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XIIèmes Journées Liégeoises de Gynécologie Obstétrique

XIIèmes Journées Liégeoises de Gynécologie Obstétrique. Place des SPRMs en contraception. A Pintiaux , JM Foidart , NChabbert -Buffet , P Bouchard et le groupe d’étude du VA 2914 APHP/UPMC- ULg Paris-Liège. Definition.

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XIIèmes Journées Liégeoises de Gynécologie Obstétrique

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  1. XIIèmes Journées Liégeoises de Gynécologie Obstétrique Place des SPRMs en contraception • A Pintiaux, JM Foidart, NChabbert-Buffet, P Bouchard • et le groupe d’étude du VA 2914 APHP/UPMC- ULg Paris-Liège

  2. Definition Selective progesterone receptor modulators (SPRM) represent a new class of synthetic steroids which can interact with the progesterone receptor (PR) and can exert agonist, antagonist or mixed effects on various progesterone target tissues in vivo

  3. Selective Action At the tissuelevel At the cellularlevel At the genelevel

  4. Mechanisms of Action

  5. PR binding an agonist

  6. PR Ligands : Mechanism of Action Agonist/antagonist COACTIVATORS COACTIVATORS Agonist PR PR Transcription activation Pol II PRE Stop transcription Antagonist COREPRESSORS COREPRESSORS

  7. First Compounds fromthis new class of steroids • Mifepristone (RU 486) • Onapristone (ZK 98 299)

  8. New Compounds • Asoprisnil (J867) • Ulipristal (VA2914)

  9. Gynaecological uses of a new class of steroids : the selectiveprogesteronereceptormodulatorsAxelle Pintiaux, Nathalie Chabbert-Buffet, Jean-Michel Foidart Medical Abortion Management of Miscarriage Emergency Contraception Long Term Contraception Treatment of UterineLeiomyomata Treatment of Endometriosis Breast Cancer GynecologicalEndocrinology, February 2009 ; 25(2) : 67-73

  10. Why the need of a new class of steroids ? To develop an estrogen-free contraception To avoidprogestin To treatgynaecologicaldiseases (myoma , endometriosis) To treat or to preventbreast cancer

  11. Avoid The Progestins Breasteffect Breakthrough bleeding Bloating Mood changes Acne, hirsutism Cardiovascular effects

  12. Contraceptive Mechanisms of SPRMs Inhibition of LH peak Inhibition of follicle rupture Endometrial action

  13. SPRMs and Emergency Pill Mifepristone (RU 486) Jin J, 2005 ; WHO, 1999 VA 2914 Creinin M, 2006

  14. VA 2914 and Emergency Contraception • Randomised double blind trial • 1672 healthywomen, withregular cycles seeking emergency contraception within 72h of UI • 50 mgr single dose VA 2914 + placebo 12h laterversus two doses of 0.75 of LNG taken 12h apart • Primaryoutcome : pregnancy rate ; secondaryoutcome : sideeffects and delay in the onset of the next menses Creinin M, Obstetrics&Gynecol 2006

  15. VA 2914 and Emergency Contraception • ProgesteroneReceptorModulator for Emergency Contraception at least as effective as LNG • VA2914 : trend of higher global effectiveness but best than LNG whenintake > 48h afterunprotected intercourse • VA2914 effective alsoafter ovulation • Mildsimilarsideeffects • Adverse effect : delay of menses (increasedrisk of late ovulation and worry about an unintendedpregnancy) • Advantage : VA2914 maybe more efficaciousthan LNG for womenwhocannotobtain emergency contraception within 48h of exposure, lessantiglucocorticoïdeffectthanmifepristone Creinin M, Obstetrics & Gynecol 2006

  16. SPRMs & Oral Contraception Mifepristone(RU486) VA 2914

  17. SPRMs & Oral Contraception Mifepristone : 2 or 5 mg/dayBrown 2002 Mifepristone : 50 mg/weekPei 2007 VA 2914 : 5 mg/dayChabbert 2007

  18. SPRMs and management of irregularbleeding on progestinonly contraceptive regimen • Control • IUD-LNG

  19. Endometriumand VA 2914 (2.5, 5, 10 mg) Ravet S, Munaut C, Blacher S, Brichant G, Labied S, Beliard A, Chabbert-Buffet N, Bouchard P, Foidart JM, Pintiaux A. J ClinEndocrinolMetab. 2008 Nov;93(11):4525-31.

  20. SPRMs and management of irregularbleeding on progestinonly contraceptive regimen Org 31710 : 150 mg 1x/month to womenusingdesogestrel 75 µg/d (GemzellDanielsson, 2002) Mifepristone : 50 mg/month to womenusing the LNG implant ( Cheng, 2000) Mifepristone : 25 mg/2 weeks for 3 months to womenusingdepot MPA ( Jain, 2003)

  21. SPRMs and Devices

  22. SPRMs and Devices ZK 230211 releasing IUD tested in monkeys and in women( Nayak, 2007 ; Heikinheimo, 2007) VA 2914 releasing IUD tested in monkeys(Population Council) VA 2914 vaginal ring for 3 months(Sitruk- Ware, 2005)

  23. Clinical Aspects 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. Chabbert-Buffet N, Pintiaux-Kairis A, Bouchard P; VA2914 Study Group. J ClinEndocrinolMetab. 2007 Sep;92(9):3582-9.

  24. Ovulation inhibition– Bleeding pattern

  25. Ultrasonographic Aspects

  26. Histologic Aspects Mutter, 2008

  27. PRM - Associated Endometrial Changes Dyssynchronousgrowthbetween glands and stroma Interspersedcyststhroughout all the endometrium Glands showing non physiologicalcombination of inactivity, secretory changes, mitosis and apoptosis Fibrous stroma withmitotic figures Vascular aspects (thickwallvessels, anastomosingcapillary network, ectaticstromalbloodvessels)

  28. Conclusions SPRM limitedactually to short term use Ideal SPRM : reducedantiglucocorticoidproperties Intermittent therapy ? Long termendometrialsafety ?

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