Ingrid Duijkers

Suppression of ovarian activity with a drospirenone-containing oral contraceptive in a 24/4 regimen

BACKGROUND This study was conducted to compare ovarian activity of an oral contraceptive containing drospirenone (drsp) 3 mg plus ethinylestradiol (EE) 20 mcg administered in 24/4 regimen compared with the conventional 21/7 regimen, during intended use and following predefined dosing errors. STUDY DESIGN Women aged 18-35 years who ovulated or had a follicular diameter of >or=15 mm on or before Day 23 during a pretreatment cycle were admitted into this double-blind, randomized study. Participants underwent 3 treatment cycles with drsp 3 mg/EE 20 mcg in a 24/4 (n=52) or a 21/7 (n=52) regimen. In the third treatment cycle, the initial three pills in both groups were replaced with placebos. Ovarian activity was classified using the Hoogland scale during pretreatment and during Cycles 2 and 3. RESULTS Suppression of ovarian activity was more pronounced with the 24/4 regimen--the odds ratio for a lower Hoogland score (i.e., greater ovarian suppression) with the 24/4 regimen compared with the conventional 21/7 regimen were 6.01 (95% CI: 2.29-17.94) and 3.06 (95% CI: 1.44-6.65) for Cycles 2 and 3, respectively. More women in the 24/4 regimen group had no ovarian activity 87.8% vs. 56.0% during Cycle 2 and 55.1% vs. 30.0% during Cycle 3. The 24/4 regimen was associated with a more consistent suppression (less fluctuation) of endogenous estradiol. CONCLUSION The drsp 3 mg/EE 20 mcg oral contraceptive in a 24/4 regimen was associated with greater ovarian suppression (despite intentional dosing error), which results in decreased hormonal fluctuations, and may increase contraceptive efficacy with the low-dose formulation.

Ovulation inhibition with four variations of a four-phasic estradiol valerate/dienogest combined oral contraceptive : results of two prospective, randomized, open-label studies

BACKGROUND Attempts to improve the tolerability of combined oral contraceptives (COCs) have included the substitution of ethinylestradiol (EE) with 17beta-estradiol (E2). However, this has proved unsatisfactory, specifically in terms of cycle control. To improve upon the poor cycle control seen previously, E2 [in the form of estradiol valerate (E2V); 1 mg of E2V contains 0.76 mg of E2] was combined with dienogest (DNG) in a novel four-phasic regimen. In the current studies, the ovulation-inhibition potency of four variations of this regimen was assessed. STUDY DESIGN Two randomized, open-label, Phase II studies were performed. The first study compared two regimens (Regimens 1A and 2A) with similar dosages of DNG but different lengths of application. Having established in Study 1 that the length of application of Regimen 2A was most suitable, but that the dosages of DNG were too low for effective ovulation inhibition, a second study, which compared two regimens (Regimens 2B and 2C) with similar lengths of application but with increased dosages of DNG, was undertaken. The primary efficacy variable in both studies was the proportion of women with a Hoogland score of 5 or 6 during Cycle 2. RESULTS The full analysis set comprised 192 and 203 women in Studies 1 and 2, respectively. In Study 1, 10 women (10.9%) in Regimen 1A and 6 women (6.4%) in Regimen 2A had a Hoogland score of 5 or 6. In Study 2, three women (3.1%) in Regimen 2B and one woman (1.0%) in Regimen 2C had a Hoogland score of 5 or 6. There were no safety concerns with any of the regimens. CONCLUSION The results of these studies identified a four-phasic COC preparation comprising E2V/DNG that provides efficient ovulation inhibition. It is expected that this regimen will lead to an innovative COC containing E2 instead of EE.

Polycystic ovaries, as defined by the 2003 Rotterdam consensus criteria, are found to be very common in young healthy women.

BACKGROUND The criteria for polycystic ovaries (PCO) as defined by the 2003 Rotterdam consensus are based on the follicle number and ovarian volume, which decrease with age. A study was performed to assess the influence of age on the PCO prevalence. In addition, the relation between follicle number and ovulation day was studied. METHODS Assessments were done in a spontaneous menstrual cycle in 171 healthy volunteers. The ovulation day and cycle duration were recorded. Transvaginal ultrasonography was performed between cycle day 6 and 9 to determine the follicle number and ovarian volume. RESULTS In the age groups between 18 and 22, 23 and 27, 28 and 32, 33 and 37, and 38 and 40 years, the prevalence of PCO was 83-84%, 66-84%, 42-79%, 19-33%, and 0-33%, respectively. Most PCO subjects had ovulatory cycles. The follicle number and ovarian volume decreased with age. There was a positive correlation between the follicle number and the ovulation day. CONCLUSIONS PCO were found to be very common in young women. The follicle number and ovarian volume decreased with age, and therefore also the PCO prevalence decreased with age. We believe the PCO criteria should be reconsidered and adapted to the womans age. Ovulation occurred later with increasing follicle number.

Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol on ovarian function in comparison to a monophasic combined oral contraceptive containing drospirenone and ethinylestradiol

Objective To compare the effects on ovarian activity of two oral contraceptives containing nomegestrol acetate (NOMAC)/17β-oestradiol (E2) or drospirenone (DRSP)/ethinylestradiol (EE). Methods In this open-label, randomised, six-cycle study, 32 subjects using NOMAC/E2 (2.5–1.5 mg; 24/4-day regimen) were compared to 16 subjects using DRSP/EE (3 mg–30 μg; 21/7-day regimen). Measurements included serum oestradiol, progesterone, follicle stimulating hormone (FSH) and luteinising hormone (LH), and ultrasonography of follicular diameter. Results No ovulations occurred during treatment. Progesterone was fully suppressed, with mean maximum values <2 nmol/l in both groups over all cycles. For NOMAC/E2, mean maximum follicular diameter decreased from 19.3 mm before treatment to between 6.9 and 8.2 mm during treatment, with no subject having a follicular diameter ≥15 mm. For DRSP/EE, a decrease from 19.6 to between 7.4 and 10.8 mm was observed, with two subjects (12.5%) having a maximum follicle diameter ≥15 mm. These findings were consistent with observed FSH reductions; full suppression of LH surges was observed in both groups. Post-treatment return of ovulation in both groups occurred on average 21 days after the last active tablet intake. Conclusions NOMAC/E2 achieves consistent ovulation inhibition, with suppressive effects on the ovaries at least similar to those of DRSP/EE.

Hemostatic effects of a novel estradiol-based oral contraceptive: an open-label, randomized, crossover study of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel.

AbstractBackground: A novel estradiol-based combined oral contraceptive (COC) is currently available in many countries worldwide, including Europe and the US. Based on previous studies, it is expected that this estradiol-based COC will have a reduced hepatic effect compared with COCs containing ethinylestradiol with regard to proteins controlling the hemostatic balance. Objective: The aim of this study was to compare the hemostatic effects of the estradiol valerate/dienogest COC with a monophasic low-estrogen dose COC containing ethinylestradiol/levonorgestrel. Study Design: Healthy women aged 18–50 years were randomized to receive a COC containing estradiol valerate/dienogest (2 days estradiol valerate 3 mg, 5 days estradiol valerate 2mg/dienogest 2 mg, 17 days estradiol valerate 2mg/dienogest 3 mg, 2 days estradiol valerate 1 mg, 2 days placebo) or ethinylestradiol 0.03mg/levonorgestrel 0.15mg in a crossover study design. Women received each treatment for three cycles, with two washout cycles between treatments. The primary efficacy variables were the intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three. Results: Data from 29 women were assessed. Intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three were less pronounced with estradiol valerate/dienogest than with ethinylestradiol/ levonorgestrel. Conclusion: The novel COC containing estradiol valerate/dienogest had similar or less pronounced effects on hemostatic parameters than ethinylestradiol/ levonorgestrel.

Ovulation‐Inhibiting Effects of Dienogest in a Randomized, Dose‐Controlled Pharmacodynamic Trial of Healthy Women

Dienogest offers pharmacological advantages for the effective treatment of endometriosis and for use in contraception and hormone replacement therapy. This pharmacodynamic study investigated the ovulation‐inhibiting effects of dienogest monotherapy in healthy women. Dienogest was administered at 0.5, 1, 2, or 3 mg daily for up to 72 days to women aged 18 to 35 years (n = 102). Ovarian activity was assessed pretreatment and during 2 treatment periods (days 0–36 and days 37–72) by the Hoogland score, based on follicle size and serum estradiol and progesterone levels. Additional hormonal parameters and endometrial thickness were assessed. Hoogland scoring indicated ovulation in all women pretreatment, decreasing to 3 of 21, 1 of 23, 0 of 20, and 0 of 23 women in the 0.5‐, 1‐, 2‐, and 3‐mg groups, respectively (per‐protocol set). Maximum serum estradiol concentrations were similar to pretreatment levels in the 0.5‐ or 1‐mg group and decreased moderately (within physiologic levels) in the 2‐ or 3‐mg group. Endometrial thickness was reduced by all dienogest doses. Hormonal changes during follow‐up indicated resumption of ovulation in most women, shortly after treatment cessation. Dienogest ≥2 mg daily provides moderate suppression of estradiol production and reliable ovulation inhibition, which reverses rapidly after treatment cessation.

Pharmacodynamic effects and plasma pharmacokinetics of single doses of cetrorelix acetate in healthy premenopausal women

OBJECTIVE To investigate the pharmacodynamic effects and plasma pharmacokinetics of single subcutaneous doses of cetrorelix acetate in healthy premenopausal women. SETTING Phase I clinical research unit. PATIENT(S) Healthy, premenopausal women aged 19 to 35 years. INTERVENTION(S) Single subcutaneous morning doses of cetrorelix acetate (1, 3, or 5 mg peptide base) were investigated in a randomized, single-blind, placebo-controlled, parallel-group design. After a control cycle, 36 women received cetrorelix acetate (12 per dose) and 12 received placebo on the eighth individual cycle day. Transvaginal ultrasound was performed, and blood samples for LH, FSH, E2 were collected during both cycles and for pharmacokinetics up to 168 hours after dosing. The serum hormone levels were determined by electrochemicoluminescence immunoassay and plasma cetrorelix concentrations by radioimmuno assay. RESULTS Cetrorelix acetate administration led to a rapid, marked, and reversible suppression of serum LH, E2, and to a lesser extent FSH concentrations. The median intra-individual shifts between treatment and control cycle were -1.0, 4.0, 8.0, and 9.5 days for serum LH maximum and -1.0, 4.5, 7.0, and 10.0 days for ovulation following placebo or 1, 3, and 5 mg cetrorelix acetate, peptide base, respectively. The area under the concentration-time curve (AUC) and peak cetrorelix concentrations in plasma (Cmax) increased proportionally with dose. CONCLUSIONS Cetrorelix acetate showed pronounced and reversible LH and E2 suppression and a dose-dependent postponement of LH surge and ovulation after single subcutaneous administrations to healthy premenopausal women. Dose proportionality over the range of 1 mg to 5 mg cetrorelix acetate, peptide base was demonstrated.

A randomised study comparing the effect on ovarian activity of a progestogen-only pill (POP) containing desogestrel and a new POP containing drospirenone in a 24/4 regimen

Abstract Objectives Progestogen-only pills (POPs) are safer with respect to cardiovascular risks than contraceptives containing estrogens. Despite the increased contraceptive efficacy of a desogestrel-only pill compared with a traditional POP, POPs are still not widely used due to an unpredictable bleeding pattern. A new POP containing 4 mg drospirenone has been developed with a 24/4 intake regimen which may improve the bleeding pattern. The objectives of this study were to investigate ovulation inhibition with the new drospirenone-only pill in comparison with the desogestrel-only pill and, in addition, to assess the effects on cervical mucus permeability and bleeding. Methods Sixty-four healthy volunteers with proven ovulatory cycles were randomised and treated with either the drospirenone-only or the desogestrel-only pill during two 28-day cycles. Follicular diameter, endometrial thickness, and serum estradiol (E2) and progesterone concentrations were measured and Hoogland scores were determined. Additionally, cervical mucus scores, bleeding and return of ovulation were assessed. Results Both treatments effectively inhibited ovulation. Follicular diameter, E2 levels and Hoogland scores were equal, demonstrating efficient ovarian suppression. One subject in each group had a Hoogland score of 6, but the criteria for normal luteal activity were not fulfilled. In both groups, ovulation did not occur before day 9 of the post-treatment cycle. Cervical mucus permeability was suppressed in both groups. The median number of bleeding and spotting days was lower in the drospirenone group. Conclusions The new drospirenone-only pill inhibited ovulation as effectively as the desogestrel-only pill despite the 4-day hormone-free interval. Chinese Abstract 摘要 目的 对于心血管疾病风险，纯孕激素避孕药比含雌激素的避孕药安全。尽管只含去氧孕烯的避孕药与传统纯激素避孕药相比，避孕效果增加了，由于不可预知的出血模式，纯孕激素避孕药仍没有被广泛应用。包含4毫克屈螺酮的新型纯孕激素避孕药已被研制出，采用24/4方案可以改善出血模式。这项研究的目的是调查仅含屈螺酮的新型避孕药与仅含去氧孕烯的避孕药相比对排卵抑制的情况，此外，也用于评估对宫颈粘液穿透性和出血的影响。 方法 经过验证有排卵周期的64名健康志愿者，在两个28天的周期中被随机给予仅含屈螺酮或者去氧孕烯的避孕药。测定卵泡直径、子宫内膜厚度、血清雌二醇和孕激素浓度，并进行Hoogland评分。此外，对宫颈粘液评分、出血及排卵抑制进行评估。 结果 两种治疗方法都能有效的抑制排卵。卵泡直径、雌二醇水平和Hoogland评分都是相同的，以及证明有效的排卵抑制。每组每一项的Hoogland评分都是6，但是黄体活动的标准还没有制定。在预处理周期的第9天以前，两个组都不会出现排卵。两个组的宫颈粘液穿透性都被抑制了。在屈螺酮组中，黄体期出血天数的中位数比较低。 结论 尽管有4天无激素的时间间隔，仅含屈螺酮的新型避孕药与仅含去氧孕烯的避孕药对排卵的抑制效果是一样的。 关键词 去氧孕烯片；去氧孕烯；屈螺酮；卵巢活动；排卵抑制；纯孕激素型避孕药

Length of the menstrual cycle after discontinuation of oral contraceptives

Objective To investigate whether the first cycle after stopping oral contraceptive (OC) intake had a normal duration. Methods A retrospective study was performed in 680 women, 300 non-OC users and 380 women discontinuing OC intake. The length of one or two menstrual cycles was recorded. Results In the non-user group, the median duration of both the first and second cycle was 29 days (range 18–97 and 20–56 days, respectively). In the OC user group the median duration from withdrawal bleeding until next menstruation was 30 (15–82) days. The second cycle lasted 29 (17–122) days. The duration of the first post-treatment cycle was not significantly different from the next cycle or the cycle length in non-users. When the subjects were divided into different age categories, a significantly longer first post–treatment cycle was observed in the group aged 18–24 years, but a shorter first post-treatment cycle in the group aged 25–29 years. No differences were seen in the higher age groups. The ethinyl estradiol dose of the OC preparation did not influence the results. Conclusions The first cycle after OC discontinuation had a normal duration.

Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study

Abstract Objectives The aim of the study was to evaluate the efficacy of different dosages of estetrol (E4) combined with one of two progestins in suppressing the pituitary–ovarian axis and ovulation in healthy premenopausal women. Methods This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E4/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E4/150 μg levonorgestrel; or 20 μg ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary–ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication. Results A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4 dosage: the highest suppression was observed in the 20 mg E4 group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe. Conclusions Combined with a progestin, E4 adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day. Chinese Abstract 摘要 目的 这项研究的目的是评估不同剂量的雌四醇联合两种孕激素中的其中一种对垂体-卵巢轴以及健康的绝经前妇女的排卵方面的抑制疗效。 方法 这是一个在18到35岁的健康女性中进行的开放的、平行的，关于II期药物剂量探索的初步研究，这些女性均有治疗前的排卵周期记录。连续三个周期的24/4-天方案,参与者接受5毫克或10毫克的雌四醇/3毫克屈螺酮;5毫克,10毫克或20毫克的雌四醇/150 μg左炔诺孕酮;或用20 μg炔雌醇/3毫克屈螺酮作比较。在第1和第3个治疗周期，通过监测卵泡的大小,血清促卵泡激素、黄体生成素、雌二醇和孕激素的水平对垂体-卵巢轴的活动和排卵进行评估。对子宫内膜厚度的评估贯穿于整个试验过程中，对排卵抑制的评估在用完药物之后。 结果 总共有109名妇女参与试验。任何一个治疗组都没有出现排卵。对卵巢活动的抑制似乎与雌四醇的剂量成正比：最严重的抑制出现在20毫克的雌四醇组，与在炔雌醇/屈螺酮组观察到的情况非常相似。所有组的子宫内膜厚度的抑制程度是相同的。在最后一次积极治疗后的第17到21天之间，所有参与者均出现了治疗后的排卵。所有的试验组合均有良好的耐受性和安全性。 结论 雌四醇联合一种雌激素能够充分的抑制卵巢活动，尤其是当雌四醇的剂量大于10毫克/天的时候。 关键词 雌四醇；雌激素；口服避孕药；排卵抑制；孕激素