Note

COMBINED TREATMENT OF PATIENTS WITH (SURGERY, MEDICAL). ALGORITHMS AND RESULTS

Leila V. Adamyan Professor, Academician of Russian Academy of Sciences

Note

I have no financial relationships to disclose.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note

ADAMYAN L. V.

HISTORY OF ENDOMETRIOSIS RESEARCH Note

Contents

1860 1978 2002 1896 Karl von Philipp Koninckx Thomas Stephen Rokitansky Jacques Donnez Cullen 1986 1921-1941 Harry Reich John Albertson Sampson

Contents 1993 Selezneva N.D. Arnaud Wattiez

Saveleva G.M 2014 Mario Malzoni 1972-2018 Strazhakov A.N. Antonio Setubal

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM MY WAY IN ENDOMETRIOSIS Note DURING 46 YEARS

1991 SP (substance of 1977 PhD 1st International sensitizing the nerve 1985 • in Congress on fibers) gynecology Gynecological Endoscopy • Changes on EEG in Classification endometriosis

1972 1972- 1986 1991 1993 2000 1985 2010- 2018

• Morphologi Different 1986-1st child cal medications using in after IVF in the 1994- substrate of endometriosis USSR L.V. Adamyan pain. treatment (from Laporoscopic Russian • Mass castration to Oocyte association of spectromet Dienogest 2 mg) retrievement – endometriosis ry, L.V. Adamyan • microRN A, ADAMYAN L. V. signaling pathways

Note INTRODUCTION TO ENDOMETRIOSIS Definition: the presence of endometrial-like tissue outside the

•

• • Disease extent varies XXI • small lesions → • ?

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note ENDOMETRIOSIS IS DISEASE INDEPENDENT OF AGE The prevalence of endometriosis in  Every 10th woman in postmenopausal women is 2-4% reproductive age  (15-49 years) is affected by endometriosis.

 50-60% of women and adolescent  According to ACOG data with  In 60% of patients with endometriosis  (from menarche to premenopause) the first symptoms were noted up to 20 have endometriosis years

I.Streuli, H.Gaitzsch et al. Endometriosis after menopause: physiopathology and management of an uncommon condition,Climacteric, 2017

ADAMYAN L. V.

Peritoneal / ovarian Note Often discrepancy between the stage score and real clinical severity rASRM, 1996

CLASSIFICATION OF ENDOMETRIOSIS AND ADENOMYOSIS

Deep infiltrative (retrocervical) Development of endometriosis from less to more severe forms is not a rule! Adamyan L.V., 1993

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM THEORIES REGARDING PATHOGENESIS OF Note ENDOMETRIOSIS NEW The role of stem cells

Sapmson’s theory

Mesothelium metaplasia ENDOMETRIOSIS

Mullerian rests

Local estrogen biosynthesis Environment Inflammation Genetics Endometriotic Angiogenesis in endometriotic Disease progression, implant implants Invasion, reccurrence

ADAMYAN L. V.

Note FACTORS, DETERMINING STRATEGY OF MANAGEMENT

Demogra Quality  Age  Genetic of life phic characteris  Immune  Reproductive tics Etiopatho function  Endocrine genetic  inflammation and factors invasion Clinical signs Anatomic/ morphologi  Endometriosis and pelvic pain cal form  Endometriosis and  Pelvic organs disorders

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note CLINICAL ASPECTS OF ENDOMETRIOSIS

Menorrhagia Pelvic pain Recurrence Pelvic organs Infertility disfunction

Endometriosis is a surgical disease – there are no available methods besides surgery which can remove morphological substrate of endometriosis

ADAMYAN L. V.

ENDOMETRIOSIS AND PAIN Note

High level of individual anxiety and Electroencephalography of patients with high frequency ofdepression are very different forms of endometriosis. common in endometriosis patients.

65% of women changes in the activity of the limbic - reticular complex 70% women change in tropho - tropic synchronizing structures of the brain steam

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note ENDOMETRIOSIS AND PAIN

• There are all types of pathogenic pain in endometriosis : The most common type of pathogenetic pain combined type with a clear predominance of neuropathic component. • Strong variations of pain infiltrative endometriosis

In endometriotic lesions thereis: Proliferation of epithelial and Oxidative stromal stress elements

Autonomous Production of steroidogenesis proinflammatory cytokines The formation Neoangio- of fibers and genesis sensory receptors

ADAMYAN L. V.

Note DIAGNOSIS OF ENDOMETRIOSIS

Clinical aspects Visualisation Prognosis Pathogenesis • US- 2D, 3D, 4D • Stem cells • Endometriosis in • Reccurrenc • 3D-printed model • Embriological theory adolescent e • CT, MDCT • Immunological • Delay of • Fertility • MRI, DCE-MRI aspects diagnosis • Malignancy • Transvaginal elastography • Hormonal owndata dependence

• Diagnosis of Endoscopy Biomarkers • Evidence-Based Medicine: infertility Pandora's Box of Medical and . Colonoscopy • Genes Surgical Treatment of Endometriosis.Koninckx PR, et al. J . Cystoscopy • Oocyte quality • CA-125 Minim Invasive Gynecol. . • 2017.Koninckx PR, Ussia A, Keckstein Colposcopy Endometrial • miRNA • J, Adamyan L, Zupi E, Wattiez A, . Gomel V. Hysteroscopy receptivity • etc. . Laparoscopy • Tubal patency

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM ENDOSCOPY IN TREATMENT AND DIAGNOSIS OF Note ENDOMETRIOSIS  Excision of cystic adenomyosis Final diagnosis – under US-control  Biopsy + immunohistochemical hystological Hysterospopy investigation confirmation!!! (adenomyosis)  Extrusion of wall  Visualisation of endometrioitic holes  Complicated dilation of uterus cavity Genital endometriosis  Endometriosis of  More than 20 forms of Adenomyosis LAPAROSCOPY peritoneal lesions  Increase of uterus size  Deep infiltrative forms  Thickening or  Combined forms deformation of uterus wall «Marble» serosa Colposcopy Vaginal Hysterosalpingography, endometriosis pneumography, pelvic cervical hydrolaparoscopy, control Ls endometriosis S. Gordts, R. Campo, I. Brosens Hysteroscopic diagnosis and excision of myometrial cystic adenomyosis Gynecol Surg (2014) Uterine Cystic Adenomyosis: A Disease of Younger Women Ivo Brosens, Stephan Gordts et al Pediatr Adolesc Gynecol, 2014

ADAMYAN L. V.

DIAGNOSIS OF ENDOMETRIOSIS- VISUALIZATION Note

MRI PET (POSITRON-EMISSION TOMOGRAPHY)

TRANSVAGINAL ELASTOGRAPHY own data

CT, MDCT Colonoscopy Cystoscopy Colposcopy US (2D, 3 D, 4D) Hysteroscopy

Laparoscopy Agency for Healthcare Research and Quality; 2006 Feb. Report No.: Evidence Report/Technology Assessment No.: 130. AHRQ Publication No.: 06-E004. Contract Importance of Transvaginal Elastography in the Diagnosis of Uterine Fibroids and Adenomyosis. No.: 290-02-0025.)) GUIDELINE NO. 34 PEER REVIEW DRAFT – SEPTEMBER Authors:Frank ML,Schäfer SD,Möllers M, Falkenberg MK, Braun J, Möllmann U, Strube F, 2015 THE MANAGEMENT OF OVARIAN CYSTS IN POSTMENOPAUSAL Fruscalzo A, Amler S, Klockenbusch W, Schmitz R.Ultraschall Med 2016 Aug; 37(4):373-8. WOMEN)

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM ENDOMETRIOSIS AND ADENOMYOSIS IN Note ADOLESCENTS, FERTILE AND MENOPAUSAL WOMEN Directions Endometriosis and of investigation malignancy Pathogenesis

Age aspects

Management of Clinical aspects: Diagnostic endometriosis pain, infertility, methods reccurenсe, etc.

ADAMYAN L. V.

ENDOMETRIOSIS IN ADOLESCENTS Note

 Up to 80% adolescents with chronic pelvic pain don’t respond to medical treatment

 The majority of adolescents have early- stage disease, but a significant proportion of adolscents can have advanced disease (up to one-third)

 An ovarian is the most common presentation of advanced endometriosis in adolescents.

 The main symptoms are chronic pelvic But in several cases pain and .  Acyclic pain seems to be more common in endometriosis in adolescents adolescents than in adults. could be find during surgery for other indications Problem of endometriosis in adolescent. Adamyan L.V., Sibirskaya E.V. et al. Problems of reproduction, 2016 Hum Reprod. 2013 Aug;28(8):2026-31. doi: 10.1093/humrep/det243. Epub 2013 Jun 5. Endometriosis in adolescents is a hidden, progressive and severe disease that deserves Eur J Obstet Gynecol Reprod Biol. 2017 Feb;209:46-49. doi:10.1016/j.ejogrb.2016.05.019. attention, not just compassion.Brosens I, Gordts S, Benagiano G. Epub 2016 Jun 16. Adolescent endometriosis.Sarıdoğan E.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note LAPAROSCOPIC EXCISION OF ENDOMETRIOSIS IN A DOLESCENTS

ADAMYAN L. V.

Note ENDOMETRIOSIS MANAGEMENT IN ADOLESCENT Management of endometriosis in adolescent depends on:  Clinical symptoms (pain, dysmenorrhea, etc.)  Morphological forms  Combined pathology  Threshold of pain, psychosomatic status

 The majority of adolescent girls with chronic pelvic pain not responding to conventional medical therapy have endometriosis

 Pelvic floor ultrasound is particularly useful to endometriotic cysts detecting during check-ups

 СT and MRI using rarely, when ultrasound is abnormal

 Interdisciplinary evaluation and management may be needed

 Laparoscopy with biopsy is the only way to diagnose external genital endometriosis in adolescent

 Surgical management is beneficial in reducing pain, progression or recurrence of endometriosis.

 Postoperative hormonal suppression helps reduce pain symptoms and recurrence of

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM ENDOMETRIOSIS IN Note

REPRODUCTIVE AGE Over 176 million women aged 15 - 49 1 of 10 women worldwide in the reproductive age Frequency of is affected by hysterectomy – endometriosis 25%; 10% are in the Adenomyosis affects age < 30, 50% - < more than 60% of 37 years women in the age of 40-50

• Rogers et al, Reprod Sci 2009;16:335–346 • World Bank. Population Projection .Tables by Country and Group, 2010 • Adamson et al, J of Endometriosis 2010;2:3–6 • Hummelshoj 11/2010 Rogers et al, Reprod Sci 2009;16:335–346.

ADAMYAN L. V.

Note ENDOMETRIOSIS AND INFERTILITY

Pathophysiology of endometriosis- The incidence of endometriosis diagnosed associated infertility: during laparoscopy is 20-55% - pro-inflammatory changes in the follicular fluid affect Genital endometriosis occurs in 5-10%of oogenesis women of reproductiveage - endometriosis negatively affects fertilization - alterations of endometrial In healthy women the chance of conception during receptivity in endometriosis each is 15-20%, in women with - peritoneal fluid in patients endometriosis without treatment it is 2-10% suffering from endometriosis contains increased level of Endometriosis is diagnosed in 35-50%of IL-1b, IL-6 (embryo- and infertile women** spermatotoxic effect), TNF-a and other)

*Mattew, Endometriosis and Infertility^ Arewieu of the pathogenesis and treatment of endometriosis-associated infertility, Obstet Gynecol ClinNorth Am.Dec2012; 39(4): 535–549.**Tsenov, D,Fiipov S,AkushGinekol (Solva); 1994; 33(2): 24-7

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM ENDOMETRIOSIS AND INFERTILITY Note  External genital endometriosis, depending on its localization and dissemination, reduces the activity of folliculogenesis, oogenesis and early embryogenesis. CocciaM.E., Hum Reprod,2012,AdamyanL.2013  External genital endometriosis IV stage and its combination with adenomyosis extremely reduce the IVF and ET (embryo transfer) effectiveness. Thalluri V., Tremellen K.Hum Reprod2012;Ballester M. et al HumReprod,2013

International consensusESHRE,ASRM, RCOG: • Laparoscopy for external genital endometriosis (1-2 stages ASRMClassification) before IVF; • Laparoscopy on endometriotic cysts (3-4 stages ASRM Classification ) before IVF; • Adjuvant therapy after surgery in the short mode before IVF

ADAMYAN L. V.

Note ENDOMETRIOSIS-ASSOCIATED INFERTILITY- THE QUALITY OF OOCYTES AND OVARIAN RESERVE ASSESSEMENT • Reduction in the quantity and quality of mitochondria • Decentralization of chromatin • • There is the detrimental effect of endometriosis on oocyte quality

J Ovarian Res. 2017 Jul 12;10(1):43. doi: 10.1186/s13048-017-0341-4. Is the oocyte quality affected by endometriosis? A review of the literature.Sanchez AM, Vanni VS, Bartiromo L, Papaleo E, Zilberberg E, Candiani M, Orvieto R, Viganò P.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM THE EFFECT OF ENDOMETRIOMAS ON OVARIAN Note RESERVE The presence of an endometriotic cyst promotes toxic effect on the ovarian tissue and follicles. - DNA mutations - Altered angiogenesis - Changes in gene expression profile, hormone receptivity, hormone biosynthesis - Oxidative stress

A.M. Sanchez P. Viganò E. Somigliana P. Panina-Bordignon P. Vercellini M. Candiani. The distinguishing cellular and molecular features of the endometriotic : from pathophysiology to the potential endometrioma-mediated damage to the .Human Reproduction Update, Volume 20, Issue 2, 1 March 2014, Pages 217–230

ADAMYAN L. V.

TUBAL FACTOR OF INFERTILITY IN Note ENDOMETRIOSIS

Endometriosis stage (DIE, endometriotic cysts) does not Genital endometriosis FALLOPIAN TUBES PATENCY can be damaged correlate with the never leads to by endometriosis fallopian tubes patency fallopian tubes decreasing occlusion

J Reprod Med.2013 Sep-Oct;58(9-10):417- Do women with deep infiltrating endometriosis have more tubal alterations? Objective evaluation of 473 patients. Mabrouk M,

Fertil Steril. 2009 Jul;92(1):68-74. doi: 10.1016/j.fertnstert.2008.04.056. Epub2008AugHigh prevalence of endometriosis in infertile women with normal and normospermic partners.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note ENDOMETRIAL RECEPTIVITY IN ENDOMETRIOSIS

Endometrial receptivity decreased in endometriosis

Fertil Steril. 2017 Jul;108(1):28-31. doi: 10.1016/j.fertnstert.2017.06.002.

There is decreasing of progesterone receptors expression in eutopic in women with endometriosis

Reprod Sci.2017 Oct;24(10):1469-1475. doi: 10.1177/1933719117691142. Epub 2017 Feb 8.

ADAMYAN L. V.

THE FOLLICULAR FLUID OF PATIENTS WITH ENDOMETRIOSIS Note GENERATES LIPID PEROXIDATION AND DNA DAMAGE IN OOCYTES • Investigation of mouse oocytes which were incubated in a culture medium containing follicular fluid from women suffering from endometriosis

• Preterm extrusion of the polar body was detected (sign of DNA damage in oocyte)

Mukhri Hamdan, Keith T. Jones, Ying Cheong & Simon I. R. Lane 2016

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Effect of peritoneal fluid in endometriosis on the Note oocyte

There are frequent errors in meiosis during in vitro Peritoneal fluid causes maturation of oocytes in the culture medium with disturbances in the meiosis II, peritoneal fluid (1% and 10%) obtained from women directly affecting the spindle with and without endometriosis. division

Degree of change depends on the percentage of peritoneal fluid

Bruna Talita Gazeto Melo Jianini, MSc1, Vanessa Silvestre Innocenti Giorgi, MSc1, Michele Gomes Da Broi, PhD, Cla ́udia Cristina Paro de Paz, PhD, 2014-2016Ju ́lio Ce ́sar Rosa e Silva, MD, PhD, Rui Alberto Ferriani, MD, PhD and Paula Andrea Navarro, MD, PhD 2017

ADAMYAN L. V.

Note ENDOMETRIOSIS AND ANEUPLOIDY RATES

1880 blastocysts obtained from 305 women with endometriosis were researched, the control group consisted of 3798 women from whom were received 23054 blastocysts.  The incidence of aneuploidy embryos in women with endometriosis is similar with the control group. Endometriosis doesn’t cause genetic disorders

Caroline Juneau, M.D.,a,b Emily Kraus, M.D.,c Marie Werner, M.D., H.C.L.D.,a Jason Franasiak, M.D., T.S.,a,b Scott Morin, M.D.,a,b George Patounakis, M.D., Ph.D.,d Thomas Molinaro, M.D., 2017 2017 by American Society for Reproductive Medicine.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM THE ROLE OF CUMULUS CELLS IN THE Note ASSESSMENT OF EMBRYOS IMPLANTATION POTENTIAL  Identification of embryos with the largest implantation potential is made by assessment of transcription activity in cumulus cells.  The PTGS2 gene expression is significantly lower in cumulus cells in women with external genital endometriosis that leads to a decreasing the quality of the oocyte.

Russell, D.L., Gilchrist, R.B., Brown, H.M., Thompson, J.G., 2016. Bidirectional communication between cumulus cells and the oocyte: Caroline M da Luz , Michele G da Broi , Flávia Cappello Donabela , old hands and new players? Theriogenology 86, 62–68. Cláudia Cristina Paro de Paz , Juliana Meola , Paula A Navarro, 2017

ADAMYAN L. V.

THE ROLE OF MITOCHONDRIAL DYSFUNCTION Note IN ENDOMETRIOSIS-ASSOCIATED INFERTILITY Endometriosis may be associated with mitochondrial dysfunction in cumulus cells.

There is a significant correlation between ATP levels in the cumulus cells and the number of mature oocytes, as well as pregnancy rates

In patients with endometriosis significantly reduced ATP level in the cumulus cells

Albert L. Hsu, Paige M, Townsend, Sergio Oehninger, Frank J, Castora 2015

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM ENDOMETRIOSIS IN POST-MENOPAUSAL WOMEN Note

The frequency of endometriosis in postmenopausal - 2-4%

 Combined pathology Clinical forms   Gynecological diseases Endometriotic cysts  (ovarian cysts, Infiltrative forms of hyperplasia, myoma) endometriosis   Extragenital diseases Adenomyosis  Extragenital forms (bladder, sigmoid colon, rectum, etc. ) Symptoms  Pelvic pain  Bloody discharge  Urinary incontinence  Constipation Methods of treatment   Hormonal therapy  Cute abdominal symptom Risk of malignancy  Surgery up to 1%

ADAMYAN L. V.

Note ENDOMETRIOSIS IN POSTMENOPAUSAL WOMEN There is not just a mechanism that can explain all types of postmenopausal endometriosis; nevertheless, the role of estrogen is crucial. ENDOMETRIOSIS  ACTIVATION OF ENDOMETRIOTIC REMENANTS

The development of endometriosis in Local estrogen postmenopause is induced by estrogens of production in extragonadal origin: adipose endometriotic tissue, adrenal glands, heterotopias MRT.

I. Streuli, H. Gaitzsch, J-M. Wenger & P. Petignat (2017) Endometriosis after menopause: physiopathology and management of an uncommon condition, Climacteric, 20:2, 138-143

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note MANAGEMENT OF ENDOMETRIOSIS IN POSTMENOPAUSAL WOMEN Management depends on:  Imaging techniques, such as  Histological investigation transvaginal ultrasound and pelvic  Anamnesis MRI, are not sufficiently accurate  Symptoms to distinguish between  Age endometriosis lesions and  Combined pathology cancer.  The diagnosis must therefore be made after surgery and histological confirmation.  Hormonal therapy may reactivate the subtle Recurrences endometriotic lesions. are common  Tamoxifen use seems to after surgery increase the risk of and second-line postmenopausal endometriosis. drug treatment  The main treatment modality is may be surgery, whereas aromatase inhibitor therapy has a valid place necessary in patients that are not suitable for surgery.

ADAMYAN L. V.

E S. H. R. E ENDOMETRIOSIS TREATMENT Note PATHWAY Patient presents with suspected endometriosis Non-invasive investigations Empirical treatment Laparoscopy

Diagnosis confirmed

Treatment of endometriosis- Treatment of endometriosis- associated pain associated infertility

Hormonal ART NSAIDs Surgery Surgery therapy (+ adjuvant GnRHa)

Pain can be treated without confirmation of ESHRE, European Society of Human Reproduction and Embryology; GnRHa, gonadotropin-releasing hormone diagnosis using invasive approaches agonist; MAR, medically assisted reproduction; NSAID, non-steroidal anti-inflammatory drug. Dunselman et al. Hum Reprod 2014; 29:400–412.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note RECOMMENDATIONS FOR SURGICAL TREATMENT  Asymptomatic peritoneal superficial endometriosis does not require any treatment, even if occasionally found at laparoscopy (SOGC 2010), or may be gently eliminated without trauma to pelvic structures (Russian Guidelines, 2012)

 Removal of endometriotic lesions provides pain relief (RCOG 2006; ASRM 2008; ACOG 2010; SOGC 2010, ESGE 2008/2013/2014, Russian Guidelines 2012) but is often followed by recurrence (* 28% after endometrioma, 32% after DIE, persistent symptoms after adenomyosis surgery).

 Surgical management of endometriosis-related infertility improve pregnancy rates, but the magnitude of improvement is unclear (ASRM 2008; ACOG 2010) . * Pregnancy is achieved in 35-40%

ADAMYAN L. V.

SURGICAL TREATMENT OF ENDOMETRIOTIC Note CYSTS • ADEQUATE SURGERY leads to TEMPORARY NEGATIVE IMPACT on the ovarian reserve (no more than 6 months) and depends on severity of endometriosis, surgical skills and energy used

• Large endometrioma (≥ 5 CM) significantly decreases the numberof oocytes (more than 2 times)

Extragenital endometriosis and ovarian reserve. E. S. Filippova, L. V. Adamyan, I. F. Kozachenko, A. G. Bykov, Moscow, Russia

Enucleation of capsule of endometriotic cyst, destruction (by CO2, fiber CO2 laser – the best one)

In vitro fertilization outcomes in women with surgery induced diminished ovarian reserve after endometrioma operation: Comparison with diminished ovarian reserve without ovarian surgery Su Been Hong, Na Ra Lee, Seul Ki Kim, Hoon Kim, Byung Chul Jee, Chang Suk Suh, Seok Hyun Kim, Young Min Choi 2017

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM SURGICAL PREPARATION FOR IVF IN ENDOMETRIOSIS Note It is shown that the combined (surgery + ART) treatment of endometriosis provides a higher pregnancy rate compared with surgery alone (56,1% vs 37,4%). Campo S, et al Reproductive BioMedicine Online, 2012, Streuli I, de Ziegler D. Hum Repr, 2012, Adamyan L, COGI 2013 The feasibility of removal of endometrial cysts before IVF is debated . It is shown that after surgical removal of cysts frequency of ovulation is decreased Benaglia L., et al Hum Reprod 2012, Adamyan L., Probl Repr 2013,2014 ESHRE recommendations Do surgery for endometrioma •risk of ovarian apoplexy when stimulated •difficulties in the oocyte obtaining •the risk of forming ovarian abscess •contamination of the cyst contents •histological verification Somigliana E., et al Fert & Steril, 2011

ADAMYAN L. V.

Note INFERTILITY IN ENDOMETRIOSIS MAY IMPROVE WITH SURGICAL OR TECHNOLOGICAL INRVENTIONTE Surgery N.B. Hormonal treatment for pain should not be withheld from • Operative laparoscopy symptomatic women in the waiting (rather than mere diagnostic period before surgery or MAR laparoscopy) • Excision of endometrioma capsule during surgery for infertility/pain Medically assisted reproduction • Intrauterine insemination with controlled ovarian stimulation

• Assisted reproduction GnRH, gonadotropin-releasing hormone agonist; IUI, intrauterine insemination; technology MAR, medically assisted reproduction. Dunselman et al. Hum Reprod 2014; 3–6 months of prior adjuvant 29:400–412. GnRHa improves pregnancy rates

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note CLASSIFICATION OF DEEP INFILTRATIVE ENDOMETRIOSIS Deep infiltrative (retrocervical)

Stage I – endometriotic lesions are within recto-vaginal septum

Stage II – invasion into , vaginal wall and rectosigmoid bowel serosa

Stage III – expansion to uterosacral ligaments, rectal serosa and muscle

Stage IV – Adamyan L.V., 1993 involvement of rectal mucosa Development of endometriosis from less to more severe forms is not arule!

ADAMYAN L. V.

Note SURGICAL TREATMENT OF DEEP INFILTRATIVE ENDOMETRIOSIS

There is no strong evidence of whether radical bowel resection for endometriosis is more effective than less aggressive techniques.

The results seem to vary individually depending on:

• The surgeon’s skills • Depth of infiltration • Location and volume • Bowel symptoms of the lesion • Recurrency • Stenosis extent • Quality of life

Adamyan L.V., Zayratyants O.V., Maksimova Yu.V., Murdalova Z.H. New pathogenetic aspects common infiltrative endometriosis: Theory and Practice. Problemyi reproduktsii. 2010; 4: 31-6.

Chernukha G.E., Ilyina L.M., Adamyan L.V., Pavlovich S.V. Deep infiltrating endometriosis: Postoperative recurrences and possible ways of their prevention. Obstetrics and Gynecology, 2015, №8

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM ENDOMETRIOSIS SURGERY IN NATIONAL MEDICAL RESEARCH CENTER Note SURGERY (1991-2017 ГГ.) > 8340 OPERATIONS Laparoscopy 4230 op – endometriotic cyst Hysteroscopy 58341 242 – endometriotic cyst rupture Vaginal approach in adolescents 6-7% malformations 2640 op – external genital endometriosis & adenomyosis Scientific Center +University  75% of patients with Hospitals #15 & #50 privies surgery Adolescent department  35-40% of patients with combined forms (external+adenomyosis 92 nodule +cyst) adenomyosis  1-2% of patients with genital malformations 1370 OP – RETROCERVICAL ENDOMETRIOSIS

Adamyan L.V. et al. 2017 II st - 750 III st - 370 IV st - 250

ADAMYAN L. V.

Note RECURRENCE OF ENDOMETRIOSIS The frequency of endometriosis recurrence after surgical treatment :

After 1-2 years – 15-21% After 5 years – 36-47% After 5-7 years – 50-55%

The highest recurrence frequency – in widespread endometriosis or in cases of the inability to remove infiltrative foci with the preservation of reproductive system organs

Endometriotic cysts recurrence within 2- 5 years after surgery - from 12 to 30%.

Endometriosis. Diagnostics. Treatment and rehabilitation. Clinical recommendations. Adamyan L.V. 2013

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note ADENOMYOSIS AND STAGING-BASED STRATEGIES

Adenomyosis Adenomyosis may be diffuse or focal (nodular or cystic) Crucial Stage I – endometriotic lesions are within difference from myoma is absence submucouse layer of distinct

Stage II – endometriotic lesions penetrate into

Stage III – involvement of entire myometrium up to serosa

Stage IV – We have our own patents on involvement of pelvic determining indications and volume peritoneum and of surgery for adenomyosis, which adjacent organs

are used in clinical practice Adamyan L., 1993

ADAMYAN L. V.

Note

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note ADENOMYOSIS IMPACT ON FERTILITY

Sebastiano Campo, Vincenzo Campo, Giuseppe Benagiano 2012

• Genes dysregulation

• Decreased endometrial receptivity

• Impaired implantation

• Disturbed decidualization

• Abnormal concentrations of intrauterine free radicals • Altered uterine peristaltic activity

ADAMYAN L. V.

Note ADENOMYOSIS AND IVF-OUTCOMES

Adenomyosis has detrimental effect on IVF outcome:

• Reduces clinical pregnancy and live birth rates • Doubles the miscarriage rate

Long-term suppression of adenomyosis with GnRH agonists or surgery might improve IVF/ICSI outcome

Younes G, T Tlandi, Fertil Steril 2017; 108: 483-90, Vercellini et al Hum Reprod 2014

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note MODERN VISUALIZATION TECHNIQUES OF ADENOMYOSIS

Ultrasound Hysteroscopy 2D,3D,4D

MRI

ADAMYAN L. V.

Note ADENOMYOSIS TREATMENT STRATEGY

The effectiveness of conservative uterine-sparing surgery for adenomyosis and/or adenomyoma is promising

Our data support the opinion of the beneficial role of the combination of uterine-sparing surgery and GnRH agonist treatment in managing infertile women with adenomyosis Laparoscopic uterine-sparing surgery can be an alternative treatment to Because of the limited amount of data the use of hypoestrogenic agents or available, the use of uterine-sparing hysterectomy in women with localized surgery in the management of uterine adenomyosis adenomyosis and/or adenomyoma is still controversial.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM SPECIFIC SURGICAL TECHNIQUES Note OF ADENOMYOSIS TREATMENT

. Laparoscopic myometrial . Endometrial ablation/resection electrocoagulation It is useful when disease is limited to It is suitable for women over years who are not endomyometrial junction and also in cases keen on pregnancy and who do not want where it is present in outer myometrium, as extensive surgeries. laparoscopic myometrial excision alone may not cure menstrual symptoms. . Uterine artery embolization (UAE) . Fundectomy Reduction of uterine blood flow by UAE has Surgery is usually incomplete for massive been shown decrease symptoms associated diffuse adenomyosis with adenomyosis and improves quality of life . Myometrial excision . Triple flap method This is a suitable fertility preserving surgery in It is a major operation with marked infertile women improvement of symptoms with 54 % . Zenomectomy pregnancy rate and no risk of uterine rupture Complete excision of adenomyotic lesion as much as possible with sufficient uterine wall . MRI guided focused ultrasound surgery conversation (MRIgUS) –

ADAMYAN L. V.

OUR EXPERIENCE Note Laparoscopic excision of adenomyotic lesion with subsequent hormonal therapy 3. Sharp and with GnRH agonists was performed in all delicate dissection patients from the healthy 4. Closure and myometrial tissue reconstruction of The technique using the bipolar the uterine wall includes the coagulator, scissor using absorbable following : suture layer by 2. Incision of and with preservation layer the uterine of maximal residual wall along the serosa or serosa- 1. Careful lesion muscular layer recognition of the adenomyotic foci and their borders by laparoscopy • Barbed sutures – 1/2 • Antiadhesive materials • Hemostatic sponge/Surgicel

Mean operating time 107.1±47.5 min Mean blood loss 157.1±69.5 ml

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note OUR EXPERIENCE

92 patients with nodule adenomyosis were enrolled in the study between 2011 and 2014

Complaints of patients with nodule adenomyosis

74 patients had infertility • – • – • –

Mean age was of 33,5 ± 2,6 years Dyspareunia 8 Pain in the 55

22.5 % of patients had Painful 65 previous surgery for Spotting 44 endometriosis Heavy menstruation 63

0 10 20 30 40 50 60 70

ADAMYAN L. V.

UTERUS-SPARING OPERATIVE TREATMENT FOR Note ADENOMYOSIS 1. Complete excision of adenomyosis - Adenomyomectomy - Cystectomy 2.Cytoreductive surgery/ partial adenomyomectomy 3.Nonexcisional techniques- Coagulation, Endometrial ablation, Progestins

Uterine-sparing surgery for adenomyosis controls dysmenorrhea and menorrhagia in more than 81% with pregnancy rates about 50 %

Fertil Steril. 2014 Feb;101(2):472-87. doi: 10.1016/j.fertnstert.2013.10.025. Epub 2013 Nov 26. Uterus-sparing operative treatment for adenomyosis Grimbizis GF, Mikos T, Tarlatzis B.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note TWO TYPES OF SURGERY FOR ADENOMYOSIS Type I complete and total eradication of adenomyosis:

1.careful and thorough recognition of the adenomyotic foci and their borders by inspection and/or palpation (possible only in exploratory laparotomy); bipolar coagulator system is 2. longitudinal incision of the uterine wall along the lesion; preferred or scissor, or knife, and 3.sharp and delicate dissection of the adenomyoma from the preservation of maximal residual surrounding relatively healthy myometrium using diathermy serosa or serosa-muscular layer 4.closure and reconstruction of the uterine cavity using 4-0 absorbable suture if the uterine cavity was opened; • Barbed sutures 5. closure of the uterine wall with 1-0 absorbable sutures layer by layer; • Antiadhesive materials 6. closure of the serosa layers with 4-0 or 5-0 absorbable sutures • Hemostatic sponge/Surgicel Laparoscopic adenomyomectomy has been successfully performed with excellent outcomes Laparoscopy is feasible either for ablation of the adenomyotic foci or for excision of adenomyomas

Grimbiziset al Uterus-sparing operative treatment for adenomyosis. FertilSteril 2014;101:472 Laparoscopic resection of cysticadenomyosisina teenager with arcurate uterus. Elizabeth Ball et al GynecolSurg(2009)

ADAMYAN L. V.

TYPE II - CYTOREDUCTIVE SURGERY OF Note ADENOMYOSIS The main components of the three interconnecting “H” incision are:

1.vertical incision with a 5-mm resection of the uterine serosae-myometrium layer and two transverse incisions perpendicular to the vertical incision along the upper and lower edges of the uterus 2.removal of slices of adenomyotic tissue by serial resection; 3.performing repeated chromopertubation tests by injecting indigo carmine solution during the operation to minimize the risk of entering the uterine cavity; 4.avoiding tension to the sutured tissue closing the defect to minimize the risk of hematoma; 5.preferred use of antiadhesive material

Hisao Osada et al Surgical procedure to conserve the uterus for future pregnancy in patients suffering from massive adenomyosis Reproductive BioMedicine Online (2011) Nishida et al Conservative surgery for adenomyosis. Fertil Steril 2010. ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM DIFFERENT MODIFICATIONS OF TYPE II Note SURGERY

Nishida et al Conservative surgery for adenomyosis. Fertil Steril2010.

A. Saremi t al Treatment of adenomyomectomy in women with severe uterine adenomyosis using a novel technique Reproductive BioMedicine Online (2014)

• The laparoscopic approach might be possible, although laparotomy is much more feasible because surgeon can palpate and recognize the adenomyotic lesions intraoperatively. • There is no doubt that type II technique might be more complicated because the disease is invaded the myometrium, and suturing the remaining uterine wedges after resection is difficult. • Use of intracorporeal absorbable barbed sutures is preferable.

ADAMYAN L. V.

Note THERAPEUTIC EFFECTS OF SURGERY • The effectiveness of conservative uterine-sparing surgery for adenomyosis and/or adenomyoma is promising • The main problem is dysmenorrhea, which can be improved significantly, in up to 80% of cases • Menorrhagia is also improved in more than two-thirds of patients after type I uterine- sparing surgery, and nearly half of the patients have improvement in their symptoms after type II uterine-sparing surgery. • The pregnancy rate is ranging from 21 to 61 %.

Because of the limited amount of data available, the use of uterine-sparing surgery in the management of adenomyosis and/or adenomyoma is still controversial.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note OPERATIVE HYSTEROSCOPY AND HYSTERORESECTOSCOPY IN THE TREATMENT OF ADENOMYOSIS Classification of cystic adenomyosis based on hysteroscopic findings (MUSCLE)

Nowadays we have compact hysteroscopes with ergonomic design which provides excellent image quality

Excision of cystic adenomyosis under US-control could be performed

Uterine Cystic Adenomyosis: A Disease of Younger Women IvoBrosens,StephanGordtset al PediatrAdolescGynecol,2014

ADAMYAN L. V.

Note ALTERNATIVE METHODS OF ADENOMYOSIS TREATMENT MRI-FUS ablation in the treatment of adenomyosis

Fabiana F. et al Effectiveness of Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) in the uterine adenomyosis treatment: technical approach and MRI evaluation Radiol med 2015

Ultrasound-guided high intensity focused ultrasound

Ultrasound-guided high intensity focused ultrasound for the treatment of gynaecological diseases: Areview of safety and efficacy Lian Zhang et al, International Journal of Hyperthermia 2015

Retrospective analysis of ultrasound-guided high intensity focused ultrasound (USgHIFU) for the treatment of adenomyosis: 2549 patients sufficient relieve of symptons

Decrease of uterine volume on 13%

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM MEDICATIONS IN ENDOMETRIOSIS TREATMENT: TODAY Note AND TOMORROW

CASTRATION PROGESTINS DHEA, IUDs GnRH- antagonists NORETHISTERONE ACETATE Antiandrogens, Tamoxifen

1960 1970- 1980- 1960 2000 2010- 1970 1980 1990 2018

• Dienogest 2

GnRHa, anti-gestagens, mg mifepristone, aromatase inhibitors • Ulipristale acetate???

COCP, GONADOTROPINS.

ADAMYAN L. V.

USE OF HORMONAL MEDICATIONS IN YOUNG Note WOMEN MAY CONTRIBUTE TO DELAYED DIAGNOSIS  Agents proposed for empiric therapy of endometriosis: • Hormonal contraceptives, progestogens,GnRHa and Dienogest  Review of 608 studies, 18 included in a meta- DO NOT WASTE TIME! analysis NO TREATMENT • Empiric treatment of pain with hormonal WITHOUT contraceptives may contribute to delayed diagnosis of thedisease CONFIRMATION OF DIAGNOSIS ! • Temporary pain suppression using hormonal contraceptives may leadto postponement of surgicalassessment • Trend towards increasing risk ofendometriosis after treatment discontinuation DIE, deep infiltrating endometriosis; GnRH, gonadotropin-releasing hormone agonist. Dunselman eta Hum Reprod 2014; 29:400–412; 2. Chapron C, et al. Hum Reprod. 2011;26:2028–2035; 3. Vercellini P et al. Hum Reprod Update 2011; 17:159–170.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM GnRHa AND PROGESTAGENS (DIENOGEST 2 MG) HAVE STRONG Note EVIDENCE OF EFFICACY

Limited data on the efficacy of Conversely, GnRHa and hormonal contraceptives in progestagens have a high level of endometriosis-associated pain evidence (Level A)

GnRH, gonadotropin-releasing hormone agonist; NSAID, non-steroidal anti-inflammatorydrug. Dunselman et al. Hum Reprod 2014;29:400–412.

ADAMYAN L. V.

Note GnRHa ARE USEFUL IN THE TREATMENT OF ENDOMETRIOSIS-ASSOCIATED PAIN AND INFERTILITY ART, assisted reproduction technology; GnRHa, 2005 and 2014 guidelines broadly similar gonatotrophin-releasing hormone agonist. Dunselman et al. Hum Reprod 2014;29:400–412.

• Main difference is the structured methodology adopted • “… a substantial part of the recommendations is … similar …”

• Clinicians are recommended to prescribe a GnRHa to reduce endometriosis-associated pain • triptorelin, nafarelin, leuprolide, buserelin, goserelin • Hormonal add-back therapy is recommended to prevent bone loss and hypoestrogenic symptoms during GnRHa therapy • Careful consideration is needed before giving GnRHa to young women and adolescents

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note LONG-TERM MANAGEMENT OF ENDOMETRIOSIS Long-term prevention of endometriosis recurrence after surgical treatment (more than 6 months after surgery) includes aGnRH + add-back therapy during 3-6 months and progestins use during 6 months or more

HTaGnR H +add- • 6 month back and • 3-6 month more surgery HTProgesti ns

ADAMYAN L. V.

ELAGOLIX– AN ORAL GNRH ANTAGONIST IN TREATMENT Note OF ENDOMETRIOSIS-ASSOSIATED PAIN AND BLEEDING Сauses a rapid dose-dependent suppression of pituitary gonadotropins reaching its peak effects 4-6 hours after oral administration

Reductions in mean menstrual blood loss were numerically greater in women treated with elagolix compared to placebo in case of endometriosis- associated uterine bleeding US FDA approves Elagolix first ever drug with an indication for management of moderate to severe pain associated with Endometriosis approved on 23 th July 2018

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note microRNA LET 7B AS A PERSPECTIVE TREATMENT FOR ENDOMETRIOSIS ‐ MicroRNA Let 7b has a pleiotropic role in endometriosis pathophysiology affecting estrogen signaling,‐ inflammation and growth factor receptors.

Let 7b treatment resulted in reduced endometriosis lesion size in murine model. Decreased‐ gene expression was noted in several genes known to promote endometriosis growth including ER α, ER ß, Cyp19a, KRAS 4A, KRAS 4B and IL 6. ‐ ‐ Local treatment of endometriosis‐ with Let 7b is a promising therapy for endometriosis that simultaneously affects multiple pathways‐ driving endometriosis without systemic hormonal side effects. Cagdas Sahin et al. microRNA Let‐7b: A Novel treatment for endometriosis. 2018 DOI: 10.1111/jcmm.13807

ADAMYAN L. V.

Note ANTICANCER DRUGS IN TREATMENT OF ENDOMETRIOSIS Ectopic endometrial tissue may use the Hypothesis – high levels of lactate in excess lactate produced by peritoneal the pelvis supports the growth of mesothelial cells as an energy source endometrial lesions outside of the enhancing both their establishment and uterus. growth as endometriosis lesions.

Kelly M Kennedy et al. Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol. 2010 January ; 6(1): 127. doi:10.2217/fon.09.145.

Treatment of human peritoneal mesothelial cells with dichloroacetate and galloflavin both reduced mRNA expression of key glycolytic markers and lactate secretion. Repurposing of anticancer drugs

Andrew Horne et al. Targeting lactate metabolism can (dichloroacetate, galloflavin) that target be a novel therapeutic for the treatment of endometriosis. 2016 DOI: 10.1530/repabs.3.P027 lactate metabolism may offer potential as therapeutics for endometriosis.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note PERSPECTIVE TARGET FOR NOVEL TREATMENT OF ENDOMETRIOSIS Researchers from the Yale School of Medicine have found that the chemokine G- protein-coupled receptor CXCR7, rarely detected in normal endometrium, is expressed in large quantities on cell membranes in endometriotic lesions in both mice and humans.

Enhances local proliferative and anti- apoptotic cellular pathways CXCR7 role in endometriosis: Promotes bone marrow- derived stem cell trafficking into endometriosis favoring Nicola Pluchino et al. G-Protein-Coupled Receptor CXCR7 Is Overexpressed in Human and Murine Endometriosis. 2018. DOI: 10.1177/1933719118766256 the development of ectopic lesions ADAMYAN L. V.

PROGNOSIS OF…. Note According to histology, tumors originating from • PROGNOSIS OF MALIGNANCY genital endometriosis correspond to: -Clear cell carcinomas (14.8%) • PROGNOSIS OF PREGNANCY RATE - endometrioid carcinomas (66.7%) IN WOMEN WITH ENDOMETRIOSIS BY FERTILITY INDEX • PROGNOSIS OF RECCURENCE

PR-α ki-67 COX-2 RECURRENCE RECURRENCE

NO NO RECURRENCE RECURRENCE

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note RISK FACTORS OF MALIGNANT TRANSFORMATION OF ENDOMETRIOSIS

High risk of malignancy Low risk of malignancy

• Not regressing foci of endometriosisin postmenopausal women, average AGE 51 YEARS • Recurrent endometriosis with a history Patients younger than 49 YEARS of more than 15 years -with the level of CA125 is less than • Prolonged exposure to the pure 43 U/ml, estrogen in postmenopausal women (MRT) -with cysts without a solid component and smaller than 11 cm • Repeated surgery for endometriosis Yfat Kadan a,*, Stephen Fiascone a, Carolyn McCourt a, Chris Raker b, C.O. Granai a, • Family history of ovarian Margaret Steinhoff c, Richard G. endometriosis, obesity Moore 2015 • Expressed clinical symptoms of hormonal dysfunction.

ADAMYAN L. V.

ONCOLOGICAL ASPECTS OF Note ENDOMETRIOSIS There is still controversy around the possibility that endometriosis-associated neoplasms may represent distinct histologic entities.

Pregnancy Infertility

Hyster- Early ectomy menarche Decreased Increased risks risks Tubal Late ligation menopause Despite being initially considered a benign disease, the wide opinion nowadays is that Oral endometriosis and especially ovarian Short intervals endometriomas are neoplastic conditions Natsuki Koike et al. Pathogenesis and malignant transformation of adenomyosis contra- with the potential to become malignant between December 2012 DOI: 10.3892/or.2012.2184, Front Surg. 2014; 1: 14. doi: 10.3389/fsurg.2014.00014, ceptives (Chene et al., 2015) Endometriosis and Ovarian Cancer Risk: A Systematic Review of Epidemiological Studies, Menelaos Zafrakas et al.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM MALİGNANT TRANSFORMATİON OF Note ENDOMETRİOSİS

Malignant transformation of endometriosis occurs generally in 1-3.6% of cases

Ovarian cancer develops in 1–5% of cases with ovarian endometriosis and in a lower percentage of cases with extra-ovarian endometriosis.

Endometriosis is present in 10 to 15% of patients with ovarian cancer.

ENDOMETRIOSIS AND CARCINOGENESIS OF THE OVARY Yu.G. Payanidi1, K.I. Zhordania1, V.I. Loginov2, N.E. Levchenko1, G.Yu.Chemeris1, N.G. Sivakova11 Federal State Budgetary Institution «N.N. Blokhin Russian Cancer Research Center» of the Ministry of Healthcare of the Russian Federation, Moscow 2 Federal State Budgetary Scientific Institution Research Institute of General Pathology and Pathophisiology, Moscow Birrer M. J. The origin of ovarian cancer — is it getting clearer? // N Eng J Med. 2010; 363 (16): 1574–1575.

ADAMYAN L. V.

THE RELATIONSHIP BETWEEN ENDOMETRIOSIS Note AND OVARIAN CANCER • •

Endometriosis-associated ovarian cancer

L Saraswat et al Impact of endometriosis on risk of further gynaecological surgery and cancer: a national cohort study. BJOG 2017

Matias-Guiu X, Stewart CJR, Endometriosis-associated ovarian neoplasia, Pathology (2017).

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note PREDICTION OF CANCER IN ENDOMETRIOSIS

miR-325 expression increased in endometriosis ovarian cance prognostic marker of transition

–

ADAMYAN L. V.

Note ENDOMETRIOSIS IS A RISK FACTOR OF BREAST CANCER

 Endometriosis is a risk factor for endometrial cancer, breast cancer, colon cancer.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note EPITHELIAL ANOMALIES IN ENDOMETRIOTIC OVARIAN CYSTS Histological examination of the clear cell and endometriotic ovarian tumors in 54% and 42% cases have signs of atypical endometriosis In 35% of cases of ovarian endometriosis, histological examination reveals atypical endometriosis 4,1% CARCINOMA

5,9% ATYPİA

Shuang Ye, MD, Jiaxin Yang, MD, Yan You, MD, Dongyan Cao, MD, Huifang Huang, MD 2017 9,4% HYPERPLASİA 12,1% METAPLASİA

ADAMYAN L. V.

Note MUTATIONS IN ENDOMETRIOSIS WITHOUT CANCER • Lesions of deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. • Ten of 39 deep infiltrating lesions (26%) carried driver mutations • ALL the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.

The same KRAS mutation in three spatially distinct lesions, raising the possibility that some sites of benign deep infiltrating endometriosis arise through the neoplastic process of metastasis.

N Engl J Med 2017;376:1835-48. DOI: 10.1056/NEJMoa1614814

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM ENDOMETRIOSIS MANAGEMENT IN Note RUSSIA Necessary Check-up is carried out at the age of 3, 7 years, 11-12 years and 14 years, after 14 years annually (According to the order of the Ministry of health of Russian Federation 12.11.2012 № 572 n, item VIII)

KEEP IN MIND ENDOMETRIOSIS!  US is a principal approach in women check-up

ADAMYAN L. V.

Note ALGORITHMS OF ENDOMETRIOSIS TREATMENT

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note ENDOMETRIOSIS AND COMBINED PATHOLOGY

endometral hyperplasia 6% polyps COMBINED PATHOLOGY – IN 57% 12% synechia ovarian cyst EXTERNAL GENITAL ENDOMETRIOSIS – 56% 17% hydro-/ 18% myoma tubal infertilty 24% adhesions FALLOPIAN TUBES 4% 27% genital endometriosis 27% 37% ENDOMETRIOSIS OF ADENOMYOSIS 56% PERITONEUM 12 % 56%

0% 20% 40% 60%

• ENDOMETRIOSIS WITH INFILTRATIVE GROWTH- 23% ENDOMETRIOSIS OF UTERO-SACRAL ENDOMETRIOTIC • RECURRENCE OF ENDOMETRIOSIS AFTER LIGAMENTS CYSTS 6 % SURGERY- 7 % 38%

ADAMYAN L. V.

ENDOMETRIOSIS AND GENITAL MALFORMATIONS Note WHAT ABOUT PATHOGENESIS? HOW EXPLAIN THE ENDOMETRIOSIS IN:

• 46% OF UTEROVAGINALANOMALIES? • FEMALE FOETUSES ON AUTOPSY? • UTEROVAGINALAPLASIA? • IN BROAD LIGAMENTS AND OVARIAN LIGAMENTS? • MALE ENDOMETRIOSIS? • IN PATIENTS WITH DISORDERS OF SEX DEVELOPMENT?

KNAPP V (1999) HAS POSTULATED THAT ENDOMETRIOSIS IS CAUSED BY SMALL DEFECTS OF EMBRYOGENESIS.

SOURIAL S, TEMPEST N, HAPANGAMA DK. THEORIES ON THE PATHOGENESIS OF ENDOMETRIOSIS. INT J REPROD MED. 2014; 2014: 179515.

SIGNORILE PG, BALDI A. ENDOMETRIOSIS: NEW CONCEPTS IN THE PATHOGENESIS. INT J BIOCHEM CELL BIOL 2010 TRONCON JK, ZANI AC1, VIEIRA AD, POLI-NETO OB, NOGUEIRA AA, ROSA-E-SILVA JC. ENDOMETRIOSIS IN A PATIENT WITH MAYER- ROKITANSKY-KÜSTER-HAUSER SYNDROME. CASE REP OBSTET GYNECOL. 2014.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM MAYER-ROKITANSKY-KÜSTER-HAUSER SYNDROME ??? Note

FUNCTIONAL RUDIMENTARY HORN

ENDOMETRIOID CYST NONFUNCTIONAL RUDIMENTARY HORN (WITHOUT CAVITY) with ADENOMYOSIS Author and Age Symptom Endometriotic site Operation published year Right ovarian and right Laparotomy and resection of Acien, 1988 26 Pain in the right iliac quadrant rudimentary horn with bilateral appendix and endometrium rudimentary horn Adenomyosis arising from Enatsu, 2000 27 Lower left abdominal pain Laparoscopic tumor resection the left rudimentary horn hysterectomy and bilateral Yan, 2002 52 Lower abdominal pain Adenomyosis. salpingo-oophorectomy Laparoscopy cyst capsule was Sönmezer, 2003 26 Lower abdominal pain Right ovarian cystic lesion extirpated Ovarian fossa, ovaries, and Increasing lower abdominal Laparoscopy bilateral salpingo- Parkar, 2009 40 utero sacral ligaments pain oophorectomy bilaterally Cho, 2009 26 Pain in the left iliac quadrant Left ovary Laparoscopic inspection

Mok-Lin, 2010 20 Increasing pelvic pain Posterior cul-de-sac Laparoscopy Lei Yan, 2011 23 No pelvic pain The right ovary Sigmoid transplantation

• EXTERNAL GENITAL ENDOMETRIOSIS IN 33% OF CASES • PERITONEAL ENDOMETRIOSIS OCCURS IN 20% OF PATIENTS WITH NONFUNCTIONAL RUDIMENTARY HORNS (WITHOUT CAVITY)

ADAMYAN L. V.

PATHWAYS OF INVESTIGATIONS IN ENDOMETRIOSIS: TODAY Note AND TOMORROW

IMMUNOLOGICAL ASPECTS HOXA11 mRNA 142 3p HOXA10

Stem cell

K-ras IGF2 TNFα

FGFR WNT4

B-CATHENIN miRNA Mass-spectrometry

VEGF E- SIGNALING PATHWAYS CADHERIN

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM ROLE OF STEM CELLS IN THE PATHOGENESIS Note OF ENDOMETRIOSIS

IMPORTANCE OF STEM CELLS investigating in common with the theory of retrograde menstruation J.A.Sampson, and independently (intravascular metastasis of cells).

Characteristics of Multipotent Mesenchymal Stromal Cells Isolated from the Endometrium and Endometriosis Lesions of Women with Malformations of the Internal Reproductive Organs.Savilova AM, et al. Bull Exp Biol Med. 2017.Savilova AM, Farkhat KN, Yushina MN, Rudimova YV, Makiyan ZN, Adamyan LV.

HOW ENDOMETRIOID HETEROTOPIES ARE ARISING IN PATIENTS WITH UTERINE APLASIA.

Caroline E. Gargett et al.Endometrial stem/progenitor cells: the first 10 years.Hum Reprod Update. 2016 Mar; 22(2): 137–163. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2014 2014 Jul7;292(1):81-5. ? •Factors affecting the differentiation of stem cells In the endometrial samples of patients who underwent • Genetic mutations bone-marrow transplantation endometrial cells with an •Disorders of epigenetic regulation HLA-type of bone marrow donor were detected. It • indicates their migration and differentiation after bone of gene expression marrow transplantation. • Tissues damage • Growth Factors

ADAMYAN L. V.

NEW APPROACHES IN DIAGNOSTICS. OWN Note DATA Mass spectrometry - technique that ionizes chemical species and sorts the ions based on their mass-to-charge ratio.

MASS-SPECTROMETRICANALYSIS of tissues in endometriosis is a promising method in the diagnosis of this disease.

0,3 Pelvic

0,25 Ovarian 0,2 Endometrium 0,15 0,1 0,05 0 52:3 52:3 42:1 20:0 41:2 44:9 36:3 49:4 40:9 34:1 32:1 38:7 38:6 40:8 40:7 40:6 - - - O O O PC TG TG PC PC PC PC PC PC TG SM DG PE PC PC Increasing of the Sphinhomilines and phosphatidylcholines levels in the ectopic endometrium is an important factor explaining the pathogenesis of the disease. Borisova A.V.,Kozachenko A.V., Adamyan L.V., Frankevich. 2016.

ADAMYAN L. V.

ESGYNECOLOGY.ORG

st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM Note SIGNALING PATHWAYS - NEW DATA  CASCADES OF PROTEIN-PROTEIN INTERACTIONS WHICH MAKE THE TRANSMISSION OF SIGNAL FROM THE CELLULAR RECEPTOR TO THE NUCLEI

Regulation of these signaling pathways is changed in endometriosis:

We revealed high correlation of signaling pathways activation in eutopic and ectopic endometrium (with a total initial normalization on the samples ofhealthy endometrium from women without endometriosis) We can conclude that the eutopic endometrium can potentially serve as a marker for the presence of ectopic foci. Kaponis A. The role of NF-kappaB in endometriosis.Front Biosci (Schol Ed). 2012 Jun 1;4:1213-34. Brett D. McKinnon et al. Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics. Human Reproduction Update, Volume 22, Issue 3, 1 April 2016, Pages 382–403 Iveta Yotova et al. Epigenetic Alterations Affecting Transcription Factors and Signaling Pathways in Stromal Cells of Endometriosis. PLoS One. 2017; 12(1): e0170859. ADAMYAN L. V.

mi-RNA EXPRESSION ANALYSIS OF CANDIDATE GENES IN THE EUTOPIC Note ENDOMETRIUM FROM WOMEN WITH ENDOMETRIOSIS - OWN DATA mRNA 74 women with 47 women without Р-value AUC expressio endometriosis endometriosis n FOS 1,97±3,22 0,6±1,14 0,0058 0,691 EGR-1 0,32±0,47 0,14±0,21 0,019 0,604 FOSB 0,337±1,045 0,031±0,076 0,0476 0,596 DUSP-1 0,30±0,56 0,12±0,12 0,037 0,550 ZNF36 0,60±1,1 0,21±0,2 0,0027 0,598 In patients with endometriosis high POSTN 0,22±0,19 0,29±0,21 0,085 0,598 expression level of genes FOS, SCGB 3,72±6,49 3,75±7,86 0,985 - EGR-1, FOSB, DUSP1, ZFP36, JUNB, JUN was revealed.In patients PAEP 1,15±3,8 0,775±1,75 0,53 - with endometriosis, low expression level of genes POSTN, FOXD4L3, JPX was revealed.

 Expression level of mRNA FOS, EGR-1, FOSB, DUSP-1, ZNF36, POSTN, SCGB, and PAEP in the eutopic endometrium from women with endometriosis seems to be promising biomarkers for real-time PCR-based diagnostic systems creation. Adamyan ADAMYAN L. V. L.V. et al. 2017

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SCIENTIFIC PROGRAM THE EXPRESSION OF MARKERS ER, PR, KI-67, P-16,PTEN IN Note ECTOPIC ENDOMETRIUM- OWN DATA Adamyan L.V. et al.2015

No differences in expression of Ki-67 and p-16 between focal and diffuse adenomyosis, endometrial tissue and surrounding myometrium The level of PTEN expression is significantly higher in the nodule of adenomyosis than in the myometrium with diffuse adenomyosis

Higher expression of hormone receptors is noted in nodular form of adenomyosis

ADAMYAN L. V.

Note ENDOMETRIOSIS BIOMARKERS: TODAY AND TOMORROW According to the World Endometriosis Research Foundation, the search for biomarkers for minimally invasive and non-invasive diagnostics of endometriosis is one of the top research priorities

There are a lot of potential in Urine biomarkers of endometriosis in in Blood Level of СА 125 FROM 35 different biological samples in Endometrium UP TO 100 UNIT / ML IS according to different researchers in Cervical mucus IMPORTANT IN from all over the world DYNAMICS In Saliva

Значение анализа онкомаркеров са 125, cea и са 19-9 в диагностике Опухолей у гинекологических больных // акушерство и гинекология. - У: медицина. - 1990. - N 12. - С. 57-58. Адамян Л. В. , Алексеева , Новиков Е. А. A. Fassbender, O. Dorien, B. de Moor et al. Biomarkers of endometriosis in Endometriosis: Pathogenesis and Treatment, T. E. Harada, Ed., pp. 321–339, Springer, Berlin, Germany, 2014.

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SCIENTIFIC PROGRAM GENETIC ASPECTS IN THE ENDOMETRIOSIS PATHOGENESIS: TODAY AND TOMORROW Note GENETIC DISTRBANCES IN THE PATHOGENESIS OF ENDOMETRIOSIS HAVE A COMMON CHARACTER INANY LOCALIZATION OF THE PROCESS

Genetic aspects of gynecological diseases. Adamyan L.V., Spicin V.A, Andreeva E.N, 2008

FAMILY FORMS! HYPERMETHYLATION

PGR-В, HOXA10,11 (70%) E-cadherin, IGFBP1, HDAC

HYPOMETHYLATION:

COX-2, ESR, CYP1B1, SF-1, WNT, DVL1, CDKN2B, CDKN2A, GALT ,CDC42, FN1, VEGF, TNFα, GM-CSF, PDGF, EGF, b-cathenin, K-ras, TGFβ,FGFR.

BUT THE EXPRESSION OF MOST OF THEM IS DISRUPTED IN OTHER GYNECOLOGICAL DISORDERS: ESR, WNT4, IGF2, VEGF, TNFΑ, GM-CSF, PDGF, EGF, B-CATHENIN, K-RAS, TGFΒ,FGFR V. S. Baranov, T. E. Ivaschenko, ADAMYAN L. V. T.Liehr,2015

Note FUTURE DIRECTIONS Disease Management in monitoring Awareness adolescents raising

Optimal Anti- management agents of pain in surgery and infertility

Diagnosis Psychosocial aspects

Primary Biomarkers Prerequisites prevention for centres of excellence MANY RESEARCH QUESTIONS REMAIN, RELATING TO MULTIPLE ASPECTS OF ENDOMETRIOSIS MANAGEMENT

ADAMYAN L. V.

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SCIENTIFIC PROGRAM Note

21-24 January 2019. FSBI "Research Center for Obstetrics, Gynecology and Perinatology" Ministry of Healthcare of the Russian Federation

XIII International Congress on Reproductive Medicine

Thank you!

Note

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st Course LAPAROSCOPIC GYNECOLOGICAL SURGERY PARIS, 13 14 DECEMBER 2018

SCIENTIFIC PROGRAM