SOGC CLINICAL PRACTICE GUIDELINE Pain...SOGC CLINICAL PRACTICE GUIDELINE Endometriosis: Diagnosis and Management Abstract Objective: To improve the understanding of endometriosis and
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Journal of Obstetrics and Gynaecology CanadaThe offi cial voice of reproductive health care in Canada
Le porte-parole offi ciel des soins génésiques au CanadaJournal d’obstétrique et gynécologie du Canada
C
daanada
care in Canada
ésiques au Canadogi
Publications mailing agreement #40026233 Return undeliverable Canadian copies and change of address notifi cations to SOGC Subscriptions Services, 780 Echo Dr. Ottawa, Ontario K1S 5R7.
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1
Chapter 1: Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . S4
Chapter 2: Pain Management . . . . . . . . . . . . . . . . . . . . . S6
Chapter 3: Medical Management of Pain Associated With Endometriosis . . . . . . . . S9
Chapter 4: Surgical Managementof Endometriosis . . . . . . . . . . . . . . . . . . . . .S15
Chapter 5: Surgical Management of Infertility Associated With Endometriosis . . . . . . .S19
Chapter 6: Medical Treatment of Infertility Related to Endometriosis . . . . . . . . . . . .S21
Chapter 7: Endometriosis in Adolescents . . . . . . . .S23
Chapter 8: Endometriosis and Cancer . . . . . . . . . . . .S26
Volume 32, Number 7 • volume 32, numéro 7 July • juillet 2010 Supplement 2 • supplément 2
Endometriosis:Diagnosis and Management
Endometriosis:Diagnosis and Management
Editor-in-Chief / Rédacteur en chef Timothy Rowe
CPL Editor / Rédactrice PPPVyta Senikas
Translator / TraducteurMartin Pothier
Assistant Editor / Rédactrice adjointeJane Fairbanks
Editorial Assistant / Adjointe à la rédactionDaphne Sams
Editorial Office / Bureau de la rédactionJournal of Obstetrics and Gynaecology Canada Room D 405AWomen's Health Centre Building4500 Oak StreetVancouver BC V6H 3N1editor@sogc.comTel: (604) 875-2424 ext. 5668Fax: (604) 875-2590
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ISSN 1701-2163
SOGC CLINICAL PRACTICE GUIDELINE
Endometriosis: Diagnosis and ManagementAbstract
Objective: To improve the understanding of endometriosis and to
provide evidence-based guidelines for the diagnosis and
management of endometriosis.
Outcomes: Outcomes evaluated include the impact of the medical
and surgical management of endometriosis on women’s
experience of morbidity and infertility.
Methods: Members of the guideline committee were selected on the
basis of individual expertise to represent a range of practical and
academic experience in terms of both location in Canada and type
of practice, as well as subspecialty expertise along with general
gynaecology background. The committee reviewed all available
evidence in the English and French medical literature and
available data from a survey of Canadian women.
Recommendations were established as consensus statements.
The final document was reviewed and approved by the Executive
and Council of the SOGC.
Results: This document provides a summary of up-to-date evidence
regarding diagnosis, investigations, and medical and surgical
management of endometriosis. The resulting recommendations
may be adapted by individual health care workers when serving
women with this condition.
Conclusions: Endometriosis is a common and sometimes
debilitating condition for women of reproductive age. A
multidisciplinary approach involving a combination of lifestyle
modifications, medications, and allied health services should be
used to limit the impact of this condition on activities of daily living
and fertility. In some circumstances surgery is required to confirm
the diagnosis and provide therapy to achieve the desired goal of
pain relief or improved fecundity. Women who find an acceptable
management strategy for this condition may have an improved
quality of life or attain their goal of successful pregnancy.
Evidence: Medline and Cochrane databases were searched for
articles in English and French on subjects related to
endometriosis, pelvic pain, and infertility from January 1999 to
October 2009 in order to prepare a Canadian consensus guideline
on the management of endometriosis.
Values: The quality of evidence was rated with use of the criteria
described by the Canadian Task Force on Preventive Health Care.
Recommendations for practice were ranked according to the
method described by the Task Force. See Table 1.
Benefits, harms, and costs: Implementation of the guideline
recommendations will improve the care of women with pain and
infertility associated with endometriosis.
JULY JOGC JUILLET 2010 l S1
SOGC CLINICAL PRACTICE GUIDELINE
This Clinical Practice Guideline has been reviewed by the ClinicalPractice Gynaecology Committee and reviewed and approved bythe Executive and Council of the Society of Obstetricians andGynaecologists of Canada.
PRINCIPAL AUTHORS
Nicholas Leyland, MD, Toronto ON
Robert Casper, MD, Toronto ON
Philippe Laberge, MD, Quebec QC
Sukhbir S. Singh, MD, Ottawa ON
SPECIAL CONTRIBUTORS
Lisa Allen, MD, Toronto ON
Kristina Arendas, MD, Ottawa ON
CLINICAL PRACTICE GYNAECOLOGY COMMITTEE
Nicholas Leyland, MD (Chair), Toronto ON
Catherine Allaire, MD, Vancouver BC
Alaa Awadalla, MD, Winnipeg MB
Carolyn Best, MD, Hamilton ON
Elizabeth Contestabile, RN, Ottawa ON
Sheila Dunn, MD, Toronto ON
Mark Heywood, MD, Vancouver BC
Nathalie Leroux, MD, Montreal QC
Frank Potestio, MD, Thunder Bay ON
David Allan Rittenberg, MD, Halifax NS
Sukhbir S. Singh, MD, Ottawa ON
Renée Soucy, MD, Chandler QC
Wendy Lynn Wolfman, MD, Toronto ON
Vyta Senikas, MD, Ottawa, ON
Disclosure statements have been received from all members ofthe committee.
The literature searches and bibliographic support for this guideline were undertaken by Becky Skidmore, Medical Research Analyst,Society of Obstetricians and Gynaecologists of Canada.
No. 244, July 2010
This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The informationshould not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictateamendments to these opinions. They should be well documented if modified at the local level. None of these contents may bereproduced in any form without prior written permission of the SOGC.
Key Words: Endometriosis, endometrioma, pelvic pain, infertility,laparoscopy
Summary Statements and Recommendations
Chap ter 1: Intro duc tion
Sum mary State ments
1. Endometriosis is com mon, affect ing 5% to 10% of the femalepop u la tion, and the sig nif i cance of the dis ease depends on theclin i cal pre sen ta tion. (II-3)
2. The cel lu lar and molec u lar etiologic the o ries of endometriosis asan inflam ma tory and estro gen-depend ent dis or der have improvedour under stand ing. (III)
Chap ter 2: Pain Man age ment
Sum mary State ments
1. Symp toms may vary; how ever, cer tain hall mark symp toms may be more likely to sug gest endometriosis. The cli ni cian should beaware of atyp i cal pre sen ta tions. (I)
2. Endometriosis can be a chronic, relaps ing dis or der, which mayneces si tate a long-term fol low-up. (I)
3. When deeply infil trat ing endometriosis is sus pected, a pel vicexam i na tion, includ ing rectovaginal exam i na tion, is essen tial. (III)
Rec om men da tions
1. Inves ti ga tion of sus pected endometriosis should include his tory,phys i cal, and imag ing assess ments. (III-A)
2. Rou tine CA-125 test ing as part of the diag nos tic inves ti ga tion ofendometriosis should not be per formed. (II-2D)
Chapter 3: Medical Management of Pain AssociatedWith Endometriosis
Rec om men da tions
1. Com bined hor monal con tra cep tives, ide ally admin is teredcon tin u ously, should be con sid ered as first-line agents. (I-A)
2. Admin is tra tion of progestin alone—orally, intra mus cu larly, orsub cu ta ne ously—may also be con sid ered as first-line ther apy.(I-A)
3. A GnRH ago nist with HT addback, or the LNG-IUS, should becon sid ered a sec ond-line ther a peu tic option. (I-A)
4. A GnRH ago nist should be com bined with HT addback ther apyfrom com mence ment of ther apy and may be con sid ered forlon ger-term use (> 6 months). (I-A)
5. While await ing res o lu tion of symp toms from the directed med i calor sur gi cal treat ments for endometriosis, prac ti tio ners should useclin i cal judge ment in pre scrib ing anal ge sics rang ing from NSAIDsto opioids. (III-A)
Chapter 4: Surgical Management of Endometriosis
Sum mary State ments
1. Treat ment of endometriosis by exci sion or abla tion reduces pain.(I)
2. For women with endometriomas, exci sion rather than drain age orfulguration pro vides better pain relief, a reduced recur rence rate,and a histopathological diag no sis. (I)
3. Lap aro scopic uter ine nerve abla tion alone does not offersig nif i cant relief of endometriosis-related pain. (I)
Rec om men da tions
1. An asymp tom atic patient with an inci den tal find ing ofendometriosis at the time of sur gery does not require any med i calor sur gi cal inter ven tion. (III-A)
2. Sur gi cal man age ment in women with endometriosis- related painshould be reserved for those in whom medical treat ment hasfailed. (III-A)
3. Sur gi cal treat ment of deeply infil trat ing endometriosis may requirepar tic u lar expe ri ence with a multidisciplinary approach. (III-A)
Endometriosis: Diagnosis and Management
S2 l JULY JOGC JUILLET 2010
Table 1. Key to evi dence state ments and grad ing of rec om men da tions, using the rank ing of the Cana dian Task Forceon Pre ven tive Health Care*
Qual ity of evidence assessmentH Clas si fi ca tion of rec om men da tionsI
I: Evi dence obtained from at least one prop erly ran dom ized con trolled trial
II-1: Evi dence from well-designed con trolled tri als with out ran dom iza tion
II-2: Evi dence from well-designed cohort (pro spec tive or ret ro spec tive) or case-con trol stud ies, pref er a bly from more than one cen tre or research group
II-3: Evi dence obtained from com par i sons between times or places with or with out the inter ven tion. Dra matic results in uncon trolled exper i ments (such as the results of treat ment with pen i cil lin in the 1940s) could also be included in this cat e gory
III: Opin ions of respected author i ties, based on clin i cal expe ri ence, descrip tive stud ies, or reports of expert com mit tees
A. There is good evi dence to rec om mend the clin i cal pre ven tive action
B. There is fair evi dence to rec om mend the clin i cal pre ven tive action
C. The exist ing evi dence is con flict ing and does not allow to make a rec om men da tion for or against use of the clin i cal pre ven tive action; how ever, other fac tors may influ ence deci sion-mak ing
D. There is fair evi dence to rec om mend against the clin i cal pre ven tive action
E. There is good evi dence to rec om mend against the clin i cal pre ven tive action
L. There is insuf fi cient evi dence (in quan tity or qual ity) to make a rec om men da tion; how ever, other fac tors may influ ence deci sion-mak ing
*Woolf SH, Battista RN, Angerson GM, Logan AG, Eel W. Cana dian Task Force on Pre ven tive Health Care. New grades for rec om men da tions from the Cana dianTask Force on Pre ven tive Health Care. Can Med Assoc J 2003;169(3):207-8.
HThe qual ity of evi dence reported in these guide lines has been adapted from the Eval u a tion of Evi dence cri te ria described in the Cana dian Task Force on Preventive Health Care.*
IRec om men da tions included in these guide lines have been adapted from the Clas si fi ca tion of Rec om men da tions cri te ria described in the Cana dian Task Force on
Pre ven tive Health Care.*
4. Ovar ian endometriomas greater than 3 cm in diam e ter in womenwith pel vic pain should be excised if pos si ble. (I-A)
5. In patients not seek ing preg nancy, ther apy with CHCs (cyclic orcon tin u ous) should be con sid ered after sur gi cal man age ment ofovar ian endometriomas. (I-A)
6. Presacral neurectomy may be con sid ered as an adjunct to thesur gi cal treat ment of endometriosis-related pel vic pain. (I-A)
Chapter 5. Surgical Management of InfertilityAssociated With Endometriosis
Sum mary State ments
1. Lap aro scopic treat ment of min i mal or mild endometriosis improves preg nancy rates regard less of the treat ment modal ity. (I)
2. The effect on fer til ity of sur gi cal treat ment of deeply infil trat ingendometriosis is con tro ver sial. (II)
3. Lap aro scopic exci sion of ovar ian endometriomas more than 3 cmin diam e ter may improve fer til ity. (II)
Chapter 6: Medical Treatment of Infertility Related to Endometriosis
Sum mary State ment
1. If a patient with known endometriosis is to undergo IVF, GnRHago nist sup pres sion with HT addback for 3 to 6 months before IVF is asso ci ated with an improved preg nancy rate. (I)
Rec om men da tion
1. Med i cal man age ment of infer til ity related to endometriosis in theform of hor monal sup pres sion is inef fec tive and should not beoffered. (I-E)
Chapter 7: Endometriosis in Adolescents
Sum mary State ments
1. Endometriosis is the most com mon cause of sec ond arydysmenorrhea in ado les cents. (II-2)
2. Ado les cents with endometriosis are more likely than adult womento pres ent with acy clic pain. (III)
3. The phys i cal exam i na tion of ado les cents with endometriosis willrarely reveal abnor mal i ties, as most will have early- stage dis ease. (II-2)
Rec om men da tions
1. Endometriosis in ado les cents is often early stage and atyp i cal.Laparoscopists should look intra-abdom i nally for clear ves i clesand red lesions in ado les cents. (II-2B)
2. All avail able ther a pies for endometriosis may be used inado les cents, but the age of the patient and the side-effect pro filesof the med i ca tions should be con sid ered. (III-A)
Chapter 8: Endometriosis and Cancer
Sum mary State ments
1. The prev a lence of ovar ian can cer in patients with endometriosis isunder 1%. (II-2)
2. Exci sion or sam pling of sus pected endometriosis lesions andendometriomas helps con firm the diag no sis and excludeunder ly ing malig nancy. (II-2)
Rec om men da tions
1. Biopsy of endometriosis lesions should be con sid ered to con firmthe diag no sis and to rule out under ly ing malig nancy. (II-2A)
2. Sus pected ovar ian endometriomas should be treated accord ing tothe SOGC guide line “Ini tial Eval u a tion and Refer ral Guide lines forMan age ment of Pel vic/Ovar ian Masses.” (III-A)
ABBREVIATIONS
ASRM Amer i can Soci ety of Repro duc tive Med i cine
BMD bone min eral den sity
CHCs com bined hor monal con tra cep tives
DMPA depot medroxyprogesterone acetate
GnRH gonad o tro pin releas ing hormone
HT hor mone ther apy
IVF in vitro fer til iza tion
LNG-IUS levonorgestrel intrauterine system
MRI mag netic res o nance imaging
NSAIDs nonsteroidal anti-inflam ma tory drugs
RCT ran dom ized con trolled trial
Abstract
JULY JOGC JUILLET 2010 l S3
CHAPTER 1
Introduction
Endometriosis, one of the most com mon dis ease enti ties con front ing gynae colo gists, is defined as the pres -
ence of endometrial glands and stroma tis sue out -side the uterus. The pres ence of this ectopic tis sue evokesan estro gen-depend ent chronic inflam ma tory pro cess. Thisdis ease affects 5% to 10% of women of repro duc tive age.1
Patients may pres ent with pain, subfertility, or a com bi na -tion of these prob lems; the dis ease may be sus pected frompel vic exam i na tion or imag ing stud ies. The pri mary focus of inves ti ga tion and treat ment should be directed at res o lu tion of the pre sent ing symp tom(s). How ever, becauseendometriosis is a chronic, relaps ing dis or der, cli ni ciansshould develop a long- term plan of man age ment with eachpatient that is depend ent on her symp toms and goals forfer til ity and qual ity of life.
At pres ent there is no con sen sus on the cel lu lar or molec u -
lar ori gins of this dis ease.2 Despite advances in the under -
stand ing of endometriosis, cli ni cians are still faced with a
pau city of rig or ous sci ence behind the man age ment of this
enig matic dis or der. This guide line serves to update the
SOGC Cana dian con sen sus con fer ences on endometriosis
of 1993 and 1999 and attempts to draw upon all lit er a ture
and inter na tional guide lines to facil i tate the care of
Canadian women with endometriosis.
INCIDENCE AND PREVALENCE
For endometriosis, the over all inci dence (annual occur -
rence) and prev a lence (pro por tion of the pop u la tion with
the dis ease) are believed to be 5% to 10% of women of
repro duc tive age.1 The stud ies whose reports were used to
derive these fig ures were com pro mised by selec tion bias,
the lim i ta tions of sur gi cal diag no sis of the dis ease, and the
detec tion bias asso ci ated with ret ro spec tive stud ies.
Cli ni cians need to be aware of a num ber of fac tors that
increase the like li hood of endometriosis in an indi vid ual
patient. Heritability stud ies indi cate that the prob a bil ity of
endometriosis is 3 to 10 times greater among first-degree
rel a tives of women with this dis ease than among con trol
subjects.3 Women with anom a lous repro duc tive tracts and
resul tant obstruc tion of men strual out flow are also at
increased risk of endometriosis. Increased par ity and
pro longed or irreg u lar men ses decrease the like li hood of the
dis ease, whereas nulliparity, subfertility, and pro longed
inter vals since preg nancy are all asso ci ated with an
increased risk of endometriosis.3
The high est inci dence of endometriosis is in women who
undergo lap aro scopic assess ment of infer til ity or pel vic
pain: endometriosis will be diag nosed in 20% to 50%. The
rec og ni tion of endometriotic lesions as hav ing a much
wider range of appear ance than pre vi ously iden ti fied has
been asso ci ated with increased iden ti fi ca tion rates.4
ETIOLOGY
The details of the com plex etiologic the o ries of
endometriosis are beyond the scope of this guide line; read ers
are referred to a recent review of this topic.5
At pres ent there is no con sen sus on the cel lu lar ori gin of
endometriosis. Fail ure of immune mech a nisms to destroy the
ectopic tis sue and abnor mal dif fer en ti a tion of endometriotic
tis sue have been sug gested as under ly ing mech a nisms in a
stromal-cell defect asso ci ated with increased estro gen and
pros ta glan din pro duc tion, along with resis tance to
progesterone.2
Sampson6 is cred ited with the the ory of ret ro grade men -
stru a tion, whereby men strual tis sue refluxes through the
fal lo pian tubes and implants on pel vic struc tures. This
mech a nism has been con sis tently observed in humans and
is sup ported by the ana tomic dis tri bu tion of implants of
endometriotic tis sue. This the ory does not explain the
observation that reflux men stru a tion occurs in most women
but the dis ease in only 5% to 10% of the female pop u la tion.
In the coelomic-metaplasia the ory, endometriotic lesions
develop when coelomic mesothelial cells of the peri to neum
undergo metaplasia. Another the ory pos tu lates the cir cu la -
tion and implan ta tion of ectopic men strual tis sue via the
venous or the lym phatic sys tem, or both.
Although none of these the o ries can com pletely explain the
origin and behav iour of this enig matic dis ease, our pres ent
under stand ing of the molec u lar mech a nisms of
endometriosis forms the basis for much of our ther a peu tic
S4 l JULY JOGC JUILLET 2010
CHAPTER 1
approach. Endometriosis cell sur vival and growth and asso -
ci ated inflam ma tion are respon si ble for the clin i cal
symptoms of infer til ity and pain. Inflam ma tion, a pre dom i nant
fea ture of endometriotic lesions, is char ac ter ized by
overproduction of cytokines, prostaglandins, and other
inflam ma tory sub stances that medi ate pain and may be
asso ci ated with subfertility. Estro gen pro motes the sur vival
and per sis tence of endometrial lesions, as may altered
immune and inflam ma tory pro cesses.
The cel lu lar and molec u lar etiologic the o ries have sig nif i -
cantly improved med i cal and sur gi cal approaches to the
resolution of endometriosis symp toms, but con tin ued
research, both basic and clin i cal, is needed to better under -
stand and man age this dis or der.
Sum mary State ments
1. Endometriosis is com mon, affect ing 5% to 10% ofthe female pop u la tion, and the sig nif i cance of thedisease depends on the clin i cal pre sen ta tion. (II-3)
2. The cel lu lar and molec u lar etiologic the o ries ofendometriosis as an inflam ma tory and estro gen-depend ent dis or der have improved our under stand ing. (III)
REFERENCES
1. Waller KG, Lindsay P, Curtis P, Shaw RW. The prevalence ofendometriosis in women with infertile partners. Eur J Obstet GynecolReprod Biol 1993;48:135–9.
2. Bulun SE. Endometriosis. N Engl J Med 2009;360:268–79.
3. Wheeler JM. Epidemiology and prevalence of endometriosis. InfertilReprod Med Clin North Am 1992;3:545–9.
4. Rawson JM. Prevalence of endometriosis in asymptomatic women. J Reprod Med 1991;36:513–5.
5. Giudice LC, Kao LC. Endometriosis. Lancet 2004;364:1789–99.
6. Sampson JA. Peritoneal endometriosis due to men strual dis sem i na tion of endometrial tis sue into the peritoneal cav ity. Am J Obstet Gynecol1927;14:422–69.
Chapter 1: Introduction
JULY JOGC JUILLET 2010 l S5
Clin i cal Tips
• Cli ni cians need to be aware of the clin i cal fac tors that increase the like li hood of endometriosis.
• The pri mary focus of inves ti ga tion andtreat ment of endometriosis should be res o lu tionof the pre sent ing symp toms.
CHAPTER 2
Pain Man age mentThe diag no sis of endometriosis-related pain requires careful
eval u a tion through his tory-tak ing, phys i cal exam i na tion,
and appro pri ate inves ti ga tions. Endometriosis should be
con sid ered early in the dif fer en tial diag no sis of pel vic pain
in young women to help avoid the reported delay, often
from 7 to 12 years, from onset of symp toms to defin i tive
diag no sis.1–3
HISTORY
The signs and symp toms of endometriosis vary greatly
and may be related to other con di tions or patho log i cal
processes. A full eval u a tion and assess ment of a patient’s
pain expe ri ence is required to assist with diag no sis and
treat ment.4,5
Pain related to endometriosis may pres ent as any of the
fol low ing.
• Pain ful men stru a tion (dysmenorrhea)
• Pain ful inter course (dyspareunia)
• Pain ful micturition (dysuria)
• Pain ful def e ca tion (dyschezia)
• Lower back or abdom i nal dis com fort
• Chronic pel vic pain (non-cyclic abdom i nal and pel vicpain of at least 6 months’ dura tion).6
Atyp i cal pre sen ta tions sug gest ing more sig nif i cant dis ease
involve ment include cyclic leg pain or sci at ica (nerve
involve ment), cyclic rec tal bleed ing or hematuria (bowel or
blad der inva sion), and cyclic dyspnea sec ond ary to
catamenial pneumothorax.
Although endometriosis may pres ent through the above
symp toms and signs, many women with endometriosis are
asymp tom atic; the lesions may be an inci den tal find ing at
sur gery. Also, the symp toms may not appear imme di ately
after men ar che but may develop later in life. Those with
pain from endometriosis often live with a con di tion that is
con sid ered a chronic, pro gres sive, and relaps ing pro cess.
For all patients with these chief com plaints a detailed pain
and gynaecologic his tory should be taken to explore and
rule out other causes of pain (Table 2.1). Focused his tory-
tak ing would also include repro duc tive health ques tions
(on age at men ar che, cycle fre quency and reg u lar ity, previous
preg nan cies, and use of oral con tra cep tion or hor monal
treat ments). Con trib u tory med i cal and sur gi cal his tory, as
well as fam ily his tory of endometriosis or gynaecologic
cancers, should be sought. Tools for eval u at ing pel vic pain
are avail able through the Inter na tional Pel vic Pain Soci ety
(http://www.pelvicpain.org).
Sum mary State ments
1. Symp toms may vary; how ever, cer tain hall mark symptoms
may be more likely to sug gest endometriosis. The clinician
should be aware of atyp i cal pre sen ta tions. (I)
2. Endometriosis can be a chronic, relaps ing dis or der,
which may neces si tate a long-term fol low-up. (I)
EXAMINATION
Phys i cal exam i na tion is essen tial to deter mine the diag no sis
and appro pri ate care, as well as to rule out other dis or ders,
includ ing acute con di tions that may require imme di ate
atten tion. Exam i na tion should include an assess ment to
deter mine the posi tion, size, and mobil ity of the uterus: a
fixed, retroverted uterus may sug gest severe adhe sive
disease. A rectovaginal exam i na tion may be nec es sary and
appro pri ate to pal pate the uterosacral lig a ments and
rectovaginal sep tum, which may reveal ten der nod ules
suggestive of deeply infil trat ing endometriosis. Adnexal
masses dis cov ered on phys i cal exam i na tion may sug gest
ovar ian endometriomas. Exam i na tion dur ing men ses may
improve the chances of detect ing deeply infil trat ing nod ules
and the assess ment of pain.7
S6 l JULY JOGC JUILLET 2010
CHAPTER 2
Clin i cal Tips
• Pel vic pain that is not pri mary dysmenorrhea should be con sid ered endometriosis until proven otherwise.
• Endometriosis should be con sid ered early in the dif fer en tial diag no sis of pel vic pain in young women since there is often a delay of 7 to 12 years fromthe onset of symp toms to defin i tive diag no sis.
INVESTIGATIONS
Ultrasonography is the first-line inves ti ga tional tool for
suspected endometriosis. It allows detec tion of ovar ian
cysts and other pel vic dis or ders such as uter ine fib roids.
There is lit tle sup port for the rou tine use of blood work or
other imag ing stud ies in the pri mary inves ti ga tion of these
cases. Although the serum level of can cer anti gen 125
(CA-125) may be ele vated in mod er ate to severe
endometriosis, its deter mi na tion is not rec om mended as
part of rou tine inves ti ga tion. In a meta-anal y sis of 23 studies
investigating serum CA-125 lev els in women with sur gi cally
con firmed endometriosis, the esti mated sen si tiv ity was only
28% for a spec i fic ity of 90%.8 How ever, any undiagnosed
pel vic mass should be eval u ated accord ing to the SOGC
guide lines,9 in which the CA-125 level is a com po nent of
the Risk of Malig nancy Index.
Rec om men da tions
1. Inves ti ga tion of sus pected endometriosis should includehis tory, phys i cal, and imag ing assess ments. (III-A)
2. Rou tine CA-125 test ing as part of the diag nos tic inves ti -ga tion of endometriosis should not be per formed.(II-2D)
When endometriosis is thought to have a deeply inva sive
com po nent (i.e., bowel or blad der inva sion), ancil lary tests
such as colonoscopy, cystoscopy, rec tal ultrasonography,
and MRI may be required.
The gold stan dard for diag no sis is direct visu al iza tion at
laparoscopy and histologic study. Dis ease sever ity is best
described by the appear ance and loca tion of the
endometriotic lesions and any organ involve ment. The
Amer i can Soci ety for Repro duc tive Med i cine has devel -
oped a clas si fi ca tion to allow stag ing of endometriosis at
lap a ros copy.10 This type of clas si fi ca tion has lim ited util ity
for clin i cal man age ment since dis ease stage may not correlate
with the patient’s symp toms. Most com mu ni ca tions to
health care pro vid ers will include a clas si fi ca tion of dis ease
as min i mal, mild, mod er ate, or severe, which is described in
the ASRM clas si fi ca tion sys tem. It is impor tant to appreciate
that the diag no sis and descrip tion of dis ease are highly sub -
jec tive and will vary among prac ti tio ners. Video and image
cap tur ing sys tems allow for objec tive doc u men ta tion of dis -
ease at lap a ros copy.
Diag nos tic lap a ros copy is not required before treat ment in
all patients pre sent ing with pel vic pain. Although laparoscopy
is con sid ered a min i mally inva sive pro ce dure, it still car ries the
risks of sur gery, includ ing bowel and blad der per fo ra tion
and vas cu lar injury. The over all risk of any com pli ca tion
with lap a ros copy, minor or major, is 8.9%.11
Sum mary State ment
3. When deeply infil trat ing endometriosis is sus pected, apelvic exam i na tion, includ ing rectovaginal examination,is essen tial. (III)
REFERENCES
1. Arruda MS, Petta CA, Abrao MS, Benetti-Pinto CL. Time elapsed fromonset of symp toms to diag no sis of endometriosis in a cohort study ofBra zil ian women. Hum Reprod 2003;18:756–9.
2. Had field R, Mardon H, Barlow D, Ken nedy S. Delay in the diag no sis ofendometriosis: a sur vey of women from the USA and UK. Hum Reprod1996;11:878–80.
3. Husby GK, Haugen RS, Moen MH. Diag nos tic delay in women with painand endometriosis. Acta Obstet Gynecol Scand 2003;82:649–53.
4. Fauconnier A, Chapron C. Endometriosis and pel vic pain: epi de mi o log i calevi dence of the rela tion ship and impli ca tions. Hum Reprod Update2005;11:595–606.
Chapter 2: Pain Man age ment
JULY JOGC JUILLET 2010 l S7
Table 2.1. Dif fer en tial diag no sis for pel vic pain
Uter ine
Pri mary dysmenorrhea
Adenomyosis
Bowel
Irri ta ble bowel syn drome
Inflam ma tory bowel dis ease
Chronic con sti pa tion
Blad der
Inter sti tial cys ti tis
Uri nary tract infec tion
Uri nary tract cal culi
Ovar ian
Mittelschmerz (ovu la tion pain)
Ovar ian cysts (rup ture, tor sion, etc.)
Ovar ian rem nant syn drome
Fal lo pian tube
Hematosalpinx (after ster il iza tion or endometrial abla tion)
Ectopic preg nancy (acute or chronic)
Pel vic inflam ma tory dis ease
Gen eral
Endometriosis
Myofascial pain
Neuropathic pain
Pel vic con ges tion
Adhe sions
5. Jarrell JF, Vilos GA, Allaire C, Bur gess S, Fortin C, Gerwin R; ChronicPel vic Pain Com mit tee. Con sen sus guide lines for the man age ment ofchronic pel vic pain, part 1. SOGC Clin i cal Prac tice Guide line No. 164,August 2005. J Obstet Gynaecol Can 2005;27:781–826.
6. Milburn A, Reiter RC, Rhomberg AT. Multidisciplinary approach to chronic pel vic pain. Obstet Gynecol Clin North Am 1993;20:643–61.
7. Koninckx PR, Meuleman C, Oosterlynck D, Cornillie FJ. Diag no sis of deep endometriosis by clin i cal exam i na tion dur ing men stru a tion and plasmaCA-125 con cen tra tion. Fertil Steril 1996;65:280–7.
8. Mol BW, Bayram N, Lijmer JG, Wiegerinck MA, Bongers MY, van der Veen F, et al. The per for mance of CA-125 mea sure ment in thedetec tion of endometriosis: a meta-anal y sis. Fertil Steril 1998;70:1101–8.
9. Le T, Giede C, Salem S. Ini tial eval u a tion and refer ral guide lines forman age ment of pel vic/ovar ian masses. J Obstet Gynaecol Can2009;31:668–73.
10. Amer i can Soci ety for Repro duc tive Med i cine (ASRM). Revised Amer i canSoci ety for Repro duc tive Med i cine clas si fi ca tion of endometriosis: 1996.Fertil Steril 1997;67:817–21.
11. Chapron C, Fauconnier A, Goffinet F, Breart G, Dubuisson JB.Lap aro scopic sur gery is not inher ently dan ger ous for patients pre sent ingwith benign gynecologic pathol ogy: results of a meta-anal y sis. Hum Reprod2002;17:1334–42.
S8 l JULY JOGC JUILLET 2010
Endometriosis: Diagnosis and Management
CHAPTER 3
Med i cal Man age ment of Pain Asso ci atedWith Endometriosis
Endometriosis is a chronic and often pro gres sive inflam -
ma tory con di tion of the pel vis whose pre dom i nant
symp tom is pain. The over all amount of endometriosis is
not related to the fre quency or sever ity of symp toms, and
the con di tion’s eti ol ogy remains unknown. Thus, by neces -
sity, med i cal ther apy is non-spe cific and aimed at alle vi at ing
symp toms. Since there is no cure, med i cal treat ments must
be effec tive and safe to use until the age of meno pause or
until preg nancy is desired. See Fig ure.
IS PRIOR LAP A ROS COPY REQUIRED?
Lap a ros copy is not always nec es sary before med i cal man -
age ment of pel vic pain is started. In women with severe
dysmenorrhea or chronic pel vic pain that is com pro mis ing
their qual ity of life, man age ment of the pain is required
whether or not endometriosis is the cause. Since all the
man age ment strat e gies for endometriosis are rel a tively gen -
eral strat e gies to decrease inflam ma tory con di tions in the
pel vis, the treat ments are appli ca ble to pel vic pain whether a
diag no sis of endometriosis is made or not.
The pres ence of endometriosis can be strongly sus pected in
cases of severe dysmenorrhea unre spon sive to NSAID
treat ment, with pel vic ten der ness and nodularity on palpation
of the uterosacral lig a ments and rectovaginal sep tum, or
with ultra sound doc u men ta tion of an ovar ian cyst with an
appear ance typ i cal of an endometrioma. In these sit u a tions,
lap a ros copy for diag no sis is not nec es sary before med i cal
treat ment. Lap a ros copy should gen er ally be per formed only
if the sur geon is pre pared to vapor ize or excise lesions if
endometriosis is dis cov ered, since there is good evi dence
that sur gi cal man age ment pro vides long-term pain relief for
up to 50% of patients with endometriosis.1–3
COM BINED ESTRO GEN AND PROGESTIN THERAPY
The use of oral con tra cep tives that com bine estro gen and
progestin is con sid ered first-line treat ment for pel vic pain
asso ci ated with endometriosis. Sur pris ingly, although oral
con tra cep tives have been used for years, only a few RCTs
com par ing their use with other meth ods of med i cal
mangement have been con ducted.
Recently, Harada et al.4 ran domly assigned 100 women with
chronic pel vic pain sec ond ary to endometriosis to ther apy
with a low-dose oral con tra cep tive or pla cebo cycli cally for
4 cycles. There was sig nif i cant relief of dysmenorrhea with
the oral con tra cep tives com pared with pla cebo but no dif -
fer ence in relief of non-men strual pel vic pain.
In a pro spec tive non-con trolled trial 71 women with
laparoscopically doc u mented endometriosis and chronic
pel vic pain were treated with CHCs for 3 months. Although
30 patients had some reduc tion in, or com plete relief of,
pain after 3 months of treat ment, 41 had no improve ment.5
Both of these stud ies used cyclic admin is tra tion of oral con -
tra cep tives. There are some data to sug gest that con tin u ous
admin is tra tion, with out a 7-day break, to avoid with drawal
bleed ing, may be more ben e fi cial in terms of pain relief.6,7
Bio log i cally this is plau si ble since it is believed that patients
with endometriosis are prone to ret ro grade men stru a tion.
Cyclic men strual bleed ing asso ci ated with the with drawal of
birth con trol pills each month may be asso ci ated with some
ret ro grade spill of blood con tain ing cytokines and other
inflam ma tory chem i cals secreted by the ischemic and
slough ing endometrium. There fore, preventing with drawal
bleed ing may improve the effi cacy of oral con tra cep tives
for relief of pain asso ci ated with endometriosis.
One of the rea sons that CHCs may not be uni ver sally
effective in man ag ing pain in patients with endometriosis
relates to the sta tus of the estro gen and progestin recep tors
in the ectopic endometrial implants. It is gen er ally agreed
that the estro gen recep tors are nor mal but that the
progesterone recep tor isoforms PRA and PRB are mark edly
dimin ished in num ber or absent. As a result, endometriotic
lesions may not rec og nize progestins, and the enzyme that
metab o lizes estradiol to estrone, 17-b-hydroxysteroid
dehydrogenase, may not be acti vated appro pri ately by
progestin action. As a result, the endometriotic implants
may rec og nize the phar ma co logic dose of estro gen in oral
JULY JOGC JUILLET 2010 l S9
CHAPTER 3
con tra cep tives that is needed to inhibit ovu la tion with out
receiv ing the estro gen-antag o nis tic effects of the progestin.
These recep tor changes are sum ma rized nicely in reviews
by Bulun et al.8,9
ORAL PROGESTIN THERAPY
Estro gen stim u lates endometriotic growth. Since oral con -
tra cep tives con tain both estro gen and progestin, progestins
alone have been used for the man age ment of chronic pain
in patients with endometriosis.
Norethindrone Acetate
Norethindrone ace tate, 5 to 20 mg daily, has been effec tive
in most patients for reliev ing dysmenorrhea and chronic
pel vic pain.10 This treat ment results in break through
bleed ing in about half the patients but seems to have a pos i -
tive effect on cal cium metab o lism, result ing in rel a tively
good main te nance of BMD. There may be neg a tive effects
on serum lev els of high-den sity lipo pro tein cho les terol.
Continuous use to treat endometriosis is approved by the
US Food and Drug Admin is tra tion, but this agent is not
avail able in Can ada.
Dienogest
Dienogest is a progestin with selec tive 19-nortestosterone
and pro ges ter one activ ity.11 It is avail able in Europe and
may soon be approved for use in Can ada. In a daily dose of
2 mg it has been sig nif i cantly better than pla cebo in relieving
pel vic pain and dysmenorrhea related to endometriosis and
as effec tive as daily GnRH ago nist ther apy in reliev ing pain
Endometriosis: Diagnosis and Management
S10 l JULY JOGC JUILLET 2010
Man age ment of Pain Asso ci ated With Sus pected Endometriosis
asso ci ated with endometriosis.12,13 Ear lier stud ies showed
the effi cacy of dienogest to be com pa ra ble with that of the
depot GnRH ago nist triptorelin.14 Data from a ran dom ized
study pre sented at the Euro pean Soci ety of Human Repro -
duc tion and Embry ol ogy annual meet ing in 2009 showed
that dienogest, 2 mg daily, was as effec tive as the GnRH
ago nist leuprolide ace tate, 3.75 mg intra mus cu larly every
4 weeks, over the 24 weeks of the study, in reliev ing
dysmenorrhea, dyspareunia, and pel vic pain in 186 women
with doc u mented endometriosis and pel vic pain.15 Qual ity
of life was slightly improved in the women receiv ing
dienogest com pared with those receiv ing leuprolide ace tate,
although no addback was used in the lat ter, and most of the
side effects were related to low lev els of estro gen. Over all,
these stud ies dem on strated that dienogest is not infe rior to
GnRH agonists and may be an effec tive long-term
treatment option for endometriosis.
DEPOT PROGESTIN THERAPY
DMPA, injected intra mus cu larly, is widely used world wide
for birth con trol and has been stud ied for the relief of
endometriosis pain. A sub cu ta ne ous for mu la tion of DMPA
(104 mg), not cur rently avail able in Can ada, has been
investigated in 2 RCTs that com pared it with leuprolide
acetate depot.16,17 Over the 6-month study period, and for
up to 12 months there af ter, DMPA-SC was equiv a lent to
leuprolide ace tate in reliev ing pain. There was some loss of
BMD but not as much as in the group receiv ing leuprolide
ace tate with out addback.
DMPA-SC appears to be effec tive in reliev ing pel vic pain in
up to three quar ters of patients and is a very eco nom i cal
alter na tive in the treat ment of symp tom atic endometriosis.
How ever, pro longed delay in resump tion of ovu la tion is a
pos si bil ity, and there fore DMPA should not be sug gested
for women want ing a preg nancy in the near future. In
addition, break through bleed ing may be pro longed, heavy,
and dif fi cult to cor rect since the progestin effect can not be
reversed quickly. Per haps an ideal indi ca tion for DMPA is
resid ual endometriosis after hys ter ec tomy with or with out
bilat eral salpingo-oophorectomy when future con cep tion
and irreg u lar uter ine bleed ing are not issues. Long-term use
of DMPA may be det ri men tal to BMD.
INTERUTERINE PROGESTIN-RELEASING SYSTEM
Levonorgestrel, a potent 19-nortestosterone-derived
progestin, has been shown to have potent anti-estro genic
effects on the endometrium. An avail able LNG-releas ing
IUS pro vides 20 mg/d of levonorgestrel locally in the pel vis,
which results in atro phic endometrium and amenorrhea in
up to 60% of patients with out inhib it ing ovu la tion.18 In
recent stud ies of the LNG-IUS, slightly more than half of
patients with chronic pel vic pain and mild to mod er ate
endometriosis were sat is fied or very sat is fied with the
treatment after 6 months.19,20
Advan tages of the LNG-IUS include that it pro vides
continuous ther apy for 5 years with out the need for replace -
ment, but any prob lems with the sys tem can be solved by
removal. In addi tion, there are high local con cen tra tions of
progestin in the pel vis and less progestin secreted into the
sys temic cir cu la tion, so that the risk of sys temic side effects
is reduced.18
Dis ad van tages of the LNG-IUS include an expul sion rate
of about 5% and a risk of pel vic infec tion of about 1.5%.
Since ovu la tion is not inhib ited, it is pos si ble that the risk
of ovarian endometriomas is increased. Endometrioma
formation is thought to be related to ovu la tion and
invagination of both ovar ian sur face epi the lium and sur face
ectopic endometrium into inclu sion cysts.21 The long-term
effect of an LNG-IUS on BMD is not known.
The LNG-IUS may be an effec tive ther apy for rectovaginal
endometriosis, less en ing dysmenorrhea and non-men strual
pel vic pain as well as sig nif i cantly reduc ing deep dyspareunia
and dyschezia22; ultrasonography dem on strated a slight
reduc tion in the size of fibronodular rectovaginal plaques.
DANAZOL
Danazol was the pre dom i nant med i cal treat ment for
endometriosis 2 decades ago. It is an oral “impeded” or
weak andro gen that is able to sup press gonad o tro pin secre tion
and induce amenorrhea.23 Although effec tive in many cases
of pel vic pain related to endometriosis, danazol is asso ci ated
with androgenic side effects such as weight gain, acne,
hirsutism, breast atro phy, and, rarely, virilization.24 As a
result, many patients were not able to tol er ate the drug for
long-term treat ment. In addi tion, danazol has an
unfavourable impact on cir cu lat ing lipid con cen tra tions,25
and a small study raised the con cern of an increased risk of
ovar ian can cer in endometriosis patients treated with
danazol.26Because of these con cerns, low-dose reg i mens or
vag i nal admin is tra tion of danazol have been described.27
GnRH AGONISTS
For women who do not respond to CHCs or progestins or
have recur rence of symp toms after ini tial improve ment,
Chapter 3: Med i cal Man age ment of Pain Asso ci ated With Endometriosis
JULY JOGC JUILLET 2010 l S11
GnRH ago nist treat ment with HT addback should be con -
sid ered as sec ond-line treat ment. A GnRH ago nist should
never be used with out HT addback. Any stan dard HT reg i -
men con tain ing 1 mg of 17b-estradiol or the equiv a lent
should be ade quate.
Since endometriosis is an estro gen-depend ent dis ease, it is
not sur pris ing that GnRH-ago nist ther apy with induced
hypoestrogenism would be effec tive for inac ti vat ing the
pel vic lesions and resolv ing the pain. How ever, use of a
GnRH ago nist alone results in many symp toms of estro gen
defi ciency, such as hot flashes, insom nia, vag i nal dry ness,
loss of libido, and loss of BMD, which is not always revers -
ible.17 For this rea son, GnRH agonists should not be used
for any length of time in the absence of HT addback. The
use of estro gen and progestin for addback is based on the
hypoth e sis, first pro posed by Barbieri28 in 1992, that there is
a thresh old serum estro gen con cen tra tion that is low
enough that endometriosis is not stim u lated but high
enough that hypoestrogenic symp toms are pre vented. In
gen eral, this con cen tra tion is essen tially the same as that
achieved with phys i o logic HT for meno pausal women.29,30
Ear lier stud ies of depot GnRH agonists avoided estro gen,31
used low-dose estradiol for addback,32 or used high doses
of progestins alone. None of these stud ies dem on strated
com plete main te nance of BMD. Two more recent stud ies
of low-dose estro gen with progestin addback have pro vided
pre lim i nary evi dence for main te nance of BMD and absence
of hypoestrogenic symp toms, together with less en ing of
endometriosis pain, for up to 5 and 10 years, respec tively.30,33
The estro gen and progestin reg i men used in these stud ies is
also asso ci ated with amenorrhea in most women, with only
a few cases of mild break through bleed ing.29,34 See Table 3.1
for GnRH agonists avail able in Can ada.
Rec om men da tions
1. Com bined hor monal con tra cep tives, ide ally admin is teredcon tin u ously, should be con sid ered as first-line agents.(I-A)
Endometriosis: Diagnosis and Management
S12 l JULY JOGC JUILLET 2010
Table 3.1. GnRH agonists avail able in Can ada
Generic name Brand name Form Dos age
Buserelin Suprecur Nasal spray Buserelin comes in a nasal spray pump. The rec om mended dos age is 2 sprays into each nos tril every 8 hours (3 times a day).
Suprefact inject able Daily injec tion Daily injec tions of buserelin start with a dos age of 200 mg and
increase up to a max i mum of 500 mg. The final dose is the min i mum needed to alle vi ate pain.
Goserelin Zoladex Monthly or3-monthly injec tion
Goserelin is embed ded in a small bio de grad able implant aboutthe size of a grain of rice. The implant is injected under the skinin the lower half of the abdo men once a month.
Leuprolide ace tate Lupron Depot Monthly or 3-monthly injec tion
Leuprolide ace tate is injected monthly or every 3 months intra mus cu larly into the arm or some times into the but tock orthigh mus cles.
Naferelin Synarel Nasal spray Nafarelin comes in a nasal spray pump. The rec om mendeddosageis 1 spray of the pump into 1 nos tril in the morn ing and 1 spray into the other nos tril in the eve ning every day. In a few womenthe rec om mended dos age does not stop men stru a tion. If symp -toms per sist in these women, the dos age may be increased to 1 sprayin both nos trils morn ing and night.
Triptorelin pamoate Trelstar Monthly or 3-monthly injec tion
Triptorelin Pamoate is injected monthly or every 3 months as a sin gle intra mus cu lar injec tion
Triptorelin Decapeptyl SR Monthly and3-monthly injec tion
Triptorelin is injected monthly or every 3 months as a sin gleintra mus cu lar injec tion
Gonapeptyl Monthly injec tion
2. Admin is tra tion of progestin alone—orally, intramuscularly,or sub cu ta ne ously—may also be con sid ered as first-linether apy. (I-A)
3. A GnRH ago nist with HT addback, or the LNG-IUS,should be con sid ered a sec ond-line ther a peu tic option.(I-A)
4. A GnRH ago nist should be com bined with HT addbackther apy from the com mence ment of ther apy and may becon sid ered for lon ger-term use (> 6 months). (I-A)
AROMATASE INHIBITORS
The use of aromatase inhib i tors for med i cal man age ment of
endometriosis is still exper i men tal and is based on the
obser va tion that endometriotic lesions express the enzyme
aromatase and are able to make their own estro gen, even in
the absence of gonad o tro pin stim u la tion.35 Two pilot studies
exam ined pain relief after 6 months of daily treat ment
with an aromatase inhib i tor together with high-dose
norethindrone ace tate36 or an oral con tra cep tive.37 Both
showed sig nif i cant (but not com plete) res o lu tion of pel vic
pain in women with endometriosis who had not responded
to first-line treat ment. Since the women were
premenopausal, the progestin or CHC was added to the
aromatase inhib i tor to pre vent ovar ian stim u la tion and cyst
for ma tion result ing from increased gonad o tro pin secre tion
once estro gen neg a tive feed back was removed.38 BMD was
sta ble over the 6 months of the study. Fur ther research is
required to deter mine if aromatase inhib i tors will be safe and
effec tive for long-term use in women with endometriosis
pain before these agents can be con sid ered an option.
ANALGESIA
Man age ment of pain asso ci ated with endometriosis with
tar geted med i cal ther a pies may require at least 1 cycle to
initiate pain relief. For exam ple, GnRH ago nist ther apy
started in the luteal phase or dur ing men ses will not pre vent
dysmenorrhea and may even accen tu ate pain because of the
ini tial flare effect in the first cycle. In this sit u a tion, it is
appro pri ate to pro vide anal ge sia in the form of NSAIDs or
even opioids to make the patient more com fort able until
the pri mary med i cal man age ment becomes effec tive.
Rec om men da tion
5. While await ing res o lu tion of symp toms from thedirected medical or sur gi cal treat ments for endometriosis,prac ti tio ners should use clin i cal judge ment in pre scrib inganal ge sics rang ing from NSAIDs to opioids. (III-A)
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2. Jones KD, Haines P, Sutton CJ. Long-term fol low-up of a con trolled trialof laser lap a ros copy for pel vic pain. JSLS 2001;5:111–5.
3. Abbott JA, Hawe J, Clay ton RD, Garry R. The effects and effec tive ness of lap aro scopic exci sion of endometriosis: a pro spec tive study with 2–5year fol low-up. Hum Reprod 2003;18:1922–7.
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10. Muneyyirci-Delate O, Karacan M. Effect of norethindrone ace tate in thetreat ment of symp tom atic endometriosis. Int J Fertil Womens Med1998;43:24–7.
11. Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K, et al.Dienogest is a selec tive pro ges ter one recep tor ago nist in transactivationanal y sis with potent oral endometrial activ ity due to its effi cientpharmacokinetic pro file. Ste roids 2008;73:222–31.
12. Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Dienogest is aseffec tive as leuprolide ace tate in treat ing the pain ful symp toms ofendometriosis: a 24-week, ran dom ized, multicentre, open-label trial. Hum Reprod 2010;25:633–41.
13. Harada T, Momoeda M, Taketani Y, Aso T, Fukunaga M, Hagino H, et al.Dienogest is as effec tive as intranasal buserelin ace tate for the relief of painsymp toms asso ci ated with endometriosis—a ran dom ized, dou ble-blind,multicenter, con trolled trial. Fertil Steril 2009:675–81.
Chapter 3: Med i cal Man age ment of Pain Asso ci ated With Endometriosis
JULY JOGC JUILLET 2010 l S13
Clin i cal Tips
• In endometriosis treat ment, all options should beadmin is tered for a min i mum of 3 months, witheval u a tion of effi cacy at the end of the trial.
• Long-term ther apy with a GnRH ago nist andaddback with estro gen and progestin is an effec tive treat ment option for reliev ing the symp toms ofendometriosis. It is pru dent to fol low the BMD.
• CHCs are not appro pri ate for addback ther apy.
14. Cosson M, Querleu D, Donnez J, Madelenat P, Konickx P, Audebert A, et al.Dienogest is as effec tive as triptorelin in the treat ment of endometriosisafter lap aro scopic sur gery: results of a pro spec tive, multicenter, ran dom izedstudy. Fertil Steril 2002;77:684–92.
15. Strowitzki T, Seitz C, Marr J, Gerlinger C, Faustmann T. Effi cacy of dienogest for the treat ment of endometriosis: a 24-week, ran dom ised, open-label trialver sus leuprolide ace tate. Abstract pre sented at: 25th Annual Meet ing of the Euro pean Soci ety of Human Repro duc tion and Embry ol ogy; June 28–July1, 2009; Amsterdam.
16. Schlaff WD, Car son SA, Luciano A, Ross D, Bergqvist A. Sub cu ta ne ousinjec tion of depot medroxyprogesterone ace tate com pared with leuprolideace tate in the treat ment of endometriosis-asso ci ated pain. Fertil Steril2006;85:314–25.
17. Crosignani PG, Luciano A, Ray A, Bergqvist A. Sub cu ta ne ous depotmedroxyprogesterone ace tate ver sus leuprolide ace tate in the treat ment of endometriosis-asso ci ated pain. Hum Reprod 2006;21:248–56.
18. Behamondes L, Petta CA, Fernandes A, Monteiro I. Use of levonogesterol-releas ing intrauterine sys tem in women with endometriosis, chronic pel vicpain and dysmenorrhea. Con tra cep tion 2007;75(6 Suppl):S134–9.
19. Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa E Silva JC, et al.Ran dom ized clin i cal trial of a levonorgestrel-releas ing intrauterine sys temand a depot GnRH ana logue for the treat ment of chronic pel vic pain inwomen with endometriosis. Hum Reprod 2005;20:1993–8. Epub 2005 Mar 24.
20. Vercellini P, Aimi G, Panazza S, De Giorgi O, Pesole A, Crosignani PG. A levonorgestrel-releas ing intrauterine sys tem for the treat ment ofdysmenorrhea asso ci ated with endometriosis: a pilot study. Fertil Steril1999;72:505–8.
21. Jain S, Dal ton ME. Choc o late cysts from ovar ian fol li cles. Fertil Steril1999;72:852–6.
22. Fedele L, Bianchi S, Zanconato G, Portuese A, Raffaelli R. Use of alevonorgestrel-releas ing intrauterine device in the treat ment of rectovaginalendometriosis. Fertil Steril 2001;75:485–8.
23. Dmowksi WP, Scholer HF, Mahesh VB, Greenblatt RB. Danazol—asyn thetic ste roid deriv a tive with inter est ing phys i o logic prop er ties. Fertil Steril 1971;22:9–18.
24. Selak V, Farquhar C, Prentice A, Singla A. Danazol for pel vic pain asso ci atedwith endometriosis. Cochrane Data base Syst Rev 2007;(4):CD000068.
25. Packard CJ, Shep herd J. Action of danazol on plasma lipids and lipo pro teinmetab o lism. Acta Obstet Gynecol Scand Suppl 1994;159:35–40.
26. Cottreau CM, Ness RB, Modugno F, Allen GO, Good man MT.Endometriosis and its treat ment with danazol or lupron in rela tion to ovar ian can cer. Clin Can cer Res 2003;9:5142–4.
27. Razzi S, Luisi S, Calonaci F, Altomare A, Bocchi C, Patraglia F. Effi cacy of vag i nal danazol treat ment in women with recur rent deeply infil trat ingendometriosis. Fertil Steril 2007:88:789–94.
28. Barbieri RL. Hor mone treat ment of endometriosis: the estro gen thresh oldhypoth e sis. Am J Obstet Gynecol 1992;166:740–5.
29. Sur rey ES, Hornstein MD. Pro longed GnRH ago nist and add-back ther apyfor symp tom atic endometriosis: long-term fol low-up. Obstet Gynecol2002;99(5 Pt 1):709–19.
30. Mitwally MF, Gotlieb L, Cas per RF. Pre ven tion of bone loss andhypoestrogenic symp toms by estro gen and inter rupted pro ges to genadd-back in long-term GnRH-ago nist down-reg u lated patients withendometriosis and premenstrual syn drome. Meno pause 2002;9:236–41.
31. Hornstein MD, Sur rey ES, Weisberg GW, Casino LA. Leuprolide ace tatedepot and hor monal add-back in endometriosis: a 12-month study. LupronAdd-Back Study Group. Obstet Gynecol 1998;91:16–24.
32. Zupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C, et al.Add-back ther apy in the treat ment of endometriosis-asso ci ated pain. Fertil Steril 2004;82:1303–8.
33. Bedaiwy MA, Cas per RF. Treat ment with leuprolide ace tate and hor monaladd-back for up to 10 years in stage IV endometriosis patients with chronicpel vic pain.Fertil Steril 2006;86:220–2.
34. Cas per RF. Estro gen with inter rupted progestin HRT: a review ofexper i men tal and clin i cal stud ies. Maturitas 2000;34:97–108.
35. Bulun SE, Zeitoun KM, Takayama K, Sasano H. Estro gen biosynthesis in endometriosis: molec u lar basis and clin i cal rel e vance. J Mol Endocrinol2000;25(1):35–42.
36.Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE. Treat ment of endometriosis and chronic pel vic pain with letrozole and norethindroneace tate: a pilot study. Fertil Steril 2004;81:290–6.
37. Amster dam LL, Gen try W, Jobanputra S, Wolf M, Rubin SD, Bulun SE.Anastrazole and oral con tra cep tives: a novel treat ment for endometriosis.Fertil Steril 2005;84:300–4.
38. Hig gins MJ, Davidson NE. What is the cur rent sta tus of ovar ian sup pres sion/abla tion in women with premenopausal early-stage breast can cer? CurrOncol Rep 2009;11:45–50.
Endometriosis: Diagnosis and Management
S14 l JULY JOGC JUILLET 2010
CHAPTER 4
Sur gi cal Man age ment of Endometriosis
Endometriosis should only be treated when either pain
or infer til ity is a pre sent ing symp tom. As an inci den tal
find ing at the time of sur gery, endometriosis does not
require any med i cal or sur gi cal treat ment. Sus pected ovar ian
endometriomas or pel vic masses should be eval u ated
accord ing to the SOGC guide lines for pel vic masses.1
The sur gi cal man age ment of endometriosis involves care ful
con sid er ation of the indi ca tions for sur gery, pre op er a tive
eval u a tion, sur gi cal tech niques, sur geon expe ri ence, and
ancil lary tech niques and pro ce dures.
INDICATIONS
Sur gi cal man age ment of endometriosis is indi cated in the
fol low ing groups.
1. Patients with pel vic pain
a. who do not respond to, decline, or have contra-indications to med i cal ther apy
b. who have an acute adnexal event (adnexal tor sionor ovar ian cyst rup ture)
c. who have severe inva sive dis ease involv ing thebowel, blad der, ureters, or pel vic nerves
2. Patients who have or are sus pected to have an ovar ian
endometrioma
a. Patients for whom the uncer tainty of the diag no sisaffects man age ment (as with chronic pel vic pain)
b. Patients with infer til ity and asso ci ated factors(i.e. pain or a pel vic mass)
Rec om men da tions
1. An asymp tom atic patient with an inci den tal find ing ofendometriosis at the time of sur gery does not require any med i cal or sur gi cal inter ven tion. (III-A)
2. Sur gi cal man age ment in women with endometriosis-related pain should be reserved for those in whom med i caltreat ment has failed. (III-A)
PRE OP ER A TIVE EVAL U A TION
A com plete pre op er a tive eval u a tion will assist in plan ning
the sur gi cal approach, intraoperative tim ing, and the need
for addi tional pro ce dures and con sul ta tions.
The value of a serum CA-125 test in pre op er a tive detec tion
of endometriosis is lim ited. There fore, the test is not rec -
om mended rou tinely before sur gery but may be per formed
as part of the eval u a tion of an undiagnosed adnexal mass.
Pel vic ultrasonography, par tic u larly transvaginal, is rec om -
mended when an adnexal mass is sus pected from phys i cal
exam i na tion. Transrectal sonography, colonoscopy, bar ium
enema radi og ra phy, and MRI may also be use ful to detect
deeply infil trat ing endometriosis of the bowel and
rectovaginal sep tum in patients with dyschezia and in those
with deep dyspareunia with nodularity on exam i na tion.
Cystoscopy should be per formed if there are cyclic blad der
symp toms such as hematuria.
Risks asso ci ated with sur gery should be thor oughly dis -
cussed with the patient, and informed con sent should be
obtained and doc u mented.
SUR GI CAL APPROACH
Sur gery may be either “con ser va tive” or “defin i tive.” Con -
ser va tive sur gi cal man age ment of endometriosis has the
goal of restor ing nor mal anat omy and reliev ing pain. This
approach is most often applied to women of reproductive age
who wish to con ceive in the future or to avoid induc tion of
JULY JOGC JUILLET 2010 l S15
CHAPTER 4
Clin i cal Tip
The deci sion to move to sur gery in women with pain and sus pected endometriosis should be based onclin i cal eval u a tion, imag ing, and effec tive ness ofmed i cal treat ment. The role of diag nos tic laparoscopy should be lim ited.
Clin i cal Tip
Imag ing should be based on the clin i cal presentationand find ings on phys i cal exam i na tion.
meno pause at an early age. It may involve direct abla tion,
lysis, or exci sion of lesions, inter rup tion of nerve path ways,
removal of ovar ian endometriomas, and exci sion of lesions
invad ing adja cent organs (bowel, blad der, appen dix, or ureter).
Defin i tive sur gery involves bilat eral oophorectomy to
induce meno pause and may include removal of the uterus
and fal lo pian tubes and, ide ally, exci sion of all vis i ble
endometriotic nod ules and lesions. It should be con sid ered
in women who have sig nif i cant pain and symp toms despite
con ser va tive treat ment, do not desire future preg nan cies
and have severe dis ease, or are under go ing hys ter ec tomy
because of other pel vic con di tions, such as fib roids or
menorrhagia.
Lap a ros copy is the pre ferred route for sur gi cal man age ment
of endometriosis, irre spec tive of sever ity, owing to the
greater visu al iza tion through a mag ni fied view and the
quicker patient recov ery and return to nor mal activ ity when
com pared with laparotomy.2 Patients with inva sive
endometriosis, includ ing bowel and blad der involve ment,
should be referred to those with expe ri ence or advanced
train ing in man ag ing these cases through a multidisciplinary
approach.3
SURGICAL OUTCOMES
Only a few RCTs have eval u ated the sur gi cal treat ment of
endometriosis. Ben e fit does appear to exist for lap aro scopic
man age ment of endometriosis. In 1994 Sutton et al.4
described the first pro spec tive RCT on this topic, in
63 women, and showed a ben e fit in more of those treated
with laser lap aro scopic abla tion and uterosacral nerve abla tion
than those treated with expec tant man age ment: 63% ver sus
23%. A fol low-up study showed that more than half of the
women under go ing abla tion were sat is fied with the treatment
after a mean of 73 months.5 In 2004, Abbott et al.6 dem on -
strated, in a group of 39 women, ben e fit 6 months after
surgery in more of those treated with lap aro scopic exci sion
of endometriotic lesions than those under go ing diag nos tic
lap a ros copy: 80% ver sus 32%. The dif fer ence in study
outcome may be attrib uted to more advanced dis ease in the
lat ter trial or to the use of exci sion ver sus laser abla tion, or a
com bi na tion of fac tors. Despite the ben e fits illus trated, it is
impor tant to note that a sub stan tial pro por tion of women
(20% to 40%) may not show improve ment after sur gery.
There is insuf fi cient evi dence as to whether super fi cial
endometriotic lesions should be excised or ablated in the
treat ment of pain. No dif fer ence in out come was illus trated
through a small RCT by Wright et al.7 in 2005. This study
included only cases of mild endometriosis and excluded
those of deeply infil trat ing dis ease and more severe dis ease.
Shakiba et al.8 in 2008 described one of the lon gest fol low-up
studies of the sur gi cal man age ment of endometriosis. This
ret ro spec tive study cal cu lated the risk of reoperation at 2, 5,
and 7 years after the ini tial oper a tions, which included lap -
aro scopic con ser va tive sur gery (pre serv ing the ova ries),
hys ter ec tomy with ovar ian pres er va tion, hys ter ec tomy with
removal of 1 ovary, and hys ter ec tomy with removal of both
ova ries. By 2 years, no fur ther sur gery had been required for
80% of the women who under went local exci sion of
endometriotic lesions ver sus 96% of those who had
undergone hys ter ec tomy with ova ries pre served. Thus, hys -
ter ec tomy may ben e fit patients with pel vic pain due to
endometriosis even with ovar ian pres er va tion.
Sum mary State ment
1. Treatment of endometriosis by exci sion or abla tionreduces pain. (I)
DEEPLY INFIL TRAT ING ENDOMETRIOSIS
In con trast to super fi cial peritoneal endometriosis, deeply
infil trat ing endometriosis refers to lesions that pen e trate
5 mm or more. See Table 4.1 for exam ples. The lesions are
often multifocal and deeper than is appre ci ated by visu al iza tion
alone. A depth greater than 10 mm is related to pain.9
Excision of these lesions is likely to be of greater ben e fit in
terms of pain relief than exci sion of super fi cial dis ease, but
the evi dence is lim ited to reports on case series in expert
hands.10,11
Sur gery in cases of rectovaginal infil tra tion, with involve -
ment of the pel vic lat eral side wall or bowel, requires a
multidisciplinary approach. Pre op er a tive con sul ta tion with
another gynae colo gist expe ri enced in min i mally inva sive
sur gery as well as a gen eral sur geon or urol o gist is rec om -
mended. Bowel resec tion may be required for pain relief12,13
and should be per formed by those with exper tise and expe -
ri ence in this approach. Often this may be done by a
laparoscopy-assisted approach, for quicker patient
recov ery.
Endometriosis: Diagnosis and Management
S16 l JULY JOGC JUILLET 2010
Table 4.1. Exam ples of deeply infil trat ing endometriosis
Rectovaginal nod ule
Bowel inva sion and con stric tion
Blad der inva sion
Ureteric inva sion or com pres sion
Nerve involve ment (e.g., sci atic nerve)
When deeply infil trat ing endometriosis is diag nosed only at
the time of diag nos tic lap a ros copy, it is pref er a ble to avoid
imme di ate exci sion. One should first obtain informed con -
sent and con duct a proper pre op er a tive eval u a tion owing to
the com plex nature of the dis ease.
Rec om men da tion
3. Surgical treat ment of deeply infil trat ing endometriosis mayrequire par tic u lar expe ri ence with a multidisciplinaryapproach. (III-A)
OVARIAN ENDOMETRIOMAS
Ovar ian endometriomas indi cate severe dis ease and pres ent
a sur gi cal man age ment chal lenge.14 It is impor tant to con -
sider the patient’s desire for fer til ity in order to deter mine
the level of inter ven tion required to pre serve the ova ries
and their func tion. Sur gi cal options include exci sion of the
cyst wall or drain age and coag u la tion of the cyst bed.
A recent Cochrane review,15 although based on only
2 RCTs16,17 and a total of 164 women, sug gests that
laparoscopic exci sion pro vides more ben e fits than sim ple
laparoscopic abla tion of ovar ian endometriomas for pel vic
pain. Exci sion resulted in reduced rates of endometrioma
recur rence, dysmenorrhea, dyspareunia, non-menstrual
pelvic pain, and require ment for fur ther sur gery. The
cumulative preg nancy rate was higher in the women who
underwent cystectomy.
Although there are ben e fits to lap aro scopic exci sion of
ovar ian endometriomas, this tech nique has been asso ci ated
with inad ver tent removal of nor mal ovar ian tis sue.18 Great
care must be exer cised to pre serve ovar ian tis sue dur ing the
exci sion. After the risks of inad ver tent removal of nor mal
ovar ian tis sue and the ben e fits of cyst exci sion are weighed,
the deci sion to treat endometriomas sur gi cally must be
based on clin i cal pre sen ta tion and sur geon pref er ences. It is
rea son able to sug gest exci sion of larger endometriomas
(> 3 cm in diam e ter) in the pres ence of pel vic pain but sim ple
drain age and abla tion or expectant man age ment of smaller
cysts.
Ovar ian endometriomas recur in up to 30% of patients after
laparoscopic exci sion.19 Postoperative hor monal suppression
has been shown to result in a lower recur rence rate and better
man age ment of symp toms.20,21 In patients not seek ing
pregnancy, CHC ther apy (cyclic or con tin u ous) should be
con sid ered after sur gery. Since the risk of malig nant dis ease
is low and there is no evi dence of improved fer til ity as an
out come, the deci sion about repeat sur gery should be based
on symp toms and size of the cyst: the greater the pain or the
size, the more likely the need for a repeat pro ce dure.
Sum mary State ment
2. For women with endometriomas, exci sion rather thandrain age or fulguration pro vides better pain relief, areduced recur rence rate, and a histopathological diag no sis. (I)
Rec om men da tions
4. Ovar ian endometriomas greater than 3 cm in diam e ter inwomen with pel vic pain should be excised if pos si ble. (I-A)
5. In patients not seek ing preg nancy, ther apy with CHCs(cyclic or con tin u ous) should be con sid ered after sur gi cal man age ment of ovar ian endometriomas. (I-A)
ADDITIONAL SURGICAL INTERVENTIONS
Sev eral sur gi cal pro ce dures have been used in addi tion to
abla tion or exci sion of endometriotic lesions to fur ther
improve pain relief. Lap aro scopic uterosacral nerve abla tion
has not been shown to be effec tive for chronic pain relief in
a large ran dom ized con trol trial.22 How ever, upstream
interruption of the presacral nerves (presacral neurectomy)
has dem on strated some midline pain relief in women with
endometriosis.23–25 Lap aro scopic presacral neurectomy is
both fea si ble and pre ferred over laparotomy when
conducted by expe ri enced endo scopic sur geons.
Appen dec tomy has been advo cated in patients with chronic
pel vic pain. The appen dix may be affected by
endometriosis, chronic inflam ma tion, or other dis or ders in
patients with endometriosis.26,27 At the time of lap a ros copy,
the appen dix should be iden ti fied, if pos si ble, and its
appear ance noted. Lap aro scopic appen dec tomy should be
con sid ered if the appen dix is obvi ously abnor mal; how ever,
patient con sent, sur gi cal con sul ta tions, and perioperative
risk need to be con sid ered.
Chapter 4: Surgical Management of Endometriosis
JULY JOGC JUILLET 2010 l S17
Clin i cal Tips
• With ovar ian endometriomas it is impor tant tocon sider the patient’s desire for fer til ity in orderto deter mine the level of inter ven tion required to pre serve the ova ries and their func tion.
• Ovar ian endometriomas are often a marker of more exten sive endometriosis.
Uter ine sus pen sion has been advo cated to cor rect the
retroverted uterus in women with dyspareunia. There is no
report of an inde pend ent trial whose results con firm the
effec tive ness or clin i cal util ity of this pro ce dure.
Sum mary State ment
3. Lap aro scopic uter ine nerve abla tion alone does notoffer sig nif i cant relief of endometriosis-related pain. (I)
Rec om men da tions
6. Presacral neurectomy may be con sid ered as an adjunct tothe sur gi cal treat ment of endometriosis-related pel vicpain. (I-A)
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2. Crosignani PG, Vercellini P, Biffignandi F, Costantini W, Cortesi I,Imparato E, et al. Lap a ros copy ver sus laparotomy in con ser va tive sur gi caltreat ment for severe endometriosis. Fertil Steril 1996;66:706–11.
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17. Alborzi S, Momtahan M, Parsanezhad ME, Dehbashi S, Zolghadri J. A pro spec tive, ran dom ized study com par ing lap aro scopic ovar iancystectomy ver sus fen es tra tion and coag u la tion in patients withendometriomas. Fertil Steril 2004;82:1633–7.
18. Matsuzaki S, Houlle C, Darcha C, Pouly JL, Mage G, Canis M. Anal y sis ofrisk fac tors for the removal of nor mal ovar ian tis sue dur ing lap aro scopiccystectomy for ovar ian endometriosis. Hum Reprod 2009;24:1402–6. Epub2009 Feb 26.
19. Koga K, Takemura Y, Osuga Y, Yoshino O, Hirota Y, Hirata T, et al.Recur rence of ovar ian endometrioma after lap aro scopic exci sion. HumReprod 2006;21:2171–4. Epub 2006 Apr 27.
20. Seracchioli R, Mabrouk M, Manuzzi L, Vicenzi C, Frascà C, Elmakky A, et al.Post-oper a tive use of oral con tra cep tive pills for pre ven tion of ana tom i calrelapse or symp tom-recur rence after con ser va tive sur gery for endometriosis. Hum Reprod 2009;24:2729–35. Epub 2009 Jul 22.
21. Seracchioli R, Mabrouk M, Frascà C, Manuzzi L, Savelli L, Venturoli S.Long-term oral con tra cep tive pills and post op er a tive pain man age ment after lap aro scopic exci sion of ovar ian endometrioma: a ran dom izedcon trolled trial. Fertil Steril 2009 May 12. Epub ahead of print.
22. Daniels J, Gray R, Hills RK, Lathe P, Buckley L, Gupta J, et al.; LUNDTrial Collaboration. Lap aro scopic uterosacral nerve abla tion for alle vi at ingchronic pel vic pain: a ran dom ized con trolled trial. JAMA 2009;302:955—61.
23. Candiani GB, Fedele L, Vercellini P, Bianchi S, Di Nola G. Presacralneurectomy for the treat ment of pel vic pain asso ci ated with endometriosis:a con trolled study. Am J Obstet Gynecol 1992;167:100–3.
24. Zullo F, Palomba S, Zupi E, Russo T, Morelli M, Cappiello F, et al.Effec tive ness of presacral neurectomy in women with severe dysmenorrheacaused by endometriosis who were treated with lap aro scopic con ser va tivesur gery: a 1-year pro spec tive ran dom ized dou ble-blind con trolled trial. Am J Obstet Gynecol 2003;189:5–10.
25. Zullo F, Palomba S, Zupi E, Russo T, Morelli M, Sena T, et al. Long-termeffec tive ness of presacral neurectomy for the treat ment of severedysmenorrhea due to endometriosis. J Am Assoc Gynecol Laparosc2004;11:23–8.
26. Frishman GN, Salak JR. Con ser va tive sur gi cal man age ment ofendometriosis in women with pel vic pain. J Minim Inva sive Gynecol2006;13:546–58.
27. Wie HJ, Lee JH, Kyung MS, Jung US, Choi JS. Is inci den tal appen dec tomynec es sary in women with ovar ian endometrioma? Aust N Z J ObstetGynaecol 2008;48:107–111.
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CHAPTER 5
Surgical Management of Infertility AssociatedWith Endometriosis
Treat ment of infer til ity caused by endometriosis con sists
of either sur gi cal removal of endometriotic tis sue with
adhesiolysis in order to restore nor mal anat omy or assisted
repro duc tive tech nol ogy. Sur gery is pref er a bly per formed
by lap a ros copy because the rate of com pli ca tions other than
major ones is approx i mately 40% lower than that of
laparotomy.1 Lap a ros copy is asso ci ated with shorter
hospitalization and recov ery time than laparotomy, but the
effec tive ness of the 2 sur gi cal approaches seems to be
identical, even though lap a ros copy is less adhesiogenic.2
INDICATIONS FOR LAPAROSCOPY
No pain; nor mal results of pel vic exam i na tion
In infer tile women with nor mal results of pel vic examinationand reg u lar ovu la tion, bilat er ally pat ent fal lo pian tubesaccord ing to hysterosalpingography, and a nor malspermogram of the male part ner, the addi tional ben e fit ofdiag nos tic lap a ros copy with con com i tant treat ment of min imalendometriosis is still con tro ver sial. One pro spec tive RCTcould not find a dif fer ence in preg nancy rates between thetreat ment and no treat ment groups.3 How ever, a largerCana dian study proved diag nos tic lap a ros copy withconcomitant treat ment of min i mal and mild endometriosisto be effec tive and worthwhile.4 The effi ciency of thisprocedure (that is, the num ber needed to treat), how ever, isquite deceiv ing: only 1 addi tional preg nancy will resultamong every 8 patients under go ing lap aro scopic sur gery.Because of lim ited access to pub lic fund ing for assistedrepro duc tive tech nol ogy, many women and their phy si cians choose laparoscopy. Some national spe cialty soci et ies,indeed, rec om mend lap a ros copy in such cases.5
The deci sion to per form diag nos tic lap a ros copy in infer tilewomen with no other appar ent prob lem should be made on an indi vid ual basis, accord ing to the woman’s age and afterdis cus sion about the ben e fits and risks of sur gery, as well asother options, such as ovu la tion induc tion and IVF.
Pain or abnor mal results of pel vic exam i na tion
Lap a ros copy is also indi cated in the fol low ing instances.
1. When there is deep dyspareunia, severe dysmenorrhea, dyschezia, or chronic pel vic pain that is severe enough to cause dis tress: then the like li hood of find ingendometriosis at lap a ros copy is greatly increased.6
Surgery is indi cated not only to improve fer til ity butalso to ame lio rate pain.
2. When ten der nod ules are pal pated in the uterosacralligaments: this find ing should alert one to the possibility of deeply infil trat ing endometriosis.7 Surgical exci sionof deep endometriotic lesions has been asso ci atedwith improved fer til ity in 1 study.8
3. When there is a per sis tent adnexal mass: in approx i mately48% of infer tile patients under go ing diag nos tic lap a -ros copy, there is evi dence of endometriotic lesions ofthe ovary, from super fi cial implants to large cysts upto 12 cm in diam e ter.9 Ultrasonography, par tic u larlytransvaginal, has been shown to be both sen si tive(84% to 90%) and spe cific (almost 100%) for thediagnosis of endometrioma.10 Endometriomas maybe asymp tom atic or can cause pain from distention orrup ture. Sur gi cal removal is often rec om mended forthose with a diam e ter greater than 3 cm. Stud iesmore than a decade ago dem on strated that med i calman age ment, inde pend ent of the pre scribed prod uct,led to a reduc tion in the size of the endometrioma but not to com plete regres sion.11,12 In addi tion, sur gi calexplo ra tion is war ranted if there is a con cern aboutmalig nant dis ease.13
SUR GI CAL PRIN CI PLES AND TECH NIQUES
Lap a ros copy is the pre ferred sur gi cal approach for treat -ment of infer til ity related to endometriosis. The goal oflaparoscopic sur gery is to remove endometriotic lesions asmuch as pos si ble, restore nor mal anat omy withadhesiolysis, and opti mize ovar ian and tubal pres er va tionand integ rity with use of the prin ci ples of micro sur gery(mag ni fi ca tion, dil i gent hemostasis, reduced fulguration,avoid ance of tis sue dry ing, and lim ited use of sutures).14
JULY JOGC JUILLET 2010 l S19
CHAPTER 5
Lap aro scopic eval u a tion
This pro ce dure is con ducted to estab lish the sever ity of thedis ease by stag ing and look ing at other areas, such as appendix, bowel, and dia phragm. In addi tion, any adnexal mass can be eval u ated by peritoneal cytol ogy and frozen sec tion in caseof doubt. The blue dye test can be per formed to eval u atetubal patency.
Adhesiolysis
Adhesiolysis is per formed to restore nor mal anat omy asmuch as pos si ble. With the adhe sions under ten sion, theyare divided far from the most vital struc ture. The ova ries are freed from their adhe sions to the pel vic side wall before anyovar ian cyst is removed; this pro cess will often rup ture theendometrioma and enable cystectomy.
Treat ment of super fi cial endometriosis
With regard to improve ment of fer til ity, there is no evidencethat exci sion is better than abla tion, and any modal ity usedfor abla tion (electrosurgery or laser) has the same effec tive ness.4
Treat ment of endometriomas and deeply infil trat ing
endometriosis
See Chapter 4 for a descrip tion of the sur gi cal approach.
Adhe sion-pre ven tion adjuncts
Even when surgery is per formed by lap a ros copy, adhe sions can occur, and for many pro ce dures the adhe sion-relatedcom pli ca tions of open and lap aro scopic gynaecologic sur geryare sim i lar.15 Phar ma co logic agents such as anti bi ot ics,corticosteroids, NSAIDs, and fibrinolytics have not beenproven effec tive. Many types of phys i cal sep a ra tors areavail able in Can ada. Other agents include gel bar ri ers, suchas 4% icodextrin solu tion (Adept). Although these agentsare poten tially use ful, and there is some clin i cal evi dence for
the reduc tion of adhe sion for ma tion, research into moreeffec tive pre ven tive agents is required since improve mentin fer til ity from the use of these agents is still unknown.14
Sum mary State ments
1. Lap aro scopic treat ment of min i mal or mildendometriosis improves preg nancy rates regard less ofthe treat ment modal ity. (I)
2. The effect on fer til ity of sur gi cal treat ment of deeplyinfil trat ing endometriosis is con tro ver sial. (II)
3. Lap aro scopic exci sion of ovar ian endometriomasmore than 3 cm in diam e ter may improve fer til ity. (II)
REFERENCES
1. Fuller J, Ashar BS, Carey-Corrado J. Trocar-asso ci ated inju ries and fatal i ties: an anal y sis of 1399 reports to the FDA. J Minim Inva sive Gynecol2005;12:302–7.
2. Winkel CA. Eval u a tion and man age ment of women with endometriosis.Obstet Gynecol 2003;102:397–408.
3. Parazzini F. Abla tion of lesions or no treat ment in min i mal– mildendometriosis in infer tile women: a ran dom ized trial. Gruppo Italiano per lo Stu dio dell’Endometriosi. Hum Reprod 1999;14:1332–4.
4. Marcoux S, Maheux R, Bérubé S. Lap aro scopic sur gery in infer tile womenwith min i mal or mild endometriosis. Cana dian Col lab o ra tive Group onEndometriosis. N Engl J Med 1997;337:217–22.
5. Royal Col lege of Obste tri cians and Gynae colo gists. The inves ti ga tion andman age ment of endometriosis (green-top guide line; no. 24). Lon don(Eng land): RCOG;2006:3.
6. Scarselli G, Rizzello F, Cammilli F, Ginocchini L, Coccia ME. Diag no sisand treat ment of endometriosis. A review. Minerva Ginecol 2005;57:55–78.
7. Cornillie FJ, Oosterlynck D, Lauweryns JM, Konickx PR. Deeply infil trat ing pel vic endometriosis: his tol ogy and clin i cal sig nif i cance. Fertil Steril1990;53:978–83.
8. Capron C, Fritel X, Dubuisson JB. Fer til ity after lap aro scopic man age mentof deep endometriosis infil trat ing the uterosacral lig a ments. Hum Reprod1999;14:329–32.
9. Rock JA, Breech LL. Surgery for anomalies of the Müllerian ducts. In: Rock JA, Jones HW, eds. Te Linde’s Operative gynecology. 9th ed. Philadelphia:Lippincott Williams & Wilkins; 2003.
10. Somigliana E, Vercellini P, Viganó P, Ragni G, Crosignani PG. Shouldendometriomas be treated before IVF-ICSI cycles? Hum Reprod2006;21:57–64.
11. Donnez J, Nisolle-Pochet M, Clerckx-Braun F, Sandow J, Casanas-Roux F.Admin is tra tion of nasal buserelin as com pared with sub cu ta ne ous buserelinimplant for endometriosis. Fertil Steril 1989;52:27–30.
12. Rana N, Thomas S, Rotman C, Dmowski WP. Decrease in the size of ovar ian endometriomas dur ing ovar ian sup pres sion in stage IVendometriosis. Role of pre op er a tive med i cal treat ment. J Reprod Med1996;41:384–92.
13. Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Can cer risk after a hos pi tal dis charge diag no sis of endometriosis. Am J Obstet Gynecol1997;176:572–9.
14. DeWilde RL, Trew RG. Post op er a tive abdom i nal adhe sions and theirpre ven tion in gynae co logi cal sur gery. Expert con sen sus posi tion. Part 2 –steps to reduce adhe sions. Gynecol Surg 2007;4:243–53.
15. Lower AM, Haw thorn RJ, Ellis H, O’Brien F, Buchan S, Crowe AM. The impact of adhe sions on hos pi tal readmissions over ten years after 8849 open gynae co logi cal oper a tions: an assess ment from the Sur gi cal andClin i cal Adhe sions Research Study. Br J Obstet Gynaecol 2000;107:855–62.
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Clin i cal Tips
• Adher ence to prin ci ples of micro sur gery such asdiligent hemostasis, reduced fulguration, and lim ited use of sutures may improve fer til ity.
• Exci sion is pre ferred over fen es tra tion, drain age, or abla tion of the cyst lin ing for the treat ment of an ovar ian endometrioma.
• Use of adhe sion-pre ven tion adjuncts may help reduce adhe sion for ma tion but improve ment in fer til ityis unknown.
CHAPTER 6
Med i cal Treat ment of Infer til ity Related toEndometriosis
The prev a lence of endometriosis in infer tile women
ranges from 25% to 50% com pared with 5% in fer tile
women.1 A com plete under stand ing of the mech a nisms
caus ing endometriosis-asso ci ated infer til ity remains elu sive.
Dis tor tion of pel vic anat omy by adhe sions, result ing in
mechan i cal block age of the fal lo pian tubes or impaired
ovum release from the ovary may explain infer til ity in more
advanced stages of endometriosis; how ever, in min i mal or
mild endometriosis the mech a nism is not clear. A recent
review points to the roles of inflam ma tion, immune
response, and angiogenesis in a com plex patho logic pro cess
impair ing fer til ity in early-stage endometriosis.2
There is an observed asso ci a tion between endometriosis
and infer til ity, although a causal rela tion ship has not been
proven. Monthly fecun dity is lower in women with
endometriosis than in women with out this con di tion, and
there is a higher prev a lence of endometriosis in infer tile
women than in fer tile women under go ing tubal liga tion.3
The most con vinc ing evi dence for an asso ci a tion between
endometriosis and infer til ity comes from a pro spec tive
study of ther a peu tic donor insem i na tion in which monthly
fecun dity was 0.12 in women with out endometriosis and
0.036 in those with min i mal endometriosis.4 It also appears
that the lesions of endometriosis play lit tle role in any
poten tial cause of infer til ity: a pro spec tive RCT of lap aro -
scopic abla tion of endometriotic lesions com pared with
expectant man age ment showed a slightly increased fecun -
dity rate in the 9 months after treat ment,5 but the rate was
still sig nif i cantly lower than that observed in nor mal fer tile
women.6 To date, there is no con vinc ing evi dence for a
plau si ble bio logic mech a nism of infer til ity in patients with
mild to mod er ate endometriosis.
HOR MONAL TREAT MENT
Hughes et al.7 con ducted a meta-anal y sis of all RCTs of
ovu la tion sup pres sion in women with endometriosis and
the effect on fer til ity. The results sug gested that sup press ing
ovar ian func tion to improve fer til ity in min i mal to mild
endometriosis is not effec tive and should not be offered for
this indi ca tion alone. In addi tion, hor monal sup pres sion
before or after sur gi cal treat ment of endometriosis is
contraindicated since there is no evi dence of increased
effec tive ness over that of sur gery alone, and the treat ment
pro longs or delays the oppor tu nity for con cep tion to occur.
ASSISTED REPRO DUC TION
There is some evi dence from RCTs that intrauterine insem -
i na tion together with con trolled ovar ian stim u la tion may be
effec tive in improv ing fer til ity in patients with
endometriosis.8 The effect appears to be pre dom i nantly due
to the ovar ian stim u la tion, since intrauterine insem i na tion
alone may not be ben e fi cial.
IN VITRO FERTILIZATION
Hor monal sup pres sion for pre-treat ment may be of use in
patients with endometriosis and infer til ity who undergo
IVF. It appears that IVF suc cess rates are slightly lower in
patients with endometriosis than in those with other diag -
no ses.9 How ever, sev eral stud ies sug gest that women with
chronic or advanced endometriosis will ben e fit from long-
term treat ment with a GnRH ago nist before an IVF cycle.
Sallam et al.10 reviewed 3 RCTs of 165 women treated with IVF
for infer til ity related to endometriosis. The clin i cal preg nancy
rate per woman was sig nif i cantly higher in those receiv ing
GnRH ago nist downregulation for 3 to 6 months before
IVF than in the con trol group (OR 4.28, 95% CI 2.0 to 9.15).
In addi tion, 1 of the stud ies that reported live birth rates also
showed a sig nif i cant benefit from pre-treat ment with a
GnRH ago nist.
CON CLU SION
It appears that med i cal man age ment of infer til ity in the
form of hor monal sup pres sion is not effec tive in improv ing
fecun dity rates in patients with endometriosis and should
not be offered. On the other hand, the use of GnRH ago nist
sup pres sion of ovar ian func tion for 3 to 6 months before an
JULY JOGC JUILLET 2010 l S21
CHAPTER 6
IVF cycle may improve the rates of clin i cal preg nancy and
live birth in endometriosis patients.
Sum mary State ment
1. If a patient with known endometriosis is to undergoIVF, GnRH ago nist sup pres sion with HT addback for 3to 6 months before IVF is asso ci ated with an improvedpreg nancy rate. (I)
Rec om men da tion
1. Med i cal man age ment of infer til ity related toendometriosis in the form of hor monal sup pres sion isinef fec tive and should not be offered. (I-E)
REFERENCES
1. Littman E, Giudice L, Lathi R, Berker B, Milki A, Nezhat C. Role oflap aro scopic treat ment of endometriosis inpa tients with failed in vitrofer til iza tion cycles. Fertil Steril 2005;84:1574–8.
2. Bulun SE. Endometriosis. N Engl J Med 2009;360:268–79.
3. D’Hooghe T, Debrock S, Hill JA, Mauleman C. Endometriosis andsubfertility: is the rela tion ship resolved? Semin Reprod Med2003;21:243–54.
4. Jansen RP. Min i mal endometriosis and reduced fecundability: pro spec tiveevi dence from an arti fi cial insem i na tion by donor pro gram. Fertil Steril1986;46(1):141–3.
5. Marcoux S, Maheux R, Bérubé S; Cana dian Col lab o ra tive Group onEndometriosis. Lap aro scopic sur gery in infer tile women with min i mal ormild endometriosis. N Engl J Med 1997;337:217–22.
6. Schwartz D, Mayaux MJ. Female fecun dity as a func tion of age: results of arti fi cial insem i na tion in 2193 nulliparous women with azoospermichus bands. Fed er a tion CECOS. N Engl J Med 1982;307:404–6.
7. Hughes E, Brown J, Col lins JJ, Farquhar C, Fedorkow DM,Vandekerckhove P. Ovu la tion sup pres sion for endometriosis. CochraneData base Syst Rev 2007 Jul18;(3):CD000155.
8. Tummon IS, Asher LJ, Mar tin JS, Tulandi T. Ran dom ized con trolled trialof superovulation and insem i na tion for infer til ity asso ci ated with min i malor mild endometriosis. Fertil Steril 1997;68:8–12.
9. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fer til iza tion. Fertil Steril 2002;77:1148–55.
10. Sallam HN, Gar cia-Velasco JA, Dias S, Arici A. Long-term pitu itarydown-reg u la tion before in vitro fer til iza tion (IVF) for women withendometriosis. Cochrane Data base Syst Rev 2006 Jan 25;(1):CD004635.
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S22 l JULY JOGC JUILLET 2010
Clin i cal Tips
• Three months of sup pres sion with a GnRHago nist and HT addback before IVF in womenwho have pel vic pain and infer til ity asso ci atedwith endometriosis will greatly improve qual ityof life and reduce dis com fort dur ing ovar ianstim u la tion and oocyte retrieval.
• Women with endometriosis-related infer til ity over the age of 35 years should be referred for IVF.
Chap ter 7
Endometriosis in Ado les cents
Endometriosis is rec og nized to be a cause of both painand infer til ity in women of repro duc tive age. How ever,
it is increas ingly appar ent that symp toms of endometriosismay begin in ado les cence. The pre sen ta tion ofendometriosis in this age group may vary from that of adultwomen. It is impor tant for health care pro vid ers assess ingyoung women with pel vic pain and dysmenorrhea to considerendometriosis in their dif fer en tial diag no sis to avoid delaysin diag no sis and man age ment.
The Endometriosis Asso ci a tion reg is try reports that 38% of women with endometriosis had symp toms start ing beforeage 15 years and that when symp toms begin before age 15an aver age of 4.2 phy si cian con sul ta tions is required beforea diag no sis is reached, more than in any other age group.1
Early diag no sis and refer ral will help young women receivethe nec es sary edu ca tion about their symp toms andappropriate treat ment.
PRE SEN TA TION
Ini tial delay in the diag no sis of endometriosis in ado les cents may in part be because the pain is attrib uted to pri marydysmenorrhea and hence a “nor mal” part of grow ing up.When pel vic pain inter feres with daily activ i ties (such asschool and work) it requires atten tion and man age ment.Ten per cent of dysmenorrhea in ado les cents is sec ond ary to other con di tions.2
Sec ond ary dysmenorrhea should be sus pected in patientsnot respond ing to first-line agents (NSAIDs and CHCs) for the treat ment of pri mary dysmenorrhea.3 Endometriosis isthe most com mon cause of sec ond ary dysmenorrhea inado les cents.2 As pri mary dysmenorrhea occurs with theestab lish ment of ovulatory cycles (in mid- and late ado les cence), the onset of dysmenorrhea soon after the onset of menarche(within the first 6 months) should raise the con sid er ation ofa sec ond ary cause and, in par tic u lar, asym met ri callyobstructed out flow tracts with Müllerian anom a lies. Coex -is tence of endometriosis and obstructed out flow tracts ispre sumed to be due in part to excess ret ro grade menstruation.Con gen i tal anom a lies of the repro duc tive tract have beenfound in up to 11% of ado les cents with endometriosis,4,5
and endometriosis is reported to be pres ent in up to 76% ofpatients with Müllerian anom a lies and out flow tractobstruc tion.6 Ini tial sur gery can be lim ited to relief of the
obstruc tion, since this may be fol lowed by res o lu tion of theendometriosis.7,8
Ado les cents with endometriosis have a vari able pain history.Whereas 9.4% will com plain of cyclic pain alone, more than90% have an acy clic pain pat tern with or with outdysmenorrhea.3 As ado les cents may not be sex u ally activewhen they pres ent and are rarely seek ing fer til ity assess -ment, dyspareunia and infer til ity are not part of the usualado les cent symptomatology.
PREV A LENCE
It is hard to pro vide a gen eral prev a lence rate for ado les centendometriosis. Endometriosis has been diag nosed bylaparoscopy among ado les cent girls and young women(under 19 to 21 years) with dysmenorrhea and chronicpelvic pain not con trolled by NSAIDs or CHCs at ratesbetween 35.5% and 70% to 73%.3,9,10
Endometriotic-like lesions (vas cu lar pro lif er a tion, hemo -sid erin depos its, stroma but no endometrial glands) havebeen doc u mented in premenarcheal girls with breast sex ualmatu rity rat ings of I to III and no Müllerian anom a lies.11
Treat ment of the lesions reduced the pel vic pain. Hence,the onset of thelarche may be con sid ered a devel op men talmile stone at which endometriosis should be con sid ered inthe dif fer en tial diag no sis of pel vic pain.
DIAG NO SIS
The approach to diag nos ing endometriosis in ado les centsshould include detailed his tory-tak ing, an age-appro pri atephys i cal exam i na tion, and diag nos tic imag ing. As adolescentsmay have lim ited expe ri ence with seek ing health care forgynaecologic issues, estab lish ing rap port is impor tant.A health risk screen ing tool such as the HEADSS assess -ment12 may assist the health care pro vider. HEADSS is aframe work for his tory-tak ing that begins with top ics theado les cent may have more com fort dis cuss ing and concludes with more sen si tive ques tions: Home or hous ing, Educationand employ ment, Activities, Drugs, Sexual activ ity and sex -u al ity, and Suicide and depres sion. Pri vacy and con fi den ti al -ity should be explained to both the ado les cent and her fam -ily early on in the health care visit.
Com plet ing a pel vic exam i na tion of the young ado les centmay be chal leng ing; how ever, it is valu able to help rule out
JULY JOGC JUILLET 2010 l S23
CHAP TER 7
pel vic masses and obstruc tive out flow tract anom a lies.Flex i bil ity should be applied when decid ing on the extent of an exam i na tion. Whereas patients with a com pletelyobstructed out flow tract (e.g., with an imper fo rate hymenor a trans verse vag i nal sep tum) may pres ent with cyclicpain, they also will have pri mary amenorrhea and often apel vic mass. Inspec tion of the exter nal gen i ta lia, withseparation and trac tion of the labia, may dem on strate lowoutflow tract anom a lies. Rul ing out asym met ric out flowtract anom a lies such as obstruct ing hemivaginal sep tum and non-com mu ni cat ing func tional uter ine horns, which maycause severe cyclic pain, is impor tant. It may be pos si ble toinsert a cot ton-tipped swab into the vagina to ensure that itis of nor mal length if a bimanual and speculum exam i na tion is not pos si ble. A recto-abdom i nal exam i na tion allowspalpation for pel vic masses. For older, sex u ally activeadolescents, a phys i cal exam i na tion is impor tant to rule outother causes of pain, such as pel vic inflam ma tory dis ease,ovar ian cysts, and com pli ca tions of preg nancy.
The phys i cal find ings will often be nor mal in this age groupeven when endometriosis is pres ent. Cul-de-sac nodularity,adnexal masses, and a fixed, retroverted uterus are uncom -mon in ado les cents with endometriosis,11,13 as the dis ease ispre dom i nantly ASRM stage I or II.3,14 Deeply infil trat ingendometriosis, although uncom mon, may occur in ado les -cents. Rectovaginal, uterovesical, full-thick ness bowel, andureteric endometriosis have been diag nosed in this agegroup, although at a median age of 19 years.10
Pel vic imag ing is an adjunct for diag no sis in the ado les cent.If the young patient declines or is unable to have a phys i calexamination, pel vic ultrasonography can assist with providingaddi tional infor ma tion to guide diag no sis and man age ment. Pel vic imag ing with ultrasonography and MRI is essen tial ifa Müllerian anom aly is sus pected.
MAN AGE MENT
Empiric treat ment with NSAIDs and CHCs is appro pri atefor most ado les cents with dysmenorrhea.15 How ever,patients who do not respond to these med i ca tions requireearly refer ral for fur ther inves ti ga tions, which may includelap a ros copy for diag no sis and treat ment. Treat ment algo -rithms for ado les cents with endometriosis are extrap o latedfrom adult research pri mar ily and are based on expertopinion. There is very lim ited infor ma tion on response toeither med i cal or sur gi cal ther apy in this age group.
Although all med i cal and sur gi cal options for endometriosis may be included in the care of ado les cents, the health carepro vider needs to con sider the patient’s age and theside-effect pro files of the var i ous agents; in par tic u lar, thereis poten tial for bone loss with GnRH agonists and depotprogestin.
A stepwise approach is usual for med i cal man age ment,start ing with CHC ther apy in an extended or con tin u ousfash ion. Empiric GnRH ago nist ther apy with HT addbackis reserved for ado les cents over the age of 18 years owing tothe con cern of det ri men tal effects on BMD.16,17 Withconfirmation of an endometriosis diag no sis at sur gery,continuous ther apy with a CHC or a GnRH ago nist withHT addback may be pre scribed for ado les cents as young as16 years who have per sis tent prob lem atic pel vic pain. AGnRH ago nist is gen er ally not rec om mended for patientsunder the age of 16 years.16 If GnRH ago nist with HTaddback ther apy is pre scribed, gen eral advice about bonehealth main te nance, such as sup ple men tal cal cium andvitamin D intake, should be pro vided and con sid er ationgiven to the mon i tor ing of BMD. Anec dotal expe ri encewith an LNG-IUS has been reported.18
The tim ing of sur gi cal man age ment of endometriosis inado les cents is con tro ver sial. Lap a ros copy, if per formed,should be done by expe ri enced sur geons who will rec og nize that youn ger patients have atyp i cal endometriotic lesions,with more clear ves i cles and red lesions and fewer clas sic“pow der-burn” lesions,5,9,13 and should include resec tion or abla tion of lesions for pain treat ment.
Lap a ros copy can con firm endometriosis before the intro -duc tion of GnRH ago nist ther apy when ado les cents haveper va sive pel vic pain despite ini tial med i cal ther apy. Theliterature on out comes of sur gi cal resec tion of endo-metriotic lesions in ado les cents is lim ited and involves small num bers of patients.5 In a study of 11 sur gi cally treatedwomen under age 21 years who had mild, mod er ate, orsevere endometriosis and were given post op er a tive med i calman age ment (LNG-IUS, extended use of CHCs, or DMPA),8 either became com pletely pain-free or had greatly reducedpain.10 Oth ers have dem on strated an up to 84% reduc tionin symp toms.5
Like other women with chronic pel vic pain, ado les centsmay be helped by multimodal ther apy and abiopsychosocial model of care. Behav ioural mod i fi ca tion
Endometriosis: Diagnosis and Management
S24 l JULY JOGC JUILLET 2010
Clin i cal Tip
The approach to pel vic exam i na tion inadolescents should be flex i ble. Inspec tion, arecto-abdom i nal exam i na tion, and test ing of thelength of the vagina with a cot ton-tipped swab can be used in not sex u ally active ado les cents to inves ti gate sec ond ary dysmenorrhea.
tech niques (such as bio feed back, relax ation, and hyp no sis),cog ni tive ther apy, and com ple men tary ther a pies (such asacu punc ture) may be used in a multidisciplinaryapproach.19,20
Sum mary State ments
1. Endometriosis is the most com mon cause of sec ond arydysmenorrhea in ado les cents.(II-2)
2. Ado les cents with endometriosis are more likely thanadult women to present with acy clic pain. (III)
3. The phys i cal exam i na tion of ado les cents with endometriosis will rarely reveal abnor mal i ties, as most will haveearly-stage dis ease. (II-2)
Rec om men da tions
1. Endometriosis in ado les cents is often early stage andatyp i cal. Laparoscopists should look intra-abdom i nallyfor clear ves i cles and red lesions in ado les cents. (II-2B)
2. All avail able ther a pies for endometriosis may be used inado les cents, but the age of the patient and the side-effectpro files of the med i ca tions should be con sid ered. (III-A)
REFERENCES
1. Ballweg ML. Big pic ture of endometriosis helps pro vide guid ance onapproach to teens: com par a tive his tor i cal data show endo start ing youn ger,is more severe. J Pediatr Adolesc Gynecol 2003;16(3 Suppl):S21–6.
2. Harel Z. A con tem po rary approach to dysmenorrhea in ado les cents. Pediatr Drugs 2002;4:797–805.
3. Laufer MR, Goietein L, Bush M, Cramer DW, Emans SJ. Prev a lence ofendometriosis in ado les cent girls with chronic pel vic pain not respond ing to con ven tional ther apy. J Pediatr Adolesc Gynecol 1997;10:199–202.
4. Goldstein DP, De Cholnoky C, Emans SJ. Ado les cent endometriosis. J Adolesc Health Care 1980;1:37–41.
5. Davis GD, Thillet E, Lindemann J. Clin i cal char ac ter is tics of ado les centendometriosis. J Adolesc Health 1993;14:362–8.
6. Olive D, Henderson D. Endometrosis and Müllerian anom a lies. ObstetGynecol 1987;69:412–5.
7. Sanfilippo J, Wakim N, Schikler K, Yussman M. Endometriosis inasso ci a tion with uter ine anom aly. Am J Obstet Gynecol 1986;154:39–43.
8. Candiani GB, Fedele L, Candiani M. Dou ble uterus, blind hemivagina, andipsilateral renal agenesis: 36 cases and long-term fol low-up. Obstet Gynecol 1997;90:26–32.
9. Reese KA, Reddy S, Rock JA. Endometriosis in an ado les cent pop u la tion:the Emory expe ri ence. J Pediatr Adolesc Gynecol 1996;9:125–8.
10. Stavroulis AI, Saridogan E, Creigh ton SM, Cutner AS. Lap aro scopictreat ment of endometriosis in teen ag ers. Eur J Obstet Gynecol Reprod Biol 2006;248–50.
11. Marsh EE, Laufer MR. Endometriosis in premenarcheal girls who do nothave an asso ci ated obstructed anom aly. Fertil Steril 2005;83:758–60.
12. Gover S. Pel vic pain in the female ado les cent. Aust Fam Phy si cian2006;35:850–3.
13. Vercellini P, Fedele L, Arcaini L, Bianchi S, Rognoni M, Candiani G.Lap a ros copy in the diag no sis of chronic pel vic pain in ado les cent women. J Reprod Med 1989;34:827–30.
14. Emmert C, Romann D, Riedel HH. Endometriosis diag nosed bylap a ros copy in ado les cent girls. Arch Gynecol Obstet 1998;261:89–93.
15. Davis AR, Westhoff C, O’Connell K, Gallagher N. Oral con tra cep tives for dysmenorrhea in ado les cent girls. Obstet Gynecol 2005;106:97–104.
16. Templeman C. Ado les cent endometriosis. Obstet Gynecol Clin North Am2009;36:177–86.
17. DiVasta AD, Laufer MR, Gordon C. Bone den sity in ado les cent treatedwith a GnRH ago nist and add-back ther apy for endometriosis. J PediatrAdolesc Gynecol 2007;20:293–7.
18. Al-Jefout M, Palmer J, Fra ser IS. Simul ta neous use of a levonorgestrelintrauterine sys tem and an etonogestrel subdermal implant for debil i tat ingado les cent endometriosis. Aust N Z J Obstet Gynaecol 2007;47:247–9.
19. Greco D. Man age ment of ado les cent chronic pel vic pain fromendometriosis: a pain cen ter per spec tive. J Pediatr Adolesc Gynecol2003;16(3 Suppl):S17–9.
20. Wayne PM, Kerr CE, Schnyer RN, Legedza ATR, Savetsky-Ger man J,Shields MH, et al. Jap a nese-style acu punc ture for endometriosis-relatedpel vic pain in ado les cents and young women: results of a ran dom izedsham-con trolled trial. J Pediatr Adolesc Gynecol 2008;21:247–5.
Chapter 7: Endometriosis in Ado les cents
JULY JOGC JUILLET 2010 l S25
Chap ter 8
Endometriosis and Can cer
Although endometriosis is a benign dis ease, it sharesmany char ac ter is tics with malig nancy, such as inva sive
and unre strained growth and a ten dency to metastasize andrecur. Epidemiologic and lab o ra tory evi dence linksendometriosis to epi the lial ovar ian car ci noma.
In 1925, Sampson1 was the first to describe cri te ria formalig nancy orig i nat ing from endometriosis:
1. the pres ence of both endometriosis and malig nancywithin the same ovary must be dem on strated,
2. the car ci noma must arise from the endometriosis andnot invade it from another source, and
3. the spec i men must con tain histological char ac ter is ticsof endometriosis includ ing stroma and glands.
The dem on stra tion of mor pho log i cal con tin u a tion between benign and malig nant epi the lium within the endometriosiswas added as a fourth cri te rion by Scott in 1953.2 Since then, a large amount of evi dence sup port ing a rela tion shipbetween endometriosis and cancer has accumulated.
EPIDEMIOLOGY
Mul ti ple large epidemiologic stud ies have been pub lished to sup port a rela tion ship between endometriosis and epi the lial ovar ian car ci noma, in par tic u lar the clear cell andendometrioid sub types.3 In their ret ro spec tive cohort study, Brinton et al.4 reviewed the cases of more than 20 000women with a diag no sis of endometriosis. They iden ti fiedan increased over all can cer risk, and a more greatly increasedovar ian can cer risk, with a stan dard ized inci dence ratio(SIR: the ratio of the observed num bers of can cers to thoseexpected) of 1.2 (95% CI 1.1 to 1.3) and 1.9 (95% CI 1.3 to 2.8),respec tively. Sev eral other pub lished reports sup port thisasso ci a tion,5–8 includ ing the study by Kobayashi et al.9 of6398 women with endometriomas, which was doc u mentedsur gi cally in one third of the women, and by ultra soundor phys i cal exam i na tion in the remain der. After 17 yearsof fol low-up, 46 ovar ian can cers were iden ti fied (SIR 8.95; 95%CI 4.12 to 15.3 ).9 Anal y sis of pooled inter view data from8 case–con trol stud ies showed that women with infer til ity,espe cially those with endometriosis, were more likely todevelop ovar ian can cer (OR 1.73; 95% CI 1.10 to 2.71).10
Despite these find ings, not all stud ies sup port anincreased ovarian can cer risk in patients with
endometriosis. Olsen et al.11 iden ti fied a cohort of 1392post-meno pausal women who self-reported a diag no sis ofendometriosis among more than 37 000 postmenopausalwomen and fol lowed them for an aver age of 13 years. Nosig nif i cant increased over all risk of can cer, includ ing ovar -ian can cer, was iden ti fied. How ever, the endometriosis wasself-reported, not med i cally con firmed, and only 3 ovar iancan cers were diag nosed, which raises ques tions of bias andunderpowering.
Prev a lence ratios have also been inves ti gated. Van Gorp et al.12
reviewed 29 stud ies (n = 857) and reported that theprevalence of endometriosis in women with epi the lial ovar iancancer was as fol lows: 1.4% for mucinous, 4.5% for serous,19.0% for endometrioid, and 35.9% for clear cell carcinoma.In another study of 22 patients with endometrioid ovar iancar ci noma, Valenzuela et al.13 con firmed malig nant trans -for ma tion of endometriosis in 3 patients, result ing in aprev a lence of 14%.
Van Gorp et al.12 also cal cu lated the prev a lence of ovar iancan cer among women with endometriosis, based on areview of 8 stud ies (n = 3401). Using the cri te ria ofSampson1 and Scott,2 they esti mated the prev a lence ofmalig nant trans for ma tion was 0.9% of all endometriosislesions. When the def i ni tion of endometriosis-asso ci atedovar ian car ci noma was broad ened to endometriosis andovar ian can cer pres ent in the same ovary, the prev a lence ofovar ian can cer among women with endometriosisincreased to 2.5%. When the def i ni tion ofendometriosis-asso ci ated ovar ian car ci noma was fur therexpanded to include ovar ian can cer that occurs in womenwith any form of pel vic endometriosis, then the prev a lenceof ovar ian cancer in endometriosis increases to 4.5%.
PATHOPHYSIOLOGY
Epidemiologic evi dence link ing endometriosis and ovar iancarcinoma may appear strong; how ever, the exact mech a nismof malig nant trans for ma tion remains unclear. In their reviewof the asso ci a tion between endometriosis and ovar ian cancer,Somigliana et al.14 put for ward two mech a nisms to explainthe asso ci a tion: (1) endometriosis cells may undergo trans -for ma tion to malig nancy, and (2) the coex is tence ofendometriosis and ovar ian can cer may be due to shared riskfac tors and ante ced ent mech a nisms. The first sce nario sug -gests endometriosis may be a pre cur sor lesion to ovar ian
S26 l JULY JOGC JUILLET 2010
CHAP TER 8
can cer. This the ory is sup ported by histologic evi dence ofmalig nant trans for ma tion of endometriosis to clear cell orendometrioid car ci noma.15 Patho log i cal and immunohisto-chemical stud ies of pro lif er a tion of endometriosis cells byOgawa et al.16 showed that atyp i cal endometriosis may be apre cur sor lesion to ovar ian clear cell and endometrioidcarcinoma. Stud ies of molec u lar genetic alter ations alsopro vide evi dence that endometriosis may be a pre cur sorlesion to car ci noma; how ever, fur ther research is needed todefine this mech a nism.17,18 In the sec ond sce nario,endometriosis and ovar ian can cer are two sep a rate bio logicalenti ties cou pled by an indi rect link, because sim i lar fac torspre dis pose to both dis eases. Sev eral com mon risk fac torshave been iden ti fied for these con di tions, in par tic u larnulliparity, early men ar che, and late meno pause.3 The coex -is tence of the two con di tions may also be a con se quence ofother shared mech a nisms such as genetic pre dis po si tion,immune dysregulation, and envi ron men tal fac tors.14
Although a rela tion ship appears to exist betweenendometriosis and ovar ian can cer, an asso ci a tion betweentwo con di tions does not prove cau sal ity. Vigano et al.19
concluded that a causal rela tion ship of low mag ni tudebetween endometriosis and spe cific histotypes of ovar iancan cer should be rec og nized, but this rela tion ship may alsobe explained by the fact that ectopic endometriumundergoes malig nant trans for ma tion just as normalendometrium does.
MANAGEMENT
All adnexal masses found on exam i na tion and/or imag ingpre op er a tively should be scru ti nized and inves ti gated forthe pos si bil ity of under ly ing malig nancy. Sus pected ovar ianendometriomas should be treated accord ing to guide linesfor the man age ment of ovar ian masses, includ ingassessment with ultra sound and pos si bly serum CA 125levels, although it is impor tant to keep in mind thatendometriosis may cause an ele vated CA 125 level.20,21 Inpatients with a mass that appears to be an ovar ianendometrioma, with out other indi ca tors of malig nancy,follow-up sur veil lance should be con sid ered if sur gery isnot indi cated. Also, ovarian endometriomas that aresurgically man aged should be biopsied to exclude aconcomitant malignancy.
The man age ment of peritoneal endometriosis has beendescribed in this guide line for patients with pain andinfertility. Although the risk of con com i tant malig nancy islow, it may be rea son able to con sider biopsy at the time ofsur gi cal man age ment to help con firm a diag no sis andexclude an atyp i cal or malig nant pro cess.
Sum mary State ments
1. The prev a lence of ovar ian can cer in patients withendometriosis is under 1%. (II-2)
2. Exci sion or sam pling of sus pected endometriosislesions and endometriomas helps con firm the diag no sis and exclude under ly ing malig nancy. (II-2)
Rec om men da tions
1. Biopsy of endometriosis lesions should be con sid ered tocon firm the diag no sis and to rule out under ly ingmalignancy. (II-2A)
2. Sus pected ovar ian endometriomas should be treatedaccord ing to the SOGC guide line “Ini tial Eval u a tion and Refer ral Guide lines for Man age ment of Pel vic/Ovar ianMasses.” (III-A)
REFERENCES
1. Sampson JA. Endometrial car ci noma of the ovary aris ing in endometrialtis sue in that organ. Arch Surg 1925;10:1–72.
2. Scott RB. Malig nant changes in endometriosis. Obstet Gynecol1953;2:283–9.
3. Nezhat F, Datta MS, Hanson V, Pejovic T, Nezhat C, Nezhat C. Therela tion ship of endometriosis and ovar ian malig nancy: a review. Fertil Steril2008;90:1559–70.
4. Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Can cer risk after ahos pi tal dis charge diag no sis of endometriosis. Am J Obstet Gynecol1997;176:572–9.
5. Brinton LA, Sakoda LC, Sherman ME, Frederiksen K, Kjaer SK, GraubardBI, et al. Rela tion ship of benign gynecologic dis eases to sub se quent risk ofovar ian and uter ine tumors. Can cer Epidemiol Biomarkers Prev2005;14:2929–35.
6. Melin A, Sparen P, Persson I, Bergqvist A. Endometriosis and the risk of can cer with spe cial empha sis on ovar ian can cer. Hum Reprod2006;21:1237–42.
7. Oral E, Ilvan S, Tustas E, Korbeyli B, Bese T, Demirkiran F, et al.Prev a lence of endometriosis in malig nant epi the lial ovary tumours. Eur JObstet Gynecol Reprod Biol 2003;109:97–101.
8. Borgfeldt C, Andolf E. Can cer risk after hos pi tal dis charge diag no sis of benign ovar ian cysts and endometriosis. Acta Obstet Gynecol Scand2004;83:395–400.
9. Kobayashi H, Sumimoto K, Moniwa N, Imai M, Takakura K, Kuromaki T, et al. Risk of devel op ing ovar ian can cer among women with ovar ian endometrioma: a cohort study in Shizuoka, Japan. Int J Gynecol Can cer 2007;17:37–43.
10. Ness RB, Cramer DW, Good man MT, Kjaer SK, Mallin K, Mosgaard BJ, et al.Infer til ity, fer til ity drugs, and ovar ian can cer: a pooled anal y sis ofcase-con trol stud ies. Am J Epidemiol 2002;155:217–24.
11. Olson JE, Cerhan JR, Janney CA, Ander son KE, Vachon CM, Sell ers TA.Postmenopausal can cer risk after self-reported endometriosis diag no sis in the Iowa women’s health study. Can cer 2002;94:1612–8.
12. Van Gorp T, Amant F, Neven P, Vergote I, Moerman P. Endometriosisand the devel op ment of malig nant tumours of the pel vis. A review oflit er a ture. Best Pract Res Clin Obstet Gynaecol 2004;18:349–71.
13. Valenzuela P, Ramos P, Redondo S, Cabrera Y, Alvarez I, Ruiz A.Endometrioid adenocarcinoma of the ovary and endometriosis. Eur J Obstet Gynecol Reprod Biol 2007; 134:83–6.
14. Somigliana E, Vigano P, Parazzini F, Stoppelli S, Giambattista E, VercelliniP. Asso ci a tion between endometriosis and can cer: a com pre hen sive review
Chapter 8: Endometriosis and Can cer
JULY JOGC JUILLET 2010 l S27
and a crit i cal anal y sis of clin i cal and epi de mi o log i cal evi dence. GynecolOncol 2006;101:331–41.
15. Feeley KM, Wells M. Pre cur sor lesions of ovar ian epi the lial malig nancy.Histopathology 2001;38:87–95.
16. Ogawa S, Kaku T, Amada S, Kobayashi H, Hirakawa T, Ariyoshi K, et al.Ovar ian endometriosis asso ci ated with ovar ian car ci noma: a clinico-pathological and immunohistochemical study. Gynecol Oncol2000;77:298–304.
17. Prowse AH, Manek S, Varma R, Liu J, Godwin AK, Maher ER, et al.Molec u lar genetic evi dence that endometriosis is a pre cur sor of ovar iancan cer. Int J Can cer 2006; 119:556–62.
18. Otsuka J, Okuda T, Sekizawa A, Amemiya S, Saito H, Okai T, et al. K-ras muta tion may pro mote carcinogenesis of endometriosis lead ing to ovar ian clear cell car ci noma. Med Elec tron Microsc 2004;37:188–92.
19. Vigano P, Somigliana E, Parazzini F, Vercellini P. Bias ver sus cau sal ity:inter pret ing recent evi dence of asso ci a tion between endometriosis andovar ian can cer. Fertil Steril 2007;88:588–93.
20. Varma R, Rollason T, Gupta JK, Maher ER. Endometriosis and theneo plas tic pro cess. Repro duc tion 2004;127:293–304.
21. Le T, Giede C; SOGC/GOC/SCC Pol icy and Prac tice Guide linesCom mit tee. Ini tial eval u a tion and refer ral guide lines for man age ment of pel vic/ovar ian masses. SOGC Joint Clin i cal Prac tice Guide line, No. 230, July 2009. J Obstet Gynaecol Can 2009;31:668–73.
Endometriosis and Cancer
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