Evaluation of ovulation and safety outcomes in a multi-center randomized trial of three 84 day ulipristal acetate regimens

Westhoff, Carolyn; Archer, David F.; Barnhart, Kurt T.; Darney, Philip D.; Gilliam, Melissa; Jensen, Jeffrey T.; Nelson, Anita L.; Teal, Stephanie; Thomas, Michael A.; Hu, Jack W.; Brown, Jill E; Blithe, Diana L.

doi:10.1016/j.contraception.2022.04.002

Cited by 6 publications

(6 citation statements)

References 16 publications

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“…This analysis uses data from a clinical trial that evaluated the safety, tolerability, and impact on ovulation of three oral ulipristal acetate regimens: continuous ulipristal acetate 10 mg or 5 mg for 84 days, or a cyclic regimen of ulipristal acetate 5 mg with 24 active pills followed by four hormone-free placebo pills for three 28-day cycles. 4 Study participants were women aged 18-35 with a regular menstrual cycle (28 ± 7 days) and were required to have ovulated during their baseline cycle. Participants received a daily ulipristal acetate regimen for 12 weeks (84 days), followed by a recovery phase that lasted until the second spontaneous menstrual bleeding episode.…”

Section: Methodsmentioning

confidence: 99%

“…Volunteers gave written informed consent before any study activities. This analysis uses data from a clinical trial that evaluated the safety, tolerability, and impact on ovulation of three oral ulipristal acetate regimens: continuous ulipristal acetate 10 mg or 5 mg for 84 days, or a cyclic regimen of ulipristal acetate 5 mg with 24 active pills followed by four hormone‐free placebo pills for three 28‐day cycles 4 …”

Section: Methodsmentioning

confidence: 99%

“…Because daily oral ulipristal acetate often inhibited ovulation in a small pilot study, 3 it may have the potential to be used as an estrogen‐free daily oral contraceptive. To evaluate ovulation inhibition, the National Institute of Child Health and Human Development Contraceptive Clinical Trials Network (CCTN) conducted a clinical trial of daily ulipristal acetate 4 . This trial used transvaginal sonography to assess follicle development and possible ovulation; however, initial analyses found that many of the study sonograms did not record any follicle‐like structures ≥10 mm (henceforth referred to as follicles), even at times when estradiol levels would suggest ovarian activity.…”

Section: Introductionmentioning

confidence: 99%

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Using transvaginal ultrasounds for the identification of follicle‐like structures ≥10 mm in a multi‐center randomized contraceptive clinical trial of three 84‐day oral ulipristal acetate regimens

Rosenberg

Westhoff

2022

J of Clinical Ultrasound

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Purpose We examine the use of transvaginal sonography in imaging ovarian follicles among non‐pregnant reproductive‐aged women enrolled in a contraceptive clinical trial. Methods Ten sites conducted a clinical trial comparing three oral ulipristal acetate regimens for ovulation inhibition. Enrollees underwent twice weekly transvaginal sonography and hormonal blood testing throughout treatment and until the second menses post‐treatment. The primary outcome of the present analysis was success in identifying follicles ≥10 mm in a subgroup of sonograms performed at times of likely follicular activity (estradiol <100 pg/ml and progesterone >3 ng/ml). Secondarily, an overall analysis assessed all sonograms regardless of timing. Results At times of likely follicular activity, 135 women underwent 969 sonograms. The proportion of sonograms without follicles ≥10 mm ranged from 8.3% to 46.3% when stratified by site (p = .01). The odds of no follicle among higher‐body mass index (BMI) women were 1.91 times those among lower‐BMI women after controlling for site and treatment arm (95% CI: 1.13, 3.22). Results were similar for the overall population. Conclusion Sonographers were less likely to identify follicles for higher‐BMI women and results varied by site. Machine quality slightly impacted sonogram results, but did not sufficiently explain site differences.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Using transvaginal ultrasounds for the identification of follicle‐like structures ≥10 mm in a multi‐center randomized contraceptive clinical trial of three 84‐day oral ulipristal acetate regimens

Rosenberg

Westhoff

2022

J of Clinical Ultrasound

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“…Several studies have reported discrepancies between ultrasound findings and serum progesterone levels when determining the Hoogland and Skouby score [37][38][39] . Therefore, our primary method for determining ovulation based on the Hoogland and Skouby scores relied on serum progesterone elevation.…”

Section: Main Findingsmentioning

confidence: 99%

A randomized single-blind non-inferiority trial of delayed start with drospirenone-only and ethinyl estradiol-gestodene pills for ovulation inhibition

Ratanasaengsuang,

Uaamnuichai,

Santibenchakul

et al. 2024

Sci Rep

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We compared the efficacy of 4 mg drospirenone (DRSP) progestin-only pills (POPs) versus combined oral contraceptive pills (COCs) containing 0.02 mg of ethinyl estradiol (EE) and 0.075 mg of gestodene (GS) in ovulation inhibition and inducing unfavorable cervical mucus changes using a delayed-starting approach. This randomized controlled trial involved 36 participants aged 18–45 years. The major outcomes included ovulation inhibition assessed using the Hoogland and Skouby score, and cervical mucus permeability, assessed using the modified World Health Organization score. The results demonstrated ovulation inhibition rates of 77.8% for the EE/GS group and 88.9% for the DRSP group. The risk ratio and absolute risk reduction were 0.50 (95% confidence interval [CI]: 0.10, 2.40) and − 0.11 (95% CI: − 0.35, 0.13), respectively, satisfying the 20% non-inferiority margin threshold. The median time to achieve unfavorable cervical mucus changes was comparable between the DRSP (3 days, interquartile range [IQR]: 6 days) and EE/GS (3.5 days, IQR: 4 days) groups. However, the DRSP group had a higher incidence of unscheduled vaginal bleeding (55.56% vs. 11.11%; p = 0.005). DRSP-only pills, initiated on days 7–9 of the menstrual cycle, were non-inferior to EE/GS pills in ovulation inhibition. However, they exhibited delayed unfavorable cervical mucus changes compared to the standard two-day backup recommendation.Clinical trial registration: Thai Clinical Trials Registry (TCTR20220819001) https://www.thaiclinicaltrials.org/show/TCTR20220819001.

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“…Given the proven toxicity of UPA on the liver, particularly evident in the post-marketing survey of the patients treated with Esmya ® 84 , and the possible interferences with the neuro-regulation of the menstrual cycle, it is surprising to find studies, like the multi-center phase 1 and/or 2 trial by Westhoff et al, that enroll randomized participants to use oral Ulipristal 10 mg or 5 mg daily or a 3 cycle regimen of 5 mg for 24 days followed by four placebo days, with the purpose of evaluating whether Ulipristal might have potential as a daily oral contraceptive 85 . Absence of any progesterone elevations, suggesting consistent ovulation inhibition throughout treatment, was reported only in 52 of 137 (37%) participants; 53%, 45%, and 15% % among those randomized to the 10 mg, 5 mg, and cyclic treatments.…”

Section: Current Perspectivesmentioning

confidence: 99%

Ulipristal Acetate (UPA) in Emergency Contraception: The Mechanism of Action, Toxicity and Perspectives

Mozzanega

2022

MRAJ

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After recalling that Levonorgestrel Emergency Contraceptive Pills never delay or suppress ovulation, but impair the luteal body functions, and, consequently, the embryo-implantation, we focus on the mechanism of action (MOA) of ellaOne®: micronized UPA (Ulipristal Acetate) 30mg and on UPA- toxicity. EMA and, after it, the National Drug Regulatory Institutions and the most renowned International Gynecological Societies present ellaOne® as an anti-ovulatory drug which is safe even in repeated assumption, also during the same menstrual cycle. We’ll try to understand whether this dogma is supported by experimental data in literature. As to the MOA, EMA reports (EMEA-261787-2009) that Ulipristal blocks the synthesis of the proteins necessary to begin and maintain pregnancy, and that Ulipristal and mifepristone were approximately equipotent as to their ability to terminate pregnancy. Besides, EMA further evidences (EMA/73099/2015) that it is unknown whether it is possible to use ellaOne® for abortion. Data in Literature evidence that ellaOne® can delay ovulation only when is taken in the very first fertile days of the cycle. In the pre-ovulatory, most fertile, days - when most intercourses do occur and over 70% fertilizations ensue - it never prevents ovulation, like placebo. On the contrary, whenever it is taken in the cycle, it consistently impairs the endometrium that becomes an inhospitable ground for the embryo: endometrial gene expression is completely subverted compared with that of the normal luteal phase. Recently, an UPA-based drug used for uterine fibroids-treatment (Esmya®) was withdrawn from the market because it caused fulminant hepatitis requiring transplantation (EMA/455818/2020). It was prescribed by the hospital for 3-6 months and carefully followed-up. The strict post-marketing surveillance allowed to link UPA-administration and tissue-accumulation to liver-failure. Surprisingly EMA, while revoking Esmya®, warranted for the safety of ellaOne®, though it is taken by millions of women unaware of the risk, repeatedly without prescription, without medical supervision and any possibility of post-marketing surveillance, in UPA-cumulating doses even greater than with Esmya®. Finally, we criticize the attempt to propose UPA in daily contraceptive pills, at doses even double than in Esmya® and for much longer periods, to fertile women aiming at preserving their fertility and health.

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Evaluation of ovulation and safety outcomes in a multi-center randomized trial of three 84 day ulipristal acetate regimens

Cited by 6 publications

References 16 publications

Using transvaginal ultrasounds for the identification of follicle‐like structures ≥10 mm in a multi‐center randomized contraceptive clinical trial of three 84‐day oral ulipristal acetate regimens

Using transvaginal ultrasounds for the identification of follicle‐like structures ≥10 mm in a multi‐center randomized contraceptive clinical trial of three 84‐day oral ulipristal acetate regimens

A randomized single-blind non-inferiority trial of delayed start with drospirenone-only and ethinyl estradiol-gestodene pills for ovulation inhibition

Ulipristal Acetate (UPA) in Emergency Contraception: The Mechanism of Action, Toxicity and Perspectives

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