Advertisement

Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women

      Abstract

      Background

      Progesterone receptor modulators (PRMs) delivered by contraceptive vaginal rings provide an opportunity for development of an estrogen-free contraceptive that does not require daily oral intake of steroids. The objective of this proof-of-concept study was to determine whether continuous delivery of 600���800 mcg of ulipristal acetate (UPA) from a contraceptive vaginal ring could achieve 80% to 90% inhibition of ovulation.

      Study Design

      This was a prospective, controlled, open-labeled, multicenter international trial to examine the effectiveness and safety of this prototype vaginal ring. Thirty-nine healthy women, 21���40 years old and not at risk of pregnancy, were enrolled at three clinic sites. Volunteers participated in a control cycle, a 12-week treatment period and a post-treatment cycle. Pharmacodynamic effects on follicular function and inhibition of ovulation, effects on endometrium, bleeding patterns and serum UPA levels were evaluated.

      Results

      Mean UPA levels during treatment were nearly constant, approximately 5.1 ng/mL throughout the study. Ovulation was documented in 32% of 111 ���4-week treatment cycles.��� A correlation was observed between serum UPA and degree of inhibition of ovarian activity. There was no evidence of hyperplasia of endometrium, but PRM-associated endometrial changes were frequently observed (41%).

      Conclusion

      In this study, the minimum effective contraceptive dose was not established. Further studies are required testing higher doses of UPA to attain ovulation suppression in a higher percentage of subjects.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Contraception
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Cleland J.
        • Bernstein S.
        • Ezeh A.
        • Faundes A.
        • Glasier A.
        • Innis J.
        Family planning: the unfinished agenda.
        Lancet. 2006; 18: 1810-1827
        • Spitz I.M.
        • Croxatto H.B.
        • Robbins A.
        Antiprogestins: mechanism of action and contraceptive potential.
        Annu Rev Pharmacol Toxicol. 1996; 36: 47-81
        • Croxatto H.B.
        • Kovacs L.
        • Massai R.
        • et al.
        Effects of long-term low-dose mifepristone on reproductive function in women.
        Hum Reprod. 1998; 13: 793-798
        • Chabbert-Buffet N.
        • Meduri G.
        • Bouchard P.
        • Spitz I.M.
        Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications.
        Hum Reprod Update. 2005; 11: 293-307
        • Brenner R.M.
        • Slayden O.D.
        Progesterone receptor antagonists and the endometrial antiproliferative effect.
        Semin Reprod Med. 2005; 23: 74-81
        • Chwalisz K.
        • Brenner R.M.
        • Fuhrmann U.U.
        • Hess-Stumpp H.
        • Elger W.
        Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium.
        Steroids. 2000; 65: 741-751
        • Palanisamy G.S.
        • Cheon Y.P.
        • Kim J.
        • et al.
        A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice.
        Mol Endocrinol. 2006; 20: 2784-2795
        • Brache V.
        • Cochon L.
        • Jesam C.
        • et al.
        Immediate pre-ovulatory administration of 30 mg. ulipristal acetate significantly delays follicular rupture.
        Hum Reprod. 2010; 25: 2256-2263
        • Chwalisz K.
        • Elger W.
        • Stickler T.
        • Mattia-Goldberg C.
        • Larsen L.
        The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.
        Hum Reprod. 2005; 20: 1090-1099
        • Brown A.
        • Cheng L.
        • Lin S.
        • Baird D.
        Daily dose mifepristone has contraceptive potential 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
        • Blithe D.L.
        • Nieman L.K.
        • Blye R.P.
        • Stratton P.
        • Passaro M.
        Development of the selective progesterone receptor modulator CDB-2914 for clinical indications.
        Steroids. 2003; 68: 1013-1017
        • Larner J.M.
        • Reel J.R.
        • Blye R.P.
        Circulating concentrations of antiprogestins CDB-2914 and mifepristone in female rhesus monkey following various routes of administration.
        Hum Reprod. 2000; 15: 1100-1106
        • Cook C.E.
        • Wani M.C.
        • Lee Y.W.
        • Fail P.A.
        • Petrow V.
        Reversal of activity profile in analogs of the antiprogestin RU 486: effect of a 16��-substituent on progestational (agonist) activity.
        Life Sci. 1992; 52: 155-162
        • Hild S.A.
        • Reel J.R.
        • Hoffman L.H.
        • Blye R.P.
        CDB-2914: anti-progestational/anti-glucocorticoid profile and post coital antifertility activity in rats and rabbits.
        Hum Reprod. 2000; 15: 822-829
        • Attardi B.J.
        • Burgenson J.
        • Hild S.A.
        • Reel J.R.
        • Blye R.P.
        CDB-4124 and its putative monodemethylated metabolite, CDB-4453, are potent antiprogestins with reduced antiglucocorticoid activity: in vitro comparison to mifepristone and CDB-2914.
        Mol Cell Endocrinol. 2002; 188: 111-123
        • Attardi B.J.
        • Burgenson J.
        • Hild S.A.
        • Reel J.R.
        In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone.
        J Steroid Biochem Mol Biol. 2004; 88: 277-288
        • Stratton P.
        • Hartog B.
        • Hajizadeh N.
        • et al.
        A single mid-follicular dose of CDB2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women.
        Hum Reprod. 2000; 15: 1092-1099
        • Glasier A.F.
        • Cameron S.T.
        • Fine P.M.
        • et al.
        Ulipristal acetate versus levonorgestrel for emergency contraception: a randomized non-inferiority trial and meta-analysis.
        Lancet. 2010; 375: 555-562
        • Fine P.
        • Math�� H.
        • Ginde S.
        • Cullins V.
        • Morfesis J.
        • Gainer E.
        Ulipristal acetate taken 48-120 hours after intercourse for emergency contraception.
        Obstet Gynecol. 2010; 115: 257-263
        • Chabbert-Buffet N.
        • Pintiaux-Kairis A.
        • Bouchard P.
        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 Endocrinol Metab. 2007; 92: 3582-3589
        • Glasier A.F.
        • Smith K.B.
        • van der Spuy Z.M.
        • et al.
        Amenorrhea associated with contraception an international study on acceptability.
        Contraception. 2003; 67: 1-8
        • Alvarez-Sanchez F.
        • Brache V.
        • Jackanicz T.
        • Faundes A.
        Evaluation of four different contraceptive vaginal rings: steroid serum levels, luteal activity, bleeding control, and lipid profiles.
        Contraception. 1992; 46: 387-398
        • Fraser I.S.
        • Weisberg E.
        • Brache V.
        • et al.
        Serum Nestorone and ethinyl estradiol levels, and ovulation inhibition in women using three different dosage combinations of a Nestorone progestogen-ethinyl estradiol contraceptive vaginal ring on a bleeding-signaled regimen.
        Contraception. 2005; 72: 40-45
        • Timmer C.J.
        • Mulders T.M.
        Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring.
        Clin Pharmacokinet. 2000; 39: 233-242
        • Brache V.
        • Faundes A.
        Contraceptive vaginal rings: a review.
        Contraception. 2010; 82: 418-427
        • Kerns J.
        • Darney P.
        Vaginal ring contraception.
        Contraception. 2011; 83: 107-115
        • Croxatto H.B.
        • Brache V.
        • Sitruk-Ware R.
        • Kumar N.
        • Sivin I.
        A study to evaluate the effect of a contraceptive vaginal ring delivering a daily dose of 400-500 ��g of CDB-2914 on pharmacokinetics and pharmacodynamics in normal cycling women. Summary study report. Protocol 312. Population Council, New York, New York2003 ([data��on file])
        • Stanczyk F.Z.
        • Cho M.M.
        • Endres D.B.
        • Morrison J.L.
        • Patel S.
        • Paulson R.J.
        Limitations of direct estradiol and testosterone immunoassay kits.
        Steroids. 2003; 68: 1173-1178
      1. Kurman R. Blaustein's pathology of the female genital tract. 5th ed. Springer-Verlag, New York2002: 383-420
        • Mutter G.L.
        • Bergeron C.
        • Deligdisch L.
        • et al.
        The spectrum of endometrial pathology induced by progesterone receptor modulators.
        Mod Pathol. 2008; 21: 591-598
        • Reel J.R.
        • Hild-Petito S.
        • Blye R.P.
        Antiovulatory and postcoital antifertility activity of the antiprogestin CDB-2914 when administered as single, multiple, or continuous doses to rats.
        Contraception. 1998; 58: 129-136
        • Horne F.M.
        • Blithe D.L.
        Progesterone receptor modulators and the endometrium: changes and consequences.
        Hum Reprod Update. 2007; 13: 567-580
        • Writing Group for the Women's Health Initiative Investigators
        Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.
        JAMA. 2002; 288: 321-333
        • Fournier A.
        • Berrino F.
        • Riboli E.
        • Avenel V.
        • Clavel-Chapelon F.
        Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort.
        Int J Cancer. 2005; 114: 448-454
        • Lakha F.
        • Ho P.C.
        • Van der Spuy Z.M.
        • et al.
        A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel).
        Hum Reprod. 2007; 22: 2428-2436