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Managing Infertility When Adenomyosis and Endometriosis Co-Exist

Managing Infertility When Adenomyosis and Endometriosis Co-Exist

Managing when and 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 • May affect 10% of women of reproductive age • Three types of pelvic endometriosis • Peritoneal Endometriosis • Ovarian • Deeply Infiltrating Endometriosis (DIE)

27th April 2018 • IPSEN symposium Adenomyosis

• Adenomyosis (AD) is defined by the presence of endometrial glands and stroma in the • Prevalence: varies significantly between studies (from 5% to 70%), generally underestimated • Most frequent symptoms: , abnormal uterine , 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 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

• 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 36% vs 55%) • IVF studies have suggested that women with more advanced endometriosis have poor , low oocyte and 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 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 ( Molecules/ Implantation Markers/ Gene for Embryonic Development)

Effect on Gametes and Embryo • Altered 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 and gynecology branch of Chinese medical association, Chinese Journal of 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 % %

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 Reproducve outcome rate (%) 0 0 0 Natural Concepon 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 Reproducve 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 • 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 . 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 et al. (2016)

27th April 2018 • IPSEN symposium Effect of AD on IVF outcome

Adenomyosis reduces pregnancy rates in infertile women undergoing IVF

N Clinical pregnancy % Ongoing pregnancy % Miscarriage % AM 19 22.2 11.1 50.0 Non-AM 256 47.2 45.9 2.8

Salim R et al. (2012)

27th April 2018 • IPSEN symposium Fertility outcome of IVF pretreated with GnRHa

Two retrospective studies compared infertile women with AD treated with long-term use of GnRHa before IVF

Results: Long-term GnRHa treatment before IVF-ET/FET might improve pregnancy outcomes in women with adenomyosis

Before IVF/ Pregnancy % Implantation % Ongoing stimulation dose of gona- retrieved clinical ICSI pregnancy % duration(d) Dotropin (IU) oocytes* pregnancy rate

194 with 51.35 32.56 48.91 87 with GnRHa 11.5±2.1 3,421±1,141 10.0±8.2 30.5% GnRHa 145 without 24.83 16.07 21.38 116 without 9.9±2.0 2,588±1,192 7.9±6.8 25.2% GnRHa GnRHa

Niu et al. (2013) Park et al. (2016)

27th April 2018 • IPSEN symposium Fertility outcome — IVF vs Surgery

Pregnant rate after in vitro fertilization Pregnant rate after cyto-reductive surgery (11-40%, total 32%) (total 47%)

After surgery, the delivery rates and PR were only slightly higher than in women with AD who underwent IVF/ICSI

Margit D et al. (2017)

27th April 2018 • IPSEN symposium EM+AD+infertility

Clinical evaluation (PE/USG/MRI) and fertility evaluation

AD with OEM DIE with AD OEM or other infertility related surgical indications Severe pain OEM recurrence or DOR No symptom Yes Or failed IVF Surgery: EM excision and fertility evaluation

GnRHa & GnRHa+IVF DIE resection expectation Failed Repeatedly failed resection Diffuse AD Focal AD

27th April 2018 • IPSEN symposium Summary

• Adenomyosis is frequently found in patients with endometriosis • Co-existence of AM and EM may have a significant impact on fertility, which may lead to worse reproductive outcome compared with endometriosis alone

• Evaluation of co-existing adenomyosis in infertile patient with EM, especially DIE, is required • GnRHa appear to be beneficial in improving pregnancy rates. Pretreatment with GnRHa may improve fertility outcomes

• The benefits on fertility of preserving surgery vary greatly: Surgery should be performed only in selected patients who have severe pain symptoms, failed medical treatment and IVF or who have focal type of adenomyosis

27th April 2018 • IPSEN symposium 27th April 2018 • IPSEN symposium

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