5. Outline
• Endometriosis as a disease- definition,
prevalence, pathogenesis?, disease
staging, implications
• Diagnostic approach- clinical examination
for diagnosis, utility of medical
technologies
• Treatment- medical/ surgical- painful
symptoms / endometriosis-associated
infertility
6. Endometriosis
• Definition- presence of endometrial-like tissue
outside the uterus, which induces a chronic,
inflammatory reaction (Kennedy, et al., 2005)
7. Prevalence
• Exact prevalence - unknown
• Estimates range: 2 to 10% within the general female
population ;
• Up to 50% in infertile women
(Eskenazi and Warner, 1997, Meuleman, et al., 2009)
• True prevalence of asymptomatic endometriosis – not
known; between 3 - 45% of women undergoing
laparoscopic sterilization has been diagnosed with
endometriosis (Rawson,1991;Gylfasonetal., 2010)
8. Pathogenesis
• No single theory can explain the
pathogenesis of endometriosis
• The Implantation - Dr Sampson (1925)
– Retrograde menstruation regurgitates viable
endometrial cells through the fallopian tubes.
These cells are capable of implantation and
development.
– Dissemination to distant sites is possible by
lymphatic and vascular spread (Halban’s theory)
– Remains the most popular ; supported by
experiments that show endometrial cells are
viable both in vitro and in vivo
• The coelomic metaplasia theory - Dr
Meyer (1919)
– Coelomic epithelium undergoes metaplasia
to become endometriosis
– Explains the unusual sites of endometriosis
but evidence for it yet to be established
9. Other theories...
• Iatrogenic dissemination occurs during
gynecological procedures
– Not clear whether the rate of transplantation
varies with the time of cycle
• Immunogenetic defects
– Aberrant expression of factors
– Steroidogenic Factor-1 activates expression of
aromatase enzyme and ↑↑ expression of
cyclooxygenase-2 in the stromal cells
• Exact mechanism of endometrioma
formation is unknown
– One possibility - formation of an adhesion between
the ovary & pelvic peritoneum and the progressive
infolding of the ovary forming a pseudo cyst called
an endometrioma
10. Classification system/ Disease
staging
• rASRM classification system(Revised American Society
for Reproductive Medicine classification of
endometriosis: 1996, 1997); rAFS (revised American
Fertility Society endometriosis classification: 1996,1997)
– Widely used staging systems
– Assigns points to the different locations of the disease
– Four stages: minimal, mild, moderate and severe
• Purpose:
– Allow clinicians to communicate the extent of disease (to patient/
colleague)
– To permit standardization and comparison of outcomes for clinical trials
• Limitation:
– Poorly reflect the severity of endometriosis-ass. pain and infertility
12. Revised AFS classification 1996. (Revised Endometriosis Classification: 1996, 1997.
Fertility and Sterility, Volume 67, Number 5 by Schenken RS, Guzick DS)
______
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13. Endometriosis Fertility
Index (EFI)
• Proposed by Adamson and
Pasta in 2010
• Predict ability of pregnancy
after endometriosis surgery
• Contains all of the
components of rAFS stage
score
• Combines conception-
related factors: age, years of
infertility, pregnancy history
• Least-Function score (LF)-
detailed score to the
appendix (Fallopian tubes,
tubal fimbriae, ovaries)
14. • Endometriosis fertility
index (EFI) has > predictive
power for IVF outcomes in
endometriosis patients cf r-
AFS classification
• Clinical pregnancy rate
(CPR) was higher in
patients with EFI >/= 6
score cf EFI </=5 score
-Endometriosis fertility index score
(EFI) maybe more accurate for
predicting the outcomes of in vitro
fertilisation than r-AFS classification in
women with endometriosis (Wang et al.
Reproductive Biology and
Endocrinology 2013,11:112)
• Endometriosis Fertility
Index (EFI) - The only
validated endometriosis
classification system that
predicts a clinical
outcome
• The EFI has now been
validated by three
additional investigators
- Endometriosis Fertility Index: is
it better than the present staging
systems? (Adamson GD Curr
Opin Obstet Gynecol 2013
Jun;25(3):186-92)
EFI score – Recent studies…
15. Implications
• Economic burden- costs arising from treatment in referral
centres at least comparable with other chronic diseases,
eg. diabetes mellitus - World Endometriosis Research Foundation (WERF)
EndoCost study. Simoens S, et al. Endometriosis cost assessment (the EndoCost study): a cost-
of-illness study protocol. Gynecol Obstet Invest 2011;71(3):170-6
• Total annual societal burden of endometriosis-
associated symptoms for Europe -> estimated to be 0.8
million - 12.5 billion euros - theoretical calculation from
annual average costs per woman treated in referral
centres across Europe (Nnoaham, et al., 2011, Simoens, et al., 2012)
• Burden on social and sexual relationships, work and
study (De Graaff, et al., 2013, Nnoaham, et al., 2011, Simoens, et al., 2012)
16. Clinical Implications
1. Endometriosis-associated pain
– more inflammatory form of superficial
disease probably causes > pain than
the ’burnt-out’ black-blue lesions.
Pain may be caused by the release
of inflammatory mediators of pain,
eg. bradykinins and prostaglandins
– Pain from endometriomas and
nodular disease, on the other hand,
could theoretically be caused by
traction on tissues or by infiltration or
constriction of nerves
2. endometriosis-
associated infertility
Several mechanisms
proposed:
•Distorted pelvic anatomy
•Altered peritoneal function
•Altered hormonal and cell-
mediated function
•Endocrine and ovulatory
abnormalities
•Impaired implantatiom
•Altered oocyte and embryo
quality
•Abnormal uterotubal
transport
Women with endometriosis are confronted with one or both of two major
problems:
17. Diagnosis
• Several studies reported a long delay in the
diagnosis of endometriosis
• Eg. For Europe-> 4-10 years
– overall diagnostic delay of 10 years in Germany & Austria,
– 8 years in the UK and Spain,
– 7 years in Norway,
– 7–10 years in Italy and
– 4–5 years in Ireland and Belgium
(Ballard et al.,2006;Nnoaham et al.,2011;Hudelist et al.,2012)
• While some women with endometriosis
experience painful symptoms and/ or infertility,
others have no symptoms at all
18. Symptoms and Signs
• Classic symptoms: Pelvic symptoms — cyclical pelvic pain,
dysmenorrhea and dyspareunia
• Other leading symptoms include chronic pelvic pain, cyclical intestinal
complaints, fatigue/weariness and infertility (Bellelis, et al., 2010, Davis, et al., 1993,
Lemaire, 2004, Luscombe, et al., 2009)
• Dyschezia and dyspareunia – ass. with deep endometriosis of the
posterior pelvis, esp. rectovaginal septum (Seracchioli, et al., 2008, Thomassin, et
al., 2004)
• Other predictors of the diagnosis of endometriosis- Abdominopelvic
pain, heavy menstrual bleeding (HMB) , postcoital bleeding (PCB) ,
diagnosis of ovarian cyst, irritable bowel syndrome (IBS) and pelvic
inflammatory disease (PID)
• Clinicians should consider the diagnosis of endometriosis in women of
reproductive age with non-gynaecological cyclical symptoms
(dyschezia, dysuria, haematuria, rectal bleeding, shoulder pain)- Good
Practice Point (GPP )
19. Clinical Examination
• Inspection of the vagina using a speculum-
visualize for deep endometriosis in the
posterior fornix (Bazot, et al., 2009)
• Vaginal examination/ VE - detection of
infiltration or nodules of the vagina,
uterosacral ligaments or pouch of Douglas
(Bazot, et al., 2009)
• Bimanual palpation and Rectovaginal digital
examination- detection of infiltration or mass
involving the rectosigmoidal colon or adnexal
masses (Bazot, et al., 2009, Chapron, et al., 2002, Condous, et al.,
2007, Eskenazi, et al., 2001, Koninckx, et al., 1996, Ripps and Martin, 1992)
20. • VE
– might be inappropriate in adolescents ; can be very painful in
some women
– in that case, rectal examination can be helpful for the diagnosis
of endometriosis, and other medical technologies should be
used as a first step towards diagnosis- Good practice point (GPP)
• Inspection and palpation of the abdomen
– Location and extent of disease can sometimes be determined by
clinical examination (Bazot, et al., 2009, Koninckx, et al., 1996, Ripps and Martin,
1992)
– Clinicians may consider the diagnosis of endometriosis in
women suspected of the disease even if the clinical examination
is normal (Chapron, et al., 2002) - C
22. Investigations
• Laparoscopy
– Gold standard for diagnosis - Combination of laparoscopy and the HPE
verification of endometrial glands and/or stroma
– Laparoscopy provides a visual diagnosis of endometriosis
• Good quality laparoscopy - include systematic checking of
1) uterus and adnexa
2) peritoneum of ovarian fossae, vesico-uterine fold, Douglas and pararectal spaces
3) rectum and sigmoid (isolated sigmoid nodules)
4) appendix and caecum
5) diaphragm
– Good quality laparoscopy - only be performed by using at least one
secondary port for a suitable grasper to clear the pelvis of obstruction from
bowel loops; or fluid suction to ensure the whole POD is inspected
– Retroperitoneally & vaginally localized endometriosis can be easily missed
23. Arguments
– If signs of deep endometriosis / ovarian
endometriosis NOT present in physical
examination & imaging -> can be argued
that a diagnostic laparoscopy SHOULD
NOT be performed just to find peritoneal
disease & treat it; dt the invasiveness of the
laparoscopic procedure
– Empirical treatment can be started without
a definitive diagnosis. This might be the
case in young adolescents / in women that
decide not to have a laparoscopy solely to
know if the disease is there
– A negative diagnostic laparoscopy (i.e. NO
endometriosis identified during laparoscopy)
seems to be highly accurate for excluding
endometriosis. However, this is under the
assumption that the diagnostic laparoscopy
is well performed and preceded by
appropriate preoperative assessment
(Wykes etal.,2004)
During laparoscopy -> typical
appearances of endometriosis
implants in the abdominal
cavity are regarded as proof of
presence of endometriosis
24. HPE
GPP:
- Clinicians are recommended to
confirm a positive laparoscopy by
histology, since positive histology
confirms the diagnosis of
endometriosis, even though
negative histology does not
exclude
- In women undergoing surgery for
ovarian endometrioma and/or
deep infiltrating disease, tissue for
histology is recommended TRO
rare instances of malignancy
25. Imagings
• Transvaginal sonography (TVS)
– Clinicians are recommended to perform TVS to diagnose / to exclude an
ovarian endometrioma (Moore, et al., 2002) - A
– Clinicians are recommended to base the diagnosis of ovarian
endometrioma in premenopausal women on the following ultrasound
characteristics: ground glass echogenicity and 1-4 compartments and
no papillary structures with detectable blood flow – GPP
• Magnetic resonance imaging (MRI)
– MRI is not useful to diagnose / exclude peritoneal endometriosis
– The usefulness of magnetic resonance imaging (MRI) to diagnose
peritoneal endometriosis is not well established (Stratton, et al., 2003). - D
26. • Overall… imaging techniques are helpful in estimating the
extent of the disease with deep endometriosis
• The focus -> predicting the extent of disease to target further
management
• These techniques are sensitive rather than specific in
diagnosing endometriosis
• If there is a suspicion based on history / physical examination
of deep endometriosis, clinicians should assess ureter,
bladder, and bowel involvement by additional imaging, in
preparation for further management - GPP
27. Biomarkers
• Serum CA-125
– Limited diagnostic performance- performance of
serum CA-125 measurement in the diagnosis of
endometriosis grade I/II is limited, whereas its
performance in the diagnosis of endometriosis grade
III/IV is better
– Not recommended to use immunological biomarkers,
including CA-125, in plasma, urine or serum to
diagnose endometriosis (May, et al., 2010, Mol, et al., 1998) –A
30. Hormonal therapies for treatment of
endometriosis-associated pain
• Endometriosis -> predominantly estrogen-dependent disease
• Hormonal suppression might be an attractive medical approach
• Recommended are: hormonal treatment [hormonal contraceptives
(level B), progestagens (level A), antiprogestagens (level A), or
GnRH agonists (level A)] as one of the options -> reduces
endometriosis-associated pain (Vercellini, et al., 1993, Brown, et al., 2012, Brown, et
al., 2010) - Recommendation A-B
• No overwhelming evidence to support particular treatment over
others
• Clinicians should take patient preferences, side effects, efficacy,
costs & availability into consideration when choosing hormonal
treatment for endometriosis-associated pain - GPP
31. • Combined hormonal contraceptives (COCP)
– reduce endometriosis-associated symptoms:- endometriosis-
associated dyspareunia, dysmenorrhea and non-menstrual pain
(Vercellini, et al., 1993) - B
– estrogen component may mask the effect of the progestin,
possibly by activating the disease
– ethinylestradiol doses in modern combined hormonal
contraceptives - too low to reach an activating threshold (low-
dose cyclic OCP)
– widely used as treatment for both endometriosis-associated pain
& pain in women suspected of endometriosis due to the practical
advantages of OCP, ie. contraceptive protection/ long term
safety /& control of menstrual cycle
32. • Vaginal contraceptive ring ; transdermal
(estrogen/progestin) patch
– reduce endometriosis-associated dysmenorrhea,
dyspareunia and chronic pelvic pain (Vercellini, et al.,
2010) – Recommendation grade C
33. • Progestagens & anti-progestagens
– Progestagens [medroxyprogesterone acetate (oral or depot), dienogest,
cyproterone acetate, norethisterone acetate, danazol] or anti-
progestagens (gestrinone) as one of the options, to reduce
endometriosis-associated pain (Brown, et al., 2012) – A
– Consider prescribing a levonorgestrel-releasing intrauterine system
as one of the options to reduce endometriosis-associated pain (Ferreira,
et al., 2010, Gomes, et al., 2007, Petta, et al., 2005) - B
– No evidence to suggest a benefit of progestagens over other treatments
– Take the different side-effect profiles of progestagens and anti-
progestagens into account when prescribing these drugs, especially
irreversible side effects (e.g. thrombosis, androgenic side effects)
34. • GnRH agonists
- GnRH agonists (nafarelin, leuprolide, buserelin, goserelin or
triptorelin), as one of the options for reducing endometriosis-
associated pain, although evidence is limited regarding dosage /
duration of treatment (Brown, et al., 2010) - A
– No difference for dysmenorrhea, pelvic pain, tenderness and induration when
women are treated for 3 or 6 months with GnRHa (leuprolide)
– No difference in effectiveness exists when GnRHa is administered
intramuscularly, subcutaneously or intranasally
- Prescribe hormonal add-back therapy to coincide with the start of
GnRH agonist therapy, to prevent bone loss and hypoestrogenic
symptoms during treatment. This is not known to reduce the effect of
treatment on pain relief (Bergqvist, et al., 1997, Makarainen, et al., 1996, Moghissi, et al., 1998,
Taskin, et al., 1997) - A
35. - There is evidence of severe side effects with GnRHa, which should
be discussed with the woman when offering this treatment- Bone
loss; menopausal symptoms eg. hot flushes, sleep disturbance,
mood swings, sweating
- Careful consideration to the use of GnRH agonists in young women
and adolescents, since these women may not have reached
maximum bone density - GPP
- No evidence exists on the efficacy of GnRH antagonists for
endometriosis-associated pain
36. • Aromatase inhibitors
- Pain from rectovaginal endometriosis refractory to other medical /
surgical treatment, consider prescribing aromatase inhibitors in
combination with oral contraceptive pills, progestagens, or GnRH
analogues, as they reduce endometriosis-associated pain (Ferrero, et
al., 2011, Nawathe, et al., 2008) - B
- Hypoestrogenic side effects (vaginal dryness, hot flushes,
diminished bone mineral density)
- Existing evidence is of moderate quality- based on small studies
and case reports ; evidence on the long-term effects of aromatase
inhibitors is lacking
37. Analgesics for treatment of
endometriosis-associated pain
• Although widely used as a first line treatment of
endometriosis-associated pain, there is virtually no
evidence on the use of NSAIDS for endometriosis,
except for one study published in 1985
(Kauppila A and Rönnberg L. Naproxen sodium in dysmenorrhea secondary to endometriosis.
Obstet Gynecol 1985; 65:379–383)
• Good evidence exists to support the use of NSAIDs for
primary dysmenorrhea (Marjoribanks, et al., 2010)
• Clinicians should consider NSAIDs / other analgesics to
reduce endometriosis-associated pain - GPP
38. Surgery for treatment of
endometriosis-associated pain
• Surgical treatment has long been an important part of
the management of endometriosis
• Elimination of endometriosis may be achieved by
excision, diathermy or ablation/evaporation
• Division of adhesions aims to restore pelvic anatomy
39. Laparotomy vs Laparoscopy
• ‘See and Treat’ : when endometriosis is identified at laparoscopy, clinicians
are recommended to surgically treat endometriosis, as this is effective for
reducing endometriosis-associated pain (Jacobson, et al., 2009) - A
• Laparotomy and laparoscopy -> equally effective in the treatment of
endometriosis-associated pain
• Operative laparoscopy (excision/ablation) - > effective for the treatment of
pelvic pain ass. with all stages of endometriosis, cf diagnostic laparoscopy
only
• Laparoscopy – usu associated with less pain, shorter hospital stay, quicker
recovery and better cosmesis, hence usu preferred to open surgery
40. Ablation versus excision of
endometriosis
• Clinicians may consider both ablation and excision of
peritoneal endometriosis to reduce endometriosis-
associated pain, as women with all stages of
endometriosis showed that ablation was as effective as
excision (Healey, et al., 2010, Wright, et al., 2005) - C
• Excision of lesions could be preferred with regard to the
possibility of retrieving samples for histology
• Ablative techniques are unlikely to be suitable for
advanced forms of endometriosis with deep
endometriosis component
41. Surgery for treatment of pain associated
with Ovarian Endometrioma
• Clinicians should perform cystectomy instead of drainage and
coagulation, as cystectomy reduces endometriosis-associated pain (Hart,
et al., 2008) - A
• Laparoscopic excision of ovarian endometriotic cysts (3 cm/ larger) vs
drainage and coagulation by bipolar diathermy
- RCT Studies demonstrated lower recurrence of dysmenorrhea and dyspareunia
after cystectomy cf drainage and coagulation only.
- Fewer cyst recurrences with the excisional approach
- Need for further surgery and recurrence of non-menstrual pain were less likely after
cystectomy.
- Conclusion- Cystectomy is superior to drainage and coagulation in women with
ovarian endometrioma (≥ 3cm) with regard to the recurrence of endometriosis-
associated pain and the recurrence of endometrioma
(Alborzi, et al., 2004, Beretta, et al., 1998, Hart, et al., 2008)
• Risk of ovarian failure after bilateral ovarian endometrioma removal is
reported to be 2.4% (Busacca, et al., 2006)
42. Surgery for treatment of endometriosis-
associated Infertility
Recommendations
• In infertile women with AFS/ASRM stage I/II endometriosis, clinicians
should perform operative laparoscopy (excision or ablation of the
endometriosis lesions) including adhesiolysis, rather than performing
diagnostic laparoscopy only, to increase ongoing pregnancy rates
(Jacobson, et al., 2010, Nowroozi, et al., 1987) - A
• In infertile women with AFS/ASRM stage I/II endometriosis, clinicians may
consider CO2 laser vaporization of endometriosis, instead of monopolar
electrocoagulation, since laser vaporisation is associated with higher
cumulative spontaneous pregnancy rates (Chang, et al., 1997) - C
• In infertile women with AFS/ASRM stage III/IV endometriosis, clinicians
can consider operative laparoscopy, instead of expectant management, to
increase spontaneous pregnancy rates (Nezhat, et al., 1989, Vercellini, et al.,
2006a) - B
43. • In infertile women with endometrioma >3 cm there is no evidence
that cystectomy prior to ART treatment improves pregnancy rates
(Donnez et al.,2001;Hart et al.,2008;Benschop et al., 2010) - A
• In women with endometrioma >3 cm, it is recommended clinicians
only to consider cystectomy prior to ART to improve endometriosis-
associated pain or the accessibility of follicles – GPP
• In infertile women with ovarian endometrioma undergoing surgery,
clinicians should perform excision of the endometrioma capsule,
instead of drainage and electrocoagulation of the endometrioma
wall, to increase spontaneous pregnancy rates (Hart, et al., 2008) - A
• The GDG recommends that clinicians counsel women with
endometrioma regarding the risks of reduced ovarian function after
surgery and the possible loss of ovary. The decision to proceed with
surgery should be considered carefully if the woman has had
previous ovarian surgery - GPP
44. Hysterectomy for endometriosis-
associated pain
• Clinicians may consider hysterectomy with removal of the ovaries
and all visible endometriosis lesions: women who have completed
their family & failed to respond to more conservative treatments.
Women should be informed that hysterectomy will not necessarily
cure the symptoms or the disease - GPP
• Difficult to establish whether endometriosis is the cause of pain / a
co-incidental finding in a woman with chronic pelvic pain
• Hysterectomy with ovarian conservation was reported to have a 6-
fold risk for development of recurrent pain and an 8.1x greater risk of
reoperation (Martin, 2006)
• Oophorectomies would lead to regression of remaining
endometriotic lesions
45. Preoperative hormonal therapies for
treatment of endometriosis-associated pain
• Clinicians should not prescribe preoperative hormonal treatment to
improve the outcome of surgery for pain in women with
endometriosis (Furness, et al., 2004) - A
• No controlled studies supporting of evidence of a benefit of
preoperative medical therapy on the outcome of surgery in terms of
pain management
• In clinical practice-> surgeons prescribe preoperative medical
treatment with GnRH analogues as this can facilitate surgery due to
reduced inflammation, vascularisation of endometriosis lesions &
adhesions
• Patient’s perspective -> medical treatment should be offered before
surgery to women with painful symptoms in the waiting period before
the surgery can be performed, with the purpose of reducing pain
before surgery
46. Postoperative hormonal therapies for
treatment of endometriosis-associated pain
• Clinicians should not prescribe adjunctive hormonal treatment in
women with endometriosis for endometriosis-associated pain after
surgery, as it does not improve the outcome of surgery for pain
(Furness, et al., 2004)
47. • Secondary prevention - defined as prevention of the recurrence of
pain symptoms (dysmenorrhea, dyspareunia, non-menstrual pelvic
pain) / the recurrence of disease (recurrence of endometriosis
lesions documented by ultrasound for ovarian endometrioma / by
laparoscopy for all endometriosis lesions) in the long-term (>6
months after surgery)
• There is a role for prevention of recurrence of disease and painful
symptoms in women surgically treated for endometriosis. The
choice of intervention depends on patient preference, cost,
availability and side effects. For many interventions considered,
there are limited data –GPP
Postoperative hormonal therapies aimed at
Secondary Prevention of endometriosis
48. • Women operated on for an endometrioma (≥ 3 cm), clinicians
should perform ovarian cystectomy, instead of drainage and
electrocoagulation, for the secondary prevention of endometriosis-
associated dysmenorrhea, dyspareunia and non-menstrual pelvic
pain (Hart, et al., 2008) - A
• After cystectomy for ovarian endometrioma in women not
immediately seeking conception, clinicians are recommended to
prescribe hormonal contraceptives for the secondary prevention of
endometrioma (Vercellini, et al., 2010) - A
• In women operated on for endometriosis, clinicians are
recommended to prescribe postoperative use of a levonorgestrel-
releasing intrauterine system (LNG-IUS) or a combined
hormonal contraceptive(COCP) for at least 18–24 months, as
one of the options for the secondary prevention of endometriosis-
associated dysmenorrhea, but not for non-menstrual pelvic pain
or dyspareunia (Abou-Setta, et al., 2006, Seracchioli, et al., 2009) - A
49. Non-medical management strategies for
treatment of endometriosis-associated pain
• General lack of well-designed research to evaluate their
effectiveness
• Use of nutritional supplements, complementary /
alternative medicine is not recommended in the
treatment of endometriosis-associated pain, because the
potential benefits and/or harms are unclear. However,
some women who seek complementary and alternative
medicine may feel benefit from this - GPP
50. Summary
• Pain and Subfertility -> $, societal burden->,
stress on relationship, work/ studies
• Pathogenesis & natural course of the disease -
unclear; No screening tool / ? primary prevention
• Diagnosis- Gold std: Laparoscopy and HPE
(Arguments- to who, why, how much / far to
go…)
• Treatment- Medical & Surgical ~half of the
recommendations based on high level evidence;
areas lacking in robust data
51. • Challenge- unsatisfactory treatment
response/ incomplete treatment/ deep
endometriosis/ complications & SE with
treatments/ recurrence
TREAT
Trick
