Dienogest ed endometriosi

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1 Dienogest ed endometriosi Prof. Ettore Cicinelli 3 Clinica Ostetrica e Ginecologica - Policlinico Università di Bari ettore.cicinelli@uniba.it

2 1 Inflammation-related processes impairs sperm-oocyte interactions: Reduced chances of in vivo fertilization Pain de Ziegler D, Borghese B, Chapron C. The Lancet 2010;376:

3 Pathogenesis of endometriosis Endocrine disruptors Cytokines + Chemochines Estrogens + _ Progesterone + _ Endometrial cell Cell proliferation and differentiation Immune function Endometriotic cell Genetic/epigenetic influences Inflammation

4 E2, P4, other fact E2, P4, other fact

5 Progestogens effective in the control of pain in approximately 3 out of 4 women with ENDO. The effect does not seem to be inferior to that of other drugs. Different compounds can be administered by the oral, IM, subcutaneous, intravaginal or intrauterine route, each with specific advantages or disadvantages. No estrogen administration

6 Cochrane Database Syst Rev Mar 14;3:CD doi: / CD pub2. Progestagens and anti-progestagens for pain associated with endometriosis. Brown J, Kives S, Akhtar M. MPA (100 mg daily) more effective at reducing all symptoms up to 12 months of follow-up (MD -0.70, 95% CI to ; P < ) compared with placebo. Evidence of significantly more cases of acne (six versus one) and oedema (11 versus one) in the MAP group compared with placebo. Amenorrhoea and bleeding were more frequently reported in the progestagen group compared with other treatment groups.

7 Progestins: side effects Acne Bloating Bleeding Weight gain Headache Depression Reduced libido Effects molecule dependent!

8 Classificazione progestinici

9 DIENOGEST: PROPRIETA FARMACOLOGICHE Derivato del 19 nortestosterone Attività antiandrogena 40% rispetto ciproterone acetato Potente effetto progestageno in vivo Selettività recettoriale: nessuna azione estrogenica, androgenica, mineralcorticoide o glucorticoide

10 DIENOGEST ED ENDOMETRIOSI: MECCANISMO D AZIONE AZIONE CENTRALE AZIONE LOCALE 1.Shimizu Y et al. Mol Hum Reprod Vercellini P et al. Hum Reprod Update Katsuki Y et al. Eur J Endocrinol 1998

11 Dienogest: effetto progestinico sulla inibizione dell ovulazione DNG dose NUMERO DI DONNE NELLO STUDIO DONNE CON OVULAZIONE, n (%) GIORNI 1 36 GIORNI mg 21 1 (5%) 2 (10%) 1 mg 23 1 (4%) 1 (4%) 2 mg mg E2 per l intero periodo di trattamento è rimasto nel range di pg/ml con 2 or 3 mg DNG, contro I pg/ml del basale Dienogest 2 mg/giorno non è stato sviluppato come contraccettivo negli studi di fase 3 DNG, dienogest; E2, estradiol Klipping C. et al. Fertil Steril 2010

12 Soglia terapeutica La finestra terapeutica o estrogen thereshold hypotesis ipotizza un blocco della crescita delle lesioni endometriosiche sotto i 50 pg/ml di concentrazione sierica di E2 Barbieri RL: Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol, 1992; 166:

13 Serum estradiol (pg/ml) LIVELLI DI ESTRADIOLO Pretreatment 0.5 mg 1 mg 2 mg 3 mg Finestra terapeutica pg/ml CON IL DIENOGEST ALLA DOSE DI 2mg AL GIORNO, I LIVELLI DI ESTRADIOLO RIMANGONO ENTRO LA FINESTRA TERAPEUTICA PER RIDURRE I SINTOMI DELL ENDOMETRIOSI Klipping C, et al. J Clin Pharmacol 2011 Barbieri R, J Repro Med 1998

14 MECCANISMO D AZIONE AZIONE CENTRALE AZIONE LOCALE 1.Shimizu Y et al. Mol Hum Reprod Vercellini P et al. Hum Reprod Update Katsuki Y et al. Eur J Endocrinol 1998

15 Dienogest: Attività antiproliferativa dose-dipendente Inibizione della proliferazione dosedipendente di cellule stromali endometriali (ESC) in cultura da parte del dienogest Okada H et al. Mol. Hum. Reprod. 2001;7:

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17 Dienogest: attività progestinica sull endometrio I risultati indicano un potente effetto endometriale Sostanziale effetto inibitorio sulla crescita endometriale già alla dose più bassa Klipping C, et al. J Clin Pharmacol 2011.

18 Dienogest: Attività Antiangiogenetica Uno dei principali fattori che provoca l invasione delle cellule endometriali in altri organi è dovuto all angiogenesi (1) La somministrazione di dienogest 1 mg/kg/day per 5 giorni consecutivi ha significativamente inibito l angiogenesi indotta dalle cellule tumorali S-180 del topo (2). VEICOLO S-180 cells + VEICOLO DNG 0.1 mg/kg DNG 1 mg/kg 1Tan XJ, Lang JH, Liu DY, et al. Fertil Steril 2002; 78: 2Nakamura M et al., Eur J Pharmacol 1999

19 Katayama H et al. Human Reproduction, Vol.25, No.11 pp , 2010 Figure 1 (A C) Intravital fluorescence microscopy of the newly formed microvascular network of endometrial grafts at Day 14 after autologous transplantation into the dorsal skinfold chamber of Wistar rats: the control group (A), the ovariectomized group (B) and the DNG from the Day 0 group (C). The graft in the control group exhibited a dense network of newly formed blood vessels with a glomerulus-like angioarchitecture (A). However, substantial parts of the endometrial graft in the ovariectomized group still lacked vascularization (asterisks) (B). The graft in the DNG from theday 0 group showed a smaller vascularized area and a lower microvessel density, but larger microvessel diameter (C). The excitation and emission wavelengths employed for 5% FITC-labeled dextran were 480 and 520 nm, respectively. Scale bars = 150 µm. (D) Microvessel density (in cm/cm2) of endometrial grafts after autologous transplantation into the dorsal skinfold chambers of Wistar rats: the control group (open triangles; n = 11 fragments), the ovariectomized group (closed triangles; n = 11), the DNG from the Day 4 group (open circles; n = 12 fragments) and the DNG from the Day 0 group (closed circles; n = 11 fragments), as assessed by intravital fluorescence microscopy and computer-assisted image analysis. Values are the mean ± SD. *P < 0.05 versus the control group at corresponding time points.

20 Katayama Human Reproduction, Vol.25, No.11 pp , 2010 Attività Antiangiogenetica Perivascular alpha smooth muscle actin (a-sma) is significantly reduced around the progestinexposed eutopic endometrial microvasculature. This is consistent with findings that endometrial perivascular pericytes decrease in number following the administration of progestins

21 Interleukin-1 β (pg/ml) Dienogest: attività antinfiammatoria 0.4 Endometriosi sperimentale indotta in topi mediante trapianto 0.3 * Riduzione IL-1b prodotta dai macrofagi peritoneali Effetto non presente con buserelina e danazolo Intact Control Dienogest ** *P<0.01 versus intact; **P<0.01 versus control Katsuki Y et al. Eur J Endocrinol 1998.

22 Dienogest: Attività antinfiammatoria Effetto del dienogest sulla espressione di mrna nelle cellule ESC a confronto con molecole a noto effetto antinfiammatorio Yamanaka et al Fertility and Sterility Vol. 97, No. 2, February 2012

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24 Studi principali Main efficacy end-points Disegno studio Trattamento Publicazione Riduzione lesione: rafs score aperto 1, 2, 4 mg/giorno per 24 settimane Köhler et al. (2010) Diminuzione del dolore pelvico: VAS doppio cieco vs placebo 2 mg/giorno 12 settimane Strowitzki et al. (2010) Diminuzione del dolore pelvico: VAS Aperto vs Leuprolide acetato 2 mg/giorno 24 settimane Strowitzki et al. (2010) Diminuzione del dolore pelvico: VAS Aperto 2 mg/die 12mesi + 6 mesi follow up senza trattamento Seitz et al. (2009) References Köhler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO. A dose-ranging study to determine the efficacy and safety of 1, 2 and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet 2010;108: Strowitzki T, Faustmann T, Gerlinger C, Seitz C. Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Hum Reprod 2010;25: Seitz C, Gerlinger C, Faustmann T, Strowitzki T. Safety of dienogest in the long-term treatment of endometriosis: a one-year, open-label, follow-up study. Fertil Steril 2009;92:S107 (abstract).

25 Dose-Range Study: Disegno In aperto, randomizzato, comparativo, multicentrico Donne con endometriosi istologicamente accertata (stadio I, II, or Ill secondo to rafs) Dienogest (DNG) 1, 2, o 4 mg 1 cpr die 24 settimane Efficacia: rafs score alla baseline e alla 24 settimana Miglioramento della sintomatologia DNG=dienogest; Köhler G, et al. Int J Gynaecol Obstet 2010;108:21 25.

26 Dose-Range Study: Disegno Prima Laparoscopia per diagnosi/rafs score alla settimana 0 DNG 1 mg/day* n=4 Seconda Laparoscopia per rafs score alla settimana 24 di trattamento R DNG 2 mg/day n=29 Settimana 0 DNG 4 mg/day n=35 Settimana 24 Criteri di Inclusione: Donne dal menarca alla menopausa Endometriosi stadio da I a III (rafs) conferma Laparoscopica e bioptica *1 mg group stopped due to insufficient bleeding control. R = randomisation. Köhler G, et al. Int J Gynaecol Obstet 2010;108:21 25.

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29 Patients (%) Dose-Range Study: Severità (rafs Score) Assenza Stadio I Stadio II Stadio III Dienogest Dienogest Dienogest Dienogest 2 mg 4 mg 2 mg 4 mg Week 0 Week 24 0, None; I, Stage I (minimal); II, Stage II (mild); III, Stage III (moderate). Missing data not included. Köhler G, et al. Int J Gynaecol Obstet 2010;108:21 25.

30 Studi principali Main efficacy end-points Disegno studio Trattamento Publicazione Riduzione lesione: rafs score aperto 1, 2, 4 mg/giorno per 24 settimane Köhler et al. (2010) Diminuzione del dolore pelvico: VAS doppio cieco vs placebo 2 mg/giorno 12 settimane Strowitzki et al. (2010) Diminuzione del dolore pelvico: VAS Aperto vs Leuprolide acetato 2 mg/giorno 24 settimane Strowitzki et al. (2010) Diminuzione del dolore pelvico: VAS Aperto 2 mg/die 12mesi + 6 mesi follow up senza trattamento Seitz et al. (2009) References Köhler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO. A dose-ranging study to determine the efficacy and safety of 1, 2 and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet 2010;108: Strowitzki T, Faustmann T, Gerlinger C, Seitz C. Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Hum Reprod 2010;25: Seitz C, Gerlinger C, Faustmann T, Strowitzki T. Safety of dienogest in the long-term treatment of endometriosis: a one-year, open-label, follow-up study. Fertil Steril 2009;92:S107 (abstract).

31 Dienogest Versus Placebo: Disegno Randomizzato, in doppio cieco, placebo controllato, multicentrico Dienogest 2 mg/day o placebo 12 settimane VAS score per EAPP ogni 4 settimane Strowitzki T, et al. Eur J Obstet Gynecol Reprod Biol 2010;151:

32 Dienogest Versus Placebo: Disegno Laparoscopia o Laparotomia da meno di un anno per la diagnosi DNG 2 mg/day n=102 R 53 settimane extension con dienogest Week 0 Placebo n=96 Week 12 Inclusion criteria: Donne tra I 18 e I 45 anni con dolore pelvico associato ad endometriosi Endometriosi accertata istologicamente stadi I to IV (rasrm) Minimo valore VAS alla baseline: 30mm EAPP=endometriosis-associated pelvic pain. Strowitzki T, et al. Eur J Obstet Gynecol Reprod Biol 2010;151:

33 VAS (mm) mean ± SEM Dienogest Versus Placebo: Reduc on of Pelvic Pain 80 Dienogest 2 mg Placebo # * * Superiority versus placebo # P< after 4 weeks, * P< after 8 and 12 weeks 20 SEM=standard error of the mean Weeks of treatment Strowitzki T, et al. Eur J Obstet Gynecol Reprod Biol 2010;151:

34 Studi principali Main efficacy end-points Disegno studio Trattamento Publicazione Riduzione lesione: rafs score aperto 1, 2, 4 mg/giorno per 24 settimane Köhler et al. (2010) Diminuzione del dolore pelvico: VAS doppio cieco vs placebo 2 mg/giorno 12 settimane Strowitzki et al. (2010) Diminuzione del dolore pelvico: VAS Aperto vsleuprolide acetato 2 mg/giorno 24 settimane Strowitzki et al. (2010) Diminuzione del dolore pelvico: VAS Aperto 2 mg/die 12mesi + 6 mesi follow up senza trattamento Seitz et al. (2009) References Köhler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO. A dose-ranging study to determine the efficacy and safety of 1, 2 and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet 2010;108: Strowitzki T, Faustmann T, Gerlinger C, Seitz C. Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Hum Reprod 2010;25: Seitz C, Gerlinger C, Faustmann T, Strowitzki T. Safety of dienogest in the long-term treatment of endometriosis: a one-year, open-label, follow-up study. Fertil Steril 2009;92:S107 (abstract).

35 Dienogest Versus Leuprolide Acetato: Disegno dello studio Randomizzato, controllato, in aperto, multicentrico Dienogest 2 mg/day o leuprolide acetate 3.75 mg intramuscolo ogni 4 settimane 24 settimane VAS score per EAPP ogni 4 settimane Strowitzki T, et al. Hum Reprod 2010;25:

36 Dienogest Versus Leuprolide Acetate: Study Design DNG 2 mg/day n=124 R Settimane 0 LA 3.75 mg IM/4 weeks n= Criteri di inclusione: Donne tra I 18 e i 45 anni con EAPP Endometriosi accertata istologicamente stadi I - IV (rafs) IM=intramuscularly; LA=leuprolide acetate. Strowitzki T, et al. Hum Reprod 2010;25:

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38 Totale severità dei sintomi (% patients) Efficacia : totale sintomi e severita dei segni Dienogest 2 mg versus Leuprolide Acetato Nessuno lieve Moderato Severo Molto severo *Biberoglu & Behrman scale Strowitzki T et al. Hum Reprod 2010 Dienogest 2 mg Leuprolide acetate Dienogest 2 mg Leuprolide acetate Basale Settimana 24

39 Mean percentage improvement in SF-36 score Dienogest Versus Leuprolide Acetato: Qualità della vita Physical Health Summary DNG LA Total Physical functioning scale Role-physical scale Bodily pain scale General health scale SF-36 punteggio al termine dello studio Strowitzki T, et al. Int J Gynecol Obstet (In press).

40 Mean percentage improvement in SF-36 score Dienogest Versus Leuprolide Acetato: Qualità della vita DNG LA Mental Health Summary Total Vitality scale Social functioning scale Roleemotional scale Mental health scale SF-36 punteggio al termine dello studio Strowitzki T, et al. Int J Gynecol Obstet (In press).

41 Studi principali Main efficacy end-points Disegno studio Trattamento Publicazione Riduzione lesione: rafs score aperto 1, 2, 4 mg/giorno per 24 settimane Köhler et al. (2010) Diminuzione del dolore pelvico: VAS doppio cieco vs placebo 2 mg/giorno 12 settimane Strowitzki et al. (2010) Diminuzione del dolore pelvico: VAS Aperto vs Leuprolide acetato 2 mg/giorno 24 settimane Strowitzki et al. (2010) Diminuzione del dolore pelvico: VAS Aperto 2 mg/die 12mesi + 6 mesi follow up senza trattamento Seitz et al. (2009) References Köhler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO. A dose-ranging study to determine the efficacy and safety of 1, 2 and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet 2010;108: Strowitzki T, Faustmann T, Gerlinger C, Seitz C. Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Hum Reprod 2010;25: Seitz C, Gerlinger C, Faustmann T, Strowitzki T. Safety of dienogest in the long-term treatment of endometriosis: a one-year, open-label, follow-up study. Fertil Steril 2009;92:S107 (abstract).

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43 VAS (mm) mean ± SEM Long-term Extension Study Pelvic Pain (VAS score) Placebo DNG 2 mg/day DNG 2 mg (prior placebo) DNG 2 mg (prior DNG) 0 PLACEBO STUDY EXTENSION STUDY Weeks of treatment TREATMENT-FREE Efficacia dimostrata fino a 15 mesi Petraglia F, et al. Arch Gynecol Obstet 2012.

44 VAS (mm) mean ± SEM Long-term Extension Study Dolore pelvico (VAS score) Placebo DNG 2 mg/day DNG 2 mg (prior placebo) DNG 2 mg (prior DNG) 0 PLACEBO STUDY EXTENSION STUDY Weeks of treatment TREATMENT-FREE Mantenimento dell effetto Petraglia F, et al. Arch Gynecol Obstet 2012.

45 Int J Womens Health Jul 16;5: doi: /IJWH.S Print Effectiveness of the cyclic administration of dienogest in a case of pathological disappearance of intestinal endometriosis. Tamura R, Tsuneki I, Yanase T.

46 SICUREZZA E TOLLERABILITA

47 Adverse Drug Reactions With Frequency 1% in Pivotal Clinical Trials With Visanne (N=303) MedDRA System Organ Class MedDRA Term n % Disordini del metabolismo e della nutrizione Aumento di peso Alterazioni psichiatriche Depressed mood Alterazioni del sonno Nervosismo Diminuzione della libido Disordini del sistema nervoso Mal di testa Emicrania Disordini Gastrointestinali Nausea Dolore Addominale Disordini della pelle e del tessuto sottocutaneo Acne Alopecia Disordini del sistema riproduttivo e della mammella Mastodinia Cisti Ovariche Sanguinamenti uterini/vaginali anche con spotting Disordini di tipo generale Condizioni di astenia Irritabilità Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, N = total number, n = number of subjects Note: The most appropriate MedDRA term (version 11.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

48 Numero di giorni con vampate Numero di vampate Dienogest 2 mg versus Leuprolide Acetate Dienogest 2 mg Leuprolide acetate Data are mean ± SEM. SEM, standard error of the mean Strowitzki T et al. Hum Reprod 2010 Settimane di trattamento

49 % change in BMD* Variazione densità minerale ossea (BMD) Dienogest 2 mg versus Leuprolide Acetate 2 1 Dienogest 2 mg Leuprolide acetate Weeks of treatment Significativa differenza in favore del dienogest versus leuprolide acetato (P=0.0003) *mean ± SEM SEM, standard error of the mean Strowitzki T et al. Hum Reprod 2010

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51 Livelli di lipidi nel plasma Dienogest 2 mg versus Placebo Parameter (normal reference range) Trigliceridi; mmol/l ( ) Total colesterolo; mmol/l ( ) HDL-C; mmol/l ( ) LDL-C; mmol/l ( ) Dienogest 2 mg Placebo Basale Fine studio Basale Fine studio Mean (± SD) lipid concentrations at baseline and after 12 weeks of dienogest or placebo treatment. SD, standard deviation; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010

52 DIENOGEST 2 mg Effetto su libido e trofismo vaginale Donne con endometriosi confermata e trattata con dienogest (2 mg orale al giorno, n=120) versus leuprolide acetato (3.75 mg IM ogni 4 settimane, n=128) per 6 mesi. Dienogest Leuprolide acetato Diminuzione della libido 4.2% 6.3% Secchezza vaginale 1.7% 7.0% IM, intramuscular Strowitzki T et al. Hum Reprod 2010

53 RITORNO DELL OVULAZIONE In uno studio su 87 donne che assumevano vari dosaggi di Dienogest il 69% di queste aveva un picco di LH entro 43 giorni, dal termine della terapia Se si considera il valore ematico di progesterone superiore a 1,6 ng/ml come indicativo di una ovulazione, solo 2 donne su 87 hanno non hanno raggiunto tale valore al termine del follow-up Klipping C, Duijkers I, Remmers A, Faustmann T, Zurth C, Klein S, Schuett B. J Clin Pharmacol. 2011

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56 SITI DI AZIONE DEL DIENOGEST ANTIINFIAMMATORIO DIENOGEST ANTIPROLIFERATIVO ANTIANGIOGENICO ESTROGENI

57 Summary: DIENOGEST Efficacy Data Reduction of endometriotic lesions Reduction in endometriosis-associated pelvic pain Superior to placebo Equal to leuprolide acetate Rare progestin-related side-effects Sustained reduction in pain scores shown over up to 15 months of treatment Pronounced benefits in quality of life Köhler G, et al. Int J Gynaecol Obstet 2010;108:21 25; Strowitzki T, et al. Eur J Obstet Gynecol Reprod Biol 2010;151: ; Strowitzki T, et al. Hum Reprod 2010;25: ; Petraglia F, et al. Arch Gynecol Obstet 2012; 285(1): , Strowitzki T, et al. Int J Gynecol Obstet (In press).