SYLLABUS REPRO-714: Reproductive Surgery - An Interactive Expert Encounter





Be a Surgical “Multiplier” in MIGS Inspire Brilliance Through Teamwork

Scientific Program Chair Honorary Chair President Jubilee Brown, MD Barbara S. Levy, MD Marie Fidela R. Paraiso, MD

Professional Education Information

Target Audience This educational activity is developed to meet the needs of surgical gynecologists in practice and in training, as well as other healthcare professionals in the field of gynecology.

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Table of Contents Course Description ...... 1 Disclosure ...... 2

Endometriomas C.E. Miller ...... 3

Deep Infiltrating Endometriosis (DIE) T. Falcone ...... 12

Hysteroscopy K.B. Isaacson ...... 22

Isthmocele C.E. Miller ...... 29

Myomectomy R.L. Flyckt ...... 35

Adenomyosis K.B. Isaacson ...... 41

Tubal Surgery in Era of ART T. Falcone ...... 49

Cultural and Linguistics Competency ...... 56

REPRO-714: Didactic: Reproductive Surgery―an Interactive Expert Encounter

Co-Chair: Rebecca L. Flyckt, Charles E. Miller

Faculty: Tommaso Falcone, Keith B. Isaacson

Course Description This course provides a novel format for exploring key procedures in modern reproductive surgery. Reproductive endocrinologists and infertility specialists, who are internationally recognized for their skills in reproductive surgery, will outline essential techniques and surgical pearls necessary to perform outstanding fertility-enhancing surgery. Ample opportunity will be available for participants to query the experts. The video session will profile fundamental surgical skills in minimally invasive reproductive surgery. Course Objectives At the conclusion of this activity, the participant will be able to: 1) Determine which patients will benefit from reproductive surgery; 2) apply best practice surgical approaches to optimize natural fertility and fertility outcomes with assisted reproductive technologies (ART); and 3) perform surgical procedures confidently and improve reproductive outcomes in fertility patients.

Course Outline

12:30 Welcome, Introductions, and Course Overview R.L. Flyckt, C.E. Miller 12:35 Endometriomas C.E. Miller

1:05 Deep Infiltrating Endometriosis (DIE) T. Falcone 1:35 Hysteroscopy K.B. Isaacson 2:05 Isthmocele C.E. Miller

2:25 Questions & Answers All Faculty 2:35 Break 2:45 Myomectomy R.L. Flyckt 3:15 Adenomyosis K.B. Isaacson 3:35 Questions & Answers All Faculty 3:45 Tubal Surgery in Era of ART T. Falcone 4:05 Questions & Answers All Faculty 4:15 Video Session 4:30 Adjourn

Page 1 PLANNER DISCLOSURE Consultant: Applied Medical, Caldera Medical, The following members of AAGL have been CooperSurgical, Olympus involved in the educational planning of this Amanda C. Yunker workshop (listed in alphabetical order by last Consultant: Olympus name). Linda Michels, Executive Director, AAGL* Art Arellano, Professional Education Director, AAGL* FACULTY DISCLOSURE Linda D. Bradley, Medical Director, AAGL* The following have agreed to provide verbal Erin T. Carey disclosure of their relationships prior to their Consultant: MedIQ presentations. They have also agreed to Mark W. Dassel support their presentations and clinical Contracted Research: Myovant Sciences recommendations with the “best available Erica Dun* evidence” from medical literature (in Adi Katz* alphabetical order by last name). Linda Michels, Executive Director, AAGL* Tommaso Falcone* Erinn M. Myers Rebecca L. Flyckt* Speakers Bureau: Laborie Medical Technologies, Keith B. Isaacson Teleflex Medical Consultant: Karl Storz, Medtronic Other: Unrestricted educational grant to Charles E. Miller support NC FPMRS Fellow Cadaver Lab: Boston Consultant: Espiner Medical, Ltd., Gynesonics, Scientific Corp. Inc. Medtronic, Pacira Pharmaceuticals, Richard Amy Park* Wolf Grace Phan, Professional Education Specialist, Contracted Research: AbbVie, Allergan, Espiner AAGL* Medical, Ltd., Gynesonics, Karl Storz Harold Y. Wu* Royalty: Thomas Medical Linda C. Yang Speakers Bureau: AbbVie Other: Ownership Interest: KLAAS LLC Stock Ownership: Gynesonics, Halt Medical Rebecca L. Flyckt* Other: Ownership Interest: Blue Seas Med Spa, Charles E. Miller Naperville, IL Consultant: Espiner Medical, Ltd., Gynesonics, Content Reviewer has nothing to disclose. Medtronic, Pacira Pharmaceuticals, Richard Wolf Asterisk (*) denotes no financial relationships to Contracted Research: AbbVie, Allergan, Espiner disclose. Medical, Ltd., Gynesonics, Karl Storz Royalty: Thomas Medical Speakers Bureau: AbbVie Stock Ownership: Gynesonics, Halt Medical Other: Ownership Interest: Blue Seas Med Spa, Naperville, IL

SCIENTIFIC PROGRAM COMMITTEE Linda D. Bradley, Medical Director, AAGL* Jubilee Brown* Nichole Mahnert* Shanti Indira Mohling* Fariba Mohtashami Consultant: Hologic Marie Fidela R. Paraiso* Shailesh P. Puntambekar* Matthew T. Siedhoff

Page 2 Disclosure

Consultant: Espiner Medical, Ltd., Gynesonics, Medtronic, Pacira Pharmaceuticals, Richard Wolf Contracted Research: AbbVie, Allergan, Espiner Medical, Ltd., Gynesonics, Karl Storz Royalty: Thomas Medical Endometriomas Speakers Bureau: AbbVie Stock Ownership: Gynesonics, Halt Medical Other: Ownership Interest: Blue Seas Med Spa

CHARLES E. MILLER, MD, FACOG

• Vice Chair, AAGL Endometriosis / Reproductive Surgery Special Interest Group • Treasurer, International Society for Gynecologic Endoscopy (ISGE) • Past President, International Society for Gynecologic Endoscopy – ISGE (2011 – 2013) • Past President, AAGL (2007 – 2008) • Clinical Associate Professor, Department OB/GYN, University of IL at Chicago, Chicago, IL USA • Director, Minimally Invasive Gynecologic Surgery, Advocate Lutheran General Hospital, Park Ridge, IL USA • Director, AAGL Fellowship in Minimally Invasive Gynecologic Surgery, Advocate Lutheran General Hospital, Park Ridge, IL USA

Origin of the endometrioma Objectives

● Discuss the impact of endometriomas on infertility ● 1899 – Russel described the endometrioma

○ The patient underwent surgery for a cystic adenocarcinoma of the left ovary ● Discuss the management of endometriomas in the infertile patient ○ The right ovary “enveloped in adhesions of the posterior face of the broad ● Discuss the various surgical techniques for the treatment of endometriomas ligament”

○ On microscopic exam, Russel was “astonished to find areas which were the exact prototype of uterine glands and interglandular connective tissue”

● 1919 – Casler described “uterine mucosa in remaining ovary”

Sutton C, Diamond M. (1988). Endoscopic Surgery for Gynecologists – 2nd Edition. London, England: WB Saunders Company, Ltd.

Origin of the endometrioma Origin of the endometrioma

● Hypothesis 1: a true epithelial cyst similar to serous or mucinous ● 1957 – Hughesdon: 90% of ovarian cyst walls consisted of ovarian cortex, as demonstrated by the presence of primordial follicles ● Hypothesis 2: invagination of the ovarian capsule at the site of endometriosis on the capsule with adhesive disease developing over the area ● The so called site of perforation as described by Sampson represents the stigma of invagination – adhesions are not the consequence, but the cause of endometrioma formation by sealing off active implants on the surface of the ovary

Sutton C, Diamond M. (1988). Endoscopic Surgery for Gynecologists – 2nd Edition. London, England: WB Saunders Company, Ltd.

Page 3 Management of endometrioma in the infertile patient Management of endometrioma in the infertile patient

● Infertile women have up to a tenfold higher risk of endometriosis than the ● The management of endometriosis-related infertility remains debated routine population (prevalence 25% - 40% versus 0.5% - 5%) 1 ● Factors impacting debate ● Endometriosis represents 10% of indication for IVF 2 ○ Improvement of effectiveness and safety of IVF ○ Surgery, often times, only modestly effective ○ The potential negative impact on ovarian reserve with endometrioma surgery ○ The risk of multiple cycles of controlled ovarian stimulation on endometriosis

1. Ozkan S, et al., Endometriosis and infertility: epidemiology and evidence-based treatments. Ann N Y Acad Sci. 2008 Apr;1127:92-100 Somigliana E, et al., Management of Endometriosis in the Infertile Patient. Semin Reprod Med. 2017 Jan;35(1):31-37 2. CDC – 2013 Assisted Reproductive Technology Fertility Clinic Success Rates Report (https://www.cdc.gov/art/pdf/2013-report/art-2013-fertility-clinic-report.pdf)

Ovarian Endometrioma Potential mechanisms for endometrioma – associated infertility

● 6-10% of women ● Endometriosis linked to dysregulation of immune system 1

○ Mainly in reproductive age 1 ○ Peritoneal fluid ■ Increased number of immune cells (macrophages, mast, natural killer, T cells) 2-4 ■ Elevated levels of growth factors, chemokines, cytokines 2-4 ○ Incidence increased in infertile women 2 ○ Impact of enhanced inflammatory state ■ Oocyte quality ■ Ovarian function ● 17% - 44% of women with endometriosis ● Resultant ○ Impaired folliculogenesis ○ Poor fertilization ○ Often associated with more severe disease 3-4

○ Presence of ovarian endometriomas is associated with ASRM’s staging of moderate to Note: since peritoneal endometriosis and endometriomas often times occur together, the severe disease 3 independent impact of inflammation on infertility is unknown.

1. Giudice LC, Clinical practice. Endometriosis. N Engl J Med. 2010 Jun 24;362(25):2389-98 1. Bulun SE, Endometriosis. N Engl J Med. 2009 Jan 15;360(3):268-79 2. Jayaprakasan K, Becker C, Mittal M on behalf of the Royal College of Obstetricians and Gynaecologists. The Effect of Surgery for Endometriomas on Fertility. Scientific Impact Paper No. 55. BJOG 2017; 125:e19–e28 2. Ryan IP, et al., Interleukin-8 concentrations are elevated in peritoneal fluid of women with endometriosis. Fertil Steril. 1995 Apr;63(4):929-32 3. Redwine DB, Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril. 1999 Aug;72(2):310-5 3. Taketani Y, et al., Comparison of cytokine levels and embryo toxicity in peritoneal fluid in infertile women with untreated or treated endometriosis. Am J Obstet Gynecol. 1992 Jul;167(1):265-70 4. Scurry J, et al., Classification of ovarian endometriotic cysts. Int J Gynecol Pathol. 2001 Apr;20(2):147-54 4. Halme J, et al., Increased activation of pelvic macrophages in infertile women with mild endometriosis. Am J Obstet Gynecol. 1983 Feb 1;145(3):333-7

Potential mechanisms for endometrioma – associated infertility Potential mechanisms for endometrioma – associated infertility

● Ovarian reserve ● Oocyte and embryo quality ○ Especially if bilateral endometriomas, response to gonadotrophins during ART can be diminished

○ Primordial follicles are decreased 1 ○ Endometriomas and pelvic endometriosis can have negative impact ■ Inflammation 2 ■ Embryo development slower in comparison to women with tubal disease 1 ■ Increased tissue oxidative stress causing fibrosis 2 ■ Free iron diffuses through cyst wall 3 ■ Potentially secondary to increased progesterone concentration, interleukin-6 and ■ Mechanical stretching of cyst 3 decreased vascular endothelial growth factor 2

○ Endometriomas are associated with a progressive decline in ovarian reserve 4 ■ Prospective observational study ○ Less impact on implantation ● N=40 ■ Recipients with moderate to severe endometriosis have similar pregnancy rates with donor ○ Median percent decline 3 ■ Endometrioma group – 26.4% egg vs. control ■ Control group – 7.4%

1. Kitajima M, et al., Changes in serum anti-Müllerian hormone levels may predict damage to residual normal ovarian tissue after laparoscopic surgery for women with ovarian endometrioma. Fertil Steril. 2011 Jun 30;95(8):2589-91.e1 1. Pellicer A, et al., Exploring the mechanism(s) of endometriosis-related infertility: an analysis of embryo development and implantation in assisted reproduction. Hum Reprod, et al., 1995 Dec;10 Suppl 2:91-7 2. Sanchez AM, et al., The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary.Hum Reprod Update. 2014 Mar-Apr;20(2):217-30 2. Garrido N, et al. Follicular hormonal environment and embryo quality in women with endometriosis. Hum Reprod Update. 2000 Jan-Feb;6(1):67-74 3. Somigliana E, et al., Fertility preservation in women with endometriosis: for all, for some, for none? Hum Reprod. 2015 Jun;30(6):1280-6 3. Garrido N, et al. The endometrium versus embryonic quality in endometriosis-related infertility.Hum Reprod Update. 2002 Jan-Feb;8(1):95-103 4. Kasapoglu I, et al., Endometrioma-related reduction in ovarian reserve (ERROR): a prospective longitudinal study. Fertil Steril. 2018 Jul 1;110(1):122-127

Page 4 Medical treatment of the ovarian endometrioma Controversies regarding the ovarian endometrioma

● Medical therapy CONTROVERSY #1

○ No benefit over close observation 1-4 Should endometriomas be removed in infertile women? ○ Potentially could reduce growth

○ No advantage in enhancing fertility

1. Chapron C, et al., Management of ovarian endometriomas. Hum Reprod Update. 2002 Nov-Dec;8(6):591-7 2. Dunselman GA, et al., ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014 Mar;29(3):400-12 3. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril. 2014 Apr;101(4):927-35 4. Alborzi S, et al., Management of ovarian endometrioma. Clin Obstet Gynecol. 2006 Sep;49(3):480-91

Treatment of the ovarian endometrioma Management Outcomes

● Treatment goals ○ Relieve symptoms ■ Pain ■ Pressure Incidental treatment not recommended except in cases of ○ Prevent related complications ■ Cyst rupture repeated response or implantation failure ■ Ovarian torsion

○ Maintain/enhance ovarian function ■ Abnormal bleeding ■ Infertility

○ Exclude Malignancy

Dunselman GA, et al., ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014 Mar;29(3):400-12

Arguments against surgical excision Arguments against surgical excision (cont’d)

● Ovarian cystectomy can have a deleterious effect on ovarian reserve . Unilateral vs. bilateral endometriomas • Kwon – only significant AMH decline seen with bilateral endometriomas 9 • Cyst size 1-2, 8-9 ● Many publications including two recent meta-analyses have shown decreased AMH post o Greater decline in AMH if cyst size ≥ 5 cm surgery for up to 6-9 months 1-7 ● Proposed mechanism why cystectomy worsens ovarian reserve ○ Unilateral vs. bilateral endometriomas ○ Removal of healthy ovarian cortex . Roman performed a retrospective study on 38 cystectomy specimens in 35 women and found a direct proportional relationship between endometrioma size and ovarian parenchyma removal 10 2 ■ Uncu - decline in AMH is progressive post surgery . Matsuzaki noted ovarian tissue on excised endometrioma was ten times more frequent than other benign ● AMH decline worse with bilateral endometrioma surgery, but not statistically significant cysts 11 Romualdi (prospective study of 77 women) noted that in younger women, smaller cysts were associated 1 . ■ Alborzi – (N = 193) with more follicle loss 12 ● Significant decline in AMH for up to 9 months ● More significant AMH decline with bilateral endometriomas ○ Thermal damage to ovarian parenchyma ● (Celik, Hirokawa concur) ○ Surgical related local inflammation

1. Alborzi S, et al., Fertil Steril. 2014 Feb;101(2):427-34 5. Tsolakidis D, et al., Fertil Steril. 2010 Jun;94(1):71-7 2. Uncu G, et al., Hum Reprod. 2013 Aug;28(8):2140-5 6. Biacchiardi CP, et al., Reprod Biomed Online. 2011 Dec;23(6):740-6 8. Hirokawa W, et al., Hum Reprod. 2011 Apr;26(4):904-10 3. Raffi F, et al., J Clin Endocrinol Metab. 2012 Sep;97(9):3146-54 7. Celik HG, et al., Fertil Steril. 2012 Jun;97(6):1472-8 9. Kwon SK, et al., Fertil Steril. 2014 Feb;101(2):435-41 11. Matsuzaki S, et al., Hum Reprod. 2009 Jun;24(6):1402-6 4. Somigliana E, et al., Fertil Steril. 2012 Dec;98(6):1531-8 10. Roman H, et al., Hum Reprod. 2010 Jun;25(6):1428-32 12. Romualdi D, et al., Fertil Steril. 2011 Aug;96(2):374-8

Page 5 Management of endometrioma in the infertile patient Drawbacks of conservative management

Conservative Management in Women with Ovarian Endometriomas and IVF ● May interfere with ovarian responsiveness for controlled ovarian stimulation 1

● May interfere with oocyte competence 2

● Increased risk of pelvic infection/pelvic abscess 1

● May effect pregnancy outcome 3

1. Somigliana E, et al., Risks of conservative management in women with ovarian endometriomas undergoing IVF. Hum Reprod Update. 2015 Jul-Aug;21(4):486-99 Somigliana E, et al., Risks of conservative management in women with ovarian endometriomas undergoing IVF. Hum Reprod Update. 2015 Jul-Aug;21(4):486-99 2. Sanchez AM, et al., Is the oocyte quality affected by endometriosis? A review of the literature. J Ovarian Res. 2017 Jul 12;10(1):43 3. Fernando S, et al., Preterm birth, ovarian endometriomata, and assisted reproduction technologies. Fertil Steril. 2009 Feb;91(2):325-30

Drawbacks of conservative management Drawbacks of conservative management (cont’d)

● Pain 9-11 ● Make retrieval more difficult ○ Primary benefit of surgical treatment ● Endometrioma and malignancy 12-15 ○ Frequency of non-complete follicular aspiration more than three times higher with ○ Risk of occult malignancy in endometriotic cysts 0.8% - 0.9% 4 endometriomas (OR 3.6, 95% CI 1.4 to 9.6) ○ 13 ovarian cancer case-control studies – significantly increased risk of invasive low grade serous, clear cell, endometrioid ovarian cancers 4 ● Accidental contamination of follicular fluid (16%, 95% CI 8 to 27%) ● Excision - presumptive benefit - reduce or reverse inherently damaging effects of endometriomas 16-20 ○ Stretching of ovarian cortex ○ Contaminated follicular fluid lowers pregnancy rate in humans 5-6 ○ Loss of follicular density secondary to increased oxidative stress in the ovarian cortex surrounding endometriomas 7 ● Increased AFC post surgery at three and six months ○ Free iron uptake by cells near endometrioma leads to gonadotoxic insult to follicles adjacent to cyst ○ Burnout hypothesis - endometriomas cause focal inflammation in the ovarian cortex leading to fibrosis and loss of cortex specific stroma. This inflammation and associated reduced vascularization and increased oxidative stress Note: would expect improved results, as hemostasis involved use of bipolar forceps 8 may lead to enhanced follicular recruitment and atresia . AFC is reduced

9. Hart RJ, et al., Cochrane Database Syst Rev. 2008 Apr 16;(2):CD004992 13. Stern RC, et al., Int J Gynecol Pathol. 2001 Apr;20(2):133-9 17. Maneschi F, et al., Am J Obstet Gynecol. 1993 Aug;169(2 Pt 1):388-93 4. Benaglia L, et al., Reprod Biomed Online. 2018 Jul;37(1):77-84 10. Alborzi S, et al., Fertil Steril. 2004 Dec;82(6):1633-7 14. Kobayashi H, et al., Int J Gynecol Cancer. 2007 Jan-Feb;17(1):37-43 18. Sanchez AM, et al., Hum Reprod. 2014 Mar;29(3):577-83 5. Suwajanakorn S, et al., J Med Assoc Thai. 2001 Jun;84 Suppl 1:S371-6 7. Pados G, et al., Hum Reprod. 2010 Mar;25(3):672-7 11. Beretta P, et al., Fertil Steril. 1998 Dec;70(6):1176-80 15. Pearce CL, et al., Lancet Oncol. 2012 Apr;13(4):385-94 19. Matsuzaki S, et al., Hum Reprod. 2009 Jun;24(6):1402-6 6. Benaglia L, et al., Eur J Obstet Gynecol Reprod Biol. 2014 Oct;181:130-4 8. Muzii L, et al., Hum Reprod. 2014 Oct 10;29(10):2190-8 12 Mostoufizadeh M et al Clin Obstet Gynecol 1980 Sep;23(3):951-63 16. Sanchez AM, et al., Hum Reprod Update. 2014 Mar-Apr;20(2):217-30 20 Kitajima M et al Fertil Steril 2014 Apr;101(4):1031-7

Drawbacks of conservative management (cont’d) Surgical treatment prior to IVF

● Concerns with progressive decline in ovarian reserve 21 ● Meta-analysis – 5 controlled studies (N = 655) 1 ○ Women with ovarian endometrioma experience a progressive decline in AMH levels, which is faster than that ○ Similar live birth rate (OR 0.9; 95% CI 0.63–1.28) in healthy women ○ Clinical pregnancy (OR 0.97; 95% CI 0.78–1.2) . Forty women with endometrioma and 40 age-matched controls . AMH levels measured at six month intervals ○ Miscarriage rates (OR 1.32; 95% CI 0.66–2.65) ○ Comparable cancellation rates ○ Follicles produced similar ○ Surgery side . Decrease in antral follicle count and follicles retrieved ○ Higher doses of gonadotrophins ● Concerns with progressive decline in ovarian reserve ○ AFC 22 women with endometrioma ● Small ovarian endometrioma should not be removed prior to IVF 2-3 . Baseline 10 (8-12) ○ 2012 Practice Committee of the American Society for Reproductive Medicine . Six months 8 (6.3-10)

1. Hamdan M, et al., The impact of endometrioma on IVF/ICSI outcomes: a systematic review and meta-analysis.Hum Reprod Update. 2015 Nov-Dec;21(6):809-25 21. Kasapoglu I, et al., Fertil Steril. 2018 Jul 1;110(1):122-127 2. Dunselman GA, et al., ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014 Mar;29(3):400-12 3. Vercellini P, et al., Estrogen-progestins and progestins for the management of endometriosis. Fertil Steril. 2016 Dec;106(7):1552-1571

Page 6 Effect of large endometriomas on response Controversies regarding the ovarian endometrioma

● Unilateral endometrioma ≥ 5cm CONTROVERSY #2

● Contralateral healthy ovary

● Retrospective analysis of a prospectively collected database Technique for endometrioma removal ○ Findings:

Ferrero S, et al., Impact of large ovarian endometriomas on the response to superovulation for in vitro fertilization: A retrospective study. Eur J Obstet Gynecol Reprod Biol. 2017 Jun;213:17-21

Management of endometriomas in the infertile patient Management of endometriomas in the infertile patient

Surgical Management of Endometriomas ● Per ESHRE 2008, ASRM 2006 and NHS 2010, laparoscopic cystectomy via excisional surgery for an endometrioma ≥4-cm improves fertility (spontaneous ● Ultrasound guided aspiration 1-2 pregnancy rates) compared to drainage and coagulation 1-2 ○ Concerns ■ High rate of recurrence 2-6 ○ Per ESHRE guidelines in 2010, endometrioma ≥3-cm should be removed prior to ■ Infection 4,6 IVF ■ Adhesions post procedure 7 ■ Potential malignancy 3,7

1. Zanetta G, et al., Radiology. 1993 Oct;189(1):161-4 2. Giorlandino C, et al., Int J Gynaecol Obstet. 1993 Oct;43(1):41-4 5. Gonçalves FC, et al., Int J Gynaecol Obstet. 2016 Jul;134(1):3-7 1. Beretta P, et al., Fertil Steril. 1998 Dec;70(6):1176-80 3. Chapron C, et al., Hum Reprod Update. 2002 Nov-Dec;8(6):591-7 6. Muzii L, et al., Hum Reprod. 1995 Nov;10(11):2902-3 2. Alborzi S, et al., Fertil Steril. 2004 Dec;82(6):1633-7 4 Zanetta G et al Fertil Steril 1995 Oct;64(4):709-13 7. Diernaes E, et al., Lancet. 1987 May 9;1(8541):1084

Management of endometriomas in the infertile patient Management of endometriomas in the infertile patient

Ovarian Endometriomas Conservative surgery for pelvic pain due to endometriomas ● Pregnancy rate – cystectomy versus drainage and coagulation ● Endometrioma surgery ● Beretta (1998)

RCT: ○ 64 patients randomized, cystectomy versus fenestration/coagulation

○ Endometrioma > 3-cm

○ Recurrence of symptoms (months)

■ Excision – 19

Significant ■ Fenestration/coagulation 9.5

Beretta P, et al., Fertil Steril. 1998 Dec;70(6):1176-80 Beretta P, et al., Fertil Steril. 1998 Dec;70(6):1176-80 Alborzi S, et al., Fertil Steril. 2004 Dec;82(6):1633-7

Page 7 Management of endometriomas in the infertile patient Techniques to potentially enhance ovarian function post surgery

Prospective randomized study comparing laparoscopic ovarian cystectomy versus ● Spot bipolar desiccation fenestration and coagulation – 17 patients with endometriomas ● Plasma energy ● Cystectomy N = 52 ● Fenestration and coagulation N = 48 ● Combined surgical/medical treatment ○ Results ■ Recurrence of symptoms at two years ● Combined excision, laser vaporization ● Cystectomy – 15.8% ● Fenestration and coagulation – 56.7% ● Suturing capsule – purse-string ■ Rate of re-operation ● Cystectomy – 5.8% ● Fenestration and coagulation – 22.9% ● Continuous purse-string from base

■ Cumulative pregnancy rate ● Cystectomy – 59.4% ● Biosurgical hemostatic agent ● Fenestration and coagulation – 23.3%

Alborzi S, et al., Fertil Steril. 2004 Dec;82(6):1633-7

Respective regressions of the volume of operated/non-operated ovary ratio and of the antral follicle count of operated/non- Patient characteristics and results of three-dimensional ultrasound examination. operated ovary ratio on four parameters: operative technique, woman’s age, cyst diameter, and previous pregnancy.

Note: Performing cystectomy instead of ablation using plasma energy is the sole risk factor that significantly decreases both ratios, after adjustment for the woman’s age, cyst diameter, and parity. The β regression coefficients represent the independent contributions of each independent risk factor to the prediction of the outcome, following the linear equation Ratio = Constant + Σβi*Factor. The deviation of a particular point from its predicted value on the regression line is called the residual value. R‐square, also known as the coefficient of determination, is a commonly used statistic to evaluate model fit, and represents 1 minus the ratio of residual variability. The R‐ square value is an indicator of how well the model fits the data (an R‐square of 0.4 means that the regression line explained 40% of the original variability, and are left with 60% residual variability). AFC = antral follicle count; CI = confidence interval. a R‐square = 0.44. Note: AFC = antral follicle count; AFSr = Revised American Fertility Society score. b R‐square = 0.42.

Roman H, et al., Ovarian endometrioma ablation using plasma energy versus cystectomy: a step toward better preservation of the ovarian parenchyma in women wishing to conceive. Fertil Steril. 2011 Dec;96(6):1396-400 Roman H, et al., Ovarian endometrioma ablation using plasma energy versus cystectomy: a step toward better preservation of the ovarian parenchyma in women wishing to conceive. Fertil Steril. 2011 Dec;96(6):1396-400

Management of endometriomas in the infertile patient

Surgical Management of Endometriomas

● Three stage technique 1-2

Surgeon attempting to turn the cyst completely ○ Stage 1 – laparoscopy, fenestration and drainage The procedure of ablation using plasma energy inside out via the site of its original invagination ○ Stage 2 – GnRH agonist x 3 months ○ Stage 3 – laparoscopy, CO2 laser ablation of cyst wall

○ RCT – three stage technique vs. stripping 2 ■ Better post operative AFC and AMH with three stage technique ● Concerns ○ Small sample site, 10 patients per arm ○ Increased recurrence post three stage technique (20% vs. 0%) ○ Cost

1. Pados G, et al., Sonographic changes after laparoscopic cystectomy compared with three-stage management in patients with ovarian endometriomas: a prospective randomized study. Hum Reprod. 2010 Mar;25(3):672-7 Roman H, et al., Ovarian endometrioma ablation using plasma energy versus cystectomy: a step toward better preservation of the ovarian parenchyma in women wishing to conceive. Fertil Steril. 2011 Dec;96(6):1396-400 2. Tsolakidis D, et al., The impact on ovarian reserve after laparoscopic ovarian cystectomy versus three-stage management in patients with endometriomas: a prospective randomized study. Fertil Steril. 2010 Jun;94(1):71-7

Page 8 Management of endometriomas in the infertile patient Management of endometriomas in the infertile patient

Surgical Management of Endometriomas Surgical Management of Endometriomas Comparison between stripping technique and combined excision/bipolar ablation over hilum technique Impact on ovarian reserve – laparoscopic ovarian cystectomy versus three stage management for endometriomas ● Multicenter RCT – 51 patients ○ Bilateral endometriomas > 3-cm ○ Different surgical techniques in each ovary randomly selected Comparison of the sonographic and serum indicators of ovarian reserve of groups 1 and 2 patients before and 6 months after laparoscopy ● Findings ○ Recurrence ■ Stripping – 5.9% ■ Combined – 2.0% ○ No change in AFC ○ Ovarian volume significantly lower with combined technique at 6 months (p = 0.04)

● Concern with study – bipolar ablation

AFC, and OV, for the striping technique and the combined technique at 1, 3 and 6-month follow-up

Values are mean ± SE. NS = not significant; AFC = antral follicle count; AMH = anti-Mullerian hormone.

Tsolakidis D, et al., The impact on ovarian reserve after laparoscopic ovarian cystectomy versus three-stage management in patients with endometriomas: a prospective randomized study. Fertil Steril. 2010 Jun;94(1):71-7 Muzii L, et al., Comparison between the stripping technique and the combined excisional/ablative technique for the treatment of bilateral ovarian endometriomas: a multicentre RCT. Hum Reprod. 2016 Feb;31(2):339-44

Management of endometriomas in the infertile patient

Laparoscopic management of endometriomas using a combined technique – excisional and CO2 laser ablation

● 52 patients with endometriomas > 3-cm ● Surgical technique ○ Step 1: 80% - 90% of cyst excised ○ Step 2: laser vaporization of 10% - 20% of endometrioma (near hilus) ● Earlier recurrences and a higher recurrence rate – laser group ● Results:

● Five year follow-up: no statistically significant differences

Donnez J, et al. Laparoscopic management of endometriomas using a combined technique of excisional (cystectomy) and ablative surgery. Fertil Steril. 2010 Jun;94(1):28-32 Carmona F, et al. Ovarian cystectomy versus laser vaporization in the treatment of ovarian endometriomas: a randomized clinical trial with a five-year follow-up. Fertil Steril. 2011 Jul;96(1):251-4

AMH 1-7 AFC 8-15 ● 8 studies ○ 62.5% - suturing conserves AMH more effectively ● 7 studies – nearly half postoperative evaluation at 12 months significantly lower, ○ 37.5% - no difference whether suturing or coagulation as compared to contralateral ovary (6% - 50% suture ○ 4 studies with suture – no change postoperatively from baseline vs 16% - 73% coagulation) ○ 4 studies with suture – 15% - 31% drop ○ 7 of 8 studies with energy (mainly bipolar) – 27% - 53% drop

1. Ferrero S, et al. Hemostasis by bipolar coagulation versus suture after surgical stripping of bilateral ovarian endometriomas: a randomized controlled trial. J Minim Invasive Gynecol. 2012 Nov-Dec;19(6):722-30 8. Mohamed ML, et al. Effect on ovarian reserve of laparoscopic bipolar electrocoagulation versus laparotomic hemostatic sutures during unilateral ovarian cystectomy. Int J Gynaecol Obstet. 2011 Jul;114(1):69-72 2. Song T, et al. Effect on ovarian reserve of hemostasis by bipolar coagulation versus suture during laparoendoscopic single-site cystectomy for ovarian endometriomas. J Minim Invasive Gynecol. 2015 Mar-Apr;22(3):415-20 9. Zhang CH, et al. Clinical study of the impact on ovarian reserve by different hemostasis methods in laparoscopic cystectomy for ovarian endometrioma. Taiwan J Obstet Gynecol. 2016 Aug;55(4):507-11 3. Mohamed ML, et al. Effect on ovarian reserve of laparoscopic bipolar electrocoagulation versus laparotomic hemostatic sutures during unilateral ovarian cystectomy. Int J Gynaecol Obstet. 2011 Jul;114(1):69-72. 10. Sahin C, et al. Which Should Be the Preferred Technique During Laparoscopic Ovarian Cystectomy. Reprod Sci. 2017 Mar;24(3):393-399. 4. Zhang CH, et al. Clinical study of the impact on ovarian reserve by different hemostasis methods in laparoscopic cystectomy for ovarian endometrioma. Taiwan J Obstet Gynecol. 2016 Aug;55(4):507-11 11. Takashima A, et al. Effects of bipolar electrocoagulation versus suture after laparoscopic excision of ovarian endometrioma on the ovarian reserve and outcome of in vitro fertilization. J Obstet Gynaecol Res. 2013 Jul;39(7):1246-52 5. Asgari Z, et al.. Comparing ovarian reserve after laparoscopic excision of endometriotic cysts and hemostasis achieved either by bipolar coagulation or suturing: a randomized clinical trial. Arch Gynecol Obstet. 2016 May;293(5):1015-22 12. Özgönen H et al. Comparison of the effects of laparoscopic bipolar electrocoagulation and intracorporeal suture application to ovarian reserve in benign ovarian cysts. Arch Gynecol Obstet. 2013 Apr;287(4):729-32 6. Sahin C, et al. Which Should Be the Preferred Technique During Laparoscopic Ovarian Cystectomy. Reprod Sci. 2017 Mar;24(3):393-399 13. Li CZ, et al. The impact of electrocoagulation on ovarian reserve after laparoscopic excision of ovarian cysts: a prospective clinical study of 191 patients. Fertil Steril. 2009 Oct;92(4):1428-35 7. Tanprasertkul C, et al. Impact of hemostasis methods, electrocoagulation versus suture, in laparoscopic endometriotic cystectomy on the ovarian reserve: a randomized controlled trial. Impact of hemostasis methods, electrocoagulation versus suture, in 14. Coric M, et al. Electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas assessed by antral follicle count: preliminary results of randomized clinical trial. Arch Gynecol Obstet. 2011 Feb;283(2):373-8 laparoscopic endometriotic cystectomy on the ovarian reserve: a randomized controlled trial. J Med Assoc Thai. 2014 Aug;97 Suppl 8:S95-101 15. Fedele L, et al. Bipolar electrocoagulation versus suture of solitary ovary after laparoscopic excision of ovarian endometriomas. J Am Assoc Gynecol Laparosc. 2004 Aug;11(3):344-7

Page 9 Pregnancy Rates16-17 ● Included in meta-analysis

○ 3 RCTs, 1 prospective ● Prospective study – 100 patients with bilateral endometriomas ○ 2 comparing BD & HS, 2 comparing BD with suture ○ Pregnancy rate – suture: 30%, bipolar: 36% ○ N = 213, 175 enrolled n 3 RCTs

● 44 women undergoing IVF post ovarian cystectomy ■ Findings ○ Bipolar: N = 21 ● HS or suture – lower decrease in ovarian reserve ○ Suture: N = 23 ○ Mean decline in AMH was 6.95% less (95% CI, -13% to -0.9%; p = 0.2) at 3 months ■ Pregnancy rates in each group – 33%

16. Ferrero S, et al. Hemostasis by bipolar coagulation versus suture after surgical stripping of bilateral ovarian endometriomas: a randomized controlled trial. J Minim Invasive Gynecol. 2012 Nov-Dec;19(6):722-30 17. Takashima A, et al. Effects of bipolar electrocoagulation versus suture after laparoscopic excision of ovarian endometrioma on the ovarian reserve and outcome of in vitro fertilization. J Obstet Gynaecol Res. 2013 Jul;39(7):1246-52 Ata B, et al. Effect of hemostatic method on ovarian reserve following laparoscopic endometrioma excision; comparison of suture, hemostatic sealant, and bipolar desiccation. A systematic review and meta-analysis. J Minim Invasive Gynecol. 2015 Mar-Apr;22(3):363-72

● HS controlled bleeding in 60 of 65 patients 1-2

● Concerns of HS ○ Viral transmission – no reports ○ Thromboembolism ○ SBO secondary to allergic reaction adhesions ○ Cancer

1. Song T, et al. Additional benefit of hemostatic sealant in preservation of ovarian reserve during laparoscopic ovarian cystectomy: a multi-center, randomized controlled trial. Hum Reprod. 2014 Aug;29(8):1659-65 Ata B, et al. Effect of hemostatic method on ovarian reserve following laparoscopic endometrioma excision; comparison of suture, hemostatic sealant, and bipolar desiccation. A systematic review and meta-analysis. J Minim Invasive Gynecol. 2015 Mar-Apr;22(3):363-72 2. Sönmezer M, et al. Can ovarian damage be reduced using hemostatic matrix during laparoscopic endometrioma surgery? A prospective, randomized study. Arch Gynecol Obstet. 2013 Jun;287(6):1251-7

Hemostasis Utilizing Tisseel™

Page 10 References References

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Fertil Steril. 2010 Jun;94(1):71-7 • Halme J, et al., Increased activation of pelvic macrophages in infertile women with mild endometriosis. Am J Obstet Gynecol. 1983 Feb 1;145(3):333-7 • Biacchiardi CP, et al., Laparoscopic stripping of endometriomas negatively affects ovarian follicular reserve even if performed by experienced surgeons. Reprod Biomed Online. • Kitajima M, et al., Changes in serum anti-Müllerian hormone levels may predict damage to residual normal ovarian tissue after laparoscopic surgery for women with ovarian 2011 Dec;23(6):740-6 endometrioma. Fertil Steril. 2011 Jun 30;95(8):2589-91.e1 • Celik HG, et al., Effect of laparoscopic excision of endometriomas on ovarian reserve: serial changes in the serum antimüllerian hormone levels. Fertil Steril. 2012 Jun;97(6):1472-8 • Sanchez AM, et al., The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to • Hirokawa W, et al., The post-operative decline in serum anti-Mullerian hormone correlates with the bilaterality and severity of endometriosis. Hum Reprod. 2011 Apr;26(4):904-10 the ovary.Hum Reprod Update. 2014 Mar-Apr;20(2):217-30 • Kwon SK, et al., Decline of serum antimüllerian hormone levels after laparoscopic ovarian cystectomy in endometrioma and other benign cysts: a prospective cohort study. Fertil • Somigliana E, et al., Fertility preservation in women with endometriosis: for all, for some, for none? Hum Reprod. 2015 Jun;30(6):1280-6 Steril. 2014 Feb;101(2):435-41 • Kasapoglu I, et al., Endometrioma-related reduction in ovarian reserve (ERROR): a prospective longitudinal study. Fertil Steril. 2018 Jul 1;110(1):122-127 • Roman H, et al., Direct proportional relationship between endometrioma size and ovarian parenchyma inadvertently removed during cystectomy, and its implication on the • Pellicer A, et al., Exploring the mechanism(s) of endometriosis-related infertility: an analysis of embryo development and implantation in assisted reproduction. Hum Reprod, et al., management of enlarged endometriomas. Hum Reprod. 2010 Jun;25(6):1428-32 1995 Dec;10 Suppl 2:91-7 • Matsuzaki S, et al., Analysis of risk factors for the removal of normal ovarian tissue during laparoscopic cystectomy for ovarian endometriosis. Hum Reprod. 2009 Jun;24(6):1402-6 • Garrido N, et al. Follicular hormonal environment and embryo quality in women with endometriosis. Hum Reprod Update. 2000 Jan-Feb;6(1):67-74 • Romualdi D, et al., Follicular loss in endoscopic surgery for ovarian endometriosis: quantitative and qualitative observations. Fertil Steril. 2011 Aug;96(2):374-8 • Garrido N, et al. The endometrium versus embryonic quality in endometriosis-related infertility.Hum Reprod Update. 2002 Jan-Feb;8(1):95-103 • Somigliana E, et al., Risks of conservative management in women with ovarian endometriomas undergoing IVF. Hum Reprod Update. 2015 Jul-Aug;21(4):486-99

References References

• Sanchez AM, et al., Is the oocyte quality affected by endometriosis? A review of the literature. J Ovarian Res. 2017 Jul 12;10(1):43 • Hamdan M, et al., The impact of endometrioma on IVF/ICSI outcomes: a systematic review and meta-analysis.Hum Reprod Update. 2015 Nov-Dec;21(6):809-25 • Fernando S, et al., Preterm birth, ovarian endometriomata, and assisted reproduction technologies. Fertil Steril. 2009 Feb;91(2):325-30 • Vercellini P, et al., Estrogen-progestins and progestins for the management of endometriosis. Fertil Steril. 2016 Dec;106(7):1552-1571 • Benaglia L, et al., Oocyte retrieval difficulties in women with ovarian endometriomas. Reprod Biomed Online. 2018 Jul;37(1):77-84 • Ferrero S, et al., Impact of large ovarian endometriomas on the response to superovulation for in vitro fertilization: A retrospective study. Eur J Obstet Gynecol Reprod Biol. 2017 • Suwajanakorn S, et al., Effects of contaminated endometriotic contents on quality of oocytes.J Med Assoc Thai. 2001 Jun;84 Suppl 1:S371-6 Jun;213:17-21 • Benaglia L, et al., IVF outcome in women with accidental contamination of follicular fluid with endometrioma content. Eur J Obstet Gynecol Reprod Biol. 2014 Oct;181:130-4 • Zanetta G, et al., Early and short-term complications after US-guided puncture of gynecologic lesions: evaluation after 1,000 consecutive cases. Radiology. 1993 Oct;189(1):161-4 • Pados G, et al., Sonographic changes after laparoscopic cystectomy compared with three-stage management in patients with ovarian endometriomas: a prospective randomized • Giorlandino C, et al., Ultrasound-guided aspiration of ovarian endometriotic cysts. Int J Gynaecol Obstet. 1993 Oct;43(1):41-4 study. Hum Reprod. 2010 Mar;25(3):672-7 • Zanetta G, et al., Ultrasound-guided aspiration of endometriomas: possible applications and limitations. Fertil Steril. 1995 Oct;64(4):709-13 • Muzii L, et al., The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis.Hum Reprod. 2014 Oct • Gonçalves FC, et al., A systematic review of ultrasonography-guided transvaginal aspiration of recurrent ovarian endometrioma. Int J Gynaecol Obstet. 2016 Jul;134(1):3-7 10;29(10):2190-8 • Muzii L, et al., Laparoscopic findings after transvaginal ultrasound-guided aspiration of ovarian endometriomas. Hum Reprod. 1995 Nov;10(11):2902-3 • Hart RJ, et al., Excisional surgery versus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD004992 • Diernaes E, et al., Ovarian cysts: management by puncture? Lancet. 1987 May 9;1(8541):1084 • Alborzi S, et al., A prospective, randomized study comparing laparoscopic ovarian cystectomy versus fenestration and coagulation in patients with endometriomas. Fertil Steril. • Roman H, et al., Ovarian endometrioma ablation using plasma energy versus cystectomy: a step toward better preservation of the ovarian parenchyma in women wishing to 2004 Dec;82(6):1633-7 conceive. Fertil Steril. 2011 Dec;96(6):1396-400 • Beretta P, et al., Randomized clinical trial of two laparoscopic treatments of endometriomas: cystectomy versus drainage and coagulation. Fertil Steril. 1998 Dec;70(6):1176-80 • Muzii L, et al., Comparison between the stripping technique and the combined excisional/ablative technique for the treatment of bilateral ovarian endometriomas: a multicentre • Mostoufizadeh M, et al., Malignant tumors arising in endometriosis. Clin Obstet Gynecol. 1980 Sep;23(3):951-63 RCT. Hum Reprod. 2016 Feb;31(2):339-44 • Stern RC, et al., Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types. Int J Gynecol Pathol. 2001 Apr;20(2):133-9 • Donnez J, et al. Laparoscopic management of endometriomas using a combined technique of excisional (cystectomy) and ablative surgery. Fertil Steril. 2010 Jun;94(1):28-32 • Kobayashi H, et al., Risk of developing ovarian cancer among women with ovarian endometrioma: a cohort study in Shizuoka, Japan. Int J Gynecol Cancer. 2007 Jan- • Carmona F, et al. Ovarian cystectomy versus laser vaporization in the treatment of ovarian endometriomas: a randomized clinical trial with a five-year follow-up. Fertil Steril. 2011 Feb;17(1):37-43 Jul;96(1):251-4 • Pearce CL, et al., Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol. 2012 • Ferrero S, et al. Hemostasis by bipolar coagulation versus suture after surgical stripping of bilateral ovarian endometriomas: a randomized controlled trial. J Minim Invasive Apr;13(4):385-94 Gynecol. 2012 Nov-Dec;19(6):722-30 • Maneschi F, et al., Ovarian cortex surrounding benign neoplasms: a histologic study. Am J Obstet Gynecol. 1993 Aug;169(2 Pt 1):388-93 • Song T, et al. Effect on ovarian reserve of hemostasis by bipolar coagulation versus suture during laparoendoscopic single-site cystectomy for ovarian endometriomas. J Minim • Sanchez AM, et al., Iron availability is increased in individual human ovarian follicles in close proximity to an endometrioma compared with distal ones. Hum Reprod. 2014 Invasive Gynecol. 2015 Mar-Apr;22(3):415-20 Mar;29(3):577-83 • Mohamed ML, et al. Effect on ovarian reserve of laparoscopic bipolar electrocoagulation versus laparotomic hemostatic sutures during unilateral ovarian cystectomy. Int J Gynaecol • Kitajima M, et al., Enhanced follicular recruitment and atresia in cortex derived from ovaries with endometriomas.Fertil Steril. 2014 Apr;101(4):1031-7 Obstet. 2011 Jul;114(1):69-72.

References

• Zhang CH, et al. Clinical study of the impact on ovarian reserve by different hemostasis methods in laparoscopic cystectomy for ovarian endometrioma. Taiwan J Obstet Gynecol. 2016 Aug;55(4):507-11 • Asgari Z, et al.. Comparing ovarian reserve after laparoscopic excision of endometriotic cysts and hemostasis achieved either by bipolar coagulation or suturing: a randomized clinical trial. Arch Gynecol Obstet. 2016 May;293(5):1015-22 • Sahin C, et al. Which Should Be the Preferred Technique During Laparoscopic Ovarian Cystectomy. Reprod Sci. 2017 Mar;24(3):393-399 • Tanprasertkul C, et al. Impact of hemostasis methods, electrocoagulation versus suture, in laparoscopic endometriotic cystectomy on the ovarian reserve: a randomized controlled trial. Impact of hemostasis methods, electrocoagulation versus suture, in laparoscopic endometriotic cystectomy on the ovarian reserve: a randomized controlled trial. J Med Assoc Thai. 2014 Aug;97 Suppl 8:S95-101 • Sahin C, et al. Which Should Be the Preferred Technique During Laparoscopic Ovarian Cystectomy. Reprod Sci. 2017 Mar;24(3):393-399. • Takashima A, et al. Effects of bipolar electrocoagulation versus suture after laparoscopic excision of ovarian endometrioma on the ovarian reserve and outcome of in vitro fertilization. J Obstet Gynaecol Res. 2013 Jul;39(7):1246-52 • Özgönen H et al. Comparison of the effects of laparoscopic bipolar electrocoagulation and intracorporeal suture application to ovarian reserve in benign ovarian cysts. Arch Gynecol Obstet. 2013 Apr;287(4):729-32 • Li CZ, et al. The impact of electrocoagulation on ovarian reserve after laparoscopic excision of ovarian cysts: a prospective clinical study of 191 patients. Fertil Steril. 2009 Oct;92(4):1428-35 • Coric M, et al. Electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas assessed by antral follicle count: preliminary results of randomized clinical trial. Arch Gynecol Obstet. 2011 Feb;283(2):373-8 • Fedele L, et al. Bipolar electrocoagulation versus suture of solitary ovary after laparoscopic excision of ovarian endometriomas. J Am Assoc Gynecol Laparosc. 2004 Aug;11(3):344-7 • Ata B, et al. Effect of hemostatic method on ovarian reserve following laparoscopic endometrioma excision; comparison of suture, hemostatic sealant, and bipolar desiccation. A systematic review and meta-analysis. J Minim Invasive Gynecol. 2015 Mar-Apr;22(3):363-72 • Song T, et al. Additional benefit of hemostatic sealant in preservation of ovarian reserve during laparoscopic ovarian cystectomy: a multi-center, randomized controlled trial. Hum Reprod. 2014 Aug;29(8):1659-65 • Sönmezer M, et al. Can ovarian damage be reduced using hemostatic matrix during laparoscopic endometrioma surgery? A prospective, randomized study. Arch Gynecol Obstet. 2013 Jun;287(6):1251-7

Page 11 Disclosure

“I have no financial relationships to disclose” Deeply Infiltrating Endometriosis

Tommaso Falcone, M.D.,FRCSC,FACOG | Professor Obstetrics & Gynecology Chief of Staff & Chief Academic Officer Cleveland Clinic London

Koninckx, Ussia, Zupi & Gomel 2017- the plea Objectives for consensus opinion?

○ Discuss the potential mechanism by which deeply infiltrating disease can affect fertility outcome

○ Discuss the impact of surgery on fertility outcome in patients with deeply infiltrating disease

○ Discuss different surgical approaches to excision of deeply infiltrating disease

Johnson NP, Hummelshoj L, for the World Endometriosis Society Controversies in Surgical Management In Montpellier Consortium. Consensus on current management of Infertile patient endometriosis. Hum Reprod 2013;28:1552–1568.

Peritoneal disease: Excision or ablation or do nothing ● Letter to the editor “ The title is misleading: an opinion paper is not a consensus paper” ● Response “It must be stated at the outset that there is no consensus in Ovarian endometrioma: Resect bowel/ the literature as to what constitutes a ‘consensus paper’.” Excise or excise lesion ablate or do or do nothing nothing

Page 12 Mechanism of Infertility: Severe tub-ovarian disease Endometriosis not involving the tube or ovary-How does it impact fertility?

Falcone & Flyckt Ob& Gyn 2018 • Angiogenesis • STF-1 expression M • Anti-apoptosis factors B cellcellB • Defective retinoid pathway • Chronic inflammation • IL-6/TNF T cellcellT Macrophages/T cells NK NK cell cytotoxicity • 17 hydroxysteroid cell dehydrogenase-2 • Estradiol synthesis via aromatase deficiency Altered immune cell • Fibrosis population and • Higher levels of ER-B Metaplastic differentiation of function • Neuronal infiltration within ovarian coelomic epithelium Endometrial Glandular and stromal cells do not superficial endometrium: tissue undergo apoptosis in Retrograde endometriosis. Sensory A menstruation Endometrial tissue Sensory C colonizes Adrenergic hemorrhagic corpus Cholinergic nerve fibers luteum Cross-talk between Fibrosis/scar tissue ectopic lesion and Endometrial tissue eutopic spreads through blood endometrium and lymph vessels

Endometria Uterus l implant Candidate epithelial T cell stem cell Vasculature Nerve fibers encapsulates invade lesion. eMSC cell and enters lesion. NK cell B cell Mullerianosis Macrophage hypothesis

Page 13 Surgery for Minimal or Mild Disease Ablation vs. Excision

● 2 RCTs - Canadian study showed a treatment effect ( inclusion only of women age 20-39 years); Italian study showed no treatment effect.

○ Combine the studies for pregnancies over 20 weeks: 27% (treated) and 18% ( non-treated): NNT=12 ( 95% CI 7,49)

■ 30% prevalence of endometriosis

■ 40 diagnostic laparoscopies to get an extra pregnancy

RCTs = randomized controlled trials; NNT = number needed to treat; CI = confidence interval

“Clinicians may consider both ablation and excision of peritoneal endometriosis to reduce endometriosis-associated pain (Healey, et al., 2010, Wright, et al., 2005).” ESHRE Endometriosis Guideline Development Group -September 2013 Deeply Infiltrating Endometriosis (DIE)

● Pain relief-RCT ● Nodules extending more than 5 ○ Wright J et al F&S 2005 mm beneath the peritoneum

■ N=24- Stage1&2 ○ Utero-sacral ligaments, vagina, ○ Healy M et al. 2010- 1year follow bowel, bladder, ureters

■ N= 178- Seems equivalent for early stage disease

■ DIE-53% in the excision group and 22 % in the ablation

○ Healy et al 2014: 5 year follow up-Excision better pain outcomes for dyspareunia ● Pregnancy rates similar-

Page 14 Why treat advanced endometriosis in the Deeply Infiltrating Endometriosis: (DIE) Infertile patient

● Exacoutos et al F&S 2016 ● Complications during pregnancy & delivery in women with untreated recto-vaginal DIE

○ ½ were ART pregnancies ● Bladder & ureter invasion ● Bowel invasion ○ Higher rate of C/S & hysterectomy, hemoperitoneum & ● Recto-cervical/ recto-vaginal septum bladder injury as well pregnancy specific disease. ● Roman H et al JMIG 2015 ● Clinicians can consider performing surgical removal of deep endometriosis, as it reduces endometriosis- ○ N=241 patients colo-rectal endometriosis advised to proceed to infertility treatment rather than surgery associated pain and improves quality of life (De Cicco, et al., 2011, Meuleman, et al., 2011b). ESHRE ○ 3 year observation period- 5% developed a bowel guideline obstruction

Laparoscopy vs. Robotic Surgery for Endometriosis (LAROSE): a multicenter, randomized, controlled trial. Soto E, Luu TH, Liu X, Magrina JF, Wasson MN, Einarsson JI, Cohen SL, Falcone T. Fertil Steril. 2017 No difference in any perioperative or long term outcomes or quality of life outcomes

Page 15 ● Isac W. Kaouk J. Altunrende F. Rizkala E. Autorino R. Hillyer SP. Laydner H. Long JA. Kassab A. Khalifeh A. Panumatrassamee K. Eyraud R. Falcone T. Haber GP. Stein RJ. Robot-assisted ureteroneocystostomy: technique and comparative outcomes. Journal of Endourology. 2013; 27:318-23.

Three possibilities with DIE in the infertile patient Semin Reprod Med 2013;31:133–143

● Surgery followed by spontaneous pregnancy ● Surgery followed by IVF ● IVF ● Issues with the studies

○ Most case series include women who were not infertile at the time of the intervention

○ Some include also pregnancies obtained using IVF.

○ Median time to pregnancy ex. 12 months with 95% CI 7-17 months

Percentages of spontaneous conception in infertile women at the end of follow-up in studies on the effect of radical surgery for rectovaginal and rectosigmoid endometriosis on reproductive performance

Surgery for deeply infiltrating endometriosis (DIE)-review

● Cohen et al Minerva Ginecol 2014;66:575-587 ● N=1295 DIE no bowel involvement surgically treated

○ Spontaneous PR 50.5% ( 95%CI46-54%)

○ Mean age- 31 & follow up to 27.9 months ● N=115- DIE-bowel involvement- not surgically treated

○ Post ART 29% ( 95 %CI 20 %-37%) ● N=1320 DIE with bowel involvement- surgically treated

○ Spontaneous PR-28% (CI 95% 25%-32%)

○ Spontaneous & ART PR 46.9 % ( 95% CI 42%-50%)

Page 16 Advanced Endometriosis- Maheux-Lacroix et al Hum Reprod 2017 Bowel Endometriosis

● Follow up 5 years ● Non-ART live births

○ 0%- at 5 years if EFI was 0-2

○ 10%-at 1 year if EFI was 3-4

○ 20%-at 1 year if EFI was 5-6

○ 40%- at 1 year if EFI >6

○ EFI score is 9-10- 46% at 1 year; 58% at 2 years and 91% at 5 years.

Deeply Infiltrating Disease-Rectal endometriosis

Page 17 Step 1- Dissect the ureter

Iliac vessel dissection

RIGHT INTERNAL iliac

Left internal iliac

Page 18 Page 19 Deeply infiltrating endometriosis (DIE) & IVF outcome

● Ballester et al F&S 2012- IVF up to 3 cycles ○ N=103 isolated endometrioma-PR-82% ○ N=73- endometrioma with DIE-PR-69% ○ DIE was associated with decreased PR ○ No pregnancies after 3 IVF cycles- consider surgery ● Bianchi et al JMIG 2009 ○ Improved outcomes with IVF after removal of DIE ○ N=105- IVF no resection of DIE- PR- 24% ○ N=64- extensive resection then IVF-41% ● Darai et al 2016 Eur J Obstet Gynecol Reprod Biol ○ Resect the DIE- leave the colo-rectal disease- spontaneous & ART- 37% ( 95% CI 29-37) ○ Resect all disease-spontaneous & ART-51% (95% CI 48- 54)

IVF after surgery for Colo-rectal endometriosis IVF with colo-rectal endometriosis ● Ballester et al Hum Reprod 2012

- Untreated colo-rectal endometriosis & infertility treated with ART; N= 75; median cycles -1 (1-3)

● Bendifallah et al Fert & Steril 2017 - CPR- after 3 cycles- 68%-no pregnancies after 3 cycles ● N=110 Infertile women- First line ART ( in situ endometriosis) vs. - Negative impact- adenomyosis, age and AMH level Surgery ( excision of all endometriosis) followed by ART ● Ballester M et al European Journal of Obstetrics & Gynecology and Reproductive Biology ● Median age was 32 years 209 (2017) 95–99 ● Cumulative Live Birth rate= ○ N=60 infertile women- surgical removal of colorectal endometriosis followed by ART ( 89 cycles)- 60% became pregnant- CPR- after 1,2 ,3 cycles was 41%,65%, 78%- no pregnancies after 3 cycles ○ First line surgery followed by ART- 32.&%, 58.9%, 70.6% ○ IVF outcome was better with conservative ( shaving/disc) than resection ○ First line ART- 13%, 24.8%, 54.9% P=.0078) ● Mathieu d’Argent et al F&S 2010

- IVF outcome the same with untreated colorectal endometriosis as controls (N=29 vs. N=157 tubal factor vs. N= 340 male factor)

Complications: Vercellini et al. 2009 New Symptoms secondary to radical resection

● Neurogenic bladder dysfunction 4–10% ● Rectovaginal fistula formation 2–10% ● Pelvic pain definitely gets better ● Inadvertent rectal perforation 1–3% ○ Significant improvement in well being ● Anastomotic leakage 1–2% ○ Soto E, Catenacci M, Bedient C, Jelovsek JE, Falcone T. Assessment of Long term Bowel ● Pelvic abscess 2-5% symptoms after segmental resection of deeply infiltrating endometriosis: A matched Cohort study. ● Post-anastomotic rectal stenosis 0.5–1% JMIG 2016 ● Segmental bowel resection for DIE may be associated with a ● Post-anastomotic ureteral stenosis 0.5–1% higher incidence of new bowel symptoms (possibly due to abdominal pain, incomplete bowel movements, and/or false alarms), but not with worse constipation or fecal incontinence, compared with surgery without bowel resection.

Page 20 References

● Soto E, Luu TH, Liu X, Magrina JF, Wasson MN, Einarsson JI, Cohen SL, Falcone T.Laparoscopy vs. Robotic Surgery for Endometriosis (LAROSE): a multicenter, randomized, controlled trial.Fertil Steril. 2017. Apr;107(4):996-1002 ● Abrão MS, Petraglia F, Falcone T, Keckstein J, Osuga Y, Chapron C. Deep endometriosis infiltrating the recto-sigmoid: critical factors to consider before management.Hum Reprod Update. 2015 May;21(3):329-339 ● Koninckx PR, Ussia A, Keckstein J, Adamyan LV, Zupi E, Wattiez A, Gomel V. Evidence-Based Medicine: Pandora's Box of Medical and Surgical Treatment of Endometriosis. J Minim Invasive Gynecol. 2018 Mar - Apr;25(3):360-365 ● Duffy JM, Arambage K, Correa FJ, Olive D, Farquhar C, Garry R, et al. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev. 2014 Apr 3;(4):CD011031. 10.1002/14651858.CD011031 ● Exacoustos C, Lauriola I, Lazzeri L, De Felice G, Zupi E. Complications during pregnancy and delivery in women with untreated rectovaginal deep infiltrating endometriosis. Fertil Steril. 2016 Oct;106(5):1129-113 ● Roman H, Puscasiu L, Lempicki M, Huet E, Chati R, Bridoux V, Tuech JJ, Abo C. Colorectal Endometriosis Responsible for Bowel Occlusion or Subocclusion in Women With Pregnancy Intention: Is the Policy of Primary in Vitro Fertilization Always Safe? J Minim Invasive Gynecol. 2015 Sep-Oct;22(6):1059-67 ● Isac W. Kaouk J. Altunrende F. Rizkala E. Autorino R. Hillyer SP. Laydner H. Long JA. Kassab A. Khalifeh A. Panumatrassamee K. Eyraud R. Falcone T. Haber GP. Stein RJ. Robot-assisted ureteroneocystostomy: technique and comparative outcomes. Journal of Endourology. 2013; 27:318-23. ● Berlanda N, Vercellini P, Somigliana E, Frattaruolo MP, Buggio L, Gattei U. Role of surgery in endometriosis-associated subfertility. Semin Reprod Med. 2013 Mar;31(2):133- 43 CC ● Cohen J, Thomin A, Mathieu D, Argent E, Laas E, Canlorbe G, et al. Fertility before and after surgery for deep infiltrating endometriosis with and without bowel involvement: a London literature review. Minerva Ginecol 2014 66:575-587 ● Maheux-Lacroix S, Nesbitt-Hawes E, Deans R, Won H, Budden A, Adamson D, Abbott JA. Endometriosis fertility index predicts live births following surgical resection of moderate and severe endometriosis. Hum Reprod. 2017 Nov 1;32(11):2243-2249 ● Ballester M, Roman H, Mathieu E, Touleimat S, Belghiti J, Darai E. Prior colorectal surgery for endometriosis-associated infertility improves ICSI-IVF outcomes: results from two expert centres. Eur J Obstet Gynecol Reprod Biol. 2017 Feb;209:95-99. ● Ballester M, Mathieu d’Argent E, Morcel K, Belaisch-Allart J, Nisolle M, Darai E. Cumulative pregnancy rate after ICSI-IVF in patients with colorectal endometriosis: results of a multicenter study. Human Reprod 2012 27(4):1043-1049. ● Ballester M, Duber nard G, Wafo E, Bellon L, Amarenco G, Belghiti J, et al. Evaluation of urinary dysfunction by urodynamic tests, electromyography and quality of life questionnaire before and after surgery for deep infiltrating endometriosis. Eur J Obstet Gynecol Reprod Biol. 2014 Aug;179:135-140.

Page 21 Fertility Enhancing Disclosures Hysteroscopy

 Consultant – Karl Storz Endoscopy Keith Isaacson, MD –Medtronic Associate Professor of Obstetrics and Gynecology Harvard Medical School Boston, MA USA

Learning Objectives Infertility Evaluation

 Describe the use of office hysteroscopy equipment  Semen Analysis  Discuss indications and findings for  Ovarian Reserve Assessment hysteroscopy in the infertile population  Tubal patency  Review hysteroscopic procedure  Uterine cavity assessment techniques

Intrauterine pathology Evaluation of the Uterine impacting fertility Cavity

 Intrauterine polyps  D&C  Uterine fibroids  Hysterosalpingogram  Intrauterine Adhesions  Ultrasound  Uterine septum  Sonohysterography  Adenomyosis  Office hysteroscopy  Proximal Tubal occlusion

Should office hysteroscopy be a routine part of the fertility evaluation?

Page 22 Diagnostic accuracy of sonohysterography, transvaginal sonography, and hysterosalpingography in patients with uterine Polyp Diagnosis cavity diseases

 69 Infertile women age 19-43

 All underwent TVUS, SIS, HSG and Hysteroscopy (gold standard)

Soares S et al. Fertil Steril 73, FEBRUARY 2000

Intrauterine Adhesions Uterine Malformations

Accuracy of Three-Dimensional Ultrasonography in Differential Hysteroscopic Findings in Diagnosis of Septate and Bicornuate Uterus Compared with ART Patients Office Hysteroscopy and Pelvic Magnetic Resonance Imaging Faivre E , MD*, Fernandez H et al, JMIG Vol 19, No 1, January/February 2012  Lorusso, F et al1 (866 cycles) – 555 pts before first IVF – 311 after 2 or more failed IVF – 40% with intrauterine pathology  Hinkley MD et al 2 1000 patients prior to IVF 32% with polyps 3% submucus myomas 3% adhesions 0.5% septum 0.3% retained POCs 0.3% bicornuate

1. Gynecol Endocrinol Aug 2008 2. JSLS April 2004

Page 23 Hysteroscopic Findings in ART Findings Following Normal Patients HSG & TVS

 Akmai-El-Mazny et al  217 patients  145 patients prior to IVF with normal HSG – 95 with prior ART failure   51 with prior ART failure 42% with intrauterine abnormality –Results – 122 with no prior ART  24% with intrauterine abnormality  33% (48) with cavity abnormality (45% with prior ART failure)  Hysteroscopic pathologic findings (217 patients) – Submucosal fibroids 28 (13%)  5.5% polyps – Polyps 26 (12%)  4% myoma – Septum 12 (6%)  4% adhesions –Synechia 3 (1.5%)  All others <3% each

Fertil Steril Jan 2011 Bakas p, Hassiakos D et al JMIG 2013

Intrauterine pathology Recurrent IVF failure impacting fertility

 421 pts - randomized  Uterine fibroids – 211 with no OH – 21% PR  Intrauterine Adhesions – 210 with OH  Intrauterine polyps  154 normal cavities – 32% PR  Proximal Tubal occlusion  56 abnormal cavities (26%) repaired at diagnosis– 30% PR P=0.044  Uterine septum  Adenomyosis

Dimirol A, Gurgan T Reproductive Med Online 8:590 2004

Do Polyps impact fertility? Palm-Coin

 Pérez-Medina et al 214 patients randomized to polyp removal or observation – Pregnancy rates in 4 IUI cycles – Treated – 63% (65% prior to first IUI) – Control – 28%  Size of polyp – No difference if <5mm, 5-10,11-20, >20

Hum Reprod June 2005

Page 24 Myomas and reproductive SM myomata and function infertility

1. Cervical displacement can reduce exposure to sperm 2. Enlargement or deformity of the uterine cavity that may  Pritts reported significantly lower pregnancy interfere with sperm migration and transport rates (risk ratio, 0.32), implantation rates 3. Obstruction of the proximal fallopian tubes 4. Altered tubo-ovarian anatomy, interfering with ovum (risk ratio, 0.28), and delivery rates (risk capture ratio, 0.75) in patients with submucosal 5. Increased or disordered uterine contractility that may hinder sperm or embryo transport or nidation myomas and abnormal uterine cavities, in 6. Distortion or disruption of the endometrium and implantation comparison with infertile control women due to atrophy or venous ectasia over or opposite without myomas. a submucous myoma 7. Impaired endometrial blood flow  Donnez and Jadoul also confirmed that only 8. Endometrial inflammation or secretion of vasoactive submucous myomas have a negative impact substances on embryo implantation. Ed Bulliten, Fertil Steril 2008;90:S125–30

Fertility after Hysteroscopic Follow-up after incomplete hysteroscopic removal of uterine fibroids Resection of Van Dongen H, Emanuel MH, Smeets J, Trimbos, B and Jansen FW Submucous Myomas

 No prospective randomized trials  Giatras et al. 1999 JMIG • 528 Hysteroscopic myomectomies – 41 infertile patients • 91 Incomplete resections (17%) – 61% pregnancy rate  56% delivery rate • 37 repeated immediately for  Betocchi et al F&S 2008 fertility – Beneficial treatment of SM myomata <1.5 cm in IVF patients. • 41 observed for menorrhagia  Shokeir TA (Arch of Gynecol Obstet 2005) – 3% to 63% after resection del rate – Ab rate reduced from 61% to 26% after resection

Incomplete myoma resection Impact on fertility

55% required  Post‐surgical or infectious damage to basalis layer of additional endometrium leading to granulation ‐ tissue bridges to cavity obliteration surgery within 3  Increased risks of ectopic pregnancy, recurrent years miscarriages, preterm labor, and abnormal placentation

Robinson J, Colimon LM, Isaacson KB. Fertil Steril 2008;90(2):409‐14 Valle RF, Sciarra JJ. Am J Ostet Gynecol 1988;158:1459‐70 Schenker JG, Margalioth EJ. Fertil Steril 1982;37:593‐610  Pregnancy wastage up to 90% Orhue AA, Aziken ME, Igbefoh JO. Int J Gynaecol Obstet 2003;82:49‐56 Klein SM, Garcia CR. Fertil Steril 1973;24:722‐35 Goldenberg M, Sivan E, Sharabi .Z et al Hum Reprod 1995;10(10:2663‐5

Page 25 Diagnosis Asherman’s Therapy

• Adhesiolysis (removal rarely necessary) • Clinical ‐ history of uterine trauma (PP D&C, C/S, myomectomy, rarely infection) • Use cold scissors (30% recurrence) • amenorrhea with normal hormonal • Avoid heat (57% recurrence) profile or negative P w/d (prolonged E2 laser and RF energy stim) • Thermal damage and risk of amenorrhea with cyclic pain • • perforation

March C. Semin Repro Endo, 2011

Endometrial Polyp In Saline

THANK YOU FOR YOUR ATTENTION!

Page 26 Normal Endometrium

Endometrial polyp

Operative Office Standard Hysteroscopy Hysteroscopy

 Standard Approach – Speculum – preferable side opening – Tenaculum  Vaginoscopic approach – No speculum or tenaculum – Bettocchi S, Selvaggi L. A vaginoscopic approach to reduce the pain of office hysteroscopy. J Am Assoc Gynecol Laparosc 1997;4:255-8. – Cicinelli E, Parisi C, Galantino P, Pinto V, Barba B, Schonauer S. Reliability, feasibility, and safety of minihysteroscopy with a vaginoscopic approach: experience with 6,000 cases. Fertil Steril 2003;80:199-202

Page 27 Vaginoscopie : Technique Office Hysteroscopic procedures

 Diagnostic Hysteroscopy  Visually directed endometrial biopsy  Polypectomy  Myomectomy 12  Adhesiolysis  Metroplasty  Proximal tubal recanalization

Page 28 Disclosure

Consultant: Espiner Medical, Ltd., Gynesonics, Medtronic, Pacira Pharmaceuticals, Richard Wolf Isthmocele Contracted Research: AbbVie, Allergan, Espiner Medical, Ltd., Gynesonics, Karl Storz Royalty: Thomas Medical CHARLES E. MILLER, MD, FACOG Speakers Bureau: AbbVie

• Vice Chair, AAGL Endometriosis / Reproductive Surgery Special Interest Group Stock Ownership: Gynesonics, Halt Medical • Treasurer, International Society for Gynecologic Endoscopy (ISGE) Other: Ownership Interest: Blue Seas Med Spa • Past President, International Society for Gynecologic Endoscopy – ISGE (2011 – 2013) • Past President, AAGL (2007 – 2008) • Clinical Associate Professor, Department OB/GYN, University of IL at Chicago, Chicago, IL USA • Director, Minimally Invasive Gynecologic Surgery, Advocate Lutheran General Hospital, Park Ridge, IL USA • Director, AAGL Fellowship in Minimally Invasive Gynecologic Surgery, Advocate Lutheran General Hospital, Park Ridge, IL USA

Objectives

● Define isthmocele

● Describe techniques in the diagnosis of an isthmocele

● Outline current hysteroscopic and laparoscopic treatment regimens for isthmocele repair

Sipahi S, Sasaki K, Miller CE. The minimally invasive approach to the symptomatic isthmocele - what does the literature say? A step-by-step primer on laparoscopic isthmocele - excision and repair. Curr Opin Obstet Gynecol. 2017 Aug;29(4):257-265

Isthmocele - Definition Isthmocele - Definition

● Isthmocele / Previous Cesarean Scar Defect / Deficient Cesarean Scar / Uterine Niche / ● First described by Morris in 1995 Diverticula / Pouch/ Transmural Hernia / Dehiscence / Uteroperitoneal Fistula . Reviewed 51 hysterectomy specimens with a history CS . No universal definition used in literature • Hysterectomy performed for menorrhagia (72%), dyspareunia, . Diverticulum at the lower uterine cavity, uterine dysmenorrhea, lower abdominal pain refractory to medical management isthmus or endocervical canal at the site of a previous cesarean section (CS) scar • Distortion and widening of LUS (75%)

. Sonographic finding of a triangular anechoic area • “Free” red blood cells in endometrial stroma of scar (59%) at the presumed site of incision (no size defined) • Fragmentation and breakdown of endometrium of scar (37%) . Myometrial thinning at site of CS scar • Iatrogenic adenomyosis (28%)

Page 29 Isthmocele – Do niches really matter? Isthmocele – Do niches really matter? Obviously – what does the literature say? Obviously – what does the literature say?

● 32 studies noted Prevalence of caesarean scar defects on transvaginal sonography (TVS), ● 18 noted to have High Risk Bias sonohysterography (SHG) or hysteroscopy . No clear definition of population . No clear definition of scar defect . No clear definition of treatment options

Tulandi T, Cohen A. Emerging Manifestations of Cesarean Scar Defect in Reproductive-aged Women. J Minim Invasive Gynecol. 2016 Sep-Oct;23(6):893-902 Tulandi T, Cohen A. Emerging Manifestations of Cesarean Scar Defect in Reproductive-aged Women. J Minim Invasive Gynecol. 2016 Sep-Oct;23(6):893-902

Isthmocele – TVUS vs. SIS Isthmocele – Do niches really matter? Obviously – what does the literature say?

● Osser 2010 . 108 women with history of one or more CS and no other uterine surgeries

. TVUS ultrasound SIS

. Scar defect= any indentation at the site of the scar

TVUS SIS ● Osser 2009 ● Prevalence . 125 of 287 patients prior vaginal delivery . TVS: 24% - 70% One CS (N = 68) 42 (62%) 53 (78%) . SHG: 56% - 84% Two CS (N = 32) 28 (88%) 31 (97%) ● Armstrong 2003 Three CS (N = 8) 8 (100%) 8 (100%) . 32 patients prior C/S – 13 with fluid in scar . All 13 of 23 labored prior to C/S . More scar defects were identified on SIS vs. TVUS

Tulandi T, Cohen A. Emerging Manifestations of Cesarean Scar Defect in Reproductive-aged Women. J Minim Invasive Gynecol. 2016 Sep-Oct;23(6):893-902 Osser OV, et al., Cesarean section scar defects: agreement between transvaginal sonographic findings with and without saline contrast enhancement. Ultrasound Obstet Gynecol. 2010 Jan;35(1):75-83 Osser OV, et al., High prevalence of defects in Cesarean section scars at transvaginal ultrasound examination. Ultrasound Obstet Gynecol. 2009 Jul;34(1):90-7 Armstrong V, et al., Detection of cesarean scars by transvaginal ultrasound. Obstet Gynecol. 2003 Jan;101(1):61-5

Isthmocele Isthmocele

● Prospective observational cohort study in 401 nonpregnant women, recruited within three days of C-section ● Saline infused sonogram at six months ● Results . N = 371 . Isthmocele in 45.6% . Elective versus emergency C-section delivery – no difference . Single layer versus two layer closure could not be evaluated, as only one patient had a single layer closure

Antila-Långsjö RM, Cesarean scar defect: a prospective study on risk factors. Am J Obstet Gynecol. 2018 Nov;219(5):458.e1-458.e8 Antila-Långsjö RM, Cesarean scar defect: a prospective study on risk factors. Am J Obstet Gynecol. 2018 Nov;219(5):458.e1-458.e8

Page 30 Isthmocele Isthmocele

Antila-Långsjö RM, Cesarean scar defect: a prospective study on risk factors. Am J Obstet Gynecol. 2018 Nov;219(5):458.e1-458.e8 Antila-Långsjö RM, Cesarean scar defect: a prospective study on risk factors. Am J Obstet Gynecol. 2018 Nov;219(5):458.e1-458.e8

Isthmocele Isthmocele - SIS vs. Hysteroscopy Other potential risk factors for isthmocele

● El-Mazny 2011 ● Vikhareva Osser – increased risk1 . Comparative Observational Cross-sectional study . 75 women with history of prior CS, complaining of menstrual disorders, infertility or recurrent pregnancy loss . > 5-cm dilatation . Compare SIS and hysteroscopy findings • Niche generally lower in cervix . Subjects • Age: Mean 27.3 ± 2.8 years 2-3 ● Coronis and Caesar Trials • Symptoms: Infertility (49.3%), Menstrual disorders (33.3%), Recurrent Pregnancy Loss (17.3%) The authors saw the same conclusions . SIS: Defect in 20 cases ● Di Spiezio Sardo analysis4 . Hysteroscopy: Defect in 22 cases Accuracy of SHG compared with DH in the diagnosis of scar defect (niche) and intrauterine adhesions. . Double versus singe layer closure – no difference

● Ceci – locked continuous single layer versus interrupted5

1. Vikhareva Osser O, et al. Risk factors for incomplete healing of the uterine incision after caesarean section. BJOG. 2010 Aug;117(9):1119-26 2. Abalos E, et al. Caesarean section surgical techniques (CORONIS): a fractional, factorial, unmasked, randomized controlled trial. Lancet. 2013 Jul 20;382(9888):234-48 3. CAESAR study collaborative group. Caesarean section surgical techniques: a randomized factorial trial (CAESAR). BJOG. 2010 Oct;117(11):1366-76 4. Di Spiezio Sardo, et al. Risk of Cesarean scar defect following single- vs double-layer uterine closure: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol. 2017 Nov;50(5):578-583 5. Ceci O, et al. Ultrasonographic and hysteroscopic outcomes of uterine scar healing after cesarean section: comparison of two types of single-layer suture. J Obstet Gynaecol Res. 2012 Nov;38(11):1302-7

El-Mazny A, et al., Diagnostic correlation between sonohysterography and hysteroscopy in the assessment of uterine cavity after cesarean section. Middle East Fertility society Journal. 2011 (16):72-76

Isthmocele – Signs and Symptoms Isthmocele – Secondary Infertility

● Abnormal uterine bleeding ● Accumulation of blood and mucus . Negatively impact cervical mucus quality . Affect sperm quality ● Pelvic pain/dysmenorrhea . Obstruct sperm transport . Interfere with embryo implantation

● Secondary infertility ● Chronic inflammatory state

● Other complications ● Evidence associated with improvement in fertility after treatment of . Abscess isthmocele . Ectopic pregnancy

Page 31 Isthmocele – Hysteroscopic Repair for Isthmocele – Do niches really matter? Secondary Infertility

● Infertility ● Gubbini 2011 . Prospective study of 41 women with . Pregnancy rates cesarean-induced isthmocele and Clinical Characteristics of Study Population secondary infertility • Other causes of female and male fertility excluded Hysteroscopy 77.8% ‐ 100% . All patients underwent hysteroscopic isthmoplasty . All patients (41/41) spontaneously conceived between 12-24 months post- Laparoscopy 55% operatively • 37/41 (90.2%) Cesarean section • 4/41 (9.8%) Spontaneous abortion

Gubbini G, et al., Surgical hysteroscopic treatment of cesarean-induced isthmocele in restoring fertility: prospective study. J Minim Invasive Gynecol. 2011 Mar-Apr;18(2):234-7

Isthmocele – Laparoscopic Repair for Isthmocele – Do niches really matter? Secondary Infertility

Results (N = 38) ● Series – 38 patients ● Symptoms . 58.1% IMB . 48.3% DIII • IMB – intermenstrual bleeding • DII – grade III dysmenorrhea . 41.9% CPP • CPP – chronic pelvic pain • DDP – deep dyspareunia . 25.8% DDP . 44.4% infertility

Donnez, O et al., Gynecological and obstetrical outcomes after laparoscopic repair of a cesarean scar defect in a series of 38 women. Fertil Steril. 2017 Jan;107(1):289-296.e2

Isthmocele – Do niches really matter? Isthmocele – Do niches really matter?

Demographic and Isthmocele Characteristics of the Study Population (N = 35)

Post Operative Results ● 8 live births (44.4%, N=8/18) and one ongoing pregnancy – no special event occurred ● 91% relief of symptoms among patients presenting pain and/or bleeding ● Failure: 7.9% (N = 3) . RMT 11.2 & 11.7 mm, hysteroscopic resection (N=2) . RMT 5 mm but larger defect, LH (N=1)

Continuous variables were compared by Mann-Whitney U test and categorical data compared by chi-square test. Data are reported as n (%) unless otherwise indicated.

Donnez, O et al., Gynecological and obstetrical outcomes after laparoscopic repair of a cesarean scar defect in a series of 38 women. Fertil Steril. 2017 Jan;107(1):289-296.e2 Calzolari, et al., Prevalence of Infertility Among Patients With Isthmocele and Fertility Outcome After Isthmocele Surgical Treatment: A Retrospective Study. Ochsner Journal, March 2019

Page 32 Isthmocele – Endoscopic Repair for Laparoscopic Isthmocele Secondary Infertility

● 22 women . 18 women with LSC secondary to myometrial thickness ≤ 2.5mm

. 4 women with LSC secondary to myometrial thickness ≥ 2.5mm

Pregnancy Results

Robotic Isthmocele Robotic Isthmocele

Robotic Assisted Isthmoplasty Robotic Isthmocele

Page 33 Uterine Uplift Uterine Uplift

Laparoscopic Isthmocele Repair – “Chicago Style” Proposed Modified Algorithm

• Can be performed via conventional laparoscopy or with robotic assistance • Perform hysteroscopy to verify isthmocele • Place cannula inside cervix/uterus • Mobilize bladder off lower uterine segment and cervix (may require back filling of bladder) • Dissect laterally to just above uterine vessels • Proceed back to hysteroscopy to identify isthmocele defect • Will often times see retracted scar laparoscopically • Use light of hysteroscope to identify isthmocele - make initial incision laparoscopically or hysteroscopically (Versapoint micro tip) under laparoscopic guidance • Replace cannula and excise isthmocele (conventional laparoscopy – ultrasonic energy, robotic assistance – monopolar scissors) • To allow better visualization, shorten cannula to enter only cervix • Repair in layers • Layer one - interrupted vs. “U” suture – placed first at angles – 3.0 monofilament • Layer two (if necessary) – similar to layer one or running suture • Layer three – 3.0 barbed suture “baseball style” • Once completed, repeat hysteroscopy to verify no stenosis and adequate repair • Perform uterine uplift if uterus retroflexed

Conclusion References

● Studies are poor in defining niche site • Sipahi S, Sasaki K, Miller CE. The minimally invasive approach to the symptomatic isthmocele - what does the literature say? A step-by-step primer on laparoscopic isthmocele - excision and repair. Curr Opin Obstet Gynecol. 2017 Aug;29(4):257-265 • Tulandi T, Cohen A. Emerging Manifestations of Cesarean Scar Defect in Reproductive-aged Women. J Minim Invasive Gynecol. 2016 Sep-Oct;23(6):893-902 ● Asymptomatic patients should not be treated without further desire of pregnancy • Osser OV, et al., Cesarean section scar defects: agreement between transvaginal sonographic findings with and without saline contrast enhancement. Ultrasound Obstet Gynecol. 2010 Jan;35(1):75-83 • Osser OV, et al., High prevalence of defects in Cesarean section scars at transvaginal ultrasound examination. Ultrasound Obstet Gynecol. 2009 Jul;34(1):90-7 ● The anterior uterine wall must be imaged in case of symptomatic patient with previous C/S to rule • Armstrong V, et al., Detection of cesarean scars by transvaginal ultrasound. Obstet Gynecol. 2003 Jan;101(1):61-5 • Antila-Långsjö RM, Cesarean scar defect: a prospective study on risk factors. Am J Obstet Gynecol. 2018 Nov;219(5):458.e1-458.e8 out isthmocele – saline infused sonogram is recommended • Vikhareva Osser O, et al. Risk factors for incomplete healing of the uterine incision after caesarean section. BJOG. 2010 Aug;117(9):1119-26 • Abalos E, et al. Caesarean section surgical techniques (CORONIS): a fractional, factorial, unmasked, randomized controlled trial. Lancet. 2013 Jul 20;382(9888):234-48 ● Symptoms are greatest in patients with larger niches • CAESAR study collaborative group. Caesarean section surgical techniques: a randomized factorial trial (CAESAR). BJOG. 2010 Oct;117(11):1366-76 • Di Spiezio Sardo, et al. Risk of Cesarean scar defect following single- vs double-layer uterine closure: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol. 2017 Nov;50(5):578-583 ● Abnormal uterine bleeding secondary to niche, responds well to surgical treatment • Ceci O, et al. Ultrasonographic and hysteroscopic outcomes of uterine scar healing after cesarean section: comparison of two types of single-layer suture. J Obstet Gynaecol Res. 2012 Nov;38(11):1302-7 • El-Mazny A, et al., Diagnostic correlation between sonohysterography and hysteroscopy in the assessment of uterine cavity after cesarean section. Middle East Fertility society ● Studies are minimal regarding pelvic pain and C/S niche Journal. 2011 (16):72-76 • Gubbini G, et al., Surgical hysteroscopic treatment of cesarean-induced isthmocele in restoring fertility: prospective study. J Minim Invasive Gynecol. 2011 Mar-Apr;18(2):234-7 • Donnez, O et al., Gynecological and obstetrical outcomes after laparoscopic repair of a cesarean scar defect in a series of 38 women. Fertil Steril. 2017 Jan;107(1):289-296.e2 ● In regards to infertility, laparoscopic treatment of the C/S niche should be reserved for the patient • Calzolari, et al., Prevalence of Infertility Among Patients With Isthmocele and Fertility Outcome After Isthmocele Surgical Treatment: A Retrospective Study. Ochsner Journal, March with fluid in the endometrial cavity, myometrium less than 3-mm, above niche, or continued 2019 implantation failure when all factors normalized

Page 34 Financial Disclosure Myomectomy : preserving and enhancing fertility through surgery • I have no financial relationships to disclose

Rebecca Flyckt, MD Division Director, Reproductive Endocrinology and Infertility University Hospitals of Cleveland Case Western Reserve University

Objectives The path to a successful outcome

• Identify appropriate candidates for MIS • Outline strategies to reduce blood loss • Determine optimal port placement • Review tips for surgical technique • Discuss options for tissue extraction

Indications : 2017 ASRM Guideline Indications : 2017 ASRM Guideline

Page 35 Indications – Recurrent losses Indications – Infertility

• Saravelos et al Hum Reprod 2011 • Pritts et al, Systematic Review, F&S 2009 – 8% prevalence in patients with RPL (n=966) – Fertility improves with resection of cavity – Cavity distorting fibroid ‐ resection distorting fibroids • Early loss‐ no change – Fertility effect is unclear with resection of non‐ • Mid‐trimester losses‐ SS reduction‐ LBR 52 % cavity distorting fibroids – Non‐cavity distorting fibroids ‐ no surgery & – Subserosal fibroids have no impact on fertility or unexplained RPL spontaneous abortion rates • LBR 70 %

Indications – OB outcomes? Indications – OB outcomes? • Increased likelihood of C‐section • Increased risk of PTD

• Increased risk of uterine rupture? – Zero cases in 134 women in our series – Range in other studies of 0‐3% • Growth during pregnancy – 49‐60 % exhibit no change in size – Mean increase is 12%

The path to a successful outcome Approach

• Hysteroscopy APPROACH • Laparoscopy – Robotics • Abdominal

Page 36 ROBOTIC SET UP ROBOTIC SET UP – SIDE DOCK

Page 37 The path to a successful outcome Dissection • BEWARE dissection in the wrong plane DISSECTION – Pseudocapsule – neurovascular bundle – Traction • BEWARE dissection around the proximal tube – Occlusion – Kinking

Dissection The path to a successful outcome • BEWARE cavity entry, especially with barbed suture BLOOD LOSS – Intracavity adhesions • Use a manipulator or pediatric foley in the uterus to inject • Suture the cavity separately with 3‐0 PDS and avoid suture within the cavity • Hysteroscopy post procedure

Page 38 Blood loss – Cochrane Database Blood loss – Meta Analysis • GnRH agonist preoperatively • Tulandi & Einarsson JMIG 2014 – No difference in rate of transfusion • Use of barbed suture – Correct anemia pre‐op - Suturing time decreased • Vasopression –sig reduction in EBL - Degree of suturing difficulty was reduced • Misoprostol (400mcg 30‐60 mins before) - Trend towards decreased blood loss • Tranexamic acid (1000mg IV, $$$$) • Gelatin thrombin matrix – Significantly dec EBL and transfusion

The path to a successful outcome Closure

• Multi layer approach CLOSURE – Eliminate dead space • Barbed suture – Avoid endometrium and consider hysteroscopy prior to conclusion of case • Closure before tissue extraction • Consider chromopertubation

CLOSURE VIDEO The path to a successful outcome EXTRACTION

Page 39 EXTRACTION VIDEO Post operative counseling

• Wait three months to conception in >35 year olds – 6 months in < 35 • No data to recommend routine use of Cesarean section

Summary

• Counsel carefully when undertaking a fertility‐based myomectomy • Select the right MIS approach and know when MIS may not be optimal! • Prioritize careful dissection, minimization of blood loss, full myometrial closure, and contained tissue extraction

Page 40 Disclosure

The Role of Endoscopy in the • Consultant Diagnosis and Treatment of – Karl Storz Endsocopy – Adenomyosis Medtronics Keith Isaacson, MD Director, MIGS Newton Wellesley Hospital Associate Professor Ob/Gyn Harvard Medical School

2

Objective Adenomyosis

Review the role of endoscopy in the diagnosis • Endometrial glands and stroma present with and treatment of adenomyosis. uterine musculature • Can be focal or diffuse • Incidence 20‐30% at time of hysterectomy

3

Clinical presentation‐ endometriosis? Recurrence of Symptoms after resection = average 35% • Sutton 1994 37.5% • Dysmenorrhea – 50‐90% • Howard 1993 51% • Dyspareunia • Deep pelvic pain • Hornstein 1993 34% • Low abdominal pain and back pain • Redwine 1991 30% • Cyclic bowel and bladder symptoms • Sutton 1990 30% • Infertility Any symptom that intensifies with the menstrual cycle All studies included post op medical suppression

Page 41 We only treat what we see: Adolescent endometriosis What are we missing? ‐ Adenomyosis Sandogan E Euro J Obstet Gynecol Repro Bio 2017 • We cannot see it at laparoscopy • Peak incidence in 40’s? • Dysmenorrhea –40‐50% of adolescents; 15% severe • Increase risk with deliveries? • In adolescents with “visual • Tissue diagnosis –TLH endometriosis” dysmenorrhea and CPP is • Imaging diagnosis – the most common symptom. Dypareunia – MRI – poor screening tool in those sexually active – US – recent and currently being • 92% with Stage I or II disease refined –no histology • 56% recurrence of symptoms in 5 years If its uterine pain –it is likely uterine disease

Avoid the mistakes we made with Endometriosis • Delayed diagnosis • Diagnosis without histology • Assumed we could see and excise all the disease • 155 women with surgically staged • Assumed the best non‐surgical therapy is endometriosis (Enzian) by compartment hormonal pre‐op MRI and/or U/S for adenomyosis • Lack of understanding on how and why the – Positive correlation of adenomyosis to disease has such varied phenotypes. pelvic pain, rectal bleeding, dysuria and • Accept unknowns ‐ why does stage I disease hematuria and association with dysmenorrhea (95% of patients) and not DIE cause dysmenorrhea, infertility...... ? Gynecol Obstet Invest. 2017 9 Gynecologic and Obstetric Investigation Oct 2016

Pregnancy rates Live birth rate

• Live birth rate per cycle was reported in 5 Implantation rates in women • Clinical pregnancy rate per embryo transfer in women without and with studies without and with adenomyosis adenomyosis • Presence of adenomyosis was associated with a 41% DECREASE in life birth rate

Younes, G and Tulandi T. Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta‐anaylsis. Fertil Steril 2017; 108: 483‐490. Younes, G and Tulandi T. Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta‐anaylsis. Fertil Steril 2017; 108: 483‐490.

Page 42 Why is adenomyosis so hard to Histologic definitions (Glands +/‐ stroma beneath the basalis of the endometrium) understand? • >1 HPF • Variation in symptoms • >0.5 LPF (1mm) • No standardized histologic definition • > 1 medium‐power field (x100) • No standardized radiologic definition • >1 LPF • >1/4 of total uterine wall thickness • Diagnosis is most often made without a tissue • 2.5 mm or more diagnosis • 3 mm or more • No standard classification of the disease (focal, • I know it when I see it diffuse, cystic etc) ‐ descriptive terms.

13 Used in 9 different references14

Histological Diagnosis Histological Diagnosis

• Ectopic endometrial tissue in myometrium • Hysterectomy • Smooth muscle cell hyperplasia • Biopsy • Posterior wall – 5mm loop electrode with hysteroscopy • Circumscribed nodular aggregates – Cutting needles at time of laparoscopy or hysteroscopy with spirotome (TROPHY hysteroscope) – Ultrasound guidance biopsy

McCausland A. Hysteroscopic myometrial biopsy: Its use in diagnosing adenomyosis and its clinical applications. Am J Obstet Gynecol 1992

Azzi R. Adenomyosis: current perspectives. Obstet Gynecol Clin. N. Am. 1989 Popp L. Myometrial biopsy in the diagnosis of adenomyosis uteri. Am J Obstet Gynecol. 1993

Hysteroscopy Hysteroscopic biopsy

• Irregular endometrium with defects • McCausland A 1992 • Altered vascularity – 90 patients with menorrhagia • Cystic hemorrhagic lesion – 50 normal cavities • 33 (66% with adenomyosis >1 mm)

Molinas C. Office Hysteroscopy and adenomyosis. Best Pract Res Clin Obstet Gynaecol 2006 Fernandez C. Adenomyosis visualized during hysteroscopy. J Minim Invasive Gynecol 2007

Page 43 Imaging studies What is the Junctional Zone (JZ)?

• Why does it have a difference in MRI appearance from the outer myometrium? (Not seen on H&E stain) • MRI • What is the relationship of a thickened JZ to – Large asymmetric uterus symptoms related to adenomyosis? – – thickening of junctional zone >12 mm Pain – – Increased ratio of JZ to myometrial thickness Bleeding – – Foci low signal intensity within the myometrium Infertility • correspond to islands of heterotopic endometrial tissue, • Role in coordinated contractions for sperm cystic dilatation of heterotopic glands, or hemorrhagic foci. transport and controlling bleeding.

20

Uterine Junctional Zone Anatomy Studies of the Inner & Outer Myometrium • Increased CD31 blood vessels in IM (increased • Embryonic Origins vascular density) – Inner Myometrium • Increased Nuclear area of myocytes. (IM) and endometrium are of • Increase water content of the IM Mullerian origin • Electron microscopy: Apparent metaplasia of – Outer stroma/myocytes. Myometrium(OM) of • Extracellular Matrix: Discordant results from non‐mullerian, different labs, immunohistochemical (IHC) mesenchymal origin. staining.

Imaging studies Ultrasound criteria

• Junctional zone max – Junctional zone min • Ultrasound >4mm (Jdiff) – Myometrial cysts • Junctional zone max > 12 mm – Ill defined hyperechoic areas, small aneochic lakes, • Myometrial asymmetry heterogeneous myometrial echotexture • Myometrial cysts – Asymmetric uterine enlargement • Striations – Indistinct endometrial, myometrial border • Hocky stick endometrium • Reduced Doppler flow

Bazot M. Ultrasound compared with magnetic resonance imaging for the diagnosis of adenomyosis: correlation with histopathology. Human Reproduction 2001

Page 44 Comparison of Imaging modalities

• 54 women with pre hysterectomy U/S Sensitivity Specificity • Two ultrasound features –diagnostic accuracy TVUS 53-89% 50-99% of 90% (no pre treatment), 50% (pretreatment) TVUS with myoma 33% 78% • Sensitivity, specificity, PPV, NPV – 92%, 83%, 88-93% 67-99% 99%, 71% MRI

MRI with myoma 67% 87%

JMIG 2013 Dueholm M. Transvaginal ultrasound or MRI for diagnosis of adenomyosis. Curr Opinion Obstet Gynecol 2007

TREATMENT OCPS and Progestins

• Medical treatment • No RCT – Suppressive hormonal therapy • Induction of amenorrhea for relief of – Inability to conceive while on therapy symptoms

• Surgical treatment – Gold standard hysterectomy

Study N Months Outcomes Side effects

MIRENA Dysmenorrhea 94 36 -Improved VAS Score -15 expulsions Baseline 78/100 11.9/100 -17 premature removals Sheng et al -decrease uterine volume -weight gain 28% • Mechanism Contraception 2009 113ml->94ml (p=.001) -satisfaction rate 72.5% – Releases 20ug Levonorgestrel daily – Decidualization of endometrium – Down‐regulating estrogen receptors MRI findings 29 6 -25% decrease in JZ -no expulsions, removal • Outcomes -decrease uterine size -27% weight gain 2kg – Decrease size of uterus up to 25% Bragheto (p=.277) -Headaches 20% Contraception 2007 -80% Improved VAS score – improvement dysmenorrhea and menorrhagia <3/10 – Studies treatment 6‐36 months Menorrhagia 25 12 -100% decrease bleeding -one expulsion -Hbg 10.112.5 -one premature removal Fedele -ferritin 2782 -28% weight gain Fertil Steril 1997 -24% headache

Page 45 DANAZOL GnRH agonists

• 19 nortestosterone derivative • Bind to receptors in pituitary gland • Limited studies given side effects • Multiple small cases reports for infertility patients • Local delivery • Grow D. Treatment of adenomyosis with long‐term GnRH analogues. Obstet Gynecol 1999 • Hirata J. Pregnancy after medical therapy of adenomyosis with gonadotropin‐releasing – IUD hormone agonist. Fertil Steril 1993 • Huang F. Effects of short‐course buserelin therapy on adenomyosis. A report of two cases. J – Intra‐cervical injections Reprod Med 1999: 44 p741‐744 • Nelson J. Long term management of adenomyosis with a gonadotropin releasing hormone agonist: a case report. Fertil Steril 1993 • Ozaki T, Live birth after conservative surgery for severe adenomyosis following magnetic resonance imaging and GnRH agonist therapy. Int J Fertil Women’s Med. 1999 • Silva P, Perkins H, Schauberger C. Live birth after treatment of severe adenomyosis with a gonadotropin –releasing hormone agonist. Fertil Steril 1994:61 p171‐2 Takebayashi T, Danazol suspension injected into the uterine cervix of patients with adenomyosis and myoma. Gynecol Obstet Invest 1995 Igarashi M. Novel conservative medical therapy for uterine adenomyosis with a danazol-loaded intrauterine device. Fertil Steril 2000

Hysterectomy

• Vaginal hysterectomy – Higher rates of bladder injury with adenomyosis in Selective Progesterone Receptor comparison to fibroids Modulators – Disruption in planes • Laparoscopic – Lower trends in bladder injury

Furuhashi M. Comparison of complications of vaginal hysterectomy in patients with leiomyomas and in patients with adenomyosis. Arch Gynecol Obstet 1998

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Endometrial ablation/resection Uterine Artery Embolization

• Rollerball electrode • Controversy whether effective – <2mm successful procedures with or without • Outcomes vary progesterone therapy – Embolic agents – – >2mm hysterectomy Co‐existence of fibroids • Largest prospective study 54 patients • Global ablation – 4.5 years – 1.5 increased risk of failure – 4 patients immediate failure, 19 with relapses for 5 years – Overall 70% satisfaction rate

McCausland A, McCausland V. Depth of endometrial penetration in adenomyosis helps determine outcome of rollerball ablation. Am J Obstet Gynecol 1996 Wood C. Surgical and medical treatment of adenomyosis. Human Reproduction Update 1998 Kim M, Kim S, Kim N. Longer term results of uterine artery embolization for symptomatic adenomyosis. El Nashar S, Prediction of treatment outcomes after global endometrial ablation. Obstet Gynecol 2009 Interventional Radiology 2007

Page 46 Myometrial electocoagulation MRgFUS

• Unipolar or Bipolar • Magnetic Resonance guided focused • Requires knowledge of exact location ultrasound surgery • May be incomplete • Sequential ultrasound beams focused on tissue • Not recommended for fertility – Thermal coagulationnecrosis of tissue – Risk of uterine rupture • New for adenomyosis

Rabinovici J. New interventional techniques for adenomyosis. Best Practice & Research Clinical Obstetrics Wood C. Surgical and medical treatment of adenomyosis. Human Reproduction Update 1998 and Gynaecology 2006

Takeuchi et al. JMIG 13; 150‐154 Surgical Excision 2006 14 women –two pregnancies • Kishi et al. F&S 102;3 802 2014 Difficult to discern planes 102 women • Can be used for fertility patients Wang P. Comparison of surgery alone and combined surgical‐medical treatment in the management of symptomatic uterine adenomoya. Fertil Steril 2009 – 49/71 women able to conceive – higher rates of spontaneous abortion (38%)

• Triple flap method. Osada H. Silber S. Kakinuma T. Nagaishi M. Kato K. Kato O. Reproductive Biomedicine Online. 22(1):94‐9, 2011 Jan. – 104 women – 14/26 pregnant – No uterine rupture

40

Treatment: medical versus Medical +/‐ surgical treatment surgical Al Jama • 2 studies examined effect of Wang

surgery + GnRH (versus GnRH • 40 sub‐fertile patients • 65 sub‐fertile patients alone). Surgery associated with with pathology‐ with pathology‐proven increased pregnancy rates but N proven adenomyosis extensive  22: GnRHa alone (6 adenomyosis small. injections) – 37: GnRHa alone (6 • 2 studies looked at GnRH  18: conservative injections) surgery + GnRHa (6) – 28: conservative treatment before IVF.  L/S surgery +/‐ GnRHa Pretreatment appeared to be “cytoreductive” • L/S “cytoreductive” surgery surgery beneficial to pregnancy rate Al Jama, FE. Management of adenomyosis in subfertile women and pregnancy outcome. Oman Med J 2011; 26: 178‐81

Younes, G and Tulandi T. Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta‐anaylsis. Fertil Steril 2017; 108: 483‐490. Wang PH et al. Is the surgical approach beneficial to subfertile women with symptomatic extensive adenomyosis? J Obstet Gynecol Res 2009; 35: 495‐502.

Page 47 Author Outcome Intervention P‐value F&S 2014

Surgery + GnRHa GnRHa • 102 women desiring fertility laparoscopic Clinical pregnancy 44.4% (8/18) 13.6% (3/22) p=0.0393 rate @ 36mo Al‐Jama adenomyomecomy – MRI diagnosis pre op Term deliveries (#) 6 1 p=0.0328 • Clinical pregnancy rates Clinical pregnancy 46.4% (13/28) 10.8% (4/37) p=0.002 rate @ 36mo – <39 y/o 41.3% (60% after prior IVF failure) Wang

Term deliveries – >40 y/o 3.7% (7% after prior IVF failure) 93p=0.022 (#) • All delivered by c/s, no ruptures, no multiples – 2 accreta, 2 preterm birth 35 and 36 weeks

Patient D.O. • 37 y.o. G7P1061 presents with h/o of recurrent pregnancy loss and abnormal HSG • Recurrent pregnancy loss: 3 SAB previous to c‐section , 2 SAB following • 6/2017 22 weeks miscarriage with cerclage , delivered • 4/15/18: HSG Uterine cavity: Enlarged, irregular contour, ?fibroids,difficult distension, no filling of tubes bilaterally • Menses: 8 years HMB, lasting 4 days, wearing tampon+ pads and diaper at night, reports quarter size clots, changing pads every 30 min • Denies dysmenorrhea • +dyspareunia, with deep penetration, sometimes post‐ coital bleeding

Page 48 Disclosure

“I have no financial relationships to disclose” Tubal Surgery in the Era of ART

Tommaso Falcone, M.D.,FRCSC,FACOG | Professor Obstetrics & Gynecology Chief of Staff & Chief Academic Officer Cleveland Clinic London

TUBAL DISEASE Objectives

○ Discuss the potential role of surgical • 25 – 35% of female infertility intervention for proximal tubal disease

○ Discuss the impact of surgery on • >50% is due to salpingitis fertility outcome in patients with distal tubal disease • Proximal block in 10 – 25% of tubal

○ Discuss different surgical disease approaches to reversal of a tubal – Obstruction – spasm or plug ligation – Occlusion – SIN, fibrosis

CANNULATION SYSTEM

Page 49 TUBAL CANNULATION

● Patency achieved >85% of the time ● ~1/3 reocclude ● Excision of the proximal tubes in cases of failed cannulation revealed SIN, chronic salpingitis or fibrosis in 93% ● Perforation in 3 – 11% but always innocuous ● Falcone & Goldberg 2008

TUBAL CANNULATION ANASTOMOSIS

Meta-analysis • ~1/3 use TL for contraception (200 M STUDIES # PTS PR SAB ECTOPIC Ongoing women) worldwide • 5-20% have regret d/t new partner, Microsurg 175 58.9 6.8 12.6 47.4 loss of child, or changed mind. More N=5 common if younger at TL & shortly HS after delivery N = 4 133 48.9 13.8 9.2 48.9 Fluoro 482 21.4 17.5 12.6 15.6 • Only 1-2% under reversal N = 9

Honore et al Fertil Steril 1999;71:785-95

TUBAL ANASTOMOSIS ANASTOMOSIS

REVERSAL IVF • Outpatient minilaparotomy

one time minimally -daily injections Inconvenience • If no other infertility factors and age <40, invasive procedure -frequent visits the LBR is 70-90% with a 2-10% ectopic Opportunity to -can try Q month rate limited attempts conceive -can conceive > 1x • 33-50% IUP in >40 yo -surgical risks -multiple pregnancy Risks -ectopic pregnancy -OHSS Berger GS et al Hum Reprod 2016;31:1120-5 Moon HS Hum Reprod 2012;27:1657-62 -faster time to preg Petrucco OM et al Med J Austral 2007;187:271-3 -more cost effective Advantages -Tx’s other factors Kim SH et al Fertil Steril 1997;68:865-70 -more natural Dubuisson JB et al Hum Reprod 1995;10:1145-51 -preserves fertility Trimbos-Kemper TC Fertil Steril 1990;53:575-7

Page 50 ANASTOMOSIS ANASTOMOSIS vs IVF 886 patients. NSD in PRs <40 80% conceived in 12 mos, mean 6 mos ● Retrospective cohort - 79 IVF, 84 anastomosis 82% IUP, 2.5% ectopic ● Cumulative LBR - IVF 52%, anastomosis 60%

○ <37 yo - IVF 54%, anastomosis 72% Age <30 31-5 36-40 >40 p=0.012

○ >37 yo – NSD PR 97.5 92.4 86.2 53.9 ● Mean of 2 IVF cycles to conceive % ● Cost to delivery: IVF €11707, anast. €6015

Moon HS et al Hum Reprod 2012;27:1657-62 Boeckxstaens et al Obstet Gynecol 2007;109:1375-80

COST

Difference Age Anastomosis IVF (IVF–TA)

<35 $16,315 $32,814 $16,500

35–40 $23,914 $45,839 $21,925

>40 $218,742 $111,445 ($107,297)

Messinger et al Fertil Steril 2015;104:32–8

daVINCI VS MINILAP: Cleveland Clinic, Obstet Gynecol 2007 daVINCI VS MINILAP

daVinci Minilap P Value (N=26) (N=41) Robotic Minilap P Surgical time (min) 226 186 0.001 (N=23) (N=32) Anesthesia (min) 279 209 <0.001 Mos. to conceive 4 6.5 0.13 EBL <100cc 19 (73%) 31 (80%) 0.48 LOS (min) 274 381 0.14 Pregnancy 14 (61%) 26 (81%) 0.10 Costs (difference in $1450 more for <0.001 median values) robot Ectopic 2 (10%) 5 (11%) 0.70 Back to work (wks) 1.5 2.5 0.013 Rodgers et al Obstet Gynecol 2007;109:1375-80

Page 51 COSMESIS ESSURE REVERSAL

● Tubo-uterine implantation 70 pts. Retrospective, bilateral, 1 yr f/u.

● 36% pregnancy rate, 25% LBR, no ectopics

Moneith et al Obstet Gynecol 2014;124:1183-9 Goebel, Goldberg J Min Invas Gynecol 2013

SALPINGOSTOMY

● Mild hydros

○ Minimal adhesions

○ < 3 cm dilated

○ Thin walls

○ Mucosal folds on HSG

○ Normal appearing mucosa ● Young patient ● No other significant factors

Page 52 SALPINGOSTOMY SALPINGOSTOMY

● Results are difficult to interpret Prognosis # of pts IUP Ectopic ● Different criteria / scoring systems ● ? other significant infertility factors ● Different techniques Good 104 67% 3% ● Variable surgeon experience ● Inconsistent follow-up intervals ● Crude PRs instead of MFRs Intermediate 141 24% 28%

Poor 196 10% 31%

Page 53 SALPINGOSTOMY HYDROS & IVF

PR IUP Ectopic ● Hydros may reduce IVF success by:

scissors, 9 (35%) 5 (19%) 4 (15%) suture n=26 ○ Mechanical flushing

unipolar ○ Impaired endometrial receptivity needle, 13 (48%) 10 (37%) 3 (11%) Bruhat n=27 ■ ↓β3 Integrin, HOXA10, VEGF, unipolar perfusion needle, 15 (52%) 14 (48%) 1 (3%) suture n=29 ○ Direct embryotoxic effect

HYDROS & IVF SALPINGECTOMY VS TL

● 2 meta-analyses comparing IVF with and without hydros

● Sig lower (~50%) PR & LBR and higher SAB rate with hydros

Xu B et al Fertil Steril 2017;108:84-95

SURGICAL TX & IVF SALPINGECTOMY & DOR

• Lowered AMH vs. No effect on AMH

• Unclear data- technique dependent

Page 54 CONCLUSIONS References ● HS tubal cannulation for PTO ● Falcone T, Goldberg J. Hysteroscopic Tubal Cannulation. In Nezhat C, Nezhat F, Nezhat C (eds): Nezhat's Operative Gynecologic Laparoscopy and Hysteroscopy. New York, Cambridge, 2008, p 162-164. ● Tubal anastomosis is more cost-effective than IVF ● Honoré GM1, Holden AE, Schenken RS. Pathophysiology and management of proximal tubal blockage. Fertil Steril 1999;71:785-95. ● Moon HS, Joo BS, Park GS, Moon SE, Kim SG, Koo JS. High pregnancy rate after microsurgical tubal reanastomosis by temporary loose parallel 4-quadrant sutures technique: a long long-term follow-up report on 961 cases. Hum Reprod 2012;27:1657-62 ● Boeckxstaens A, Devroey P, Collins J, Tournaye H Getting pregnant after tubal sterilization: surgical reversal or IVF? Hum Reprod 2007;109:1375-80 ● LS salpingostomy for good prognosis hydros ● Messinger LB, Alford CE, Csokmay JM, Henne MB, Mumford SL, Segars JH, Armstrong AY. Cost and efficacy comparison of in vitro fertilization and tubal anastomosis for women after tubal ligation. Fertil Steril 2015;104:32–8 ● Hydros reduce IVF success by ~50% ● Rodgers AK*, Goldberg JM, Hammel J, Falcone T. Tubal Anastomosis by Robotic Compared with Outpatient Minilaparotomy. Obstet Gynecol 2007 109:1375-1380 ● Goebel K1, Goldberg JM2. Women's preference of cosmetic results after gynecologic surgery. J Minim Invasive Gynecol. 2014 Jan-Feb;21(1):64-7 ● Monteith CW, Berger GS, Zerden ML. Pregnancy success after hysteroscopic sterilization reversal. Obstet Gynecol 2014;124:1183-9 ● LS salpingectomy & TL restore IVF success rates- perhaps ● Flyckt R, Goldberg JM Tubal disease and ectopic pregnancy. Clinical Reproductive Medicine and Surgery: A Practical Guide third edition. Falcone T, Hurd WW. Editors Springer 2017 salpingostomy ● Essure- has been withdrawn and only of historical significance

Page 55 CULTURAL AND LINGUISTIC COMPETENCY

Governor Arnold Schwarzenegger signed into law AB 1195 (eff. 7/1/06) requiring local CME providers, such as the AAGL, to assist in enhancing the cultural and linguistic competency of California’s physicians (researchers and doctors without patient contact are exempt). This mandate follows the federal Civil Rights Act of 1964, Executive Order 13166 (2000) and the Dymally-Alatorre Bilingual Services Act (1973), all of which recognize, as confirmed by the US Census Bureau, that substantial numbers of patients possess limited English proficiency (LEP).

US Population California Language Spoken at Home Language Spoken at Home

Spanish English Spanish

Indo-Euro English Indo-Euro Asian Other Asian

Other 19.7% of the US Population speaks a language other than English at home In California, this number is 42.5%

California Business & Professions Code §2190.1(c)(3) requires a review and explanation of the laws identified above so as to fulfill AAGL’s obligations pursuant to California law. Additional guidance is provided by the Institute for Medical Quality at http://www.imq.org

Title VI of the Civil Rights Act of 1964 prohibits recipients of federal financial assistance from discriminating against or otherwise excluding individuals on the basis of race, color, or national origin in any of their activities. In 1974, the US Supreme Court recognized LEP individuals as potential victims of national origin discrimination. In all situations, federal agencies are required to assess the number or proportion of LEP individuals in the eligible service population, the frequency with which they come into contact with the program, the importance of the services, and the resources available to the recipient, including the mix of oral and written language services. Additional details may be found in the Department of Justice Policy Guidance Document: Enforcement of Title VI of the Civil Rights Act of 1964 http://www.usdoj.gov/crt/cor/pubs.htm.

Executive Order 13166,”Improving Access to Services for Persons with Limited English Proficiency”, signed by the President on August 11, 2000 http://www.usdoj.gov/crt/cor/13166.htm was the genesis of the Guidance Document mentioned above. The Executive Order requires all federal agencies, including those which provide federal financial assistance, to examine the services they provide, identify any need for services to LEP individuals, and develop and implement a system to provide those services so LEP persons can have meaningful access.

Dymally-Alatorre Bilingual Services Act (California Government Code §7290 et seq.) requires every California state agency which either provides information to, or has contact with, the public to provide bilingual interpreters as well as translated materials explaining those services whenever the local agency serves LEP members of a group whose numbers exceed 5% of the general population.

~

If you add staff to assist with LEP patients, confirm their translation skills, not just their language skills. A 2007 Northern California study from Sutter Health confirmed that being bilingual does not guarantee competence as a medical interpreter. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2078538.

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