Hoogland Score Research Articles

Mechanism of action of a 0.075 mg norgestrel progestogen-only pill 2. Effect on cervical mucus and theoretical risk of conception

ObjectiveTo evaluate the cervical mucus effects of a norgestrel 0.075 mg progestin-only contraceptive pill over a 28-day cycle. Study DesignWe recruited persons ages 18 to 35 with normal cycles at 2 US academic medical centers. Participants took norgestrel 0.075 mg daily for 28 days at the same time (within a 3 hour window) daily, recorded through a text-message based e-diary. We extracted cervical mucus using a standardized aspiration technique on the day of pill initiation and then at least every 3 to 4 days over the cycle. We monitored subjects for follicular activity with transvaginal ultrasound examination and blood sampling for ovarian hormones and gonadotropins at each visit. We assessed cervical mucus scoring using a 4-category/12-point modified Insler scale (score ≥9 [favoring fertility], 5–8 [intermediate], and ≤4 [unfavorable to fertility]). We stratified cervical mucus scores by serum estradiol levels and ovulatory status based on a modified Hoogland score. ResultsExcluding enrollment, we collected and evaluated 413 mucus samples from 51 participants. Participants had a median mucus score of 0 (Interquartile Range 0, 2); most had scores ≤4 (samples = 385, 93%) and none had a score ≥9 favoring fertility. Seventeen (33%) participants ovulated, of which 14 (82%) had unfavorable mucus scores (≤4) at the time of ovulation and 3 (18%) had intermediate scores (5-8). ConclusionsNorgestrel 0.075 mg daily prevents mucus changes that favor fertility, even during ovulatory cycles. ImplicationsDaily administration of norgestrel 0.075 mg over an initial 28-day cycle did not result in fertile cervical mucus. Although approximately one-third of users ovulated in this first cycle of pill use, contraceptive efficacy may be maintained by mucus effects.

Mechanism of action of norgestrel 0.075 mg a progestogen-only pill. I. Effect on ovarian activity

ObjectiveTo explore the effect on ovarian activity and ovulation of 28 days of correct daily use of a progestogen-only pill containing norgestrel 0.075 mg. Study designWe performed a prospective, randomized, crossover study at 2 US sites, recruiting healthy women of reproductive age to use norgestrel 0.075 mg daily for three 28-day treatment cycles. We monitored ovarian activity every 3 to 4 days with reproductive hormone measurements and ovarian ultrasonography. Participants recorded pill use in daily diaries. An adjudication committee independent of the research sites assessed ovarian activity using a modified Hoogland score combining hormone concentrations and follicle diameter and appearance (quiescence 1–3, ovarian activity without ovulation 4–5, and ovulatory/postovulatory 6–7). ResultsWe report here the findings of the initial 28-day treatment cycle in which 51 of 52 recruited participants provided data sufficient for analysis. Two thirds of subjects had no evidence of ovulation (34/51, 66.6%); eight of these (15.7%) had quiescent ovaries (follicle <13 mm diameter) and 26 (51%) had follicular development (follicle >13 mm diameter) without ovulation. Seventeen participants ovulated, of whom 12 (23.5%) had a normal, and 5 (9.8%) an abnormal luteal phase. Persistent ovarian follicles were common among women who had ovarian activity without ovulation, 17 of 26 participants (65.4%) had a large follicle which persisted beyond 28 days. ConclusionDuring 28 days of exposure to a norgestrel 0.075 mg progestogen-only pill, most women had no evidence of ovulation. ImplicationsOvulation inhibition and follicle growth disturbance are important in the mechanism of action of a progestogen-only pill containing norgestrel 0.075 mg.

P562 A Phase 1 Study Evaluating the Effect of Coadministration of Etrasimod on the Pharmacokinetics and Pharmacodynamics of a Monophasic Oral Contraceptive in Healthy Female Volunteers

Abstract Background Etrasimod (ETR) is a once-daily (QD), oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders including inflammatory bowel disease (IBD) and atopic dermatitis. At diagnosis, ~50% of patients with IBD are &amp;lt;35 years old. Oral contraceptives (OC) are the most common birth control among women in the US. It’s important to ensure an IBD therapy does not impact the pharmacokinetic (PK)/pharmacodynamic (PD) performance of the OC. This study evaluated the effect of coadministration of ETR on the PK/PD performance of a monophasic OC. Methods This open-label Phase 1 study enrolled 21 premenopausal healthy female adults (18–40 years). On Days 1–21 of Period 1 (Days 1–28), participants received OC containing 30mcg ethinylestradiol (EE) and 50mcg levonorgestrel (LVG). On Day 23, participants initiated ETR 2mg QD such that steady-state concentrations were achieved by Day 28 and thereafter. On Days 29–49 of Period 2 (Days 29–50), the OC was coadministered with ETR 2mg QD. Samples for measuring the pharmacologically active components of the OC (EE and LVG) were collected over 24 hours on Days 21 and 49. Log-transformed primary PK parameters were calculated and compared using analysis of variance with treatment as fixed effect and participant as random effect. PD markers (follicle-stimulating hormone [FSH], luteinizing hormone [LH], estradiol, progesterone) were measured at baseline (Days 1 and 29) and throughout Periods 1 and 2. Largest ovarian follicle size measured by transvaginal ultrasound (TVUS), sex hormone–binding globulin (SHBG) levels, and Hoogland score were measured on Days 1 (before OC dosing), 11, 29 (before OC+ETR dosing), and 39. Safety and tolerability were also evaluated. Results Only minor-to-mild increases in EE and LVG Cmax,ss and AUCtau,ss exposure measures were observed when the OC was coadministered with ETR vs when the OC was administered alone (Table). These changes were not considered clinically relevant. Markers of ovarian activity (FSH, LH, estradiol, progesterone, SHBG, TVUS/Hoogland score) demonstrated no clinically relevant impact of coadministration of ETR on the PD performance of the OC. All treatments were generally well tolerated. Most treatment-emergent adverse events (AEs) were mild or moderate; 2 participants had severe AEs. No abnormalities in laboratory parameters, vital signs, or 12-lead electrocardiogram assessments were noted. Conclusion The PK/PD performance of the monophasic OC was not altered to a clinically relevant extent; thus contraceptive efficacy was maintained during coadministration with ETR. ETR and the monophasic OC, administered alone or in combination, were generally well tolerated.

The Effect of Estetrol/Drospirenone on Ovarian Function Is Similar to a Well-Established Combined Oral Contraceptive: Results From a Phase 2 Study

Background: Combined oral contraceptives (COCs) often contain ethinylestradiol (EE), an estrogen known to be associated with several side effects including venous thromboembolism. Estetrol (E4) is a native estrogen synthesized by the human fetal liver during pregnancy. Results from a phase 2 dose-finding study showed that E4 15 mg in combination with drospirenone 3 mg (E4/DRSP) resulted in a good bleeding profile and cycle control. Here, we present phase 2 results showing the effect of E4/DRSP on ovarian function. Study Design: A single-center, randomized, open-label, parallel study was conducted in healthy young volunteers with proven ovulatory cycles. Study subjects received either E4 15 mg/DRSP 3 mg (n=41) or EE 20 µg/DRSP 3 mg (n=41) in a 24/4-day regimen for three consecutive cycles. Both in cycle 1 and 3, serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH), estradiol and progesterone levels were determined, and follicular size and endometrial thickness were measured every three days using transvaginal ultrasound. Ovarian function was assessed using the Hoogland score, which considers follicular size and estradiol/progesterone levels. Return of ovulation was determined after treatment cessation. Safety and tolerability were assessed by monitoring adverse events (AEs), vital signs, physical and gynecological examination, clinical laboratory parameters, 12-lead electrocardiogram and echocardiogram. Results: No ovulations were reported during the use of E4/DRSP, while three ovulations occurred in two subjects in the EE/DRSP group. In both groups, most participants had no ovarian activity according to the Hoogland score. In cycle 1, Hoogland scores and follicular diameters were similar in both groups. In cycle 3, these parameters were slightly less suppressed in the E4/DRSP group when compared to EE/DRSP. While mean FSH and LH concentrations were less inhibited by E4/DRSP, mean estradiol and progesterone concentrations and endometrial thickness were similarly suppressed in both groups. Return of ovulation occurred on average 15.5 days after discontinuation of E4/DRSP intake. The number of frequently reported AEs considered to be related to study medication was similar for both treatment groups except for breast pain (11 subjects in the E4/DRSP group versus 4 subjects with EE/DRSP). Most related AEs were of mild or moderate intensity. Three subjects discontinued due to an AE, one with E4/DRSP (severe stress, emotional lability), and two with EE/DRSP (emotional lability, depressed mood). Other safety assessments did not show significant abnormalities. No serious AEs were reported. Conclusions: The combination of E4 15 mg and DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, which is similar to a well-established COC containing EE/DRSP. E4/DRSP is considered safe and well-tolerated.

Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function

ObjectiveTo evaluate the effects of estetrol 15 mg/drospirenone 3 mg on ovarian function. Study designSingle-center, randomized, open-label, parallel study in healthy young women with proven ovulatory cycles. Participants received either estetrol 15 mg/drospirenone 3 mg (E4/DRSP) (n = 41) or ethinylestradiol 20 µg/drospirenone 3 mg (EE/DRSP) (n = 41) in a 24/4-day regimen for 3 consecutive cycles. Follicular size and endometrial thickness were measured by transvaginal ultrasound every 3 days in cycles 1 and 3. Blood was sampled for hormone analysis. Ovarian function expressed as Hoogland score was based on follicular size, serum estradiol (E2) and progesterone (P) concentrations. Ovulation was defined as a ruptured follicle-like structure >13 mm with serum E2 concentrations >100 pmol/L and serum P concentrations >5 nmol/L. We assessed return of ovulation after treatment cessation, and safety throughout the study. ResultsNone of the participants ovulated with E4/DRSP use, while one participant ovulated once and one participant ovulated twice during EE/DRSP treatment. Most participants had a Hoogland score of 1 (no ovarian activity) in cycle 1 (85.0% and 82.9% of participants on E4/DRSP and EE/DRSP, respectively) and in cycle 3 (65.8% and 83.8%, respectively). E4/DRSP suppressed follicle-stimulating hormone and luteinizing hormone to a lesser extent than EE/DRSP, whereas both treatments comparably suppressed E2 and P and endometrial thickness. Return of ovulation occurred, on average, 15.5 days after E4/DRSP treatment discontinuation. E4/DRSP was safe and well-tolerated. ConclusionsE4 15 mg/DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, comparable to a marketed combined oral contraceptive containing EE/DRSP. Implications statementTreatment with E4 15 mg/DRSP 3 mg showed complete ovulation inhibition, despite less suppression of follicle-stimulating hormone and luteinizing hormone compared to EE/DRSP. If it becomes commercially available, E4/DRSP, containing a naturally occurring estrogen, should be as effective as EE/DRSP.

The effects of vilaprisan on the pharmacodynamics and pharmacokinetics of a combined oral contraceptive-A randomized controlled trial.

AimsThe primary objective was to explore whether the suppression of ovarian activity induced by a combined oral contraceptive (COC) is influenced by the simultaneous intake of the selective progesterone receptor modulator (SPRM) vilaprisan (VPR).MethodsIn this exploratory randomized, double‐blind, parallel‐group study, 71 healthy premenopausal women were randomized (1:1) to receive either 2 mg/d VPR or placebo for 3 months. Concomitantly, a COC (0.15 mg levonorgestrel, 0.03 mg ethinyloestradiol) was administered in a cyclic regimen. Ovarian activity (Hoogland score based on follicle size and hormone concentrations), cervical function (Insler score), bleeding pattern and endometrial thickness/histology were assessed before treatment, in treatment cycle 3 and during follow‐up.ResultsThe known COC‐driven suppression of ovarian activity was mildly affected by VPR. COC+VPR group: 22, 0 and 6% of the subjects had Hoogland scores of 4 (active follicle‐like structures), 5 or 6 (ovulation). COC+placebo group: 14% of the subjects had a score of 4 and none a score of 5 or 6 (Bayesian analysis for Hoogland score = 4, median difference in response rate: 7.5%; 90% credible interval [−8.5; 23.5%]). COC effects on cervical function were moderately affected (mucus more sperm permeable under COC+VPR). COC withdrawal bleeding, in contrast, was absent in 81% of the subjects receiving COC+VPR vs 0% receiving COC+placebo.ConclusionThe SPRM VPR interfered with the pharmacodynamic effects of the COC. Therefore, full contraceptive effectiveness cannot be assumed without final judgement by a Pearl index study. Women on SPRMs should be advised to use nonhormonal contraception methods.

The effects on ovarian activity of delaying versus immediately restarting combined oral contraception after missing three pills and taking ulipristal acetate 30 mg

ObjectiveAmong combined oral contraception (COC) users, to determine the effect on ovarian activity and ovulation of waiting five days before restarting COC, versus restarting immediately, having taken ulipristal acetate 30 mg (UPA, the dose used for emergency contraception) after missing three consecutive COC pills. Study designWomen already using COC were enrolled for two cycles of COC use (21/7 regimen). In cycle 2, all women omitted COC pills for three consecutive days (days 5,6,7), and on day 8 took UPA 30 mg. They were randomized either to restart their COC pills that same day (immediate restart) or to wait five days (delayed restart). Transvaginal ultrasound, and blood sampling for estradiol and progesterone were undertaken on days 4,8,11,13,15,18,22 and 26. A modified Hoogland score was used to quantify ovarian activity/ovulation and to assess whether luteal phase progesterone concentrations were sufficiently ‘adequate’ to have conferred a theoretical risk of pregnancy. ResultsNo one ovulated with risk of pregnancy during the five days following UPA. Among 26 women with immediate restart, none ovulated with a theoretical risk of pregnancy at any time in the cycle. Four of 23 women (17.4% CI [5.0; 38.8]) with delayed restart ovulated with theoretical risk of pregnancy before the end of the cycle. This difference was statistically significant (p = 0.042). ConclusionWomen who delay restarting COC for five days after taking UPA 30 mg are at much greater risk of ovulation, and therefore theoretically of pregnancy, than if they restart their COC on the same day as taking UPA. Current recommendations should be revisited. ImplicationsWomen who take UPA-EC after having missed combined oral contraceptive pills are advised to wait five days before restarting the COC. This delay puts them at risk of ovulation and, if intercourse occurs, theoretically therefore of pregnancy. Women who restart their COC pills immediately are much less likely to ovulate. The label for UPA-EC and clinical guidelines on using EC after missed pills should be revisited.

Effect of the Novel Selective Progesterone Receptor Modulator Vilaprisan on Ovarian Activity in Healthy Women.

This randomized, double‐blind, parallel‐group study in healthy young women investigated the effect of treatment with vilaprisan (0.5, 1, 2, or 4 mg/day for 12 weeks) on ovarian function by assessing the Hoogland score, which is based on the size of follicle‐like structures as determined by transvaginal ultrasound and on estradiol and progesterone serum concentrations. Ovulation inhibition (ie, Hoogland score <6 in treatment weeks 1‐4 and 8‐12) was observed in >80% of the subjects receiving vilaprisan ≥1 mg/day. The effect was dose dependent. With a Bayesian approach, the percentage of subjects with ovulation inhibition was estimated to increase from 37% in subjects receiving 0.5 mg/day vilaprisan to 76%, 86%, and 88% in subjects receiving 1, 2, and 4 mg/day, respectively. Follicle growth was not suppressed during treatment. The majority of subjects receiving ≥1 mg/day had a Hoogland score of 4 (active follicle‐like structures, ie, follicle diameter >13 mm, estradiol >27.2 pg/mL, no progesterone increase) both at beginning and end of treatment. Mean average estradiol as well as mean maximum progesterone concentrations were noticeably decreased during treatment with vilaprisan ≥1 mg/day compared to pretreatment, but estradiol concentrations remained >80 pg/mL. Both hormones returned to pretreatment levels after the end of treatment, indicating a rapid resumption of normal ovarian activity. Amenorrhea occurred in the majority of subjects during treatment at dosages ≥1 mg/day. The adverse events observed in this study confirm the known safety profile of vilaprisan. All in all, the results of this study support the development of vilaprisan for the long‐term treatment of uterine fibroids.

A two-centre, open-label, randomised study of ovulation inhibition with three transdermal contraceptive patches, each containing different amounts of ethinyl estradiol and gestodene in healthy, young women

Here we report the findings of a two-centre, open-label, randomised, Phase IIa study designed to investigate whether an ethinyl estradiol (EE)/gestodene (GSD) patch that has been developed (referred to herein as the ‘EE/GSD patch’) reliably inhibits ovulation in comparison with patches delivering lower doses of these hormones. The study rationale was to provide justification of the doses of EE and GSD selected for the EE/GSD patch. Healthy women, aged 18–35 years, were randomised to receive treatment with either the EE/GSD patch, a ‘reduced-GSD patch’ (delivering similar amounts of EE and approximately half the amount of GSD) or a ‘reduced-EE/GSD patch’ (delivering half the amount of EE and GSD). Treatment was administered for three 28-day cycles (three × 7 patch-wearing days, plus a 7-day patch-free interval). The primary pharmacodynamic variable was the percentage of women with ovulation in at least one of Cycles 2 and/or 3, as indicated by Hoogland score. Pharmacokinetic parameters for EE and GSD were also measured. Results indicated that the EE/GSD patch effectively suppressed ovulation, while patches delivering lower doses of EE and GSD were less effective for this purpose. All three patches showed comparable tolerability.

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

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 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

No interacting influence of lavender oil preparation silexan on oral contraception using an ethinyl estradiol/levonorgestrel combination.

PurposeSilexan is an oral Lavender oil preparation with proven anxiolytic efficacy. Given the high prevalence of anxiety and restlessness in younger women, oral contraceptives and Silexan will likely be co-administered.MethodsA double-blind, randomised, 2-period crossover study was performed to investigate the effects of Silexan on the pharmacokinetics and pharmacodynamics of Microgynon®, a combination oral contraceptive containing ethinyl estradiol 0.03 mg (EE) and levonorgestrel 0.15 mg (LNG) in healthy, fertile, adult females. During 2 consecutive cycles of 28 days, oral contraception was given for 21 days combined with 1 × 160 mg/day Silexan or placebo. Plasma concentration–time profiles of EE and LNG were obtained on day 18 ± 1 up to 24 h after dosing. The primary outcome measure was the area under the concentration–time curve over a dosing interval of τ = 24 h (AUCτ) for EE and LNG plasma levels. An interaction with Silexan was formally excluded if the 90 % confidence interval for the AUCτ ratio during co-administration with Silexan or placebo was included within the range of 0.80–1.25. Secondary outcomes included EE and LNG peak concentration (C max) and time to C max (t max), follicle size, endometrial thickness, the Hoogland score, and serum levels of estradiol, progesterone, and sex hormone-binding globulin.ResultsA total of 24 women (mean age 27.3 years; mean body mass index 22.2 kg/m2) participated. The confidence intervals for the EE and LNG AUCτ and C max ratios fell within the pre-specified limits, indicating no interaction (point estimates [Silexan/placebo] AUCτ EE 0.97, LNG 0.94; C max EE 0.99, LNG 0.96). For LNG, t max was slightly delayed. No secondary outcome indicated any impairment of contraceptive efficacy.ConclusionsCo-administration of Silexan did not affect the efficacy of a combination oral contraceptive containing EE and LNG and was well tolerated.

Impact of body mass index on suppression of follicular development and ovulation using a transdermal patch containing 0.55-mg ethinyl estradiol/2.1-mg gestodene: a multicenter, open-label, uncontrolled study over three treatment cycles

BackgroundBody mass index (BMI) may influence ovulation inhibition resulting from transdermal hormone delivery. Investigation of this effect is important given the high prevalence of obesity in the US. Study DesignThis open-label, uncontrolled, Phase 2b trial stratified 173 women (18–35 years) according to three BMI groups (Group 1, n=56, ≤30kg/m2; Group 2, n=55, >30kg/m2 and ≤35kg/m2; and Group 3, n=47, >35kg/m2). Women used a contraceptive patch containing 0.55-mg ethinyl estradiol (EE) and 2.1-mg gestodene (GSD). The EE/GSD patch was used weekly for three 28-day cycles (one patch per week for 3 consecutive weeks followed by a 7-day, patch-free interval), and its effect on ovulation was assessed by the Hoogland score, a composite score that comprises transvaginal ultrasound and estradiol (E2) and progesterone levels every 3days in Cycles 2 and 3. Evaluation of pharmacokinetic parameters was a secondary aim of the study, and blood samples for analytic determination of EE, GSD and sex hormone-binding globulin were taken during the pretreatment cycle, Cycle 2 and Cycle 3. Compliance was assessed using diary information and serum drug levels. ResultsIn the per-protocol set, there were only six ovulations during the study, and no participant ovulated in both study cycles. One ovulation occurred in Group 1, three in Group 2 and two in Group 3. Ovulation inhibition was unaffected by BMI; in all groups, most participants had Hoogland scores of 1 or 2 (i.e., follicle-like structures <13mm: Group 1, ≤30kg/m2, 80.0% in Cycle 2, 85.7% in Cycle 3; Group 2, >30kg/m2 and ≤35kg/m2, 61.4% in Cycle 2, 75.0% in Cycle 3; Group 3, >35kg/m2, 78.0% in Cycle 2, 72.5% in Cycle 3). Serum levels of follicle-stimulating hormone, luteinizing hormone, E2 and progesterone were similar between groups. Body weight had a limited effect on EE clearance that was unlikely to be clinically relevant. ConclusionThe EE/GSD patch provided effective ovulation inhibition, even in women with higher BMI. ImplicationsThis is the largest-to-date study of physiologic endpoints and found no clinically important differences in ovarian suppression among obese and normal-weight users of the EE/GSD contraceptive patch, thus providing reassurance that obese women can achieve the same high level of contraceptive protection as normal-weight users.

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.

Suppression of ovarian activity with a low-dose 21/7-day regimen oral contraceptive containing ethinylestradiol 20 mcg/drospirenone 3 mg in Japanese and Caucasian women

BackgroundTwo studies assessed the effect of a low-estrogen-dose 21/7-day oral contraceptive containing ethinylestradiol and drospirenone (EE 20 mcg/drsp 3 mg) on ovarian activity in Japanese and Caucasian women. Study DesignStudy 1 was conducted in Japanese women (20–35 years), and Study 2 was conducted in Caucasian women (18–35 years). All women received EE 20 mcg/drsp 3 mg in a 21-day active pill regimen. The primary endpoint was the proportion of women with ovulation inhibition (Hoogland score <6; as assessed by transvaginal ultrasonography) during treatment cycle 2. ResultsJapanese (n=23) and Caucasian (n=30) women received two cycles of study treatment. During treatment cycle 2, ovulation was inhibited in 100% and 92.9% of Japanese and Caucasian women, respectively. ConclusionsEE 20 mcg/drsp 3 mg in a 21/7-day regimen provides comparable ovarian suppression in Japanese and Caucasian women, with normal ovarian function resuming shortly after treatment end in both populations.

Follicular development in a 7-day versus 4-day hormone-free interval with an oral contraceptive containing 20 mcg ethinyl estradiol and 1 mg norethindrone acetate

Background Combined oral contraceptive (COC) formulations with 20 mcg ethinyl estradiol (EE) have a greater incidence of ovarian hormone production and follicular development, which can be managed by shortening the number of hormone-free days per COC cycle. This study evaluates differences in follicular development during a 7-day versus 4-day hormone-free interval in a COC regimen with 20 mcg EE and 1 mg norethindrone acetate. Study Design Forty-one healthy women were randomized in an open-label fashion to this formulation in either a 24/4 or a 21/7 day regimen for three cycles. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and inhibin B were measured daily from Cycle 2, Day 21 to Cycle 3, Day 3 and on Day 7 of Cycle 3. Follicular diameter and Hoogland score were calculated on Cycle 2, Days 21, 24 and 28 and Cycle 3, Days 3 and 7. Results Sixty-six percent of subjects in the 21/7 group and 70% of the subjects in the 24/4 group developed a follicle greater than 10 mm diameter. Ovarian steroid hormone levels, Hoogland scores and bleeding patterns were not statistically significant between the groups. Conclusion In contrast to prior studies, this analysis suggests no difference in follicle development or bleeding patterns among women receiving a 21/7 or 24/4 regimen of a 20-mcg EE/1-mg norethindrone acetate COC.

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 17β-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.

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

BackgroundThis 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 designWomen aged 18–35 years who ovulated or had a follicular diameter of ≥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. ResultsSuppression 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. ConclusionThe 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.

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.

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 studieswith 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) andcycle 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 withoutintermenstrual bleeding. Also ,women with intermenstrual bleeding had significantly larger follicle-like structures than those without intermenstrual bleeding. For example ,in the second treatment cyclethe 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 highovarian suppression is positively correlated with improved cycle control in terms of less frequent intermenstrual bleeding - slight and heavy.