Sponsored by

AAGLAdvancing Minimally Invasive Gynecology Worldwide

Clinical Management of Endometriosis –

From Mild to Severe (Didactic)

PROGRAM CHAIR

Emilio O. Fernandez, MD

PROGRAM CO-CHAIR

Carlos Fernandez Ossadey, MD

Marc R. Laufer, MDRadha Syed, MD

Paulo Ayrosa Ribeiro, MDFulvio Zullo, MD

John F. Steege, MD

Professional Education Information   Target Audience This educational activity is developed to meet the needs of residents, fellows and new minimally invasive specialists in the field of gynecology.  Accreditation AAGL is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.  The AAGL designates this live activity for a maximum of 3.75 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.   DISCLOSURE OF RELEVANT FINANCIAL RELATIONSHIPS As  a  provider  accredited  by  the Accreditation  Council  for  Continuing Medical  Education, AAGL must ensure balance, independence, and objectivity in all CME activities to promote improvements in health care and not proprietary interests of a commercial interest. The provider controls all decisions related to identification  of  CME  needs,  determination  of  educational  objectives,  selection  and  presentation  of content,  selection  of  all  persons  and  organizations  that will  be  in  a  position  to  control  the  content, selection  of  educational methods,  and  evaluation  of  the  activity.  Course  chairs,  planning  committee members,  presenters,  authors, moderators,  panel members,  and  others  in  a  position  to  control  the content of this activity are required to disclose relevant financial relationships with commercial interests related  to  the subject matter of  this educational activity. Learners are able  to assess  the potential  for commercial  bias  in  information  when  complete  disclosure,  resolution  of  conflicts  of  interest,  and acknowledgment of  commercial  support are provided prior  to  the activity.  Informed  learners are  the final safeguards in assuring that a CME activity is independent from commercial support. We believe this mechanism contributes to the transparency and accountability of CME.   

Table of Contents 

 Course Description ........................................................................................................................................ 1  Disclosure ...................................................................................................................................................... 3  Endometriosis as a Progressive Disease: Understanding the Pathogenesis of Endometriosis in Order to Develop Strategies to Diagnose and Treat the Disease F. Zullo ........................................................................................................................................................... 4  How to Diagnose the Endometriosis: Which Are the Modern Tools to Have a Precocious Disgnosis? C. Fernandez Ossadey  ................................................................................................................................ 10  Surgical Treatment: Radical towards Disease and Conservative towards Function P.A. Ribeiro .................................................................................................................................................. 17  Specific Strategy and Techniques: Cul de Sac Endometriosis 

F. Zullo ............................................................................................................................................ 28  Endometrioma Management of the Generalist: How to Maximize Ovarian Preservation R. Syed ......................................................................................................................................................... 34  Infertility: How to Manage an Adequate Fertility Window after Surgery E.O. Fernandez ............................................................................................................................................ 38  Pain: How to Be Successful in the Long Term in Patients with Endometriosis and Pain J.F. Steege ................................................................................................................................................... 44  Adolescent Endometriosis and Early Diagnosis M.R. Laufer .................................................................................................................................................. 48  Cultural and Linguistics Competency  ......................................................................................................... 59   

 

PG 111 Clinical Management of Endometriosis – From Mild to Severe (Didactic)

Emilio O. Fernandez, Chair

Carlos Fernandez Ossadey, Co-Chair

Faculty: Marc R. Laufer, Paulo Ayrosa Ribeiro, John F. Steege, Radha Syed, Fulvio Zullo

Endometriosis is a complex disease. Although recognized for many years, its clinical management still represents a great challenge for gynecologists. The diagnosis of endometriosis is usually delayed, leading to the compromise of nearby structures and organs with devastating consequences, which may adversely affect the patient’s quality of life and reproductive potential. Reviewing basic aspects of the physiopathology will help you understand how endometriosis progresses and how to explain its multiple clinical manifestations. Considering these fundamentals will improve your clinical approach in order to construct a better preoperative evaluation. This will play a pivotal role in dimensioning the extent and severity of the disease, which in turn will help you to structure an adequate clinical management.

Learning Objectives: At the conclusion of the course the clinician will be able to: 1) Describe the essentials of physiopathology and how they explain progression and clinical manifestation of the disease; 2) discuss how to do an early diagnosis using the adequate tools; 3) review the different alternatives for the surgical treatment of the disease; 4) discuss how to approach the pelvis in severe cases; 5) identify surgical strategies for endometrioma, avoiding ovarian damage; 6) discuss strategies to optimize fertility after surgery “The Fertility Window;” and 7) discuss how to manage pain to improve quality of life.

Course Outline 1:30 Welcome, Introductions and Course Overview E.O. Fernandez

1:35 Endometriosis as a Progressive Disease: Understanding the Pathogenesis of Endometriosis in Order to Develop Strategies to Diagnose and Treat the Disease F. Zullo

2:00 How to Diagnose the Endometriosis: Which Are the Modern Tools to Have a Precocious Diagnosis? C. Fernandez Ossadey

2:25 Surgical Treatment: Radical towards Disease and Conservative towards Function P.A. Ribeiro

2:50 Specific Strategy and Techniques: Cul de Sac Endometriosis F. Zullo

3:15 Questions & Answers All Faculty

3:25 Break

3:40 Endometrioma Management for the Generalist: How to Maximize Ovarian Preservation R. Syed

4:05 Infertility: How to Manage an Adequate Fertility Window after Surgery E.O. Fernandez

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4:30 Pain: How to Be Successful in the Long Term in Patients with Endometriosis and Pain J.F. Steege

4:55 Adolescent Endometriosis and Early Diagnosis M.R. Laufer

5:20 Questions & Answers All Faculty

5:30 Course Evaluation/Adjourn

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PLANNER DISCLOSURE The following members of AAGL have been involved in the educational planning of this workshop and have no conflict of interest to disclose (in alphabetical order by last name). Art Arellano, Professional Education Manager, AAGL* Viviane F. Connor Consultant: Conceptus Incorporated Kimberly A. Kho* Frank D. Loffer, Executive Vice President/Medical Director, AAGL* Linda Michels, Executive Director, AAGL* M. Jonathan Solnik* Johnny Yi* SCIENTIFIC PROGRAM COMMITTEE Ceana H. Nezhat Consultant: Ethicon Endo-Surgery, Lumenis, Karl Storz Other: Medical Advisor: Plasma Surgical Other: Scientific Advisory Board: SurgiQuest Arnold P. Advincula Consultant: Blue Endo, CooperSurgical, Covidien, Intuitive Surgical, SurgiQuest Other: Royalties: CooperSurgical Linda D. Bradley* Victor Gomel* Keith B. Isaacson* Grace M. Janik Grants/Research Support: Hologic Consultant: Karl Storz C.Y. Liu* Javier F. Magrina* Andrew I. Sokol* FACULTY DISCLOSURE The following have agreed to provide verbal disclosure of their relationships prior to their presentations. They have also agreed to support their presentations and clinical recommendations with the “best available evidence” from medical literature (in alphabetical order by last name). Emilio O. Fernandez* Carlos Fernandez Ossadey Stock Ownership: IMH Ltda. Marc R. Laufer* Paulo Ayrosa Ribeiro Consultant: Covidien Speakers Bureau: Bayer-Sherring, Covidien John F. Steege* Radha Syed Consultant: Neosurgical Speakers Bureau: Myriad Genetics Lab Fulvio Zullo* Asterisk (*) denotes no financial relationships to disclose.

I have no financial relationship to disclose

1. Have briefly reviewed the pathogenetic theories of endometriosis and howthey explain progression and clinical manifestation of the disease

2. Be aware that the knowledge of pathogenesis could help surgeons toidentify a patient oriented treatment with a reliable and precocious nonsurgical diagnosis, an early medical management of pain and a wise and safesurgical approach.

It is well defined as an inflammatory, estrogen‐dependent condition associated with pelvic pain 

and infertility

It is well defined as an inflammatory, estrogen‐dependent condition associated with pelvic pain 

and infertilityBurney et al., Fertil Steril 2012 Mullerian 

rests

Bone marrow‐Mesenchymal‐Hematopoietic 

stem cells‐Endothelial precursors

MesotheliumOther cell type

Metaplasia

Endometrial tissue and cell reflux (Sampson) Lymphatic or 

hematogenous spread 

Adapted from Burney et al., Fertil Steril 2012

EstrogensInflammation

GeneticsEnvironment

Endometriosis

Although retrograde menstruation is supported by multiple lines of scientific evidence and explains the physical displacement of endometrial fragments into the peritoneal cavity, additional steps are necessary for the development of endometriotic implants

Escape from immune clearance

Attachment and invasion of the peritoneal epithelium

Establishment of local neurovascularityand angiogenesis 

Continuedgrowth and survival

Molecular hallmarksof this disease:

Genetic predisposition

Estrogen dependence

P resistance

Inflammation

Factor/factors that influence a propensity toward implantation of the 

displaced endometrial cells

Striking differences in gene and proteinexpression in eutopic endometrium

from women with and without endometriosis

Burney et al., Fertil Steril 2012 Soares et al., Fertil Steril 2012.

CHEMOTAXIS AND RECRUITMENT OF IMMUNE CELLS

Reis et al., Hum Reprod Update 2013

ESTROGENS

4

High levels of local estradiol and prostaglandin E2 (PGE2) are maintained in endometriotic tissue by autoregulatory positive‐feedback mechanisms that involve nuclear receptors [SF1] and estrogen receptor β [ER‐β], enzymatic 

pathways, cytokines, and growth factors

Bulun et al., New Eng J Med 2009

These findings support the capacityof endometriotic lesions for E2biosynthesis and substantiate 

treatments aimed at promoting a hypoestrogenic peritoneal

microenvironment.

These findings support the capacityof endometriotic lesions for E2biosynthesis and substantiate 

treatments aimed at promoting a hypoestrogenic peritoneal

microenvironment.

Burney et al., Fertil Steril 2012

In addition to estrogen dependence, there is increasing evidence to support a profile of P resistance in the pathophysiology of endometriosis

In addition to estrogen dependence, there is increasing evidence to support a profile of P resistance in the pathophysiology of endometriosis

Bulun et al., Mol Cell Endocrinol 2006Bulun et al., Mol Cell Endocrinol 2006

In addition to estrogen dependence, there is increasing evidence to support a profile of P resistance in the pathophysiology of endometriosis

Bulun et al., Mol Cell Endocrinol 2006

Endometriotic lesions exhibit an overall reduction in P receptor expressionrelative to eutopic endometrium and an absence of P receptor‐B

Endometriotic lesions exhibit an overall reduction in P receptor expressionrelative to eutopic endometrium and an absence of P receptor‐B

Additionally, endometrial expression profiling has documented dysregulation of P‐responsive genes in the luteal phase

Attia et al., J Clin Endocrinol Metab 2000

Burney et al., Endocrinology 2007

Incomplete endometrial transition from the proliferative to secretory phase

Enhancement of the survival and implantation of refluxed 

endometrium!!

Reis et al., Hum Reprod Update 2013

* In endometriotic cells

*  * 

Up‐regulation of gene BCL‐2Enhanced proliferationHereditary genomic alterations: asusceptibility locus in the regions ofchromosome10q26 and 7p15Acquired genomic alterations: Loss ofheterozygosity and somatic mutation ofgene PTENAberrant DNA methylation ofpromoters of genes involved in normalendometrial P response with resulting Presistance

Up‐regulation of gene BCL‐2Enhanced proliferationHereditary genomic alterations: asusceptibility locus in the regions ofchromosome10q26 and 7p15Acquired genomic alterations: Loss ofheterozygosity and somatic mutation ofgene PTENAberrant DNA methylation ofpromoters of genes involved in normalendometrial P response with resulting Presistance

ENDOMETRIAL CELL SURVIVALINFLAMMATION

An increased number of activated macrophagesCytokines and chemokines increased: MMIF, TNF‐ α, IL‐1b, IL‐6, IL‐8, RANTESand monocyte chemotactic protein‐1 Higher levels of COX‐2 and PGEsTNF‐ α promotes endometrial cell production of F2α and PGE2IL‐1b increases production of PGE2, which activates steroidogenic acute 

regulatory protein and aromatase (E2)

An increased number of activated macrophagesCytokines and chemokines increased: MMIF, TNF‐ α, IL‐1b, IL‐6, IL‐8, RANTESand monocyte chemotactic protein‐1 Higher levels of COX‐2 and PGEsTNF‐ α promotes endometrial cell production of F2α and PGE2IL‐1b increases production of PGE2, which activates steroidogenic acute 

regulatory protein and aromatase (E2)

Burney et al., Fertil Steril 2012

E2 has pro‐inflammatory and anti‐apoptotic effects that are exacerbated in endometriotic lesions.

Reis et al., Hum Reprod 2013

Women with endometriosis have an aberrant CC chemokines response to sex steroid both in their stroma and in 

microvascular endothelium.

Estrogen is not only proliferativebut also proinflammatory and antiapoptotic in endometrial 

epithelial cells and stromal cells.

These aspect are exacerbated in women with endometiosis, in whom local estradiol reinforcesboth inflammation and cell 

survival, mediated by chemokines, kinases and Bcl‐2

Amaral et al., Curr Med Chem 2009Reis et al., Hum Reprod Update 2013

High levels of ERβ suppress EαHigh Erβ‐to‐ ERα ratio suppresses PR and increases COX‐2 levels contributing to P 

resistance and inflammation. 

High levels of ERβ suppress EαHigh Erβ‐to‐ ERα ratio suppresses PR and increases COX‐2 levels contributing to P 

resistance and inflammation. 

The increased sensitivity of endometriotic cells to the survival message 

mediated by E2 appears to be related  to theup‐regulated ERβ

Bulun et al., New Engl J Med 2009

In endometrial lesion physiological levels of E2 reinforce mechanisms of cell survival and proliferation through the up‐regulation of anti‐apoptotic

(BCL‐2) and the down‐regulation of pro‐apoptotic genes (PTEN)

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* In endometriotic cellsEstrogens induce a rapid activation of he s/t protein kinase B, or Akt, whichplays a central role in endometriosis by

increasing cell survival throughdecreased apoptosis

One of the most putative factorsresponsible for higher Akt activation in 

endometriotic cell may be the continuous local stimulation of ERs due to intralesional production of estradiol

NME1 is a wide‐spectrum tumor metastasis suppressor gene that plays an important role in 

suppressing the invasion and metastasis of tumor cells

Abnormally estrogen dependent low expression of NME1 in ESCs, may be involved in the pathogenesis 

of endometriosis by activating the Akt and MAPK/Erk1/2 signal pathways

Li et al., Hum Reprod 2013

Reis et al., Hum Reprod 2013

CXCL8 and CXCR1 are involved in the pathogenesis of endometriosis by up‐regulating proliferation and growth and restricting apoptosis in ESCs by activating the PTEN/Akt pathway and mediating the 

expression of survivin and Bcl‐2Li et al., Hum Reprod 2012

…additional steps are necessary for the development of endometriotic implants and progression of disease

Reis et al., Hum Reprod Update 2013

Although endometriosis is a benign disorder, it is  characterized by the acquisition of some of the properties of malignant tissues such as increased cell proliferation, invasion and the induction of metastasis

The perturbation of apoptotic mechanism mediated by E2 allows the proliferating endometrial cells regurgitated into the peritoneal cavity to 

escape immune clearance, attach and invade surfaces, induce neo‐vascularization and establish an endometriotic implant

Hapangama et al., Hum Reprod 2009; 2012

IMMUNE CLEARANCE  ESCAPE

Larger tissue fragments have anincreased capacity to implant owing tothe protection from immune clearanceThe ectopic endometrium is moreresistant to lysis by NK cells than theeutopic oneThe constitutive shedding of ICAM‐1by ESCs is the potential mechanismthrough these cells escape NK cell–mediated clearanceA high concordance of autoimmuneand atopic disease

Larger tissue fragments have anincreased capacity to implant owing tothe protection from immune clearanceThe ectopic endometrium is moreresistant to lysis by NK cells than theeutopic oneThe constitutive shedding of ICAM‐1by ESCs is the potential mechanismthrough these cells escape NK cell–mediated clearanceA high concordance of autoimmuneand atopic disease

Normally, refluxed endometrial tissue is cleared from the peritoneum by the 

immune system

The dysregulation of this clearance mechanism has been implicated in the predisposition to implantation and 

growth of endometrial cells.

Burney et al., Fertil Steril 2012

Phagocytic functionappears to bedownregulated

Endometriotic cells fail to be eliminatedbecause of a defective immune 

response probably due to a decrease in the activity of NK cells, macrophages, 

dendritic cells, or CD4 and CD8 lymphocytes that may be suppressed by 

the action of the T‐reg cells

Endometriotic cells fail to be eliminatedbecause of a defective immune 

response probably due to a decrease in the activity of NK cells, macrophages, 

dendritic cells, or CD4 and CD8 lymphocytes that may be suppressed by 

the action of the T‐reg cellsBellelis et al., Fertil Steril 2013

Epithelial to mesenchymal transition‐like and mesenchymal to epithelial 

transition‐like processes might be a key mechanism underlying the induction of metastasis, attachment and invasion of 

endometrial cells

CELL ATTACHMENT AND INVASION

Burney et al., Fertil Steril 2012

Matsuzaki and Darcha, Hum Reprod 2012

Less epithelial markers (cytokeratin) in red lesions and endometriomas and more 

mesenchymal markers (vimentin) on black peritoneal lesions and DIE

Less epithelial markers (cytokeratin) in red lesions and endometriomas and more 

mesenchymal markers (vimentin) on black peritoneal lesions and DIE

The process by which endometrial cells attach and invade surfacesshares features of malignancy.

TGF‐b induces cell invasion of theperitoneumMMPs and their inhibitors are involved inextracellular matrix remodeling and cyclicendometrial turnover with conseguentmatrix breakdown and cellular invasionUp‐regulation of MAP‐3 in the lutealphase and of ICAM‐1, TGF‐ β and IL‐6 in themenstrual phase improve cell attachmentand invasion and reduce the immuneclearanceMIPs (Metastasis induction proteins) suchas OPN and POST

TGF‐b induces cell invasion of theperitoneumMMPs and their inhibitors are involved inextracellular matrix remodeling and cyclicendometrial turnover with conseguentmatrix breakdown and cellular invasionUp‐regulation of MAP‐3 in the lutealphase and of ICAM‐1, TGF‐ β and IL‐6 in themenstrual phase improve cell attachmentand invasion and reduce the immuneclearanceMIPs (Metastasis induction proteins) suchas OPN and POST

Epithelial to mesenchymal transition‐like andmesenchymal to epithelial transition‐like processes might be a key mechanism 

underlying the induction of metastasis, attachment and invasion of endometrial cells

As in the cancer, EMT allows cells to become motile and invasive, and leave the primary site. 

A distal MET event promotes the formation of a secondary localization and disease progression in other organs. 

Less epithelial markers (cytokeratin) in redlesions and endometriomas and more 

mesenchymal markers (vimentin) on black peritoneal lesions and DIE.

Less epithelial markers (cytokeratin) in redlesions and endometriomas and more 

mesenchymal markers (vimentin) on black peritoneal lesions and DIE.

Matsuzaki and Darcha, Hum Reprod 2012

6

Hapangama , Hum Reprod 2012

In the endometrium of healthy women MIPs (S100P, AGR2 and OPN) showed a cyclical variation. MIPs was increased in the late secretory

endometrial samples of women with endometriosis

MIPs may enhance endometrial cell invasiveness and contribute to the establishment of ectopic endometriotic

deposits and progression of disease

All active peritoneal endometriotic lesions showed 

strong expression for each of the MIPs studied.

The inflammation E2 mediated leads to a proliferative response in the extracellular matrix (ECM) such as  POSTN and OPN which are proteins involved 

in the metastasis induction (invasion and dissemination)

A role of POSTN in the pathophysiology of endometriosis 

was suggested

Shen et al., Gynecol Endocrinol. 2012 

NEO‐ANGIOGENESIS 

IL‐8 and TNF‐a promoteproliferation and adhesion ofendometrial cells and angiogenesisVEGF is abundantly expressed inthe glandular compartment ofperitoneal implants, inendometriomas, and is secreted byactivated peritoneal macrophagescompelling Other angiogenic factorsimplicated in diseasepathophysiology includeangiogenin, PDGF, and MMIF

Focal vascularity inimmediate vicinity of lesions

In addition, nerves frequentlyaccompany angiogenesis 

(NEUROANGIOGENSIS), likely contributing to the pain associated 

with this disorder.Asante et al., Annu Rev Physiol 2011

Rocha et al., Obstet Gynecol Intern 2013

Endometriotic lesions can develop their own nerve supply, thereby creating a direct and two‐way interaction between lesions and the CNS with a mechanism by which the nervous system is brought directly into play to produce a variety of individual 

differences in pain that can, in some women, become independent of the disease itself.Stratton et al., Hum Reprod Update 2011

All visceral pain must be managed as early as possible to avoid severe chronicization.

All visceral pain must be managed as early as possible to avoid severe chronicization.

Sengupta, Handb Exp Pharmacol 2009Sikandar et al., Curr Opin Support Palliat Care. 2012

If the nociceptive stimulation lasts over time, modifications in the neural circuits are created with 

specific pattern of functional brain activation and brain anatomical 

reorganization

If the nociceptive stimulation lasts over time, modifications in the neural circuits are created with 

specific pattern of functional brain activation and brain anatomical 

reorganization

Contribute to the chronicity of the pain and even to an increase in its intensity

Since the etiology and pathophysiology of endometriosis have notyet been established, there is no treatment to permanently cure the disease yet

Since the etiology and pathophysiology of endometriosis have notyet been established, there is no treatment to permanently cure the disease yet

Given the evidence that the ectopic endometrium is modulated by E2and P, however, current medical management of endometriosis is based 

on hormones, acting by two major mechanism:

Given the evidence that the ectopic endometrium is modulated by E2and P, however, current medical management of endometriosis is based 

on hormones, acting by two major mechanism:

Iatrogenic menopause to create a hypoestrogenic hormonal climate

to reduce the tropism of endometriotic lesions 

GnRH agonists, GnRH antagonists, and aromatase inhibitor

Iatrogenic menopause to create a hypoestrogenic hormonal climate

to reduce the tropism of endometriotic lesions 

GnRH agonists, GnRH antagonists, and aromatase inhibitor

Pseudopregnancy to createa pseudodecidualization of the 

endometrium 

Progestins, LNG‐IUD, intrauterine or vaginal danazol, 

and EP combination

Pseudopregnancy to createa pseudodecidualization of the 

endometrium 

Progestins, LNG‐IUD, intrauterine or vaginal danazol, 

and EP combination

Acien et al., ISRN Obstet Gynecol 2013

Strategies to block E2 production and its effects are the mainstream of pharmacologic treatment of endometriosis.

Strategies to block E2 production and its effects are the mainstream of pharmacologic treatment of endometriosis.

Central production

Periphericproduction

Local production

7

Pain relief after the administration of GNRH‐agonist  for a period of 3–6 months  can be 

used as an “ex adiuvantibus” confirmation ofcatamenial ethiology

By reducing estrogen levels to the lowest possible, GnRH‐a are the are most effective antinflammator

molecules for the treatment of pain. 

Their effect is exerted by reducing estrogen‐mediated inflammation and cell survival promotion. 

By blocking the conversion of C19 steroids to estrogens, aromatase inhibitors effectively eliminates all intracellular estrogen production. 

They should be used as first line therapy together with GnRH‐aBulun et al., New Engl J Med 2009

Soares et al., Fertil Steril 2012.

TNF‐α blockers(in vitro)

NF‐kB inhibitors (in vitro)

GnRH agonists

Statins(in vitro)

Melatonin(in vitro)

Immuno‐modulators(in vitro)

MMP inhibitors(in vitro)

Apoptotic Agents(in vitro)

Metformin(in vitro) Hyaluronic acid

(in vitro)

AntiangiogenicAgents

Dopamine agonists

COX‐2 inhibitors

PPAR‐γ agonists

Pentoxifylline

Continuous OC pills

Danazol

Aromataseinhibitors

Progestins

Dienogest

GnRH‐a and Aromatase Inhibitors as first line treatment to immediately reduce E2 and inflammation

Continuous OC and Dienogest for long‐term maintenance  

Evaluate possible early association with Antiangiogenetic agents  

Develop effective long‐term medical treatment to delay first surgery and to reduce re‐intervention risk

Avoid unnecessary surgery, particularly if inadequate

ASRM page. Fertil Steril 2012

Vercellini et al., Hum Reprod 2011

To do an accurate diagnosis using the adequate tools

Vercellini et al., Hum Reprod 2009 Berlanda N, et al. Curr Opin Obstet Gynecol 2010

The deep knowledge of pathogenesis is the key in helping the clinical research of new medical treatment for a patient oriented 

management with:

The comprehension of pathogenesis could help clinicians in identifying the different progressivity and clinical manifestations

of the various entities of endometriosis

Early and reliable not surgical diagnosis

Early and effective  medical management 

of pain

Wise and safe surgical approach

8

•Acién P, Velasco I. Endometriosis: a disease that remains enigmatic. ISRN Obstet Gynecol. 2013 Jul17;2013:242149•Asante A, Taylor RN. Endometriosis: the role of neuroangiogenesis. Annu Rev Physiol. 2011;73:163‐82• Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR, Bulun SE. Progesterone receptor isoform A but not B isexpressed in endometriosis. J Clin Endocrinol Metab. 2000 Aug;85(8):2897‐902.• Bellelis P, Barbeiro DF, Rizzo LV, Baracat EC, Abrão MS, Podgaec S. Transcriptional changes in the expression ofchemokines related to natural killer and T‐regulatory cells in patients with deep infiltrative endometriosis. FertilSteril. 2013 Jun;99(7):1987‐93• Berbic M, Fraser IS. Regulatory T cells and other leukocytes in the pathogenesis of endometriosis. J ReprodImmunol. 2011Mar;88(2):149‐55• Bulun SE, Cheng YH, Yin P, Imir G, Utsunomiya H, Attar E, Innes J, Julie Kim J.•Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006 Mar27;248(1‐2):94‐103.•Bulun SE. Endometriosis. N Engl J Med. 2009 Jan 15;360(3):268‐79•Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012; 98(3):511‐9•Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC. Gene expression analysisof endometrium reveals progesterone resistance and candidate susceptibility genes in women withendometriosis. Endocrinology. 2007 Aug;148(8):3814‐26.•Hapangama DK, Raju RS, Valentijn AJ, Barraclough D, Hart A, Turner MA, Platt‐Higgins A, Barraclough R, RudlandPS. Aberrant expression of metastasis‐inducing proteins in ectopic and matched eutopic endometrium of womenwith endometriosis: implications for the pathogenesis of endometriosis. Hum Reprod. 2012 Feb;27(2):394‐407•Koninckx PR, Ussia A, Adamyan L, Wattiez A, Donnez J. Deep endometriosis: definition, diagnosis, and treatment.Fertil Steril. 2012 Sep;98(3):564‐71

•Li MQ, Shao J, Meng YH, Mei J, Wang Y, Li H, Zhang L, Chang KK, Wang XQ, Zhu XY, Li DJ. NME1 suppressionpromotes growth, adhesion and implantation of endometrial stromal cells via Akt and MAPK/Erk1/2 signal pathwaysin the endometriotic milieu. Hum Reprod. 2013 Jul 14•Matsuzaki S, Darcha C. Epithelial to mesenchymal transition‐like and mesenchymal to epithelial transition‐likeprocesses might be involved in the pathogenesis of pelvic endometriosis. Hum Reprod. 2012Mar;27(3):712‐21•Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis andapoptosis. Hum Reprod Update. 2013 Jul‐Aug;19(4):406‐18•Shen L, Liu P, Zhang P, Zhang X, Cui J. Characterization of periostin expression in human endometrium andendometriotic lesions. Gynecol Endocrinol. 2012 Oct;28(10):815‐8•Sikandar S, Dickenson AH. Visceral pain: the ins and outs, the ups and downs. Curr Opin Support Palliat Care. 2012Mar;6(1):17‐26•Soares SR, Martínez‐Varea A, Hidalgo‐Mora JJ, Pellicer A. Pharmacologic therapies in endometriosis: a systematicreview. Fertil Steril. 2012 Sep;98(3):529‐55.•Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship andimplications. Hum Reprod Update. 2011 May‐Jun;17(3):327‐46.•Venturella, D’Alessandro, Gallo, Morelli, Zullo. CA 125 modifications throughout menstrual cycle and followingGnRH‐analog administration to diagnose endometriosis as cause of chronic pelvic pain.A prospective controlledstudy. Journal of Endometriosis 2011; 3(3): 151 – 158•Vercellini P, Crosignani P, Somigliana E, Viganò P, Frattaruolo MP, Fedele L. 'Waiting for Godot': a commonsenseapproach to the medical treatment of endometriosis. Hum Reprod. 2011 Jan;26(1):3‐13.

References

9

ENDOMETRIOSIS

How to Diagnose EndometriosisWhich are the modern tools to have a precocious diagnosis?

Fernández Carlos MD & Albornoz Jaime MD

Clinica Las Condes, Chile

Disclosure

Stockholder: IMH Ltda.

Objective

• To discuss how to do an early diagnosis using the adecuate tools.

Why...

How to Diagnose Endometriosis

What for...

Why is it important to diagnose Endometriosis in an early stage?

• Endometriosis can be a progressive diseasein up to 50% of patients.

• Early non-invasive diagnosis has the potential to offer early treatment and prevent progression.

D’Hooghe Hum Reprod Update 2002

10

Progression will compromise...

• Quality of life

• Reproductive potential

Garry R, BJOG 2000Nnoaham K, Fertil Steril 2011

Nevertheless, diagnosis is delayed...

1979 - 1984 9.2 years1984 - 1990 4.6 years

• What´s the delay? A qualitative Study of women experiences of reaching a diagnosis of endometriosis.

• Time elapsed from onset of symptoms to diagnosis of endometriosis in a cohort study of brazilian women.

Ballard K Fert Steril 2006

Arruda M Hum Reprod 200

Why diagnosis is delayed...

• Lack of awareness of the disease

• Poor understanding of the disease

Ballard K, Fertil Steril 2010

Causes

• Medical level

• Pain normalized by family doctors

• Intermittent hormonal suppression of symptoms

• Use of nondiscriminatory investigations

• Patient level

• “Inability to make clear distinctions between normal and abnormal menstrual experiences”

The availability of a non-invasive tool to evaluate the likelihood of finding endometriosis at laparoscopy could reduce the diagnostic delay and the number of women undergoing surgery unnecessarily.

Kennedy S, 2005 Hum Reprod

Future tools to have a precocious diagnosis...

• Although CA 125, Citokines, Angiogenic and Growth Factors, all show altered levels in the peripheral blood of women with endometriosis when compared to controls.

• Thus far neither a single biomarker nor a panel of biomarkers has been validated for clinical use as a diagnostic test in women with endometriosis.

Biomarkers

May KE, Hum Reprod Update 2010Surinova S, J Proteome Res 2011

11

• Symptoms - High risk groups

• Physical examination

• Ultrasound

• Magnetic Resonance Imaging

How can we improve our diagnosis

• Symptoms

• High risk groups

How can we improve our diagnosis

What kind of pain

• Chronic pain - is the most frequent, but not specific.

• Dysmenorrhoea, - progressive both in length and severity.

• Progression of dysmenorrhoea to the perineal region - is almost diagnostic of DIE.

• Dyspareunia - in case of infiltration of the cul-de-sac structures.

• Dyschesia - in cases of bowel endometriosis

• Dysuria in association to hematuria - is highly indicative of DIE.

Can specific pain symptoms help in the diagnosis of endometriosis

Can specific pain symptoms help in the diagnosis of endometriosis? A cohort study in women with chronic pelvic pain.

• “women with endometriosis are more likely to report their pain as throbbing and are more likely to experience dyschesia when compared with women with an apparent normal pelvis”

• “Currently is not possible to triage women with chronic pelvic pain effectively on history alone”

• “Women deserve referral to a specialized center”

Ballard K Fertil Steril 2010

Vaginal examination... menstrual period

12

Correlation to Laparoscopy Findings

Routine vaginal examination alone might be insufficient to detect endometriosis before laparoscopy

• “Although digital vaginal examination may be successful in detecting painful nodules in the posterior cul de sac or along the uterosacral ligaments, for many patients physical examination may not reveal abnormalities”

Hudelist G, Ultrasound OG 2011D’Hooghe TM, Gynecol Obstet Invest 2006

Nevertheless…

13

• l a p a r o s c o p y

Imaging...

• Is an adequate diagnostic method for detecting ovarian endometriotic cysts...

• It may be useful in detecting DIE located in the rectovaginal septum...

• It does not rule out peritoneal endometriosis and endometriosis-associated adhesions.

Transvaginal Ultrasound

Kennedy S, Hum Reprod 2005Moore J, Ultrasound OG 2002

Bazot M, Fertil Steril 2009

Imaging...

• Provides information regarding the degree of invasion of the rectal wall in case of rectal infiltration by DIE

Transrectal Ultrasound

Kennedy S, Hum Reprod 2005

Imaging...

fotos de ultrasonido transrectal

Transrectal Ultrasound

Imaging...

• Useful in cases of high-degree of suspicion of DIE.

• Provides valuable information about the specific location and extension of the disease.

• In case of high probability of bowel endometriosis, it can help to plan the surgical strategy

Magnetic Resonance Imaging (MRI)

14

Conclusions...

• Aware

• History

• Pelvic examination

• Imaging

• Laparoscopy

Pelvic Surgeon

References1

• D'Hooghe TM,Debrock S.Endometriosis,retrogrademenstruationandperitonealinflammationinwomenandinbaboons.HumReprod Update2002;8:84–8.

• Kjerulff KH,EriksonBA,Langenberg PW.Chronic gynaecological conditionsreportedbyUSwomen:findingsfromanationalhealthinterviewsurvey1984–1992.AmJPubHealth1996;86:195–9.

• Peveler R,EdwardsJ,ThomasE.Psychosocialfactorsandchronicpelvicpain:acomparisonofwomenwithendometriosisandwithunexplainedpain.JPsychosom Res1996;403:305–15.

• WhelanE.Puttingpaintopaper:endometriosisandthedocumentationofsuffering.Health(Lond)2003;74:463–82.

• GarryR,ClaytonR,Hawe J.Theeffectofendometriosisanditsradicallaparoscopicexcisiononqualityoflifeindicators.BJOG2000;1071:44–54.

• WrightJ,Shafik A.Qualityoflifefollowingexcisionofrectovaginalendometriosisassociatedwithcompleteobliterationoftheposteriorcul desac.Gynaecol Endosc 2001;10:107–11.

• AbbottJA,HaweJ,ClaytonRD,GarryR.Theeffectsandeffectiveness oflaparoscopicexcisionofendometriosis:aprospectivestudywith2–5yearfollow‐up.HumReprod 2003;189:1922–7.

• NnoahamK,Hummelshoj L,WebsterP,D'Hooghe T,DeCicco Nardone F,DeCicco Nardone,etal.Impactofendometriosisonqualityoflifeandworkproductivity:amulti‐centre studyacross10countries.Fertil Steril 2011;96:366–738.

15

References2

• HadfieldR,Mardon H,BarlowD,KennedyS.Delayinthediagnosisofendo‐ metriosis:asurveyofwomenfromtheUSAandtheUK.HumReprod 1996;11:878–80.

• Husby GK,HaugenRS,MoenMH.Diagnosticdelayinwomenwithpainandendometriosis.ActaObstet Gynecol Scand 2003;82:649–53.

• BallardK,Lowton K,WrightJ.What'sthedelay?Aqualitativestudyofwomen'sexperiencesofreachingadiagnosisofendometriosis.Fertil Steril 2006;86:1296–301.

• Hudelist G,BallardK,EnglishJ,WrightJ,BanerjeeS,Mastoroudes H,etal.Transvaginalsonography vs. clinicalexaminationinthepreoperativediagnosisofdeepinfiltratingendometriosis.UltrasoundObstet Gynecol 2011;37:480–7.

• D'Hooghe TM,Mihalyi AM,Simsa P,Kyama CK,Peeraer K,DeLoecker P,etal.Whyweneedanoninvasivediagnostictestforminimaltomildendometriosiswithahighsensitivity.GynecolObstet Invest2006;62:136–8.

References3

• LucianaPardini Chamié,MD,PhD•RobertoBlasbalg,MD,PhD•RicardoMendesAlves Pereira,MDGiseleWarmbrand,MD,PhD•PauloCesarSerafini,MD,PhD.RadioGraphics 2011;31:E77–E100•Publishedonline10.1148/rg.314105193•

• Chapron C,Dubuisson JB,Pansini V,VieiraM,Fauconnier A,Barakat H,etal.Routineclinicalexaminationisnotsufficientfordiag‐ nosingandlocatingdeeplyinfiltratingendometriosis.JAmAssoc Gyne‐ colLaparosc 2002;9:115–9.

• Bazot M,Detchev R,CortezA,Amouyal P,Uzan S,Darai E.Transvaginalsonography andrectalendoscopicsonography fortheassessmentofpelvicendometriosis:apreliminarycomparison.HumReprod 2003;18:1686–92.

• Bazot M,Thomassin I,Hourani R,CortezA,Darai E.Diagnosticaccuracyoftransvaginalsonography fordeeppelvicendometriosis.Ultra‐ soundObstet Gynecol 2004;24:180–5.

• Dessole S,FarinaM,Rubattu G,Cosmi E,Ambrosini G,Nardelli GB.Sonovaginography isanewtechniqueforassessingrectovaginalendo‐ metriosis.Fertil Steril 2003;79:1023–7.

• KennedyS,Bergqvist A,Chapron C,D'Hooghe T,Dunselman G,Greb R,etal.ESHREguidelineforthediagnosisandtreatmentofendometriosis.HumReprod 2005;20:2698–704.

• MooreJ,CopleyS,MorrisJ,Lindsell D,GoldingS,KennedyS.Asystematicreviewoftheaccuracyofultrasoundinthediagnosisofendometriosis.UltrasoundObstet Gynecol 2002;20:630–4.

References4

• Bazot M,Lafont C,Rouzier R,RoseauG,Thomassin‐Naggara I,Darai E.Diagnosticaccuracyofphysicalexamination,transvaginal sonography,rectalendoscopicsonography,andmagneticresonanceimagingtodiagnosedeepinfiltratingendometriosis.Fertil Steril 2009;92:1825–33.

• TakahashiK,OkadaM,OkadaS,Kitao M,Imaoka I,SugimuraK.Studiesonthedetectionofsmallendometrialimplantsbymagneticresonanceimagingusingafatsaturationtechnique.GynecolObstet Invest1996;41:203–6.

• TanakaYO,Itai Y,AnnoI,MatsumotoK,Ebihara R,NishidaM.MRstagingofpelvicendometriosis:roleoffat‐suppressionT1‐weightedimages.Radiat Med1996;14:111–6.

• Endometriosis.Giudice LC,KaoLC..Lancet2004;364:1789–99.

• Kingsmore SF.Multiplexedproteinmeasurement:technologiesandapplicationsofproteinandantibodyarrays.NatRevDrugDiscov 2006;5:310–20.

References5

• OthmanEelD,Hornung D,Al‐HendyA.Biomarkersofendometriosis.ExpertOpin MedDiagn 2008;2:741–52.

• MayKE,Conduit‐HulbertSA,Villar J,Kirtley S,KennedySH,BeckerCM.Peripheralbiomarkersofendometriosis:asystematicreview.HumReprod Update2010;00:1–24.

• Vodolazkaia A,El‐Aalamat Y,Popovic D,Mihalyi A,Bossuyt X,Kyama CM,etal.Evaluationofapanelof28biomarkersforthenon‐invasivediagnosisofendometriosis.HumReprod2012;27:2698–711.

• Surinova S,Schiess R,Huttenhain R,Cerciello F,Wollscheid B,Aebersold R.Onthedevelopmentofplasmaproteinbiomarkers.JProteomeRes2011;10:5–16.

16

Obstetrics and Gynecology Department

Santa CasaMedical School

Surgical Gynecology Clinic

Gynecological Endoscopy and Endometriosis Division

Prof. Dr. Paulo Ayroza Ribeiro

Surgical Treatment ofDeep Endometriosis

Radical Towards Disease and Conservative towards Function

Prof. Dr. Paulo Ayroza Ribeiro, M.D.

Surgical Treatment ofDeep Endometriosis

Radical Towards Disease and Conservative towards Function

Prof. Dr. Paulo Ayroza Ribeiro, M.D.

Disclosure

• Consultant: Covidien 

• Speakers Bureau: Bayer‐Sherring, Covidien  

Surgical Treatment of EndometriosisRadical Towards Disease and Conservative towards Function

• Objectives

– At the conclusion of this activity, the participant will be able to list and compare the value of preservation to adjust the radicality in the surgical treatment of deep endometriosis

• Concept

• Problem

• Concept–Surgical Treatment: Gold Standard

–Nodule Excision: Gold Standard 

–Fertility Sparing: mandatory

17

Conservative

Radical

• Problem

Radicality

Complication

• Urinary (16‐80%)

– Sensitive loos

– Blader distentionreduction

– Urgency

– Voiding difficulty

– Post miccional 

– Hipotony

– vesico‐uretheral reflux

• Rectal (0‐3,4%)

– Sensitive loss

– Urgency

– Incontinence

– Constipacy

– Dificuldade na diferenciação entre flatos e fezes

– Reduction of rectalsensibility

Urinary and Rectal Disfunction in DeepEndometriosis Surgical Treatment

Dennis Oppenheim, 1974http://www.metmuseum.org/Collections

Nerve Sparing in Deep Endometriosis Surgery

80’s e 90’s: coagullation

Fim 90’s: Radicality Related Complications 

Início 2000: Complications “boom" 

2002/2003: Nerve Sparing

2003/2010: Dissemination of Technique

80’s e 90’s: coagulação

Fim 90’s: complicações da radicalidade

Início 2000: boom das complicações

2002/2003: Nerve Sparing

2003/2010: disseminaçãoda Técnica

• 1st case of urinary retention

• Anxiety

• Searching for knowledge

• A decade dedicated to that theme

Nerve Sparing in Deep Endometriosis Surgery

18

“There is no uterosacral ligament, buta network of simpathetic andparasimpathetic nerve fibers”

Possover,M (2003)

Identification and Preservation of the Motoric Innervation of the Bladder in Radical Hysterectomy Type III.Marc Possover, M.D., Steffi Sto¨ber, M.D., Karin Plaul, M.D., and AchimSchneider, M.D. 

Gynecologic Oncology 79, 154–157 (2000)

Objective. To decrease postoperative morbidity associated with radical hysterectomy Rutledge type III, we identified the parasympathetic innervation of the bladder in the cardinal ligament.

Conclusion. Using the middle rectal artery as a landmark the neural part of the cardinal ligament can be preserved, resulting in preservation of the motor function of the bladder.

Laparoscopically assisted vaginal resection of rectovaginal endometriosisMarc Possover, MD, Herbert Diebolder, MD,Karin Plaul, MD, and Achim Schneider, MD, MPHObstet Gynecol 2000;96:304–7.

Technique: The procedure is started by vaginally excising the involved area which is left on the rectum, followed by bilateral dissection of the pararectaland retrorectal spaces.Para‐ and retrosigmoido‐rectal spaces are developed laparoscopicallyalong the coccygeosacral bone and medially to the pelvic splanchnic nerves …

Conclusion: The combination of laparoscopic and vaginal approaches is useful for removing extensive endometriotic infiltration of the rectosigmoid; bladder and rectal function and fertility can be preserved.

http://www.alltheevents.co.za

…Conservative towards function  

Radical towards disease …

19

Conservative Uterus

Tubes

Ovary

Nerves

Conservative to the Nerves

Knowledge

Identification

Preservation

• Nerve Sparing– Reduce urinary and rectal functional complications

– Reduce surgical trauma

– Adjust surgical radicality to the patients needs

urether

urether

Uterine aa.

IP ligament

20

Hypogastric Nerve R

Pararectal spaceUS ligament

Pararectal space

Retrocervical nodule

Pararectal space

Retrocervical Nodulel

Retrocervical nodule

Rectovaginal space

TRANSVAGINAL ECHOGRAPHYDEEP ENDOMETRIOSIS

Urether

21

Urether

TRANSVAGINAL ECHOGRAPHYDEEP ENDOMETRIOSIS Case Report

Hydronefrosis + hydrourether bilat.

22

Mabrouk, M., et al. (2012). "What is the impact on sexual function of laparoscopic treatment and subsequent combined oral contraceptive therapy in women with deep infiltrating endometriosis?" J Sex Med 9(3): 770‐778.

• No significant difference was found in SHOW‐Q scores between patients submitted to intestinal resection and patients submitted to intestinal nodule excision (P>0.05). 

• Six months after surgery and postoperative COC treatment, a significant improvement was observed in the SHOW‐Q domains of pelvic problem interference, sexual satisfaction and desire (P<0.05).

Mabrouk, M., et al. (2012)

• Both groups had better post‐operative outcomes when compared with the preoperative assessments. 

• Mean BDI and DAS levels were comparable with the normal population.

• Overall assessment points, the bowel resection patients had better outcomes for DAS (P < 0.05) and SSFS 'arousal' (P < 0.05) than the no bowel resection patients. 

• Radical surgery for endometriosis in both groups improved the levels of depression and sexual functioning, but only the bowel resection patients showed improvements in relationship satisfaction. 

Van den Broeck, U., et al. (2013)

What is Nerve Sparing?

• Nerve Sparing

• Neurolisis

• Pelvic Neuro Surgery (Neuropelveology)

23

•Nerve Sparing

•Neurolisis• Neuropelveology

Surgical Treatment of Endometriosis

• Nerve Sparing

• Neurolisis ‐ nodules– somatic

• Pudendal• Sciatic• Obturator• Femoral

– autonomic

• Nerve Sparing Classification

– Sperior Hipogastric Plexus + Hipogastric Nerves

– Inferior Hipogastric Plexus

– Pelvic Splancnic Nerves

• VIDEO

• Level of Preservation

– Inferior HypogastricPlexus

Pouch of Douglas

Uterine Cervix

24

• VIDEO • Level of Preservation

– Pelvic Splanchnic Nerves

• VIDEO

• VIDEO

25

Nerve Sparing

Surgical philosophy

Respect

26

Knowledge Public Domain

Surgical Technique Gold Standard

Results Published

Nerve Sparing

More than a need... ... A Must Do Procedure!

http://www.run‐fast.net

References• CECCARONI, M., CLARIZIA, R., ALBONI, C., RUFFO, G., BRUNI, F., ROVIGLIONE, G., SCIOSCIA, M., PETERS, I., DE PLACIDO, G. & MINELLI, L. 

2010a. Laparoscopic nerve‐sparing transperitoneal approach for endometriosis infiltrating the pelvic wall and somatic nerves: anatomical considerations and surgical technique. Surg Radiol Anat, 32, 601‐4.

• CECCARONI, M., PONTRELLI, G., SCIOSCIA, M., RUFFO, G., BRUNI, F. & MINELLI, L. 2010b. Nerve‐sparing laparoscopic radical excision ofdeep endometriosis with rectal and parametrial resection. J Minim Invasive Gynecol, 17, 14‐5.

• KAVALLARIS, A., BANZ, C., CHALVATZAS, N., HORNEMANN, A., LUEDDERS, D., DIEDRICH, K. & BOHLMANN, M. 2011a. Laparoscopicnerve‐sparing surgery of deep infiltrating endometriosis: description of the technique and patients' outcome. Arch Gynecol Obstet, 284, 131‐5.

• KAVALLARIS, A., MEBES, I., EVAGYELINOS, D., DAFOPOULOS, A. & BEYER, D. A. 2011b. Follow‐up of dysfunctional bladder and rectumafter surgery of a deep infiltrating rectovaginal endometriosis. Arch Gynecol Obstet, 283, 1021‐6.

• KELM JUNIOR, A. R., LANCELLOTTI, C. L., DONADIO, N., AUGE, A. P., LIMA, S. M., AOKI, T. & RIBEIRO, P. A. 2008. Nerve fibers in uterosacral ligaments of women with deep infiltrating endometriosis. J Reprod Immunol, 79, 93‐9.

• MABROUK, M., MONTANARI, G., DI DONATO, N., DEL FORNO, S., FRASCA, C., GERACI, E., FERRINI, G., VICENZI, C., RAIMONDO, D., VILLA, G., ZUKERMAN, Z., ALVISI, S. & SERACCHIOLI, R. 2012. What is the impact on sexual function of laparoscopic treatment andsubsequent combined oral contraceptive therapy in women with deep infiltrating endometriosis? J Sex Med, 9, 770‐8.

• POSSOVER, M., DIEBOLDER, H., PLAUL, K. & SCHNEIDER, A. 2000a. Laparascopically assisted vaginal resection of rectovaginalendometriosis. Obstet Gynecol, 96, 304‐7.

• POSSOVER, M., STOBER, S., PLAUL, K. & SCHNEIDER, A. 2000b.  Identification and preservation of the motoric innervation of the bladderin radical hysterectomy type III. Gynecol Oncol, 79, 154‐7.

• RIBEIRO, P. A., RODRIGUES, F. C., KEHDI, I. P., ROSSINI, L., ABDALLA, H. S., DONADIO, N. & AOKI, T. 2006. Laparoscopic resection ofintestinal endometriosis: a 5‐year experience. J Minim Invasive Gynecol, 13, 442‐6.

• RIBEIRO, P. A., SEKULA, V. G., ABDALLA‐RIBEIRO, H. S., RODRIGUES, F. C., AOKI, T. & ALDRIGHI, J. M. 2013. Impact of laparoscopiccolorectal segment resection on quality of life in women with deep endometriosis: one year follow‐up. Qual Life Res.

• VAN DEN BROECK, U., MEULEMAN, C., TOMASSETTI, C., D'HOORE, A., WOLTHUIS, A., VAN CLEYNENBREUGEL, B., VERGOTE,  I., ENZLIN, P. & D'HOOGHE, T. 2013. Effect of laparoscopic surgery for moderate and severe endometriosis on depression, relationship satisfactionand sexual functioning: comparison of patients with and without bowel resection. Hum Reprod.

27

I have no financial relationship to disclose

1. Have briefly reviewed the specific surgical techniques to deal with all forms of Cul the Sac Endometriosis (superficial endometriosis, kissing ovaries and deep endometriosis). 

2. Be aware that deep endometriosis is a delicate surgical indication and the whole management should include an early non‐surgical diagnosis and an adequate integration with medical treatment.

Sampson et al., Am J Obstet Gynecol 1925

A correct description 80 years old

The cul‐de‐sac obliteration was defined as “extensive adhesions in the cul‐de‐sac obliterating its lower portion and uniting the cervix or the lower portion of the uterus to the rectum, with adenoma of the endometrial type invading the cervical and the uterine tissue and probably also the anterior wall of the rectum”. 

Deep endometriosis

Embryonic Mullerianosisexplains…

DIE, endometriosis in Rokitansky patients,  male 

endometriosis

DIE, endometriosis in Rokitansky patients,  male 

endometriosis

DIE, endometriosis in Rokitansky patients,  male 

endometriosis

as well as in any location along the migration pathway of the embryonic mullerian system. 

Sasson et al., Ann N Y Acad Sci 2008

Peritoneal and ovarian endometriosis, adenomyosisPeritoneal and ovarian 

endometriosis, adenomyosisPeritoneal and ovarian 

endometriosis, adenomyosis

Batt et al., Hist Pat 2007

Ovarian endometriosis

Adenomyosis

Peritoneal endometriosis 

Deep endometriosis

Deregulation affect cell migration and differentiation of Mullerian structures 

determining a misplacing of the embryonic müllerian tissue

4 benign müllerian diseases: 

adenomyosis, deep endometriosis,endosalpingiosis, endocervicosis

4 benign müllerian diseases: 

adenomyosis, deep endometriosis,endosalpingiosis, endocervicosis

Batt and Yeh, Reprod Scid 2013

Painter et al., Nat Genet 2011

Wnt NFE2L3

organogenesis of the Mullerian 

reproductive  tract

HOXA

E and P regulation

DEEP

Van Langendonckt et al., Fertil Steril 2010

Zanatta et al., J Assist Reprod Genet 2010

HOXA13

Donnez et al.,Hum Reprod 1996Nisolle and Donnez, Fertil Steril 1997

Burney et al.,  Fertil Steril 2012

The nodule is not the consequence ofdeep‐infiltrating endometriosis but is the same as an adenomyotic nodule.

The nodule is not the consequence ofdeep‐infiltrating endometriosis but is the same as an adenomyotic nodule.

Ovarian steroids

Acien et al., ISRN Obstet Gynecol 2013

28

Only a 5% are pain free!!!

The main clinical hallmark…

The positive predictive value of severe  dysmenorrhea with 

nodularity of the cul‐de‐sac and/or uterosacral ligaments was 94.0%

Pain relief after the administration of GNRH‐agonist for a period of 3–6 months can be used as an “ex adiuvantibus”  confirmation of catamenial ethiology

Pain relief after the administration of GNRH‐agonist for a period of 3–6 months can be used as an “ex adiuvantibus”  confirmation of catamenial ethiology

Koninckx et al., Fertil Steril 1996; 2012

Whitehill et al., J Obstet Gynaecol Can 2012

Nodules of the Douglas’s pouch are easily reached by the gynecologist’s examining 

fingers.

Vercellini et al., Gynecol Obstet Invest 2009

The diagnostic  sensitivity and specificity of US for DIE are 

85‐100%.Hudelist et al., Ultrasound Obstet Gynecol 2011 Ghezzi et al., Fertil Steril 2005

MRI give more information about lesions of the sigmoid.

Contrast enema can occasionally confirm a sigmoid or 

high rectosigmoid lesion. 

Colonoscopyis frequently negative.

The decision to perform surgery is mainly clinical.

Koninckx et al.,  Fertil Steril 2012

Useful for the preoperative estimation of:size and lateral extension of lesionsdegree and length of bowel occlusion

Operator‐dependent!!

Not useful for the diagnosis of sigmoid endometriosis!!

They should not be an indication for surgery in the absence of clinical symptoms

“kissing ovaries” is a good marker of the most severe form of this 

disease.

pain relief (60‐90%)lesion reduction (30%)

health related‐quality of life improvement 

patient satisfactionVercellini et al., Hum Reprod 2009

Endometriosis as a chronic disease that requires a

life‐long management plan with the goal of

maximizing the use of medical treatment and

avoiding repeated surgical procedures’.ASRM, Fertil Steril 2008

Roman et al., Hum Reprod 2011; Fertil Steril 2013Donnez et al., Fertil Steril 2013

GnRH‐a, P, AIs for 6‐12 months

Post‐operative pain andlesion recurrence 

reduction

Appropriate surgical timing in order to attempt conception 

shortly after surgery

Noel et al., Fertil Steril 2010

Kitano et al., Int J Gynecol Pathol 2007

Aromatase and steroidogenic acute regulatory protein (StAR), leading to a 

local E2 and P biosynthesis, are overexpressed in endometriosis

Aromatase and steroidogenic acute regulatory protein (StAR), leading to a 

local E2 and P biosynthesis, are overexpressed in endometriosis

ER and PR were observed in the smooth muscle component of DIE, cycle’s phases

independently, except colonic endometriosis, where ER were absent.

ER and PR were observed in the smooth muscle component of DIE, cycle’s phases

independently, except colonic endometriosis, where ER were absent.

Anti‐inflammatory and anti‐proliferative GnRH a

Suppression of receptors expression in the 

smooth muscle cells

Elevated local levels of E2 promote the growth of smooth muscle fibers in the endometriotic lesions and induce cell 

survival and immune alteration.

Elevated local levels of E2 promote the growth of smooth muscle fibers in the endometriotic lesions and induce cell 

survival and immune alteration.

Healey  et al., Fertil Steril 2010

Excision is also advisable to confirm the 

diagnosis by histology

A superficial lesion could not be a progressive disease.A transition to deep 

infiltrating disease is highly unlikely.

A superficial lesion could not be a progressive disease.A transition to deep 

infiltrating disease is highly unlikely.

If surgery is required for severe pelvic pain unresponsive to 

medical  treatment, the surgical excision of the lesion seems 

to be the best strategy.

If surgery is required for severe pelvic pain unresponsive to 

medical  treatment, the surgical excision of the lesion seems 

to be the best strategy.

Koninckx et al., Fertil Steril 2012Acien et al., ISRN Obstet Gynecol 2013

29

adhesion between the adjacent peritoneal surfaces and organsadhesion between the adjacent peritoneal surfaces and organs

In the most severe form of endometriosis both ovaries are cystic, thickened, and adhere to the posterior side of the uterus and to the broad and uterosacral ligaments

ovaries are displaced medially and caudally into the Douglas

ovaries are displaced medially and caudally into the Douglas

Severe Pelvic Pain unresponsive to medical  

treatment

Reproductivedesire

Ghezzi  et al., Fertil Steril 2005Taylor et al., Ann NY Acad Sci 2002 

Indicationto surgery

Peritoneal fluid Inflammation triggered

When US reveals the presence of kissing ovaries, the surgeon should 

expect to find a tangled pelvis with subverted anatomy.

When US reveals the presence of kissing ovaries, the surgeon should 

expect to find a tangled pelvis with subverted anatomy.

Carry ovaries on the lateral pelvic wall to detach from parametrium and to 

secure the ureter.

Carry ovaries on the lateral pelvic wall to detach from parametrium and to 

secure the ureter.

Incision of the ovarian capsule by cold scissors. 

After cleavage plane identification, enucleation of the cyst by atraumatic

dissection.

Incision of the ovarian capsule by cold scissors. 

After cleavage plane identification, enucleation of the cyst by atraumatic

dissection.

Control of hemostasis by means of bipolar forceps (40 W), coagulating only the sites of 

bleeding. Cyst removal from abdomen by endo‐bag.

Control of hemostasis by means of bipolar forceps (40 W), coagulating only the sites of 

bleeding. Cyst removal from abdomen by endo‐bag.

Ghezzi et al., Fertil Steril  2005

Hormonal treatments must not be offered in the presence of 

obstructive uropathy, symptomatic bowel stenosis and adnexal mass of a doubtful nature. 

Severe Pelvic Pain unresponsive to medical  

treatment

Reproductive desire

If DIE is only anexternal

adenomyiosiswithout typical lesions …

..it is NOT a progressivedisease

..Rarelymultifocal

..Low recurrence

rate

..it is close to impossible to remove all endometriotic cells 

from all sites …

…surrounding fibrotic layer may be left 

behind…

…pain may be related to Central 

Sensitization and Hyperalgesia

The complete surgical management could be curative treating disease that cause pain...

Stratton et al., Hum Reprod Update 2011Koninckx et al.,  Fertil Steril 2012

Central sensitization Generalized hypersensitivity Chronicization of the pain

Central sensitization Generalized hypersensitivity Chronicization of the pain

In long‐term nociceptive stimulation there could be morphological changes of 

neurons (e.g., sprouting), central synaptic connectivity, expression of receptor molecules, an altered descending modulatory system, and cortical 

processing

In long‐term nociceptive stimulation there could be morphological changes of 

neurons (e.g., sprouting), central synaptic connectivity, expression of receptor molecules, an altered descending modulatory system, and cortical 

processing

Sengupta, Handb Exp Pharmacol 2009Stratton et al., Hum Reprod Update 2011

Sikandar et al., Curr Opin Support Palliat Care 2012

All visceral pain must be 

managed as early as possible to avoid severe chronicization.

All visceral pain must be 

managed as early as possible to avoid severe chronicization.

PR were 23–57% with a 

cumulative PR of 58–70% within 4 

years.

Few studies of the 49 included in the review reported fertility (37%). 

No RCTs or meta‐analyses are available

Comparison of clinical outcome 

between different surgical techniques was not possible.

Meuleman et al., Hum Reprod Update 2011

30

Lower complications rate‐ Leakage 0.1%‐ Fistula 0.1%‐ Infection <1%‐ Bladder, sexual and bowel 

dysfunctions <1 %‐ Repeat surgery <1%‐ Recurrence rate 1%

Technically more demanding Slower

Darai et al., Am J Obstet Gynecol 2005De Cicco et al, BJOG 2010

Koninckx et al., Fertil Steril 2012

Higher complications rate‐ Leakage 3‐5%‐ Fistula  6‐9%‐ Infection 4‐6%‐ Bladder, sexual and bowel

dysfunctions 2‐4%‐ Repeat surgery 10%‐ Recurrence rate 8% 

Deep sigmoid nodules Deep and large (>3cm and >1/3 of

circumference) rectal nodules Multifocal

Reimbursement for resection is more higher than discoid excission

Bowel resection makes bowel surgeons co‐responsabile

(DEFENSIVE MEDICINE)

Classical Shaving

Discoid Excision

Deep lesions affecting the rectum up to the muscular 

layer of the bowel

For recto‐sigmoid lesions infiltrating deeper than the muscular layer of the bowel

Kondo et al., Gynecol Obstetric 2013

Classical Shaving for Deep Endometriosis

Monopolar delimitation of the nodulethrough the vagina.Dissection between the bowel and the sidewall.Dissection of the ovary from the side wall.

Monopolar delimitation of the nodulethrough the vagina.Dissection between the bowel and the sidewall.Dissection of the ovary from the side wall.

Both ureters need to be identified if closeto or involved in the endometrioticnodule.

Both ureters need to be identified if closeto or involved in the endometrioticnodule.

The aim should be to leave theendometriotic nodule attached to the centralarea between the rectum and the posteriorvaginal fornix.

The aim should be to leave theendometriotic nodule attached to the centralarea between the rectum and the posteriorvaginal fornix.

Dissection of the nodule from the bowel.When the muscularis of the bowel isreached, dissection with minimal use ofenergy is suggested to prevent late bowellesions.To avoid risks of perforation of bowelmucosa the outer fibrotic layer of thenodule may be left behind.Dissection from the vagina is finallycarried out as a last step.

Dissection of the nodule from the bowel.When the muscularis of the bowel isreached, dissection with minimal use ofenergy is suggested to prevent late bowellesions.To avoid risks of perforation of bowelmucosa the outer fibrotic layer of thenodule may be left behind.Dissection from the vagina is finallycarried out as a last step.

Classical Shaving for Deep Endometriosis

Vaginectomy should be always performedto reduce recurrences.Vaginectomy should be always performedto reduce recurrences.

Shaving excision for Deep Endometriosis

Classical Shaving Reverse technique

Separate the posterior surface ofthe nodule from the anterior wallof the rectum, and then performthe separation of the lesion fromthe posterior vaginal fornix and theretrocervical region.

Separate the anterior surface ofthe nodule from the posteriorsurface of the cervix and uppervagina. The nodule will remain beattached to a rectum alreadymobilized.

Kondo et al., Gynecol Obstetric 2013; Front Biosci (Elite Ed) 2013

Discoid resection for Deep Endometriosis

Full‐thickness resection is necessary onlyfor lesions infiltrating the bowel lumen.Full‐thickness resection is necessary onlyfor lesions infiltrating the bowel lumen.

Resection of the endometriotic nodule bymonopolar crochet, followed by rectalrepair suturing in two layers.

Resection of the endometriotic nodule bymonopolar crochet, followed by rectalrepair suturing in two layers.

31

Identification of the healthy area inthe rectovaginal septum, distal to theintestinal DIE lesion.Cranial dissection of mesorectum andmobilization of left parietocolic gutter.

Identification of the healthy area inthe rectovaginal septum, distal to theintestinal DIE lesion.Cranial dissection of mesorectum andmobilization of left parietocolic gutter.

Opening of the mesorectum adjacent tothe sacral promontory and dissection ina caudal direction. Opening theperitoneal layer lateral to the rectum onthe right side.

Opening of the mesorectum adjacent tothe sacral promontory and dissection ina caudal direction. Opening theperitoneal layer lateral to the rectum onthe right side.

Bowel resection for Deep Endometriosis

No differences between bowel resection and discoid excision in 

the early steps.

Step 1

Bowel resection for Deep Endometriosis

Stapling distal to the intestinal DIElesion. End‐to‐end anastomosis usinga circular stapler inserted transanally.

Stapling distal to the intestinal DIElesion. End‐to‐end anastomosis usinga circular stapler inserted transanally.

The resection of the rectum or therectosigmoid could be performed bya transverse minilaparotomy ortransvaginally.

The resection of the rectum or therectosigmoid could be performed bya transverse minilaparotomy ortransvaginally.

If possible, vaginal excision should be avoid to perform a 

“safer” bowel resection

Distal bowel resection at least 7 cm from anal border.

Deep endometriosis is a specific non‐progressive diseasehaving its own pathogenesis and histology.

Medical and surgical treatment  are two effective approaches not mutually exclusive.

Clinical examination remains the key strategy to suspectingdisease and deciding to perform surgery.

..are highly nedeed independent studies to identify the best integrated management 

(early diagnosis, medical treatment, adequate surgery)

For surgical treatment of deep endometriosis is definitively necessary a “high volume surgeons”

To focus on “woman and her pain”

NEVERTHELESS…

References (1)•Acién P, Velasco I. Endometriosis: a disease that remains enigmatic. ISRN Obstet Gynecol. 2013;2013:242149.•Batt RE, Smith RA, Buck Louis GM, Martin DC, Chapron C, Koninckx PR, Yeh J. Müllerianosis. Histol Histopathol. 2007Oct;22(10):1161‐6.•Batt RE, Yeh J. Mullerianosis: four developmental (embryonic) mullerian diseases. Reprod Sci. 2013 201030‐7.•Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012 ;98(3):511‐9.•Darai E, Thomassin I, Barranger E, Detchev R, Cortez A, Houry S, Bazot M. Feasibility and clinical outcome of laparoscopiccolorectal resection for endometriosis. Am J Obstet Gynecol. 2005 ;192(2):394‐400.•De Cicco C, Corona R, Schonman R, Mailova K, Ussia A, Koninckx P. Bowel resection for deep endometriosis: a systematic review.BJOG. 2011118(3):285‐91•Donnez J, Nisolle M, Smoes P, Gillet N, Beguin S, Casanas‐Roux F. Peritoneal endometriosis and "endometriotic" nodules of therectovaginal septum are two different entities.Fertil Steril. 1996 ;66(3):362‐8•Donnez O, Soares M, Defrère S, Dehoux JP, van Langendonckt A, Donnez J, Dolmans MM, Colette S.Nerve fiber density in deepnodular endometriotic lesions induced in a baboon experimental model. Fertil Steril. 2013•Ghezzi F, Raio L, Cromi A, Duwe DG, Beretta P, Buttarelli M, Mueller MD. "Kissing ovaries": a sonographic sign of moderate tosevere endometriosis. Fertil Steril. 2005;83(1):143‐7.•Healey M, Ang WC, Cheng C. Surgical treatment of endometriosis: a prospective randomized double‐blinded trial comparingexcision and ablation.Fertil Steril. 2010 Dec;94(7):2536‐40.•Hudelist G, Ballard K, English J, Wright J, Banerjee S, Mastoroudes H, Thomas A, Singer CF, Keckstein J. Transvaginal sonographyvs. clinical examination in the preoperative diagnosis of deep infiltrating endometriosis.Ultrasound Obstet Gynecol.2011;37(4):480‐7•Kitano T, Matsumoto T, Takeuchi H, Kikuchi I, Itoga T, Sasahara N, Kinoshita K. Expression of estrogen and progesterone receptorsin smooth muscle metaplasia of rectovaginal endometriosis.Int J Gynecol Pathol. 2007;26(2):124‐9.•Kondo W, Bourdel N, Zomer MT, Slim K, Botchorischvili R, Rabischong B, Mage G, Canis M. Surgery for deep infiltratingendometriosis: technique and rationale.Front Biosci (Elite Ed). 2013;5:316‐32.•Kondo W, Ribeiro R, Trippia CH, Zomer MT. Spontaneous healing of a rectovaginal fistula developing after laparoscopic segmentalbowel resection for intestinal deep infiltrating endometriosis.Case Rep Obstet Gynecol. 2013;2013:837903•Koninckx PR, Meuleman C, Oosterlynck D, Cornillie FJ.Diagnosis of deep endometriosis by clinical examination duringmenstruation and plasma CA‐125 concentration. Fertil Steril. 1996;65(2):280‐7•Koninckx PR, Ussia A, Adamyan L, Wattiez A, Donnez J. Deep endometriosis: definition, diagnosis, and treatment. Fertil Steril.2012;98(3):564‐71•Meuleman C, Tomassetti C, D'Hoore A, Van Cleynenbreugel B, Penninckx F, Vergote I, D'Hooghe T. Surgical treatment of deeplyinfiltrating endometriosis with colorectal involvement.Hum Reprod Update. 2011 ;17(3):311‐26.

References (2)• Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are

three different entities. Fertil Steril 1997 ;68(4):585‐96.• Noël JC, Chapron C, Bucella D, Buxant F, Peny MO, Fayt I, Borghese B, Anaf V. Estrogen and progesterone receptors in smooth

muscle component of deep infiltrating endometriosis. Fertil Steril. 2010;93(6):1774‐7.• Painter JN, Anderson CA, Nyholt DR, Macgregor S, Lin J, Lee SH, Lambert A, Zhao ZZ, Roseman F, Guo Q, Gordon SD, Wallace L,

Henders AK, Visscher PM, Kraft P, Martin NG, Morris AP, Treloar SA, Kennedy SH, Missmer SA, Montgomery GW, Zondervan KT.Genome‐wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat Genet. 2011;43(1):51‐4.

• Practice Committee of American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis.FertilSteril. 2008;90(5):S260‐9.

• Roman H, Vassilieff M, Gourcerol G, Savoye G, Leroi AM, Marpeau L, Michot F, Tuech JJ. Surgical management of deep infiltratingendometriosis of the rectum: pleading for a symptom‐guided approach. Hum Reprod. 2011;26(2):274‐81.

• Roman H, Vassilieff M, Tuech JJ, Huet E, Savoye G, Marpeau L, Puscasiu L. Postoperative digestive function after radical versusconservative surgical philosophy for deep endometriosis infiltrating the rectum. Fertil Steril. 2013;99(6):1695‐704.

• Sampson J.A. Heterotopic or misplaced endometrial tissue. Am. J. Obstet. Gynecol 1925. 10, 649‐664.• Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci. 2008 Apr;1127:106‐15.• Sengupta JN. Visceral pain: the neurophysiological mechanism.Handb Exp Pharmacol. 2009;(194):31‐74.• Sikandar S, Dickenson AH. Visceral pain: the ins and outs, the ups and downs. Curr Opin Support Palliat Care. 2012 Mar;6(1):17‐

26..• Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications.Hum

Reprod Update. 2011;17(3):327‐46.• Taylor RN, Lebovic DI, Mueller MD. Angiogenic factors in endometriosis.Ann N Y Acad Sci. 2002;955:89‐100; discussion 118, 396‐

406.• Van Langendonckt A, Luyckx M, Gonzalez MD, Defrère S, Donnez J, Squifflet J. Differential expression of genes from the

homeobox A cluster in deep endometriotic nodules and peritoneal lesions. Fertil Steril. 2010;94(6):1995‐2000• Vercellini P, Carmignani L, Rubino T, Barbara G, Abbiati A, Fedele L. Surgery for deep endometriosis: a pathogenesis‐oriented

approach. Gynecol Obstet Invest. 2009;68(2):88‐103.• Vercellini P, Crosignani PG, Somigliana E, Berlanda N, Barbara G, Fedele L. Medical treatment for rectovaginal endometriosis:

what is the evidence? Hum Reprod. 2009 ;24(10):2504‐14.• Whitehill K, Yong PJ, Williams C.Clinical predictors of endometriosis in the infertility population: is there a better way to

determine who needs a laparoscopy?J Obstet Gynaecol Can. 2012;34(6):552‐7.• Zanatta A, Rocha AM, Carvalho FM, Pereira RM, Taylor HS, Motta EL, Baracat EC, Serafini PC. The role of the Hoxa10/HOXA10

gene in the etiology of endometriosis and its related infertility: a review. J Assist Reprod Genet. 2010 ;27(12):701‐10.

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33

AAGL ANNUAL MEETINGGAYLORD NATIONAL RESORT WASHINGTON 

DCNOV.10‐13TH 2013

Endometrioma Management for generalist‐How to maximize Ovarian 

PreservationRADHA SYED MD,FACOG

STATEN ISLAND UNIVERSITY HOSPITAL’STATEN ISLAND,NEW YORK

DISCLOSURES

• Consultant: Neosurgical

• Speakers Bureau: Myriad Genetics Lab

LEARNING OBJECTIVES

• At the end of this presentation,participant will be able to:

• Define endometriomna

• Describe the Etiology and pathogenesis of endometrioma

• Review Management strategies

• Discuss Surgical Vs Medical management

• Discuss Implications of treating vs non treatment

• Identify Risk of malignancy in Endometrioma

DEFINITION OF ENDOMETRIOMA

• Also called “Choclate Cysts”,Endometrioma is a grossly  hemorrhagic Cyst formed out of a follicular or corpus luteal cyst secondarily invaginated with Endometriotic cells from surface of the ovary into the cyst wall‐inflammation and scarring causes adhesion to surrounding structures like pouch of Douglas and broad ligament.As it enlarges,endometrioma can rupture implanting futher endometriotic glands in the pelvis (1,2,3)‐(Histological studies by various authors have proved this theory).

• Most commonly encountered dx in ovarian sx /present in 17‐44% of pts w/endo (4)

ETIOLOGY AND PATHOGENESIS

• 1921‐Sampson noted varied histology in different areas of Endometrioma including funtional lutealmembrane and ovarian epithelium

• 1979‐Czernoblisky&Morris‐described a variety of epithelium in endometrioma

• Nisolle‐pochet:1988‐113 cases histological evidence of typical glandular epith and stroma of endometrial glnds before and after hormonal rx(18%‐cyst lining only,47% oviduct like epithw/cilia,others‐flattened epith and gld and stromaof endomet)

Etiology and Pathogenesis‐2

• 1990‐Martin&Berry‐41 choc cysts‐61% microscopically proven endo,27% C.Luteal cysts

• 1991‐Vercillini et al‐confirmed 97.7% of visual dxof Endo Cysts histologically‐endometglds,endomet stroma,hemosiderin laden macrophage,or endomet like glds

• 1991‐Fayez &Vogel‐found NO endomet lining in 66  endomet Cysts out of 50 pts‐either inadeqsampling or 2nd theory of celomic metaplasia

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Etiology and Pathogenesis‐3

• 1992‐Nezhat et al‐Classified into 2 major types‐Small Type I‐1‐2 cm pure endometriomas contain dark fluid develop from surface Endo‐histology proven

• Type II A‐Large Endo Cysts‐cyst wall can be easily separated‐implants do not penetrate cysts‐follicular or luteal origin

• Type II B/C‐functional cysts deeply involved w/surface endometriosis‐excision more diff due to adhesions at deep implants

• Pathogenesis and Physiopathology of endometriomasremain widely debated

Pathology

• Variable morphology of Endometriomacharacterizes the debate on Histogenesis of the entity

• Presence of Endomet Glands and stromathough a must for dx ,other pathology may exist‐ like hemosiderin laden macrophages‐endometrial lining alone w/o stroma or stroma w/o lining,hemorrhagic Corpus Luteum or Follicular cysts with hemorrhage

Pathology/Histogenesis

• Ridley (5) reviewed the theories on histogenesisof Endometriosis

• A)Transplantation(transplantation and metaplasiaand growth of Mullerian rests can be best explained 

by Sampson’s Theory)

• B)Celomic Metaplasia

• C)Metaplasis induced by factors introduced into peritoneum

Diagnosis of Endometrioma

• S/S‐Dysmenorrhea,Chr Pelvic pain ,Dyspareunia,Infertility

• Redwine (6) reported 100% of pts w/endo Cysts had pelvic or Intestinal endo‐advanced disease

• Exam: Pelvic tenderness/Mass adherent to uterus

• Sonography:has dramatically improved the dx of ov endo‐providing reliable criteria for sx‐Kurjak et al(7),Valentin et al(8)

Diagnosis‐2‐SONO

• U/S morphology‐Zupi et al(9) described:• Round homogeneous ,hypoechoic low level echoes w/w/o int septa/no vascularization of capsule

• As above w/echogenic portion• As above w/thin internal trabeculations• Adhesions suspected w/probe and palpation ‐to ut/broad lig/Rectovag/bladder

• AFS(revised 1985) classification uses size and laterality of u/s dx cysts to classify severity of endo

Biomarkers/Malignancy • CA125‐frequentliy elevated‐low specificity‐also elevated in non‐endo ca like endometrial ca,pancreatic,lung,breast and colorectal.TB,Cirrhosis,pregnancy,menses can raise value

• Newer‐Circulating miRNA (Wang et al)(10)• CALD1(Meola et al) (11)• Suspicious for malignancy: markers used • HE4/CA72‐4‐are used to separate clinically suspected endo cysts from malignancy(Emanuela Anastasi et al) (12)

• Commercially available‐OVA1/ROMA are using several markers to distinguish benign endo cysts from malignancy

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Final Diagnosis/Management‐Surgery

• Laparoscopy is the procedure of choice for Dxand Mgt of Endometriotic Cysts(Nezhat et al) (13)

• Medical mgt  proven ineffective

• Simplest Technique‐Fenestration and drainage of “choclate cyst”‐50% recurrence rate(Nezhat et al)

• Puncture and aspiration of cyst with washing of capsule ineffective(Vercillini et al) (14)

• Hasson (15)‐simple aspiration and drainage ‐8/9 endometrioma recurred

Surgical Technique

• Nezhat et al have advocated: (15)  

• Small(Type I):(surface cystic lesions) Endometrioma‐diff to remove‐biopsy and drain and vaporize w/CO2 laser or bipolar coag

• Larger Type I lesions‐must excise completely

• Type II‐A(c.lut like or follicular w/endo):Lyseadhesion of Ov/evaluate cortex/open cyst wall and eval/bx wall 

Surgical technique‐2

• Type II B/C(functional cysts invoved deeply with Endo) w/severe adhesions: diff to remove‐Lyseadhesions/develop plane betn cyst wall and capsule w/hydro‐strip cyst wall/control bleeding at hilum w/bipolar

• Redundant ov tissue sutured(4/0 polydaxon) from inside to avoid adhesions/bipolar for bleeders

• Development of plane by hydro avoids rem of healthy ov follicles preserving fertility potential

Video clip

• Courtesy Nezhat et al

Impact of Surgery on Fertility

• Y.M.Hwu et al(4)‐studied 1642 pts of Lap ovcystectomy in endo cysyts for infertiliy in a retrospective analysis .AMH levels were measured preop and 3mos postop as biomarkers for ov reserve

• Control grp of 1323 pts of ov cystectomy w/o endometrioma

• Conclusion:Both Ov endometrioma and cystectomy cause sig.reduction in ov reserve‐Bilatendometriomas cause a profound neg impact on ov reserve vs unilat regardless of conserv/sx

Impact of Surgery on Fertility

• Important to counsel pt w/Endometriomaw/poor ov reserve prior to sx –ov failure after sx may occur 

• AMH can be considered as a preop routine test prior to Endometrioma sx

• Considered a more universal test than AntralFollicle count(AFC)

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Endometrioma and Malig potential

• Y.Higashiura,Kobayashi et al (15)‐did a review of lit.to investigate malig transf of Endo‐483 pts  from 1966‐2011‐89% Epith Ov Ca and 11% mesenchymal ca

• Several immune factors are modified in endolesions/eutopic endomet‐endomet is an inflamcondition w/dysregulated immune response

• Higher incidence of melanoma,nonhodgkins,endomet ca,breast ca in pts w/endomet

Malignancy and Endo‐2

• Endo assoc with synchronous endomet ca/ovca

• Mabrouk et al‐mixed clear cell ca /endometrioid adeno ca arising from DIE assow/ endometrioid adeno ca of endometrium

• Malig transf incidence 0.6‐0.8%

• Associated malig in Endo‐EOC/other Mulleriantype(MMBT,SBT,LG‐ET)/Sarcomas

Summary

• Endometriosis is complex and needs careful evaluation prior to treatment considering most will present for Infertility

• Ovarian reserve must be preserved for fertility potential when contemplating sx

• Lap ov cystectomy is the procedure of choice• Consider AMH eval preop and postop• Rule out malignancy prior to sx• Consider the higher risk of malig in Endo/also assoc mailgnancies

37

Infertility: How to Manage an Adequate Fertility Window after

Surgery

Emilio Fernández MD , Jaime Albornoz MD.Clinica Las Condes - Chile

Disclosure

I have no financial relationships to disclose.

Objective:

• To Discuss strategies to optimize fertility after surgery during “ The Fertility Window”.

Endometriosis and infertility

• “The Infertility specialist when aproaching Endometriosis needs to answer three fundamental questions”:

• Why endometriosis cause Infertility?

• How are we going to treat the disease?

• What for? To get the patient pregnant...

Endometriosis and Infertility

Why?

• By compromising the reproductive enviroment by a dramatic immune-inflamatory reaction and the disruption of the anatomy of the reproductive organs, endometriosis cause infertility.

Endometriosis and Infertility:Mechanisms

• Alteration of follicular develpment

• Disruption of ovulation and oocyte quality.

• Lower Fertilization rate

• Poorer embryo quality

• Alteration of tubal transport

• Lower Implantation rate

Role of inflammatory mediators

•FNT ∝•VEGF•EGF•IL-6

Role of mechanical factors

• Disruption of ovulation

• Alteration of ovum pick-up and tubal transport

•Ovarian adhesions•Peritubal adhesions•Tubal obstruction

Barnhart K, et al. Effect of endometriosis on in vitro fertilization. Fertility and Sterility 2002;77(6):1148-1155.

Littman E, et al. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertility and Sterility 2005; 4(6): 1574-1578.

38

• By a maximal resection of the ectopic endometrial tissue (reducing the inmune-inflamatory reaction) and by restoring the anatomy of the reproductive organs.

Endometriosis and InfertilityHow?

• TO OPEN A FERTILITY WINDOW

Endometriosis and InfertilityWhat for?

Can we predict fertility potential after surgery?

Fertility Predictive Factors

• Anatomical disruption of reproductive organs:

✓ Endometriosis Fertility Index (EFI)

• Age

• Infertility duration

• Ovarian reserve status (AMH, AFC, FSH) Concomitant Male and Inmunological factors

• Access to Assisted Reproduction Techniques (ART)

Endometriosis Fertility Index (EFI)

• Historical data:

• Age

• Duration of Infertility

• Prior pregnancy

• AFS/ASRM Endometriosis Score

• Functional score at the conclusion of the surgery

Adamson, Endometriosis Fertility Index, Fertil & Steril 2009

Anatomical disruption of Reproductive Organs after surgery:

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EFI: Least Functional Score

Is an anatomical observation of the tube, fimbria and ovary at the end of the surgery

Adamson, Endometriosis Fertility Index, Fertil & Steril 2009

SART:Influence of Age over Pregnancy Outcome

SART, Fertility & Sterility 2000

Influence of Infertility duration over Conception

Pregnacy rate in IUI cycles according to duration of Infertility

Pregnancy Rate

Years of Infertility

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Influence of Ovarian Reserve on Pregnancy Rate

Pregnancy Rate

Diagnosis

Access to ART Treatment

Women population 8.381.981Women in Reproductive Age (25-40 yo) 1.810.742Number of infertile women 181.074Number of women requiring ART 54.322ART cycles 1.446 (2.7%)

ART Registry: Chile 2009

So.......What can we do to manage adequately the Fertility Window?

ManagementExpectant

Management IVFIVFIUI/COS

Fertility Window

Time to spontaneous pregnancy after deep infiltrating endometriosis surgery

Fertility Window

Fernandez E et al (Unpublished Data)

Months after surgery

Pregnant Patients

(%)

Reproductive performance in infertile women with colorectal endometriosis after surgery

Darai et al, Fertility and Sterility 2011

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Fertility and clinical outcome after bowel resection in infertile women with endometriosis

Stepniewska et al, RBM Online 2010 ASRM Practice Comittee, Fertility and Sterility 2012

Cicle fecundity in women with Stage I or II Endometriosis:COS and IUI results

Medical Therapies for Infertility Treatment:

• In Infertile women with AFS/ASRN stage I/II endometriosis, clinicians may perform IUI with COS, instead of expectant management, as it increases live birth rate.

ESRHE Guideline for Endometriosis, 2013

Intrauterine Insemination (IUI)Controled Ovarian Stimulation

• In Infertile women with AFS/ASRN stage I/II endometriosis, clinicians may perform IUI with COS, instead of IUI alone, as it increases pregnancy rates.

ESRHE Guideline for Endometriosis, 2013

Medical Therapies for Infertility Treatment:

Intrauterine Insemination (IUI)Controled Ovarian Stimulation

IVF: When?

• Low Endometriosis Fertility Index Score (EFI)

• Women > 35 years old

• Diminished Ovarian Reserve

• Male or Inmunological Factors

Assisted Reproduction Techniques:

• IVF should be recomended for infertility associated with endometriosis, specially if tubal function is compromised or if there is male factor infertility, and/or other treatments have failed.

ESRHE Guideline for Endometriosis, 2013

In vitro Fertilization (IVF)

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• In stage III/IV endometriosis, cumulative endometriosis recurrences are not increased after controlled ovarian stimulation for IVF/ICSI.

ESRHE Guideline for Endometriosis, 2013

Assisted Reproduction Techniques:

In vitro Fertilization (IVF)

• IVF is the treatment alternative associated to the higher pregnancy rates in Endometriosis Infertility.

Barnhart et al, Fertil Sterility 2002

Pregnancy rate in infertile patients after resection of DIE (n=25)

Pregnancies according to type of treatment after surgery

Our Experience:Pregnancy rate in infertile patients after endoscopicresection of Deep-infiltrating endometriosis

Fernandez E et al (Unpublished Data)

Thank you!

References• Barnhart et al, Fertil Sterility 2002

• Schenken RS. J Reproductive Medicine 1998

• Vercellini et al, Am J Obstet and Gynecology 2006

• Stepniewska et al, RBM Online 2010

• Somigliana et al, Fert Sterility 2012

• Adamson, Endometriosis Fertility Index, Fertil & Steril 2009

• Darai et al, Fertility and Sterility 2011

• SART Registry 2000

• ESRHE Guideline for Endometriosis, 2013

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Pain: How to be Successful in the Long Term in Patients with Endometriosis and Pain.

Or: Don’t Worship the Implant

John F. Steege, MDUniversity of North Carolina

Department of Obstetrics and GynecologyDivision of Advanced Laparoscopy 

and Pelvic Pain

I have no financial relationships to disclose.

Objectives 

• Understand the neurologic overlaps among organ systems.

• Be aware of visceral cross‐talk and central sensitisation.

• Know how to examine the patient with chronic pain.

The conventional wisdom

• The correlation between the amount of endometriosis present and the pain experienced is low, if present at all.

• Type of endometriosis may make a difference: infiltrative vsperitoneal implants

• Cases in which stage I disease is observed to progress to stage IV disease are very few.

• Not all women with endometriosis have pain.

• If pain increases despite reduction of lesions, then psychological factors may be in play.

Common practices

• Diagnosis made by history and physical exam.

• Therapeutic trial of GnRH agonist.

• If no improvement, then perform laparoscopy.

• If pain recurs after laparoscopic treatment, then laparoscope again.

• If pain recurs despite repeat laparoscopy, then remove organs.

• If pain recurs after organ removal, then refer to a pain clinic or for mental health care.

• Other subspecialty consultations along the way, as indicated (GI, Urology, Neurology, etc.)

How’s that workin’ ?

• Pain comes back 12‐18 mos later– Change pills

– Lupron

– Add norethindrone

– Add Femara (aromatase inhibitor)

• Re‐laparoscopy: less disease than before– Have you ever seen stage I progress to stage IV?

– Re‐cook, re‐excise, presacral neurectomy

• Start taking things out– If pain lateralizes, take out a tube/ovary

– Sweep at a young age.

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The real disease

• Implant worship

• To be disease, I have to be able to see it.

• If I see it, it must be disease!

But what determines response to treatment?

• Bajaj: altered somatic pain thresholds in women with endometriosis

• As‐Sanie: thumb pressure‐pain thresholds correlate well with response to laparoscopic treatment of endometriosis.

• Johnson, et al (UNC): relief of pain 1 year after laparoscopic treatment of endometriosis best predicted by catastrophisation score.

Meaning?

• Assess the host, as well as the disease

• Set yourself up for success with a more complete assessment of pain from the start.

• Consider the implant as a possible trigger for pain, or possibly nothing at all.

Pain mechanisms in endometriosis

• Bleeding from implants: no

• Uterine contractility: probably (Mirena)

• Entrapment of nerves: maybe

• Ingrowth of nerves: Anaf, Berkley

• Prostaglandin production

• Inflammatory mediators: substance P, neurokinin A, calcitonin gene‐related peptide, transient receptor potential vanilloid 1 (TRPV1)

Assessing the host

• You’re looking for contributing factors, not single alternative diagnoses.

• Pain is the disease.

• Organ systems do not exist in isolation.– “Multi‐specialty evaluation” is an excuse for not doing a good evaluation yourself

– Multiple organ endoscopies, in the absence of true signs of illness, are a waste of time.

– The probability of independently contracting IBS, IC, FM, CFS, and “osis” is very low.

• Psychological issues may develop during the course of illness, but are seldom the prime movers.

– History of abuse

– Depression

Cross‐talk, central sensitization

• Cross‐talk

– Pelvic organ systems share innervation

– Pain syndromes overlap with each other

– Probabilities 

• Central sensitization

– Over time, central nervous system may become the pain generator

– Less dependence on nociceptive signals from periphery

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But how come laparoscopic surgery works so well?

• Severing of peritoneal nerves?

• Non‐specific effect of surgery?

• Reduction of cognitive dissonance?

• Why is the endometriosis often less prominent at the second laparoscopy?

So what should the doctor do?• Initial evaluation: history

– Thorough history of pelvic pain.

– Baseline sexual history.

– History of other illnesses, especially pain disorders.

– History of childhood illnesses: frequent UTIs?

• Initial evaluation: physical exam– Low back, SI joints

– Abdominal single digit, TPs, Carnett sign

– Single digit visceral exam

– Muscles: pelvic floor, hips, referral to abdominal wall

• Patient education– The scope does not tell all.

– Chronic pain can change the neurology

Initial steps

• Initial pharmacologic measures

– Not a Lupron trial

– Shutting off the HPO axis may alter pain sensitivity

• Laparoscopy

• Post‐op medication

• Close observation

When the pain comes back

• Start over again

• Re‐check muscles, etc.

• Re‐review other organ symtems

• Assess overall adjustment– Are there other pain syndromes?

• Plan multiple treatments accordingly

• Pain is the illness

• Exam: look for visceral allodynia: vaginal cotton‐tipped applicator

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If you re‐scope…

• Prepare the patient for the possibility that you won’t find much.

– Don’t say that it’s the worst endometriosis you’ve ever seen.

• Prepare yourself for the possibility that you won’t find much.

– Don’t say, “I want to do everything I know how to do.”

– Be ready to say, “I think there may be many factors in your pain.”

• Have your other treatment suggestions ready to go:

– PT for muscle elements

– Psychotropics for pain

– Muscle relaxants

– Re‐interpretation of pain episodes. (de‐catastrophising)

And when it doesn’t work:

• Don’t say, “When in doubt, take it out.”

• Don’t say, “A chance to cut is a chance to cure.”

• Don’t say, “ I want to do everything I know how to do” before referring

• Do not be afraid to say, “I don’t know.”

Summary 

• Look beyond the implant

• Deal with the patient’s mythology about ‘osis.

• Deal with your own mythology about ‘osis.

• Understand the non‐specific effect of surgery.

• Check the muscles, check the muscles, check the muscles.

• Understand other pain syndromes, visceral cross‐talk, central sensitization.

• If several treatments for ‘osis don’t work, reconsider the diagnosis, as opposed to taking things out.

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Adolescent Endometriosis and Early Diagnosis

Marc R. Laufer, M.D.Chief of Gynecology

Children’s Hospital Boston

Center for Reproductive Medicine Brigham & Women’s Hospital

Director, Boston Center for Endometriosis

Harvard Medical School

Disclosure

I have no financial relationships to disclose.

Objectives

• At the conclusion of this presentation the participant will be able to:– identify common adolescent endometriosis lesions

– Recommend treatment options for adolescents with endometriosis

15 year old with pelvic pain

• Pain for 6 months• Worse with period• Missing school• Called your office with

increased pain• Sent to EW and found to

have 6cm ovarian cyst• Asked to follow up in

Gyn

• Seen in Gyn 2 days after EW visit

• Asked to start OCP for dysmenorrhea and ovarian cyst suppression

• US 4 weeks later: normal• Pain persists

Dysmenorrhea

• Accompanies 20 - 90% of adolescent menstrual cycles

• Dysmenorrhea that significantly interferes with function 1 - 3 days/month affects 5- 42% of adolescents

• More likely be primary than secondary in origin

Medical Management of Pelvic Pain/Dysmenorrhea

• Combined oral contraceptives (COC’s)– Numerous overall benefits

• Progestin-only OC’s may also be beneficial is special circumstances

• If there is a persistence of pain on COC and NSAIDS then we need to proceed with a diagnosis

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How do we decide when it is no longer dysmenorrhea and further evaluation

is required?

Don’t “normalize” symptoms

• Dysmenorhea that fails to respond to conventional treatment is not a “normal” occurrence

• Women should not be led to believe that they simply have to endure pelvic pain because it is their lot in life to do so.

A young woman’s dreams Costs of Endometriosis

• Yearly total (direct & indirect)– Europe: 30 billion Euros

– US: 22 billion dollars

Gao X, Outley J et al, Economic burden of endometriosis. Fertil Steril 2006;86:1561.

Simoens S, Hummelshoj L, D’Hooghe T. Endometriosis: cost estimates and methodological perspective. Hum Reprod Update 2007;13:395.

Fourquet J, Gao X, et al. Patients’ report on how endometriosis affects health, work, and daily life. Fertil Steril 2010;93:2424.

Data From the International Endometriosis Association

Ballweg ML. J Pediatr Adolsc Gynecol 2003;16:S21-S26.

• Registry of 4000 women with endometriosis • Most women see approximately 9 health care providers

prior to diagnosis• Most women have had symptoms that they associate

with endometriosis since adolescence – 21% had severe pain under age 15 – 17% age15-19– 12% age 20-24– 50% 24 or younger

Endometriosis: Etiologies

• Sampson’s theory: retrograde menstruation

• Hematogenous and/or lymphatic spread of endometrial tissue

• Metaplastic transformation

• Immune system abnormality to ectopic endometrium

• Environmental exposures [Dioxin]

• Genetic predisposition

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Endometriosis: Symptoms

• None

• Pain: dysmenorrhea; localized pain; dyspareunia; noncyclic pain

• GI: constipation, diarrhea, hematochezia, melena

• GU: hematuria, dysuria, frequency, urgency

• Pelvic Mass/Cyst [not usually seen prior to age 22]

• Subfertility/Infertility: Stage I to Stage IV

GI=gastrointestinalGU=genitourinary

Endometriosis: Co-Occurrences

• Interstitial Cystitis

• IBS

• Kidney/uteteral stones

• Temporo-mandibular disorders

• Migraines

• Fibromyalgia

• Vulvodynia

Adolescent Physical Exam

• What is the goal? – Rule out:

• Obstructive anomaly• Ovarian mass

• Bimanual– May not be possible

• Q-tip test• Recto-abdominal• Unlikely findings

– Uterosacral nodularity– Endometrioma

Adoelscent Endometriosis: Diagnosis

• No diagnostic blood test

• No diagnostic imaging study

• History

• Physical Exam- A pelvic exam should not be barrier for evaluation [patency, ? Mass]

• Trial of NSAIDs & CHT

• Laparoscopy for diagnosis AND surgical management

Incidence of Endometriosisin Adolescents With Pelvic Pain Diagnosed by

Laparoscopy

• 67% – Rock (1996)

• 69% – Laufer (1997)*

• 97% – Laufer (2012)

*data from early ’90s, optics now better, ie higher rates

Characteristics of Subjects With & Without Endometriosis

(Laufer MR, Goitein L, Bush M, Cramer DW, Emans SJ. Prevalence of endometriosis in

adolescent women with chronic pelvic pain not responding to conventional therapy. J Pediatr Adolesc Gynecol 1997;10:199-202.)

Characteristics

Patients with Endometriosis

N=32, Number (Percent)

Presenting Symptoms Acyclic and cyclic pain 20 (62.5) Acyclic pain 9 (28.1) Cyclic pain 3 (9.4) Gastrointestinal pain 11 (34.3) Urinary symptoms 4 (12.5) Irregular menses 3 (9.4) Vaginal discharge 2 (6.3)

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Data From the International Endometriosis Association

Ballweg ML. J Pediatr Adolsc Gynecol 2003;16:S21-S26.

• Registry of 4000 women with endometriosis • Most women see approximately 9 health care providers

prior to diagnosis• Most women have had symptoms that they associate

with endometriosis since adolescence – 21% had severe pain under age 15 – 17% age15-19– 12% age 20-24– 50% 24 or younger

What’s the delay? A qualitative study of women’s experiences of reaching a diagnosis of

endometriosisBallard K, Lowton K, Wright JFertil Steril 2006;86:1296-301.

• Significant delay in diagnosis [11.8y in US, 6.7 in UK]

• Diagnostic laparoscopy after failure of first line

• Women suffer at physical, emotional and social levels when they remain undiagnosed

Patients’ report on how endometriosis affects health, work, and daily life

Fourquet J, Gao X, et al. Fertil Steril 2010;93:2424-8.

• 108 patients in Puerto Pico

• Majority had symptoms starting 11-19 year of age

• Mean delay in diagnosis was 8.9 years

• Many patients consulted 5 or more physicians prior to diagnosis

• Endometriosis impairs health-related quality of life

There is no correlation between amount of disease and pain.

ASRM Staging Relates to Fertility Potential, Not Pain

Staging and Pain Are Unrelated

Incidence:• Stage I: 40%• Stage II: 24%• Stage III: 24%• Stage IV: 12%

Fedele, et al. Stage and localization of pelvic endometriosis and pain. Fertil Steril. 1990;53:155-158.

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Endometriosis in adolescents is a hidden, progressive and severe disease that deserves attention, not just compassion

Brosens I, Gordts S, Benagiano G. Hum Reprod 2013; 28:2026-31.

Author Year Subjects Age Range St I % St II % St III % St IV %

Goldstein et al 1980 66 10-19 58 38 0 4

Vercellini et al 1989 18 11-19 67 33 0 0

Davies et al 1993 36 13-20 28 22 19 31

Reese et al 1997 49 11-19 80 12 6 2

Laufer et al 1997 32 13-21 77 23 0 0

Emmert et al 1998 37 11-19 92 8 0 0

Bai et al 2002 39 14-21 10 44 28 18

Ventolini et al 2005 28 12-18 14 39 43 4

Stravroulis et al 2006 11 13-20 45* 55^

Vicino et al 2010 38 15-21 18 13 34 34

Roman 2010 20 14-20 40 45 5 10

Yang 2012 63 12-20 8 3 52 37

*=St 1&2, ^=St 3&4

Endometriosis:Types of Lesions and Pain

• Clear 76%

• Red 84%

• White 44%

• Black 22%

• Pain perception 1-27 mm from lesion

Demco L. JAAGL. 1998.

Immune Dysregulation and Inflammation in Endometriosis

Tariveridan N, Theoharides TC, et al. Semin Immunopathol 2007;29:193-210.

Protective Immunity Chronic InflammationAmerican Society for Reproductive Medicine. Fertil Steril 1997;67:817.

Different appearances of endometriotic implants

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Identification of Clear Lesions

• use of liquid medium to improve visualization

• improve magnification

• 3-dimensional effect

Laufer MR. Fertil Steril 1997;68:739-40.

Surgical Approaches

• Laparoscopy [laparotomy is not a failure]

• Open laparoscopy vs. direct insertion

• Resection or Ablation

• Laser, scissors, harmonic scalpel, electrosurgery

• Hysterectomy

• Hysterectomy with bilateral oophorectomy

Surgical Excision vs Ablation[Wright J., Lotfallah H, et al. Fertil Steril 2005;83:1830-6.]

• Randomization at initial laparoscopy for CPP if Stage I or II diagnosed: ablation with cautery or excision

• 24 patients with 12 in each group with 6 month follow up

• Significant improvement in pain in both groups• No difference in either group• 1 patient in each group had worsening of

symptoms

Clear lesions & destruction

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Plaque lesions & destruction

Surgical Outcomes in Adults

Now we have published follow up in adolescents!

Medical Treatment for All Patients

• No surgical cure of endometriosis• Treatment until childbearing is

complete or fertility is no longer desired

• Limit the life-time surgical procedures

• Hysterectomy should not be a recommendation for an adolescent

Medical Treatment Options in Adults

• Estrogen/Progestin• Continuous [OCPs/Ring]

• Progestins• Depo-Provera• Aygestin [5-15mg/day]

• Danazol• GnRH agonists with add-back

• Aygestin [5mg]• PremPro [.625/2.5]• Do Not Use OCPs for Add-back

• GnRH-antagonists with add-back• Anti-estrogens or anti-progestins

Continuous Combination Hormonal Therapy

Monophasic progestin dominant pill-21Disp# 4 packs [3 months]Sig: 1 po q D without breaks or placebos for Rx of endometriosis

Progestins and Endometriosis

• +/- ovulation inhibition

• Decidualization

• Decreased menstrual flow

• Formulations– progestin only pill

– Norethindrone acetate [5-15mg]

– Depo-provera

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Use of norethindrone acetate alone for postoperative suppression of endometriosis symptoms

Kaser DJ, Missmer SA, Berry KF, Laufer M. J Ped Adol Gyn 2012;25:105-8.

• 194 patients with surgically confirmed endometriosis• Median age 18.9 years [10.2 – 41.9]• 92.2% had Stage I or II disease• Pain 0-10 severity scale• Bleeding 0-4

0 = no bleeding, 1 = spotting, 2 = irregular bleeding once monthly, 3 = weekly bleeding, 4 = daily bleeding

• FDA approved dose: 5-15mg

• Self-titrate to amenorrhea and decreased pain

Results

• 55.2% had no SE

–16.1% wt gain

–9.9% acne

–8.9% mood swings

• 64.7% reported lower pain scores

• 58.1% reported reduced bleeding

Bone Density in Adolescents Treated with a GnRH Agonist and Add-Back Therapy for Endometriosis

DiVasta AD, Laufer MR, Gordon CCJ Pediatri Adolesc Gynecol 2007;20:293-7.

• BMD at the hip normal in most adolescents with endometriosis receiving leuprolide and add-back therapy with norethindrone acetate

• 1/3 of subjects had clinically significant skeletal deficits (Z-score ≤ -1.0) at the spine– Greater than expected in normal population

– Likely due to GnRH-a induced low-estrogen state

• Duration of treatment not associated with BMD at hip or spine

Outcomes in Adolescents

The Effect of Standard Surgical-Medical Intervention on the Progression of EndometriosisDoyle JO, Missmer SA, Laufer MR. J Pediatri Adolesc Gynecol, 2009;22:257.

• 90 patients age 12-24• Laparoscopy for diagnosis & surgical treatment• Medical treatment

– Continuous E/P [91%]– LA + NA or Prempro [78%]– P only [12%]

• 2nd laparoscopy due to pain• Trend towards disease progression not seen• Standard surgical-medical management retards disease

progression

Necessity of Post-op medication?

• 20 prospectively enrolled ages 12-19 – Pre-op questionnaire

– Laparoscopy with “complete excision of endometriosis”

– F/u questionnaire @ 1-2 yr intervals (median f/u 23 months)

• No specific post surgical recommendation made to participants regarding hormonal therapy– May use for contraception or suppression “patient's choice”

Yeung P, Sinervo K, et al. Fertil Steril, 2011;95:1909-1912.

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Results

• 6/17 subjects OCP– Duration 10-22 months

• 1/17 subjects utilized GnRHa– Duration 6 months

• 8/17 subjects had recurrent pain and underwent repeat laparoscopy. No endometriosis appreciated [visually or histologically]

Conclusions• Author’s conclusions

– “Careful/complete excision of endometriosis” improves quality of life

– Pain relief from surgery persist without medical therapy (up to 2 years)

• Problems:– Pain persisted in 50% of patient regardless of

operative findings

– 50% of patients required a 2nd operation within 2 years due to pain

– Does not address fertility concerns

Adolescent Endometriosis Management

• Need for Diagnosis/surgery– ACOG: “ After a comprehensive evaluation and and

adequate trial of hormone therapy and NSAIDs, laparoscopy should be offered for diagnosing and treating presumed endometriosis”

• Surgical Treatment: excision/ablation of all visible lesions – Importance of adolescent lesions

• Since there is no cure for the disease, post-operative medical therapy until child bearing is complete

Endometriosis in adolescents is a hidden, progressive and severe disease that deserves

attention, not just compassionBrosens I, Gordts S, Benagiano G. Hum Reprod 2013; 28:2026-31.

• Importance of early diagnosis

• Early intervention to avoid progression

Boston Center for Endometriosis • Biorepository and Clinical Database

– $3 million gift - J. Willard & Alice S. Marriott Foundation

– Additional $1.5 million for research

• Development of a non-invasive diagnostic

• New treatments on the way to a cure

• Life long endometriosis data base from adolescence through adulthood [BCH & BWH]– Genetic predisposition, Environmental exposure, Diet, Long term

follow up [% need for additional surgery, future fertility]

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Current Research: Biorepository• Collect blood, urine, saliva, fluid from the pelvic

cavity, and tissue from adolescents and adult women with endometriosis

• Development of a non-invasive diagnostic

• New treatments on a way to a cure

Clinical Data Base

• Life long endometriosis data base– Genetic predisposition

• “Fast track” evaluation and treatment

• How should we manage the daughter of a woman with a history of infertility, Stage IV endometriosis, and no pelvic pain?

– Associated diseases

– Environmental exposure

– Long term follow up [% need for additional surgery, future fertility]

The Importance of Awareness• If adolescent endometriosis can be kept from

progressing with surgical destruction followed by medical therapy

• And if early diagnosis can save a woman’s fertility and prevent extreme physical and emotional pain

• Need to improve awareness– www.endometriosisassn.org– www.youngwomenshealth.org– www.bostoncenterendometriosis.org

Education and Life Long Support

Educating Professionals

www.youngwomenshealth.org

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Conclusions

• Endometriosis does occur in adolescents

• Early diagnosis to decrease pain & progression

• Education and awareness is the key to decreasing pain, suffering and infertility

ReferencesGao X, Outley J et al. Fertil Steril 2006;86:1561.

Simoens S, Hummelshoj L, D’Hooghe T. Hum Reprod Update 2007;13:395.

Fourquet J, Gao X, et al. Fertil Steril 2010;93:2424.

Ballweg ML. J Pediatr Adolsc Gynecol 2003;16:S21-S26.

Laufer MR, Goitein L, et al. J Pediatr Adolesc Gynecol 1997;10:199-202.

Reese KA, Reddy S, Rock JA. J Pediatr Adolesc Gynecol 1996;9:125.

Ballard K, Lowton K, Wright J. Fertil Steril 2006;86:1296-301.

Fourquet J, Gao X, et al. Fertil Steril 2010;93:2424-8.

Brosens I, Gordts S, Benagiano G. Hum Reprod 2013; 28:2026-31.

Demco L. J Am Assoc Gynecol Laparosc 1998;5:241.

Tariveridan N, Theoharides TC, et al. Semin Immunopathol 2007;29:193-210.

American Society for Reproductive Medicine. Fertil Steril 1997;67:817.

Laufer MR. Fertil Steril 1997;68:739-40.

Wright J., Lotfallah H, et al. Fertil Steril 2005;83:1830-6.

Kaser DJ, Missmer SA, Berry KF, Laufer M. J Pediat Adolesc Gynecol 2012;25:105-8.

DiVasta AD, Laufer MR, Gordon CC. J Pediatri Adolesc Gynecol 2007;20:293-7.

Doyle JO, Missmer SA, Laufer MR. J Pediatri Adolesc Gynecol, 2009;22:257.

Yeung P, Sinervo K, et al. Fertil Steril, 2011;95:1909-1912.

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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).

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.

US Population

Language Spoken at Home

English

Spanish

AsianOther

Indo-Euro

California

Language Spoken at Home

Spanish

English

OtherAsian

Indo-Euro

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

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