Dr Pietro Santulli. Inserm, Unité de recherche U1016 équipe Pr F. Batteux, Institut Cochin, Paris, France

Transcription

1 Endometriosis related infertility: Treatment modalities and strategies Dr Pietro Santulli MD, PhD VENDREDI 20 NO Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine, AP-HP, Cochin Saint Vincent de Paul, Department of Gynecology Obstetrics II and Reproductive Medicine, Paris, France Inserm, Unité de recherche U1016 équipe Pr F. Batteux, Institut Cochin, Paris, France Inserm, Unité de recherche U1016 équipe Dr D. Vaiman, Institut Cochin, Paris, France ème

2 Endometriosis related infertility - Specifications and pathogenesis - What are the therapeutic options? - How to choose between the therapeutic options? - Proposition for a strategy

3 Endometriosis related infertility - Specifications and pathogenesis - What are the therapeutic options? - How to choose between the therapeutic options? - Proposition for a strategy

4 Endometriosis: Heterogeneous disease SUP OME DIE Adenomyosis Asymptomatic Pain Infertility

5 Endometriosis and infertility: Pathogenesis Pelvic cavity: Inflammation-related process interferes with sperm-oocyte intercations: Reduced chances of IN VIVO fertilization Uterus: Alterations of eutopic endometrium: - PTGS2 overexpression - CYP-19 and NR5A1 activation - Resistance to P4 (PR-D) Ovaries: Decreased ovarian response to COH: - More FSH / hmg needeed - Less oocytes obtained de Ziegler, Borghese and Chapron The Lancet 2010 Santulli P et al. JCEM 2014

6 Endometriosis related infertility - Specifications and pathogenesis - What are the therapeutic options? - How to choose between the therapeutic options? - Proposition for a strategy

7 Endometriosis related infertility Management options - Medical treatment - Surgery - Assisted Reproductive Technologies

8 Endometriosis related infertility Management options - Medical treatment - Surgery - Assisted Reproductive Technologies

9 Endometriosis related infertility Medical treatment? All options are contraceptive Hughes E et al. Cochrane Database 2007

10 Endometriosis related infertility Management options - Medical treatment - Surgery - Assisted Reproductive Technologies

11 Endometriosis related infertility surgery in infertile women Cumulative PR Consider Sx Mo in vivo N=222 Stages I-IV 50% 6 18 Time (months) Vercellini et al., Human Reprod 2009;24:

12 Endometriosis related infertility : Postoperative delayed initiation of attempted conception < 12 months 12 months Pregnancy: 0.79 (95% CI: ) Vercellini et al., RBMO 2010

13 1 Year 2 Years 3 Years Deep endometriosis related infertility : Laparoscopic surgery in women with moderate to severe endometriosis Patients operated Wishing to conceive Pregnant (74%) 48 (51%) (71%) 27 (50%) 73% 44% 58% Meuleman C et al., Ann Surg (2013)

14 Deep endometriosis related infertility : Laparoscopic surgery in women with moderate to severe endometriosis 20% conceived spontaneously Meuleman C et al., Ann Surg (2013)

15 Pregnancies (%) Intestinal DIE: Surgical techniques Spontaneous conception P=0.03 Conception No Conception 12/30 7/23 24/34 Bowel resection Residual bowel endometriosis No bowel endometriosis 1 year 2 years 4 years P=0.005 IVF treatment Residuel bowel endometriosis No bowel endometriosis Bowel resection 5/13 1/13 4/6 Time after surgery (days) Bowel resection Residual bowel endometriosis No bowel endometriosis Stepniewska et al., Hum Reprod 2009

16 Surgery for endometriosis and infertility Deep endometriosis: Complications Table I Major intra- and post-operative complications of radical surgery for rectovaginal endometriosis Com plicat ion Obser ved incidence (%)... Neurogenic bladder dysfunction 4 10 Rectovaginal fistula formation 2 10 Blood transfusion 2 6 Inadvertent rectal perforation 1 3 Anastomotic leakage 1 2 Pelvic abscess 1 2 Temporary diverting loop ileostomy/ colostomy Intraoperative ureteral lesion Post-operative ureteral fistula formation Post-anastomotic rectal stenosis Post-anastomotic ureteral stenosis From Vercellini et al. (2009, in press). Literature data, : Possover et al. (2000), Anaf et al. (2001), Chapron et al. (2001), Redwine and Vercellini W right et al., (2001), Hum Reprod W right (2009)

17 Web Appendix: Effects of surgery on infertility associated with endometriosis. OMAs: Laparoscopic excision Laparoscopic excision of endometrioma (OM A) N # IUP % IUP Daniell et al., Marrs et al., Bateman et al., Crosignani et al., Montanino et al., Donnez et al., Sutton et al., Beretta et al., Milingos et al., Busacca et al., Jones and Sutton, Alborzi et al., Fedele et al., Vercellini et al., Total % The Lancet (2010)

18 Raffi et al., JCEM (2012) Pre op AMH levels 3.1ng/ml

19 Endometriosis and ovarian reserve Impact of endometriosis per se on ovarian reserve? Impact of endometriosis per se on ovarian reserve? Quantity Quality

20 Endometriosis and ovarian reserve Quality Sanchez AM et al, Hum Reprod Update (2014)

21 Endometriosis and ovarian reserve Quality N=244 (183-75% DIE) Follow up 6 months 1199 cycles of spontaneous ovulation 105 (43.2%) spontaneous pregnancy Leone Roberti Maggiore et al., Human Reprod (2014)

22 Endometriosis and ovarian reserve Quantity AMH N=726 Streuli I et al, Hum Reprod (2012)

23 Endometriosis and ovarian reserve Quantity AMH N=726 Previous OMA surgery OR= 3.0 ( ); p=0.01 Streuli I et al, Hum Reprod (2012)

24 Endometriosis and ovarian reserve Quantity

25 Endometriosis and ovarian reserve Quantity AMH trol group = 106) AMH serum level (ng/ml) Age OC use Infertility Study group (n = 122) p = Control group (n = 106) AMH serum level (ng/ml) With (n Marcellin - Santulli - Chapron et al, submitted 2015

26 Endometriosis and ovarian reserve Quantity AMH AMH/SIZE OMA CORRELATION 10 AMH serum level (ng/ml) p = OMA < 5 cm (n = 83 ) p = OMA 5 (n = 39) AMH serum level (ng/ml) AMH serum level (ng/ml) R p square = = p = sum OMA 5 < 5 cm sum 10 OMA 5 OMA (n = 72 size ) (cm) (n = 50) 4 2 AMH/SIZE OMA SUM CORRELATION Marcellin - Santulli - Chapron et al, submitted 2015

27 Endometriosis and ovarian reserve The impact of OMA on IVF outcomes N=64 Coccia et al. Reprod biomed online 2014

28 Endometriosis and ovarian reserve The impact of OMA on IVF outcomes Hamdan et al. Human Reprod Update 2015

29 IVF and diminished ovarian reserve: Post OMA cystectomy versus idiopathic Diminished ovarian reserve AMH < 2ng/ml OMA Cystectomy Idiopathic Retrospective study Roustan et al., Hum Reprod (2015)

30 Endometriosis related infertility Management options - Medical treatment - Surgery - Assisted Reproductive Technologies

31 Hamdan et al., Obstet Gynecol (2015) pendix 1: A. Overall live birth Endometriosis: rate in women with endometriosis compared to contr Overall clinical pregnancy rate in women with endometriosis compared to control. C erall mean number of oocytes IVF outcome: retrieved from Life women birth rate with endometriosis compared ntrol. D. Overall miscarriage rates in women with endometriosis compared to contro

32 Endometriosis and IVF The Phenotype n=359 DIE Oma Sup P value Patients No. of cycles No. of ET 282/425 (66.4) 141/200 (70.5) 77/95 (81.1) Clinical pregnancy rate per cycle 98/425 (23.1) 55/200 (27.5) 29/95 (30.5) 0.22 Clinical pregnancy rate per ET 98/282 (34.8) 55/141 (39) 29/77 (37.7) 0.67 Implantation rate 111/513 (21.6) 62/265 (23.4) 35/140 (25.0) 0.66 Abortion rate 30/98 (30.6) 22/55 (40.0) 16/29 (55.2) Santulli P, Maignien C, Chapron C. Submitted 2015

33 Ovarian suppression before COH Effects of GnRH-a IVF outcome Effects of OC IVF outcome P <0.05 * ** P <0.01 Center 1 & 2 PR % ** controls Osis IV OMA present w/ OC pretreatment pre-art OC x6-8 wks * No pretreatment the administration of GnRH-a or OC prior to IVF/ICSI in women w/ endometriosis increases the odd of pregnancy > 4 fold. Sellam et al Cochrane (2006) de Ziegler et al., Fertil Steril (2010)

34 Endometriosis related infertility Surgery vs ART Fertility DIE surgery complications Ovarian reserve damage Limits Post retrieval Infection Pain? Pain treatment Advantages OMA surgery not necessary Surgery ART

35 Endometriosis related infertility - Specifications and pathogenesis - What are the therapeutic options? - How to choose between the therapeutic options? - Proposition for a strategy

36 How to choose between the therapeutic options? - Endometrioma: to remove or not? - Clinical symptoms - Adenomyosis - Iterative Surgery - Large endometrioma

37 Pain progression Endometrioma and IVF: To remove or not to remove That is the question Post retrieval infection

38 Fertility preservation in women with endometriosis Pain progression N=104 N=102 Santulli-Bourdon-Chapron et al., Fertil Steril in press 2015

39 Fertility preservation in women with ART in global population endometriosis Pelvic infection after oocyte retrieval Oocyte retrieval Post procedure infection Bennett SJ et al. J Assist Reprod Genet (1993) (0.67%) Dicker D et al. Fertil Steril (1993) (0.24%) Moini A et al. J Assist Reprod Genet (2005) (0,16%) TOTAL (0.30%) ART in endometriotic women Oocyte retrieval Post procedure infection Tsai YC et al. J Assist Reprod Genet (2005) (1.9%) Benaglia L et al. Fertil Steril (2008) (0.0%) de Ziegler et al. In press (2015) (0.38%) TOTAL (0.48%)

40 Endometrioma and IVF: To remove or not to remove That is the question No systematic surgery before IVF Somigliana, et al., Human Reprod Update (2015)

41 Endometriosis: n = 870 patients Asymptomatic % SUP % OMA % DIE % Pelvic pain Infertility % % % SUP % OMA % DIE % SUP % OMA % DIE % * Oma % * Oma % p < SUP % OMA % DIE % * Oma % * Oma % Chapron and Santulli, (2014)

42 Endometriosis related infertility: Pelvic pain Determinants for pain 7 in endometriotic women with infertility results from muliple logistic regression analysis OR (95%IC) P value DIE intestine 3.9 ( ) Previous endometriosis surgery 2.7 ( ) Santulli-Lamau-Chapron, Submitted (2015)

43 Endometriosis: Preoperative work-up Questionning and Imaging Questionning Pelvic examination Biochemical markers Trans-vaginal US Trans-rectal US MRI Uro-MRI Kidney scintigraphy

44 Endometriosis and infertility: Phenotype Adenomyosis SUP OME DIE Adenomyosis

45 Adenomyosis and infertility Intestinal DIE Vercelllini et al RBMO 2014

46 Endometriosis: Surgical management Disease Progression Recurrence? Surgery Unnecessary Inappropriate n = 790 patients Sibiude, Santulli, Chapron, Obstet Gynecol 2014

47 Repetitive surgery: 24-month cumulative pregnancy rate Endometriosis Endometriosis-related infertility 40% First line S. 22% Repetitive S. First line S. 34% 19% Repetitive S. Vercellini et al., Fertil Steril 2009

48 OMA: Ovarian reserve and repetitive cystectomy Ferrero et al., Fertil Steril (2015)

49 Fertility preservation in endometriosis Validity of fertility preservation Somigliana, et al., Human Reprod (2015)

50 Large EndometriOMAs : Surgery before ART? Pre-ART intervention: GnRH-a + OMA aspiration vs. GnRH-a Contemporary Clinical Trials (2012)

51 Endometriosis related infertility - Specifications and pathogenesis - What are the therapeutic options? - How to choose between the therapeutic options? - Proposition for a strategy

52 - Global approach Take home messages Strategy Endometriosis and OMAs Adenomyosis DIE Pelvic pain Patients Infertility - Multidisciplinary management Surgery Medical Ttt AR T

53 Infertility Work up pre ART Ovarian reserve Time available for in vivo Semen analysis Fallopian tubes Emergency I V F IVF for severe male factor IVF for tubal factor de Ziegler, Borghese, and Chapron The Lancet, 2010 Surgery Provide 6-18 mo for spontaneous preg. if not pregnant Pelvic pain Hydrosalpinx Large oma??? in principle NO surgery (3 months) IVF / ICSI

54 Infertility: management A Infertility B Pelvic pain Surgery? Phenotype? ART without surgery Previous surgery Adenomyosis Endometrioma x2 Classical center Surgery? Phenotype «Emergency ART» Ovarian reserve OC Referral center Fertility preservation?

55 Take home messages Best indication for surgery in cases of endometriosis related infertility is pelvic pain

56 Take home messages - DIE surgery should be complete - Risks of DIE surgery - Endometrioma alters the ovarian responsiveness per se - Endometrioma surgery alters the ovarian reserve - OMA surgery unnecessary before ART One goal - One surgery in «the endometriosis life» - Fertility preservation should be considered as part of preoperative counselling in young women with severe endometriosis - Oocyte vitrification

57 Gynecology Surgical unit: C Chapron, B Borghese, P Santulli, H Foulot, MC Lafay-Pillet, A Bourret, G Pierre, M Even, MC Lamau, L Marcellin, P Marzouk Medical unit: A Gompel, G Plu-Bureau, L Maitrot Reproductive endocrinology unit: D de Ziegler, P Santulli, V Gayet, P Pirtea, FX Aubriot Intestinal surgery B Dousset, S Gaujoux, M Leconte Laboratory: Genetic D Vaiman, F Mondon, S Barbaux Laboratory: Imunulogy F Batteux, S Chouzenoux, C Nicco, C Chéreau, B Weill Laboratory: Reproducive biology JP Wolf, V Lange, K Pocate, JM Kuntzman, C Chalas Statistical unit F Goffinet, PY Ancel Radiology D de Ziegler, Professor and Head, Reproductive Endocrinology and Infertility unit, AE Millischer, L Maitrot A Gompel, Professor and Head, Medical Gynecological unit, C Chapron, Professor and Chair, Gynecology Obstetrics II and Reproductive Medicine

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