1 Marco Serrani,2 Annalena Lahav2 1Universitats-Frauenspital Basel, Basel, Switzerland; 2Bayer HealthCare AG, Berlin, Germany Abstract: The aim of this study was to gain an in-depth understanding of women's current knowledge, attitudes, and beliefs around heavy menstrual bleeding (HMB) and gain a further understanding of how HMB affects women's lives, while identifying current misconceptions and gaps in the knowledge. A total of 6179 women, 18–55 years old, currently using, or open to using, hormonal contraception at the time of the study, were recruited from 15 countries. All participants completed a 52 question online survey designed to assess the impact of HMB on quality of life, as well as current levels of awareness and knowledge of this condition. Of the women who perceived themselves as having above average menstrual flow, a significantly greater proportion identified their menstrual bleeding as problematic compared to those women who perceived themselves as having below average menstrual flow. Further questioning indicated that the impact of diagnosed or perceived HMB stretched across multiple aspects of women's lives, including social life, relationships, and work, with significantly greater proportions of women reporting negative effects in these domains in the above average menstrual flow subgroup relative to the below average menstrual flow subgroup (P < 0.05). In addition, awareness and understanding of HMB within the survey population were found to be poor, with 48% of participants claiming that they were "not at all" or "not very" knowledgeable regarding HMB and 39% of those diagnosed with the condition believed that no treatment was available to them. This study confirms previous findings indicating that HMB has a profound negative effect on many aspects of women's lives and shows that, despite its common occurrence, gaps in women's current knowledge and understanding of HMB remain. Keywords: menorrhagia, quality of life, (QoL), menstrual flow

Johannes Bitzer,1 Ariane von Stenglin,2 Ralf Bannemerschult3 1Department of Obstetrics and Gynecology, University Women’s Hospital of Basel, Basel, Switzerland; 2Global Market Research, Bayer HealthCare Pharmaceuticals, Berlin, Germany; 3Women’s Healthcare Medical Affairs and Pharmacovigilance Region Europe, Bayer HealthCare Pharmaceuticals, Berlin, Germany Objective: To investigate the awareness and use of folic acid in European women of child-bearing age, particularly in the setting of pregnancy and pregnancy planning. Methods: Between November 2009 and December 2009, women aged 15–49 years old from 18 European countries completed a 30-minute structured questionnaire either online or via face-to-face interviews. To achieve nationally representative samples for each country quotas were set for age, education, income, and regional distribution. Results: A total of 22,925 women participated in the survey. Of the respondents, 58% had at least one biological child, and of these 38% reported that their first pregnancy was not planned. Nearly 60% of women who planned their pregnancy indicated that they had stopped using their method of contraception without first consulting a doctor or another health care professional. Overall, 70% reported that they had heard of folic acid and 40% stated that they knew the benefits of folic acid. However, when prompted to indicate which diseases and/or birth defects folic acid can protect against, only 17% knew that folic acid can reduce the risk of neural tube defects/spina bifida. Conclusions: A large proportion of European women of child-bearing age in this survey were unaware that periconceptional folic acid supplementation reduces the risk of birth defects. Keywords: folic acid supplementation, neural tube defects, pregnancy, women, periconceptional period, survey

Johannes Bitzer1, Susanne Parke2, Thomas Roemer3, Marco Serrani21University Hospital of Basel, Women's Clinic, Basel, Switzerland; 2Global Clinical Development, Bayer HealthCare Pharmaceuticals, Berlin, Germany; 3Head of the Department of Gynecology and Obstetrics, Evangelist Hospital Cologne-Weyertal, Cologne, GermanyBackground: The purpose of this study was to investigate the endometrial safety of an oral contraceptive containing estradiol valerate/dienogest (E2V/DNG) administered as an estrogen step-down and progestogen step-up regimen in women of reproductive age (18–50 years), using histological assessment of endometrial biopsy samples.Methods: Endometrial biopsies were taken in a subset of healthy women who took part in a multicenter, open-label, noncomparative study assessing the contraceptive efficacy and safety of an E2V/DNG oral contraceptive. In each 28-day cycle, women received E2V 3 mg on days 1–2, 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 25–26, and placebo on days 27–28. Women underwent endometrial biopsy between days 12 and 19 of the cycle, both at screening and at cycle 20 (or at the final examination).Results: Of the 283 women who underwent an endometrial biopsy at screening, 218 underwent a follow-up biopsy at cycle 20. At screening, abnormal biopsy results, both classified as ‘simple hyperplasia without atypia’, were seen in two women, who were withdrawn from the trial. At cycle 20, there were no abnormal findings of endometrial hyperplasia or malignancy, and 80.9% of women had atrophic, inactive, or secretory endometrium.Conclusion: After 20 cycles of treatment, an oral contraceptive containing E2V and DNG is safe and effective to transform the endometrium into a secretory/inactive or atrophic status, and exhibits no deleterious effects on endometrial histology in women aged 18–50 years.Keywords: estradiol valerate, dienogest, endometrial safety, oral contraceptive

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