Teaching breast ultrasound skills including core-needle biopsies on a phantom enhances undergraduate student's knowledge and learning satisfaction.

PURPOSE: To investigate whether a training program on breast ultrasound skills including core-needle biopsies to undergraduate students can improve medical knowledge and learning satisfaction. METHODS: Medical students attending mandatory classes at the Medical School of the University of Saarland received a supplemental theoretical and hands-on training program on ultrasound (US) breast screening and on US-guided core-needle biopsy using an agar-agar phantom. Experienced breast specialists and ultrasound examiners served as trainers applying Peyton's 4-step training approach. The students' theoretical knowledge and hands-on skills were tested before and after the training program, using a multiple-choice questionnaire (MCQ), the Objective Structured Clinical Examination (OSCE) and a student curriculum evaluation. RESULTS: The MCQ results showed a significant increase of the student's theoretical knowledge (50.2-75.2%, p < 0.001). After the course, the OSCE showed a mean total of 17.3/20 points (86.5%), confirming the practical implementation of the new skills. The student curriculum evaluation in general was very positive. A total of 16/20 questions were rated between 1.2 and 1.7 (very good) and 3 questions were rated as 2.1 (good). CONCLUSION: Undergraduate student's medical education can be enhanced by teaching breast US skills.

Efficacy and safety of two post-operative drains: results of a prospectively randomized clinical study in breast cancer patients after breast conserving surgery.

OBJECTIVE: To compare the efficacy and safety of two post-operative drains in breast cancer patients after breast conserving surgery. METHODS: This was a prospectively randomized comparative study of two drains investigated in breast cancer patients after breast conserving therapy. The Redon drain ends in a tip with 28 double perforations while the Quadrain drain features 4 flexible flaps of about 0.15 m length. The drains cost 0.28 € and 3.54 €, respectively. Primary target parameter was the duration of the drains staying in the surgical site. Secondary target parameters were pain post-surgery, seroma volume, final cosmetic result and surgical site infections. RESULTS: A total of 88 patients were randomized, 47 and 41 received the Redon drain and the Quadrain drain, respectively. The mean duration of the drains staying in the surgical site was not different between the Redon and the Quadrain drain, 42.6 h (± 25.8 h) and 50.1 h (± 28.5 h), respectively (p = 0.1959). The post-operative pain score, seroma size, cosmetic result and surgical site infections were not different for both systems. CONCLUSION: The Redon drain and the new Quadrain drain were not significantly different with respect to duration in the surgical site, post-operative pain, seroma volume and cosmetic result.

Safety and perioperative morbidity of laparoscopic sacropexy: a systematic analysis and a comparison with laparoscopic hysterectomy.

PURPOSE: The high prevalence of Pelvic Organ Prolapse (POP) along with the demographic trend of the ageing population raises the value of sacropexy in the treatment of POP. Thus, efforts to decrease risks associated with this procedure have the potential for public health impact. We examined the perioperative morbidity of laparoscopic sacropexy regarding the surgical access and compared it with the morbidity of one of the most common gynecological procedure, the laparoscopic hysterectomy. Our aim was to prove the safety of laparoscopic sacropexy. METHODS: A retrospective evaluation of 80 consecutive laparoscopic sacropexies performed from Sept. 2012 until Oct. 2014 and 126 laparoscopic hysterectomies for a benign indication were undertaken. We assessed the anatomical outcome and the intra- and postoperative complications using the classification system according to Clavien-Dindo (CD). RESULTS: Apical success rate after sacropexy was 100% and global success rate was 95% (POP-Q stage ≤1). The decline in hemoglobin was low in both groups and showed no statistically significant differences. Both operative time (P < 0.001) and the duration of hospitalization (P < 0.001) were longer in case of a sacropexy. Although overall intraoperative complications seemed more frequent during a sacropexy, differences were not statistically significant. Both early and late postoperative complications showed a higher rate of mild complications (CD-I/II) and a lower rate of severe complications (CD-IIIa/IIIb) after a sacropexy. The differences were not statistically significant. CONCLUSION: The laparoscopic sacropexy represents a safe procedure with good anatomical outcome. Despite higher technical severity, it doesn't seem to bare higher risks for perioperative morbidity than the laparoscopic hysterectomy does.

0.5 vs. 1.0 mg estradiol in combination with drospirenone for the treatment of hot flushes.

OBJECTIVE: To compare the efficacy of 0.5 and 1.0 mg estradiol in combination with different doses of drospirenone for the treatment of menopausal hot flushes. METHODS: This retrospective analysis included data from two prospective, randomized, double-blind, multicenter, placebo-controlled studies. Inclusion criteria were seven to eight moderate to severe hot flushes per day during the 1-week screening period. The focus was the rate of responders. A responder was defined as a subject that had at least a perceptible improvement of 19.1 hot flushes per week at 4 weeks and a substantial improvement of 40.3 hot flushes per week at 12 weeks compared to baseline. Secondary focus was the absolute change of moderate to severe hot flushes per week over 12 weeks. RESULTS: A total of 832 subjects were included. At baseline, the median weekly number of moderate to severe hot flushes was between 62 and 67. After 12 weeks of treatment, combinations of 0.5 and 1 mg estradiol achieved a median reduction of 54-55 and 57-64 moderate to severe hot flushes, respectively. In the 0.5-mg estradiol group, the responder rates for combinations with drospirenone 0.25 and 0.5 mg were 62.7% and 75.8%, respectively. In the 1-mg estradiol group, the responder rates for combinations with drospirenone 1, 2 and 3 mg were 86.7%, 100% and 89.7%, respectively. CONCLUSION: Effective relief from hot flushes can be reached within 12 weeks with estradiol doses of 0.5 and 1 mg in combination with different drospirenone doses.

One-year randomized study of the endometrial safety and bleeding pattern of 0.25 mg drospirenone/0.5 mg 17ß-estradiol in postmenopausal women.

OBJECTIVES: To investigate the long-term endometrial safety and bleeding pattern of the 0.25 mg drospirenone/0.5 mg 17ß-estradiol (DRSP/E2) dose combination compared with 0.5 mg norethisterone acetate (NETA)/1.0 mg E2, in postmenopausal women. METHODS: A total of 662 postmenopausal women aged between 40 and 65 years with an indication for hormone therapy verified by the investigator were randomized to participate in this 1-year, double-blind, active comparator-controlled study. The primary efficacy variable was the proportion of women with an endometrial biopsy assessment of 'hyperplasia or worse' at any time during or after 13 cycles of treatment. RESULTS: No evaluable women in the DRSP/E2 or NETA/E2 groups had an endometrial biopsy result of 'hyperplasia or worse'. The incidence of amenorrhea was higher in the DRSP/E2 group than the NETA/E2 group during months 1-3 (69.0% vs. 56.0%), with comparable amenorrhea rates of approximately 80% during months 10-12. Improvements in menopausal symptoms (exploratory efficacy variables) were similar in the two groups, while there were fewer women with treatment-related adverse events (18.4% vs. 25.6%) or adverse events leading to discontinuation of study drug (8.4% vs. 15.1%) in the DRSP/E2 group than the NETA/E2 group. There were no treatment-related thromboembolic or cardiovascular events in the DRSP/E2 group vs. two events in the NETA/E2 group. CONCLUSIONS: The low-dose, 0.25 mg DRSP/0.5 mg E2 dose combination met the criteria for endometrial safety and demonstrated a favorable risk/benefit profile in this 1-year, double-blind, randomized study of postmenopausal women.

Recommendation for the collection and analysis of endometrial biopsies for hormone therapies.

The assessment of endometrial safety is one of the key requirements for the clinical development of new products for hormone therapy (HT) to treat menopausal symptoms in women who have a uterus. Both the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) provide detailed guidance on the requirements for the evaluation of biopsies to prove endometrial safety. However, there are some discrepancies between the European and the US requirements, making it difficult to fulfil both guidelines simultaneously. In order to facilitate multinational clinical trials performed within clinical programs to develop novel HT products, we developed an approach considering both guidance documents as far as possible and proposed solutions for issues that are inconsistently described in these guidelines. A table with the required sample sizes is given. Our recommendation for a unified approach for the estimation of the hyperplasia rate for hormone therapies fulfils the intent of the recommendations of both the FDA and the EMA and thus leads to a globally harmonized drug development for hormone therapies.

Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial.

BACKGROUND: Dienogest is a selective progestin that has been investigated in a clinical trial programme for the treatment of endometriosis. The current non-inferiority trial compared the efficacy and safety of dienogest against leuprolide acetate (LA) for treating the pain associated with endometriosis. METHODS: Patients with confirmed endometriosis were randomized to treatment with dienogest (2 mg/day, orally) or LA (3.75 mg, depot i.m. injection, every 4 weeks) for 24 weeks. The primary efficacy variable was absolute change in pelvic pain from baseline to end of treatment, assessed by visual analogue scale (VAS). Safety variables included adverse event profile, laboratory parameters, bone mineral density (BMD), bone markers and bleeding patterns. RESULTS: A total of 252 women were randomized to treatment with dienogest (n = 124) or LA (n = 128); 87.9 and 93.8% of the respective groups completed the trial. Absolute reductions in VAS score from baseline to Week 24 were 47.5 mm with dienogest and 46.0 mm with LA, demonstrating the equivalence of dienogest relative to LA. Hypoestrogenic effects (e.g. hot flushes) were reported less frequently in the dienogest group. As expected, bleeding episodes were suppressed less with dienogest than with LA. Changes in mean lumbar BMD between screening and final visit were +0.25% with dienogest and -4.04% with LA subgroups (P = 0.0003). Markers of bone resorption increased with LA but not dienogest. CONCLUSIONS: Dienogest 2 mg/day orally demonstrated equivalent efficacy to depot LA at standard dose in relieving the pain associated with endometriosis, although offering advantages in safety and tolerability.

Evaluation of menstrual bleeding patterns: a new proposal for a universal guideline based on the analysis of more than 4500 bleeding diaries.

OBJECTIVE: To develop a universal guideline allowing the comparison of interventions like oral contraceptives and hormone replacement therapy with an impact on menstrual bleeding pattern. METHODS: Literature analysis and cluster analysis of 4612 bleeding diaries. RESULTS: We summarized key definitions needed for the evaluation of menstrual bleeding patterns from the literature. We developed a methodology to systematically evaluate menstrual bleeding patterns that distinguishes between cyclical and continuous hormonal regimens. CONCLUSION: This universal guideline can be applied to all prospective clinical studies that affect menstrual bleeding patterns. It allows regulatory agencies and prescribing physicians to make meaningful comparisons of different products.

A randomized study on the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on lipid and lipoprotein metabolism over a period of 13 cycles.

In this open-label, randomized study we compared the influence of a new oral contraceptive containing 30 microg ethinylestradiol and 3 mg drospirenone (EE + DRSP = Yasmin), with a reference preparation containing 30 microg ethinylestradiol and 150 microg desogestrel (EE + DSG = Marvelon) on the lipid profile. The primary target variables were total high-density lipoprotein (HDL) cholesterol, HDL2 cholesterol and low-density lipoprotein (LDL) cholesterol. These and additional lipid and lipoprotein fractions were measured at baseline and in the 3rd, 6th and 13th treatment cycles in a total of 50 volunteers, and also assessed after density gradient ultracentrifugation. A slight increase in mean total HDL cholesterol vs. baseline was found for the DRSP group (+12.8%) and the DSG group (+11.8%) after 13 treatment cycles. HDL2 cholesterol did not change remarkably in both groups. The mean LDL cholesterol values increased by 10.6% vs. baseline in the DSG group and remained nearly stable in the DRSP group (+1.8%). All measured values remained within the reference ranges. No statistically significant differences were found between the two treatment groups for those primary endpoints. A slight rise in mean total cholesterol was found for all cycles after the initiation of treatment. The mean increase after 1 year of treatment was approximately 8% in both treatment groups. Mean triglyceride levels increased for both treatment groups without leaving the reference range. The increase for total triglycerides was +73.6 % in the DRSP group and +61.3% in DSG group. For total phospholipids, an increase of +13.6% (DRSP) and +18.5% (DSG) over 13 cycles was measured. The apolipoproteins Apo A-I, Apo A-II and Apo B increased slightly more during DRSP treatment than during DSG treatment. The reduction of Apo E was similar in both groups. Lipoprotein (a) remained stable in the DRSP group, whereas it increased by +10.8% in the DSG group. In conclusion, the combined low-dose oral contraceptive Yasmin, with 30 microg ethinylestradiol and 3 mg of the novel progestogen drospirenone, as well as the reference preparation, had little impact on the lipid profile. While both preparations displayed a favorable lipid profile with increased total HDL cholesterol, the antiandrogenic or missing androgenic activity of Yasmin may be regarded as responsible for the stable LDL cholesterol levels. As a result, the ratio of total HDL:LDL was increased, a pattern that is usually considered clinically beneficial with respect to cardiovascular disease risk.

A 3-year double-blind, randomized, controlled study on the influence of two oral contraceptives containing either 20 microg or 30 microg ethinylestradiol in combination with levonorgestrel on bone mineral density.

In this first prospective, double-blind, randomized, parallel-group study we evaluated the influence of two combined oral contraceptives on bone mineral density (BMD) and metabolic bone parameters. One dose-reduced preparation contained 20 microg ethinylestradiol (EE) in combination with 100 microg levonorgestrel (LNG) (20/100) was compared with the reference preparation which contained 30 microg EE in combination with 150 microg LNG (30/150). Data from 48 volunteers aged 20-35 years were obtained over an observation period of 36 treatment cycles. The direction of the change (increase or decrease) in all investigated bone-related variables was similar in both treatment groups. As compared to baseline, bone mineral density decreased by 0.4% in the 20/100 group and by 0.8% in the 30/150 group after 36 treatment cycles. These changes were not significantly different between the two treatment groups (p = 0.902). For bone-specific alkaline phosphatase, we measured a mean increase of 55.4% (20/100 group) and of 113.2% (30/150 group) after 36 treatment cycles. The two treatments did not differ statistically significantly (p = 0.522). With respect to cross-linked N-telopeptides (NTx), we detected a decrease of the mean NTx urine concentrations of 21.1% (20/100) and of 13.4% (30/150). These changes also did not significantly differ between the two treatments (p = 0.613). Both study treatments were safe and well-tolerated by all volunteers participating in the study. In conclusion, BMD did not change during the 3-year observation period. Thus, both trial preparations containing either 20 or 30 microg EE in combination with LNG were capable of maintaining BMD in young fertile women. There is no reason to assume that the EE dose reduction had any negative impact on BMD. Because there were no differences in BMD between the treatment groups, it can be assumed that even lower dosages than 20 microg EE might be sufficient for bone protection. Biochemical markers provided evidence for a reduced bone resorption.

Combined ethinylestradiol/gestodene contraceptive patch: two-center, open-label study of ovulation inhibition, acceptability and safety over two cycles in female volunteers.

OBJECTIVES: Determination of the ovulation inhibition efficacy of a new, transparent, transdermal, combined hormonal contraceptive patch (area 10 cm2) containing 0.9 mg ethinylestradiol and 1.9 mg gestodene in an open-label study of healthy, female volunteers (aged 18-35 years). METHODS: A total of 199 volunteers from two centers were requested to use the contraceptive patch (one patch/week for 3 weeks, followed by 1 week of no treatment), throughout two menstrual cycles. Ovarian activity was monitored by transvaginal ultrasonography and serum hormone determinations, and classified according to the Hoogland score. RESULTS: Ovulation inhibition was achieved in all participants (Hoogland score < 6). Secondary efficacy measures, including suppression of serum concentrations of estradiol and progesterone, and of the mid-cycle luteinizing hormone surge, confirmed ovulation inhibition. Ovulation returned in 85.7% of participants during the first cycle after cessation of treatment. There were no abnormal changes in safety parameters. A large majority of users rated the contraceptive patch as 'very convenient'. CONCLUSIONS: This study showed that the new, combined ethinylestradiol/gestodene contraceptive patch was highly effective in reversibly inhibiting ovulation, well tolerated and regarded as 'very convenient' by the majority of users. This new, transparent, transdermal matrix patch is an attractive alternative form of contraception.

Recommendation for confidence interval and sample size calculation for the Pearl Index.

A new guideline on the clinical investigation of steroid contraceptives in women, which has been released by the European Agency for the Evaluation of Medicinal Products (EMEA), calls for the calculation of a confidence interval for the Pearl Index, a widely used measure to describe the effectiveness of a contraceptive method. However, the interpretation of the Pearl Index as a statistical parameter, for which a confidence interval can be calculated, needs further clarification. The guideline does not provide the necessary definitions. In this paper, two statistical models, the Bernoulli model and the Poisson model, are compared; both can be used for the calculation of the Pearl Index and its upper confidence limit. The Poisson model proved to be more suitable, because it can accommodate incomplete treatment cycles. Unambiguous definitions and statistical formulae for the calculation of overall Pearl Index and the Method Failure Pearl Index are given. Finally, the sample sizes required to fulfill the EMEA's guideline are given.

A randomized study over 13 cycles to assess the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on carbohydrate metabolism.

In this open-label, randomized study we compared the influence of a new oral contraceptive containing 30 microg ethinylestradiol and 3 mg drospirenone (Yasmin) with a reference preparation containing 30 microg ethinylestradiol and 150 microg desogestrel (Marvelon) on variables of carbohydrate metabolism by means of oral glucose tolerance tests at baseline and in the 6th and 13th treatment cycle. The mean levels of fasting glucose and insulin were similar at baseline and after 13 treatment cycles, whereas C-peptide and free fatty acid levels decreased slightly in both groups. All blood glucose and insulin values measured in the oral glucose tolerance tests were within normal ranges, despite a slight increase in the mean areas under the curves of 0-3 h [AUCs (0-3 h)] of both variables from baseline to treatment cycle 13. Differences between both treatments were not statistically significant. The mean AUCs (0-3 h) for C-peptide were not markedly changed in any treatment group. Free fatty acid levels decreased by 42% in the drospirenone group and increased by 48.9% in the desogestrel group, in terms of means of individual changes. Both preparations were well tolerated and equally efficacious regarding contraception and cycle control. The mean body weight was slightly decreased in most cycles during treatment with the drospirenone combination, as compared to baseline, while it was slightly increased versus baseline in all cycles during treatment with the desogestrel combination. The combination with drospirenone had less impact on blood pressure than the combination with desogestrel. In conclusion, Yasmin, a combined low-dose oral contraceptive with 30 microg ethinylestradiol and 3 mg of the novel progestogen drospirenone, as well as the reference Marvelon, containing 30 microg ethinylestradiol and 150 microg desogestrel had little impact on carbohydrate metabolism when used for 1 year. The observed changes were small and not suggestive of a clinically relevant deterioration of carbohydrate metabolism.

A meta-analysis on the correlation between ovarian activity and the incidence of intermenstrual bleeding during low-dose oral contraceptive use.

We aimed to evaluate potential correlation between ovarian activity during use of combined oral contraceptives and the incidence of intermenstrual bleeding. Data from seven prospective clinical studies with five different combined low-dose oral contraceptives were retrospectively analyzed to determine ovarian activity measured by the Hoogland Score (follicle diameter and endogenous hormone levels) and cycle control. A total of 227 young fertile women were evaluated over three treatment cycles each. Women with intermenstrual bleeding had statistically significantly higher estradiol levels than those without intermenstrual bleeding. Also, women with intermenstrual bleeding had significantly larger follicle-like structures than those without intermenstrual bleeding. For example, in the second treatment cycle the difference of the mean follicle diameters between women without intermenstrual bleeding (12.5 mm) and women with spotting (16.9 mm) or breakthrough bleeding (16.1 mm) was statistically significant (p = 0.0179). Less than 17% of women with Hoogland Score 1, 2 or 3 (low ovarian activity) reported intermenstrual bleeding. On the other hand, 35.2% of women with Hoogland Score 4 (active follicle-like structures) reported intermenstrual bleeding. The association between bleeding and Hoogland Score was statistically significant (p < 0.0011). The findings of this retrospective analysis provide evidence that high ovarian suppression is positively correlated with improved cycle control in terms of less frequent intermenstrual bleeding - slight and heavy.

A pharmacokinetic study with a low-dose oral contraceptive containing 20 microg ethinylestradiol plus 100 microg levonorgestrel.

This study investigated the pharmacokinetics of a dose-reduced oral contraceptive containing 20 microg ethinylestradiol (EE) + 100 microg levonorgestrel (LNG) in 18 young, healthy females. Serum levels of EE and LNG were determined after single and repeated daily oral administration over three treatment cycles, each consisting of 21 treatment days followed by a 7-day treatment-free period. Additionally, the time courses of sex hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and total and free testosterone serum levels were analyzed. Both active ingredients were rapidly absorbed and maximum concentrations in serum were reached between, on average, 1 and 2 h after single and multiple administrations, respectively. Concentrations of EE increased during repeated daily administration. An approximate two-fold accumulation was calculated based on the comparison of EE area under the curve (AUC) (0-24 h) values determined after the first and the last tablet administration within a treatment cycle. LNG serum concentrations also increased during repeated daily administration, reaching steady-state levels after about 11 days. Based on the comparison of AUC (0-24 h) values determined after the first and the last tablet administration, LNG accumulated approximately by a factor of 3 within a treatment cycle. Steady-state pharmacokinetics of LNG were similar at the end of the first and the third treatment cycles, indicating no further accumulation of LNG beyond a treatment cycle under long-term use of this combined oral contraceptive. The clearance and volume of distribution of LNG decreased and the terminal half-life increased after repeated daily administration, compared with single administration. These effects have also been reported for other LNG/EE combinations. SHBG serum concentrations increased during repeated daily intake by, on average, 1.5-1.6-fold, and for CBG, an average increase of 1.4-1.8-fold was found. Although free testosterone concentrations declined during repeated daily administration by about 40%, total testosterone remained relatively unchanged at a low level. In conclusion, the pharmacokinetics of EE and LNG determined in the present study were in good agreement with those previously reported for 30 microg EE + 150 microg LNG, taking the 33% dose reduction into account.

An open label, comparative study of the effects of a dose-reduced oral contraceptive containing 20 microg ethinyl estradiol and 100 microg levonorgestrel on hemostatic, lipids, and carbohydrate metabolism variables.

In this open label, randomized study we compared the influence of a dose-reduced oral contraceptive containing 20 microg ethinyl estradiol (EE) and 100 microg levonorgestrel (20 EE) with a reference preparation containing 30 microg EE and 150 microg levonorgestrel (30 EE) on hemostatic, lipids, and carbohydrate metabolism variables. Data from 48 volunteers were obtained. The direction of the change (increase or decrease) in most of the hemostatic variables were similar in both treatment groups. In particular, prothrombin fragment 1 + 2 increased during treatment, reaching a median percent change of 40% in the 20 EE group and of 17% in the 30 EE group after one year. D-Dimer fibrin split products remained virtually unchanged, with no change at Cycle 13. The median HDL2 cholesterol levels decreased by 26% in the 20 EE group and by 39.8% in 30 EE group (p = 0.0045 for group difference) after one year. The median one year change for LDL cholesterol was 3.23% in the 20 EE group, compared to 25% in the 30 EE group, for VLDL 11.1% compared to 38.8%, respectively, and for total triglycerides 10.0% compared to 37.5%, respectively. The median absolute change for the area under the curve (AUC)(0-3h) for glucose at treatment Cycle 13 was 41.25 mmol/L x min in the 20 EE group and 73.50 mmol/L x min in the 30 EE group. The AUC(0-3h) insulin at treatment Cycle 13 decreased in the 20 EE group by 1635.0 pmolL x min and increased in the 30 EE group by 11797.5 pmolL x min (p = 0.0491 for group difference). Both study treatments were safe and well tolerated by the volunteers. In conclusion, the balanced one-third dose reduction in this new oral contraceptive evoked similar effects on the hemostatic variables, but favorable results for the lipid and carbohydrate profiles.

A double-blind comparative study of the effects of a 23-day oral contraceptive regimen with 20 microg ethinyl estradiol and 75 microg gestodene and a 21-day regimen with 30 microg ethinyl estradiol and 75 microg gestodene on hemostatic variables, lipids, and carbohydrate metabolism.

In this double-blind study we compared the influence of two oral contraceptives, a 23-day regimen with 20 microg ethinyl estradiol and 75 microg gestodene (23-day 20/75) and a 21-day regimen with 30 microg ethinyl estradiol and 75 microg gestodene (21-day 30/75), on hemostatic variables, lipids, and carbohydrate metabolism. The volunteers received the preparations daily for six 28-day cycles. Hemostatic variables and lipids were measured at baseline and after six treatment cycles. Carbohydrate metabolism was assessed by determination of the area under the curve (AUC) of carbohydrate parameters after oral glucose tolerance tests performed at baseline and after three treatment cycles. Data from 33 volunteers in each group were obtained. No significant differences between the effects of both treatments on the hemostatic system were detected. Neither the overall change of all hemostatic variables from baseline to treatment Cycle 6 [defined as primary target variable in the study] nor the change of any of the individual hemostatic parameters differed significantly between the treatment groups. Likewise, no significant nor clinically relevant differences in the effects of both treatments on the volunteers' lipid profiles were detected. The data on carbohydrate variables suggested a slightly more favorable influence of the 23-day 20/75 regimen. The increase of the glucose AUCs after three cycles tended to be stronger with the 21-day 30/75 regimen than with the 23-day 20/75 regimen. In addition, the AUCs for insulin and C-peptide were slightly reduced after three cycles with the 23-day 20/75 regimen but slightly increased with the 21-day 30/75 regimen. Both study treatments were safe and well tolerated by the volunteers as shown by the nature and frequency of adverse events, the routine laboratory examinations, and the physical and gynecological examinations. Both preparations provided adequate contraceptive reliability. The only pregnancy during treatment was attributable to intake errors. In conclusion, the prolongation of the treatment phase of an oral contraceptives with 20 microg ethinyl estradiol does not evoke more pronounced metabolic effects than a conventional 21-day regimen with 30 microg ethinyl estradiol.

Impact of oral contraceptive use on APC-resistance: a prospective, randomized clinical trial with three low-dose preparations.

The evaluation of the study was of the impact of oral contraceptive (OC) use on activated protein C (APC-resistance). Eight hundred eighteen young fertile women were screened for a study designed to compare three different marketed OC preparations. The women could have used either other oral contraceptive preparations before switching to the study medications (switchers) or were not using hormonal contraceptives (new starters) before the study began. Prior to study drug intake and during treatment, APC-resistance was determined with three different tests. Forty-one of 809 women evaluated (5.07%) carried the Factor V Leiden mutation. Twenty-two further participants (2.72%) had a positive screening test, but did not provide samples for the confirmatory mutation test. Two women with homozygous Factor V Leiden mutations and 39 women with heterozygous mutations were identified. The homozygous carriers were identified in all three of the screening tests employed, whereas none of the tests detected all 39 heterozygotes. In the pretreatment screening tests, previous OC users (switchers) had slightly lower APC ratios than the women using non-hormonal birth control methods (starters). During treatment the difference between starters and switchers was no longer apparent, but the APC ratio values of the screening tests slightly increased for both. The homozygous carriers were not treated. Differences in APC-resistance between users of the three different oral contraceptive preparations were not found. In conclusion, laboratory screening for APC-resistance using Coatest APC, ProC Global, or ProC APC-FV-Leiden clearly identifies homozygous mutant carriers. However, with regard to heterozygous mutant carriers, the sensitivity and specificity of the tests, especially during OC intake, is limited. The results of APC screening tests should have, at present, no impact on contraceptive counseling because the predictive value for thromboembolic risk of the test results and even the mutant status is low.

Double-blind, multicenter comparison of efficacy, cycle control, and tolerability of a 23-day versus a 21-day low-dose oral contraceptive regimen containing 20 microg ethinyl estradiol and 75 microg gestodene.

This prospective, double-blind, randomized study was conducted to compare the contraceptive reliability, cycle control, and tolerability of a 23-day versus a 21-day oral contraceptive regimen containing 20 microg ethinyl estradiol and 75 microg gestodene. Participants took trial medication daily for 28 days, either 23 tablets with active substances plus 5 placebo tablets or 21 tablets with active substances plus 7 placebo tablets. Contraceptive efficacy, cycle control, and tolerability were evaluated over a period of seven cycles. Efficacy data gathered from 4,878 treatment cycles (23-day regimen: 2,362 cycles; 21-day regimen: 2,516 cycles) were obtained from 703 participants (23-day regimen, n = 342; 21-day regimen, n = 361). Both preparations proved to be effective contraceptives and provided good cycle control. One pregnancy because of method failure was recorded in each treatment group. This resulted in a study Pearl Index of 0.5 for each treatment. For the 23-day regimen, 36.0% of participants reported at least one intracyclic bleeding episode during Cycles 2-4 (primary target) compared to 37.1% in the 21-day regimen. In the 23-day regimen group, intracyclic bleeding episodes were reported by 42.4% of the participants in Cycle 1 but only in 14% in Cycle 7 and in the 21-day regimen group by 44.6% in Cycle 1 and only 17.3% in Cycle 7. Overall, intracyclic bleeding was reported in 21.9% of the 23-day regimen cycles and in 22.7% of the 21-day regimen cycles.A greater number of 23-day regimen participants had shorter withdrawal bleeding periods than with the 21-day regimen. In significantly (p <0.0001) more cycles in the 23-day regimen group, participants reported withdrawal bleeding periods that lasted only 1-4 days compared to the 21-day regimen group. For the majority of the treatment cycles, the median number of bleeding days in the 23-day regimen group was 4 days and in the 21-day regimen group 5 days. Both preparations were well tolerated and showed a similar adverse events pattern. The discontinuation rate because of adverse events was low (23-day regimen, 6%; 21-day regimen, 4%). No serious vascular adverse events were reported. More than 75% of the women in both groups either lost more than 2 kg of weight or did not gain weight during the study. The treatment effect on blood pressure was negligible. There were no appreciable changes in mean laboratory values over the course of the study.

Open, multicenter comparison of efficacy, cycle control, and tolerability of a 23-day oral contraceptive regimen with 20 microg ethinyl estradiol and 75 microg gestodene and a 21-day regimen with 20 microg ethinyl estradiol and 150 microg desogestrel.

This prospective, open, randomized study was conducted to compare the contraceptive reliability, cycle control, and tolerability of a 23-day regimen with 20 microg ethinyl estradiol (EE) and 75 microg gestodene (GSD) and a 21-day regimen with 20 microg EE and 150 microg desogestrel (DSG). Participants took either 23 tablets with active substances plus 5 placebo tablets (23-day EE/GSD) or 21 tablets with active substances followed by 7 days without pill-taking (21-day EE/DSG). Contraceptive efficacy, cycle control, and tolerability were evaluated over a period of seven cycles. Efficacy data gathered from 5967 treatment cycles (23-day EE/GSD: 2975 cycles; 21-day EE/DSG: 2992 cycles) were obtained from 890 participants (445 in each group). Both preparations proved to be effective contraceptives and provided good cycle control. No pregnancy during treatment was recorded. This resulted in a study Pearl Index of 0.0 for both treatments. For 23-day EE/GSD, 32.4% of participants reported at least one intracyclic bleeding episode during Cycles 2-4 (primary target) compared to 31.5% for 21-day EE/DSG. In the 23-day EE/GSD group, intracyclic bleeding episodes were reported by 48.8% of the participants in Cycle 1 but in only 15.1% in Cycle 7, and in the 21-day regimen group by 43.4% in Cycle 1 and only 14.2% in Cycle 7. Overall, intracyclic bleeding was reported in 20.9% of cycles for both treatments.A greater number of 23-day EE/GSD participants had shorter withdrawal bleeding periods than with 21-day EE/DSG. In significantly (p <0.0001) more cycles in the 23-day EE/GSD group participants reported withdrawal bleeding periods that lasted only 1-4 days compared to the 21-day EE/DSG group. For the majority of the treatment cycles, the median number of bleeding days in the 23-day EE/GSD group was 4 days and in the 21-day EE/DSG group 5 days. Both preparations were well tolerated and showed a similar adverse events pattern. The discontinuation rate because of adverse events was low (23-day EE/GSD: 6.1%; 21-day EE/DSG: 5.6%). No serious vascular adverse events were reported. More than 82% in the 23-day EE/GSD group and 79% in the 21-day EE/DSG group either lost more than 2 kg of weight or did not gain weight during the study. The treatment effect on blood pressure was negligible. There were no appreciable changes in mean laboratory values over the course of the study compared to baseline.