Original Research Article| Volume 112, P54-60, August 2022

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



      : To describe ovulation inhibition and safety of daily oral ulipristal acetate (UPA) over 84 days.

      Study Design

      : This multi-center phase 1 and/or 2 trial 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. We stratified randomization by body mass index (BMI) <32 or 32-40 kg/m2. To estimate ovulation inhibition, the primary outcome, participants underwent transvaginal ultrasound and blood sampling twice weekly; we analyzed compliant participants who completed the 84 day study. Safety endpoints included 3 endometrial biopsies and liver chemistry tests.


      : We enrolled 180 participants and included 137 in the ovulation inhibition analyses. Progesterone values that remained below 3ng/mL throughout treatment suggested consistent ovulation inhibition in 52 of 137 (38%) participants; 25 of 47(53%), 20 of 44(45%), and 7 of 46(15%) among participants randomized to the 10 mg, 5 mg, and cyclic treatments, respectively (p < 0.01). Progesterone values consistently <3 ng/mL were more frequent in participants with a BMI > 32kg/m2 (25/50(50%) vs 27/87(31%), p = 0.01). Average ulipristal concentrations were higher among participants with low progesterone concentrations (p < 0.01). Endometrial biopsies during treatment showed progesterone-receptor-modulator-associated endometrial changes in 52 of 164 participants (32%); 22 of 49(40%), 16 of 48(29%), and 14 of 51(26%) in women randomized to the 10 mg, 5 mg, and the cyclic treatments, respectively (p = 0.07, test-for-trend); these changes resolved after treatment cessation. Liver transaminase changes were rare.


      : Oral ulipristal acetate over 12 weeks did not reliably suppress ovulation, particularly in the 5 mg cyclic-dose group. Ovulation inhibition and endometrial changes were dose dependent. Reversible endometrial changes occurred during treatment.


      : Progesterone-receptor modulators have been suggested for daily oral contraception. Since progesterone concentrations suggest that ovulation occurred during treatment, further studies would be necessary to assess whether these were functional ovulations and to evaluate other possible mechanisms of contraception.


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        • Blithe DL
        • Nieman LK
        • Blye RP
        • Stratton P
        • Passaro M.
        Development of the selective progesterone receptor modulator CDB-2914 for clinical indications.
        Steroids. 2003; 68: 1013-1017
        • Brown A
        • Cheng L
        • Lin S
        • Baird DT.
        Daily low-dose mifepristone has contraceptive potential by suppressing ovulation and menstruation: A double-blind randomized control trial of 2 and 5 mg per day for 120 days.
        J Clin Endocrinol Metab. 2002; 87: 63-70
        • Lahka F
        • Ho Pc Van der Spuy ZM
        • Dada K
        • Elton R
        • Glasier AF
        • Critchley HOD
        • et al.
        A novel estrogen-free oral contraceptive pill for women: multicenter double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel).
        Human Reproduction. 2007; 22: 2428-2436
        • Small B
        • Millard CEF
        • Kisanga EP
        • Burman A
        • Anam A
        • Flannery C
        • et al.
        The selective progesterone receptor modulator ulipristal acetate inhibits the activity of the glucocorticoid receptor.
        J Clin Endocrin Metab. 2020; 10593: 716-734
        • Creinin MD
        • Schlaff W
        • Archer DF
        • Wan L
        • Frezieres R
        • Thomas M
        • et al.
        Progesterone receptor modulator for emergency contraception: A randomized controlled trial.
        Obstet Gynecol. 2006; 108: 1089-1097
        • Glasier AF
        • Cameron ST
        • Fine PM
        • Logan SJS
        • Casale W
        • Van Horn J
        • et al.
        Ulipristal acetate versus levonorgestrel for emergency contraception: a randomized non-inferiority trial and meta-analysis.
        Lancet. 2010; 375: 60101-60108
        • Glasier A
        • Cameron ST
        • Blithe D
        • Scherrer B
        • Mathe H
        • Levy D
        • et al.
        Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel.
        Contraception. 2011; 84: 363-367
        • Chabbert-Buffet N
        • Pintiaux-Kairis A
        • Bouchard P
        • VA2914 Study Group
        Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial.
        J Clin Endocrin Metab. 2007; 92: 3582-3589
        • Brache V
        • Sitruk-Ware R
        • Williams A
        • Blithe D
        • Croxatto H
        • Kumar N
        • et al.
        Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women.
        Contraception. 2012; 85: 480-488
        • Huang Y
        • Jensen JT
        • Brache V
        • Cochon L
        • Williams A
        • Miranda M
        • et al.
        A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: Research for a novel estrogen-free method of contraception.
        Contraception. 2014; 90: 565-574
        • Donnez J
        • Tatarchuk TF
        • Bouchard P
        • Puscasiu l
        • Zakharenko NF
        • Ivanova T
        • et al.
        Ulipristal acetate versus placebo for fibroid treatment before surgery.
        N Engl J Med. 2012; 366: 409-420
        • Donnez J
        • Vazquez F
        • Tomaszewski J
        • Nouri K
        • Bouchard P
        • Fauser BC
        • et al.
        Long-term treatment of uterine fibroids with ulipristal acetate.
        Fertil Steril. 2014; 101 (e1-18): 1565-1573
        • Curtis KM.
        U.S. Medical Eligibility Criteria for Contraceptive Use, 2010.
        MMWR Recomm Rep 2010. 2010; 59: 1-6
      1. Praditpan P, Hamouie A, Basaraba CN, Nandakumar R, Cremers S, Davis AR, et al. Pharmacokinetics of levonorgestrel and ulipristal acetate emergency contraception in women with normal and obese body mass index. Contraception. 2017:464-9. doi: 10.1016/j.contraception.2017.01.004

        • Westhoff CL
        • Torgal AH
        • Mayeda ER
        • Stanczyk FZ
        • Lerner JP
        • Benn EKT
        • et al.
        Ovarian suppression in normal-weight and obese women during oral contraceptive use.
        Obstet Gynecol. 2010; 117: 275-283
        • Edelman AB
        • Carlson NE
        • Cherala G
        • Munar MY
        • Stouffer RL
        • Cameron JL
        • et al.
        Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity.
        Contraception. 2009; 80: 119-127
        • Donnez J.
        Liver injury and ulipristal acetate: an overstated tragedy?.
        Fertil Steril. 2018; 110: 593-595
        • Dinh A
        • Sriprasert I
        • Williams AR
        • Archer DF.
        A review of the endometrial histologic effects of progestins and progesterone receptor modulators in reproductive age women.
        Contraception. 2015; 91: 360-367