Managing infertility when adenomyosis and endometriosis co-exist Jinhua Leng Beijing,China 27th April 2018 • IPSEN symposium Endometriosis • Endometriosis (EM) is a common, benign, ovary hormone-dependent gynecologic disorder which affects mainly reproductive-age women • Endometriosis is considered to be responsible for infertility and pelvic pain • May affect 10% of women of reproductive age • Three types of pelvic endometriosis • Peritoneal Endometriosis • Ovarian Endometrioma • Deeply Infiltrating Endometriosis (DIE) 27th April 2018 • IPSEN symposium Adenomyosis • Adenomyosis (AD) is defined by the presence of endometrial glands and stroma in the myometrium • Prevalence: varies significantly between studies (from 5% to 70%), generally underestimated • Most frequent symptoms: dysmenorrhea, abnormal uterine bleeding, etc. • Two types: diffuse form, focal form 27th April 2018 • IPSEN symposium PEM DIE OEM AD+EM 27th April 2018 • IPSEN symposium Macroscopic and microscopic appearance of AD 27th April 2018 • IPSEN symposium MRI Features of AD—focal and diffuse 27th April 2018 • IPSEN symposium Prevalence of EM in patients with AD Adenomyosis Endometriosis Author N N(%) Leng JH et al.(2011) 72(histology) 24(33.3%) Di Donato et al. (2014) 217(ultrasound) 165(76.0%) Chapron et al. (2017) 175(MRI) 153(87.4%) Leyendecker et al. (2015) 67(MRI) 54(80.6%) Em and AD often coexist Several authors reported the prevalence of EM in patients with AD. Our study showed in 72 histologically diagnosed AD, 33.3% had concomitant EM. Chapron and another 2 authors reported in US/MRI diagnosed AD, 76-87% had coexistant EM 27th April 2018 • IPSEN symposium What is the relationship between endometriosis phenotypes and adenomyosis? EM subtype N Diffuse form Focal form PEM 40 8(20.0%) 3(7.5%) OEM 31 14(45.2%) 6(19.3%) DIE 166 59(35.5%) 110(66.3%) • Surgery findings of 175 preoperatively MRI diagnosed AD and histologically diagnosed of EM • Among EM women, diffuse AD had no correlation with EM phenotypes. In contrast, focal AD was correlated significantly with EM phenotype Study summary: Focal adenomyosis located in the outer myometrium (FAOM) was observed more frequently in women with endometriosis, and was significantly associated with the DIE phenotype Chapron et al. Hum Reprod. 2017 27th April 2018 • IPSEN symposium Prevalence of AD among EM patients – data from China A retrospective study including 10,579 patients who had undergone surgery for endometriosis from 2000-2009 The prevalence of AD among EM patients significantly increased with age: ≤30y 30-40y 40-50y >50y P AD 5.5% 22.4% 52.5% 70.8% ҕ 0. 001 Leng JH et al. Chin Practical Obs Gyn, 2011, 27(3):188 A retrospective study of 600 patients who had undergone laparoscopic surgery for ovarian endometrioma from 2003 to 2008 OEM+AD group: 15.5% of all patients with ovarian endometrioma older age:≥35y 64.2%; higher infertility rate 20.8% vs 10.7% lower pregnancy rate after surgery:1/9(11.1%) vs 19/52 (36.5%) Leng JH et al. Chin Practical Obs Gyn (2009) 27th April 2018 • IPSEN symposium Demographic data and symptoms of AD with and without EM Woman with AD+DIE were younger, more frequently nulliparous and have a history of previous surgery, with severe pain symptoms. While, women with AD alone represented the older age (37yrs vs 34yrs) and associated with AUB Nadine Di Donato N et al. (2014) 27th April 2018 • IPSEN symposium Impact on fertility • 30–50% of women with endometriosis have infertility • Women with mild endometriosis have a significantly lower probability of pregnancy than women with unexplained fertility (3 year pregnancy rate 36% vs 55%) • IVF studies have suggested that women with more advanced endometriosis have poor ovarian reserve, low oocyte and embryo quality, and poor implantation rate • Adenomyosis is an independent cause of infertility among women with EM • The rates of implantation, clinical pregnancy rate, and live birth rate among women with AD were significantly lower than in those without • The miscarriage rate in women with AD was higher than in those without • Adenomyosis, in addition to EM, may further impact on reproductive outcome. This remains a subject of discussion 27th April 2018 • IPSEN symposium Pathogenesis of infertility Altered Endometrial Function and Abnormal Uterotubal Transport Receptivity • Intrauterine Abnormalities • Aberrant Endometrial Metabolism • Disturbed Uterine Peristalsis and ҁSteroid and their receptors) Sperm Transport • Altered Uterine Oxidative Stress • Destruction of Normal Myometrial Environment Architecture and Function • Impaired Implantation (Adhesion Molecules/ Implantation Markers/ Gene for Embryonic Development) Effect on Gametes and Embryo • Altered ovulation and oocyte production Uterine Junctional Zone (JZ) • Luteal phase disruption JZ thickness (MRI) is the best negative • Peritoneal fluid predictive factor of implantation failure • Inflammatory effects + increased ---- Piver et al. activated macrophages damage the oocytes, sperm and embryo 27th April 2018 • IPSEN symposium Recommendation for infertility associated with EM NICE 2017 ESHER 2014 27th April 2018 • IPSEN symposium Endometriosis and infertility treatment – Chinese guideline (2015) 1.Endometriosis collaborative group of obstetrics and gynecology branch of Chinese medical association, Chinese Journal of Gynaecology and Obstetrics, 2015, 50(3):1-9. Endometriosis and infertility Perform examination and fertility assessment according to the diagnosis and treatment path of infertility Laparoscope-hysteroscope surgery Relapse type of endometriosis or diminished Endometriosis confirmation, staging, lesion resection and tubal function assessment ovarian reserve Endometriosis at Stage I-II, EFI score ≥ 5 Moderate to severe Age > 35 years, EPI ≤ 4 points, (Stage III-IV) with severe male factors Age > 30 years, infertility or deep infiltrating duration> 3 years, with moderate endometriosis to severe male factors Expecting Not pregnant in half Not pregnant in 3 – 4 cycles treatment year COH/IUI IVF - ET How to manage infertility when AD and EM co-exist? Conservative surgery Medication ART (GnRHa) (IVF/ICSI) Evidence and protocol for endometriosis-related infertility are relatively well established. But so far, limited data are available concerning the efficacy of different treatment options for adenomyosis or coexisting EM and AD on fertility outcomes. Treatment options include conservative surgery, medication and ART, or combined treatment. 27th April 2018 • IPSEN symposium Reproductive Outcomes of Fertility A systematic review about fertility-sparing surgery, including 18 studies and 1,396 infertile women with focal and diffuse adenomyosis Adenomyosis mean pregnancy % miscarriage % uterine rupture % preterm birth % focal 52.7 21.1 0 10.9 diffuse 34.1 21.7 6.8 4.5 Reproductive outcome appeared to be better in the focal AD group following surgery compared to the diffuse AD group. A higher incidence (6.8%) of uterine rupture was reported after surgery for diffuse AD. Tan J et al. (2018) 27th April 2018 • IPSEN symposium Reproductive Outcomes or focal vs diffuse adenomyosis. (a) Total (b) Natural conception vs ART 60 a) 70 b) 60 52,7 52,5 45 43,5 33,7 35 34,1 30 25 21,1 21,7 18,2 Pregnancy rate (%) 15 17,5 Reproducave outcome rate (%) 0 0 0 Natural Concepaon ART Focal adenomyosisPregnancy rate(%) Successful delivery rate(%)Diffuse adenomyosis Focal adenomyosis Diffuse adenomyosis Miscarrage rate(%) 27th April 2018 • IPSEN symposium Reproductive outcomes following surgery alone vs combined surgery & medical treatment for women diffuse and focal adenomyosis 70 67,1 Pregnancy rate(%) Successful delivery rate(%) Miscarrage rate(%) 61,3 54,8 52,5 49,1 45,1 38,5 38,6 33,3 35 31,3 31,3 27,6 23,8 21,8 19,6 17,6 17,5 16,2 11,6 9,8 Reproducave outcome rate (%) 0 Surgery alone Surgery&Medical All (n=147) Surgery alone Surgery&Medical All (n=241) ҁn=96҂ (n=51) Diffuse ҁn=165҂ (n=76) Focal 27th April 2018 • IPSEN symposium What are the problems of conservative surgery for AD? • Complete resection of the lesion impossible • Removal of healthy myometrial tissue inevitable • Difficult to repair uterine defect • Poor healing of the scar • Decreasing the tensile strength of the uterus • Increasing the risk of uterine rupture during pregnancy or labour • Uterine Rupture is the most severe problem in perinatal management • 6% after AD surgery vs 0.26% (myomectomy) vs 0.005% (non-scarred uterus ) Surgery should be performed only in selected patients who have severe pain symptoms, failed medical treatment and IVF or who has focal type of adenomyosis. Less rupture in laparotomy with surgical scapel than that in laparoscopy. If surgery is indicated, laparotomy is the surgery of choice for local AD patients with fertility desire 27th April 2018 • IPSEN symposium What is the role of resection of DIE on fertility outcome when DIE and AD coexist A systematic review and meta-analysis to evaluate fertility outcome of surgery for DIE, when adenomyosis co- exists with DIE. AD was never excised. Result: DIE with adenomyosis: 7/59 (11.9%) conceived DIE without adenomyosis: 74/172 (43.0%) conceived Suggestion: women with DIE and concomitant adenomyosis should be informed that surgery may not have an appreciable effect on the likelihood of conception and that the same or possibly better chances of pregnancy could be obtained through IVF/ICSI Vercellini P et al. (2014) 27th April 2018 • IPSEN symposium Medical Treatment and reproductive outcome Some beneficial effect for fertility of GnRHa therapy in AD Tasuku Harada