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Mifepristone for luteal phase contraception

      Abstract

      The concept of luteal phase contraception and the use of mifepristone in clinical trials, which allows for testing of its validity, as well as clinical pharmacological research designed to understand its mode of action, are reviewed. Early luteal phase administration has a variety of morphological, physiological and biochemical effects on the endometrium that are likely to interfere with embryonic–endometrial interactions. In fact, specifically designed pilot clinical trials as well as data derived from emergency contraception studies indicate that early luteal phase administration of mifepristone is highly effective in preventing pregnancy, with minimal disturbance of hormonal parameters or menstrual cyclicity. Mid and late luteal phase administration of mifepristone at doses above 25 mg are highly effective in inducing endometrial bleeding in nonconceptional cycles. However, administration of mifepristone within the period between implantation and expected menses fails to induce bleeding in a significant proportion of cases, and furthermore the bleeding induced does not insure the termination of pregnancy. While the data suggest there is potential for a once-a-month contraceptive pill, it is likely that no molecule endowed with partial agonistic properties, like mifepristone, will completely and reliably suppress the essential functions of progesterone in order to achieve contraceptive efficacy comparable to that of modern contraceptive methods.

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      References

        • Gemzell-Danielsson K.
        • Swahn M.L.
        • Svalander P.
        • Bygdeman M.
        Early luteal phase treatment with RU486 for fertility regulation.
        Hum Reprod. 1993; 8: 870-873
        • Hapangama D.K.
        • Brown A.
        • Glasier A.F.
        • Baird D.T.
        Feasibility of administering mifepristone as a once a month contraceptive pill.
        Hum Reprod. 2001; 16: 1145-1150
        • Marions L.
        • Danielsson K.
        Contraceptive efficacy of low doses of mifepristone.
        Fertil Steril. 1998; 70: 813-816
        • Marions L.
        • Viski S.
        • Gemzell-Danielsson K.
        • et al.
        Contraceptive efficacy of daily administration of 0.5 mg mifepristone.
        Hum Reprod. 1999; 14: 2788-2790
        • Baird D.T.
        • Brown A.
        • Critchley H.O.
        • Williams A.R.
        • Lin S.
        • Cheng L.
        Effect of long-term treatment with low-dose mifepristone on the endometrium.
        Hum Reprod. 2003; 18: 61-68
        • Swahn M.L.
        • Bygdeman M.
        • Cekan S.
        • Xing S.
        • Masironi B.
        • Johannisson E.
        The effect of RU 486 administered during the early luteal phase on bleeding pattern, hormonal parameters and endometrium.
        Hum Reprod. 1990; 5: 402-408
        • Glasier A.
        • Thong K.J.
        • Dewar M.
        • Mackie M.
        • Baird D.T.
        Mifepristone (RU 486) compared with high-dose estrogen and progestogen for emergency postcoital contraception.
        N Engl J Med. 1992; 327: 1041-1044
        • Webb A.M.
        • Russell J.
        • Elstein M.
        Comparison of Yuzpe regimen, danazol, and mifepristone (RU486) in oral postcoital contraception.
        BMJ. 1992; 305: 927-931
        • WHO Task Force on Postovulatory Methods of Fertility Regulation
        Comparison of three single doses of mifepristone as emergency contraception.
        Lancet. 1999; 353: 697-702
        • Ashok P.W.
        • Wagaarachchi P.T.
        • Flett G.M.
        • Templeton A.
        Mifepristone as a late post-coital contraceptive.
        Hum Reprod. 2001; 16: 72-75
        • Von Hertzen H.
        • Piaggio G.
        • Ding J.
        • et al.
        Low dose mifepristone and two regimens of levonorgestrel for emergency contraception.
        Lancet. 2002; 360: 1803-1810
        • Xiao B.L.
        • Von Hertzen H.
        • Zhao H.
        • Piaggio G.
        A randomized double-blind comparison of two single doses of mifepristone for emergency contraception.
        Hum Reprod. 2002; 17: 3084-3089
        • Van Santen M.R.
        • Haspels A.A.
        Interception. III.
        Contraception. 1987; 35: 423-431
        • Van Santen M.R.
        • Haspels A.A.
        Interception. IV.
        Contraception. 1987; 35: 433-438
        • Lähteenmäki P.
        • Rapeli T.
        • Kaariainen M.
        • Alfthan H.
        • Ylikorkala O.
        Late postcoital treatment against pregnancy with antiprogesterone RU 486.
        Fertil Steril. 1988; 50: 36-38
        • Dubois C.
        • Ulmann A.
        • Baulieu E.E.
        Contragestion with late luteal administration of RU 486 (Mifepristone).
        Fertil Steril. 1988; 50: 593-596
        • Wu X.J.
        • Shao J.Y.
        • Zhuang L.Q.
        • et al.
        A multicentre clinical trial on postcoital contraception with mifepristone and misoprostol.
        Reproduc Contracep. 1994; 14: 439-446
        • Swahn M.L.
        • Bygdeman M.
        • Chen J.K.
        • et al.
        Once-a-month treatment with a combination of mifepristone and the prostaglandin analogue misoprostol.
        Hum Reprod. 1999; 14: 485-488
        • Croxatto H.B.
        • Fuentealba B.
        • Salvatierra A.M.
        • Massai R.
        Clinical strategies for the achievement of endometrial contraception with progesterone antagonists.
        in: Beier H.M. Harper M.J.K. Chwalisz K. The endometrium as a target for contraception. Ernst Schering Research Foundation Workshop 18. Springer, Berlin1997: 259-278
        • Elger W.
        • Bartley J.
        • Schneider B.
        • Kaufmann G.
        • Schubert G.
        • Chwalisz K.
        Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonist.
        Steroids. 2000; 65: 713-723
        • Chwalisz K.
        • Garg R.
        • Brenner R.M.
        • Schubert G.
        • Elger W.
        Selective progesterone receptor modulators (SPRMs).
        Ann N Y Acad Sci. 2002; 955: 373-388
        • Croxatto H.B.
        Clinical prospects of progesterone receptor modulators.
        in: Schneider H.P.G. Menopause: state of the art in research and management. Proceedings of the 10th Word Congress on the Menopause. The Parthenon Publishing Group, Boca Raton (FL)2002: 43-46
        • Christow A.
        • Sun X.
        • Gemzell-Danielsson K.
        Effect of mifepristone and levonorgestrel on expression of steroid receptors in the human Fallopian tube.
        Mol Hum Reprod. 2002; 8: 333-340
        • Sun X.
        • Christow A.
        • Marions L.
        • Gemzell-Danielsson K.
        Progesterone receptor isoform B in the human Fallopian tube and endometrium following mifepristone.
        Contraception. 2003; 67: 319-326
        • Schaison G.
        • George M.
        • Lestrat N.
        • Reinberg A.
        • Baulieu E.E.
        Effects of the antiprogesterone steroid RU 486 during midluteal phase in normal women.
        J Clin Endocrinol Metab. 1985; 61: 484-489
        • Garzo V.G.
        • Liu J.
        • Ulmann A.
        • Baulieu E.
        • Yen S.S.C.
        Effects of an antiprogesterone (RU 486) on the hypothalamic-hypophyseal-ovarian-endometrial axis during the luteal phase of the menstrual cycle.
        J Clin Endocrinol Metab. 1988; 66: 508-517
        • Li T.C.
        • Dockery P.
        • Thomas P.
        • Rogers A.W.
        • Lenton E.A.
        • Cooke I.D.
        The effects of progesterone receptor blockade in the luteal phase of normal fertile women.
        Fertil Steril. 1988; 50: 732-742
        • Gemzell-Danielsson K.
        • Svalander P.
        • Swahn M.L.
        • Johannisson E.
        • Bygdeman M.
        Effects of a single-postovulatory dose of RU486 on endometrial maturation in the implantation phase.
        Hum Reprod. 1994; 9: 2398-2404
        • Croxatto H.B.
        • Salvatierra A.M.
        • Croxatto H.D.
        • Spitz I.M.
        Variable effects of RU486 on endometrial maintenance in the luteal phase extended by exogenous hCG.
        Clin Endocrinol. 1989; 31: 15-23
        • Swahn M.L.
        • Johannisson E.
        • Daniore V.
        • de la Torre B.
        • Bygdeman M.
        The effect of RU 486 administered during the proliferative and secretory phase of the cycle on the bleeding pattern, hormonal parameters and the endometrium.
        Hum Reprod. 1988; 3: 915-921
        • Dockery P.
        • Ismail R.M.J.
        • Li T.C.
        • Warren M.A.
        • Cooke I.D.
        The effect of a single dose of mifepristone (RU486) on the fine structure of the human endometrium during the early luteal phase.
        Hum Reprod. 1997; 12: 1774-1778
        • Berthois Y.
        • Salat-Baroux J.
        • Cornet D.
        • De Brut J.
        • Kopp F.
        • Martin P.M.
        A multiparametric analysis of endometrial estrogen and progesterone receptors after the postovulatory administration of mifepristone.
        Fertil Steril. 1991; 55: 547-554
        • Greene K.E.
        • Kettel L.M.
        • Yen S.S.C.
        Interruption of endometrial maturation without hormonal changes by an antiprogesterone during the first half of the luteal phase of the menstrual cycle.
        Fertil Steril. 1992; 58: 338-343
        • Gemzell-Danielsson K.
        • Swahn M.L.
        • Bygdeman M.
        The effect of various doses of mifepristone on endometrial leukaemia inhibitory factor expression in the midluteal phase—an immunohistochemical study.
        Hum Reprod. 1997; 12: 1293-1297
        • Cameron S.T.
        • Critchley H.O.
        • Buckley C.H.
        • Kelly R.W.
        • Baird D.T.
        Effect of two antiprogestins (mifepristone and onapristone) on endometrial factors of potential importance for implantation.
        Fertil Steril. 1997; 67: 1046-1053
        • Mäentausta O.
        • Slavander P.
        • Gemzell-Danielsson K.
        • Bygdeman M.
        • Vihko R.
        The effects of an antiprogestin, mifepristone, and an antiestrogen, tamoxifen, on endometrial 17β-hydroxysteroid dehydrogenase and progestin and estrogen receptors during the luteal phase of the menstrual cycle.
        J Clin Endocrinol Metab. 1993; 77: 913-918
        • Slayden O.D.
        • Nayak N.R.
        • Burton K.A.
        • et al.
        Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium.
        J Clin Endocrinol Metab. 2001; 86: 2668-2679
        • Graham R.A.
        • Li T.C.
        • Seif M.W.
        • Aplin J.D.
        • Cooke I.D.
        The effects of the antiprogesterone RU486 (mifepristone) on an endometrial secretory glycan.
        Fertil Steril. 1991; 55: 1132-1136
        • Marions L.
        • Hultenby K.
        • Lindell I.
        • Sun X.
        • Stabi B.
        • Gemzell Danielsson K.
        Emergency contraception with mifepristone and levonorgestrel.
        Obstet Gynecol. 2002; 100: 65-71
        • Marions L.
        • Gemzell-Danielsson K.
        • Swahn M.L.
        • Bygdeman M.
        The effect of antiprogestin on integrin expression in human endometrium.
        Hum Reprod. 1988; 4: 491-495
        • Kumar S.
        • Zhu L.J.
        • Polihronis M.
        • et al.
        Progesterone induces calcitonin gene expression in human endometrium within the putative window of implantation.
        J Clin Endocrinol Metab. 1998; 83: 4443-4450
        • Marions L.
        • Gemzell-Danielsson K.
        Expression of cyclo-oxigenase in human endometrium during the implantation period.
        Mol Hum Reprod. 1999; 5: 961-965
        • Critchley H.O.
        • Tong S.
        • Cameron S.T.
        • Drudy T.A.
        • Kelly R.W.
        • Baird D.T.
        Regulation of bcl-2 gene family members in human endometrium by antiprogestin administration in vivo.
        J Reprod Fertil. 1999; 115: 389-395
        • Gemzell-Danielsson K.
        • Hamberg M.
        The effect of antiprogestin (RU 486) and prostaglandin biosynthesis inhibitor (naproxen) on uterine fluid prostaglandin F2α concentration.
        Hum Reprod. 1994; 9: 1626-1630
        • Beier-Hellwig K.
        • Sterzik K.
        • Bonn B.
        • et al.
        Hormone regulation and hormone antagonist effects on protein patterns of human endometrial secretion during receptivity.
        Ann N Y Acad Sci. 1994; 734: 143-156