Endometriosis

Benha University Hospital, Egypt
Email:elnashar53@hotmail.com
Aboubakr Elnashar

Define
Ectopic (outside the uterus)
endometrial glands & stroma.
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Prevalence
•5% of women in the
reproductive age group.
•25% of infertile women.
•50% of chronic pelvic pain.
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Age At Diagnosis
< 19
6%
19 – 25
24%
26 –35
52%
36 –45
15%
> 45
3%
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Pelvic
 Uterine= Adenomyosis
(50%).
 Extrauterine:
- Ovary 30%
- Pelvic peritoneum 10%.
- F. tube.
- Vagina.
-Bladder & rectum.
- Pelvic colon.
- Ligaments.
Extra pelvic
Umbilicus.
Scars (Lap.).
Lungs & pleura.
Others.
Sites
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Types
I. Superficial peritoneal lesions
Typically located on the pelvic organs or pelvic
peritoneum.
Classic bluish or blue-black “powder-burn” lesion
resembles the endometrium and may be
associated with hemosiderin deposits.
Non-classic lesions:
clear and red “flame-like” lesions or white lesions.
Endometriosis can also be found in the base of a
peritoneal defect called an “Allen-Masters” window.
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II. Endometrioma (Endometriotic Cyst)
>90% are pseudocysts [formed by invagination of the ovarian
cortex, which is sealed off by adhesions]
(Brosens et al, 2003).
• Characterized by:
fibrosis
retraction of the cortex,
islands of glandular endometrial tissue
organized blood clots.
• The remainder of the cyst wall:
Smooth
lined by a thin endometrial-like tissue that consists of surface
epithelium and highly microvascularized stroma.
• There is no evidence that endometriotic tissue invades the
ovarian stroma; however, large multilocular cysts frequently
combine endometriomas with a hemorrhagic corpus luteum
or lutein cyst.
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III. Deep endometriosis
Define: Endometriosis infiltrating deeper than 5mm.
It is very active
Includes
1. Rectovaginal lesions
2. Infiltrative forms of bowel, ureters, bladder.
It originates intraperitoneally rather than
extraperitoneally.
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Pathogenesis:
intraperitoneal seeding of regurgitated endometrial cells, which
collect and implant in the most dependent portions of the
peritoneal cavity and the anterior& posterior cul-de-sac,
trigger an inflammatory process leading to adhesion of
contiguous organs with creation of false peritoneal bottoms
Treatment:
Drugs induce temporary quiescence of active deep lesions
Progestins should be considered as first-line medical treatment
for temporary pain relief.
Surgery is the final solution.
Mirena
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Ovarian Endometriosis:
Usually bilateral.
Two forms:
1- Multiple spots on the surface of the ovary.
2- Endometriotic (Chocolate) cysts
can reach the size of a fetal head, but is rarely
larger.
usually difficult to remove the cysts intact out of
surrounding adhesions.
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Pathogenesis
I- Endometrial implantation:
Retrograde.
Vascular & lymphatic.
Mechanical.
II- In situ development:
Coelomic metaplasia.
Induction.
III- Immunological.
IV- Composite.
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Donnez et al (2003)
Red lesions= early endometriosis
Black lesions= advanced endometriosis
White lesions are believed to be
- healed endometriosis or
- quiescent or latent lesions.
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Pathogenesis Hypothesis (Donnez et al, 2003)
- quiescent or
latent lesions .Red lesions
White lesions
Black lesions
White lesions
Advanced
endometriosis
Early
endometriosis
Healed
endometriosis
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Atypical (subtle) E:
Incidence:
More common than the classic dark blue-black
lesions in adolescents.
Common in age < 25 yr.
Types:
Red
White
Symptoms: like that characterize classic E.
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Significance:
1. Paraphysiological or self-limiting condition
which exist in all reproductive women as a
results of retrograde menstruation.
2. Biochemically & morphologically more active
than the classic lesions {synthesize more PG
F2}
Treatment:
E. does not itself demand treatment unless it is
causing, or it is likely to cause symptomsAboubakr Elnashar

Risk factors
(Odukoya & Cooke, 1996)
I- Associated:
First or second degree relation.
Menstrual cycle < 27 days.
Menstrual duration > 7 days.
Genital outflow obstruction.
II- Inconclusive:
Obesity,
Exercise,
Age at menarche,
uterine retroversion.
III- Not associated:
Age,
Race,
Social class,
duration of marriage,
ICUD,
Miscarriage. Aboubakr Elnashar

Factors associated with a reduced risk
{reduced estrogen levels}
(ACOG, 1999) :
Menstrual disorders
Decreased body-fat content
Smoking.
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Classification
The revised American Fertility Society
(rAFS) (1985)was produced to
standardize the documentation of
findings in patients who have pelvic pain
& endometriosis.
Staging Involves:
1. Location
2. Depth of Disease,
3. Extent of Adhesions.
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>3cm1-3cm< 1cmEndometriosis
421Superficial
642Deep
421R Superficial
20164Deep
421L Superficial
20164Deep Aboubakr Elnashar

COMPLETEPartialPOSTERIOR
CULDESAC
OBLTTERATION 404
> 2/3 Enclosure1/3-2/3
Enclosure
< 1/3 Enclosure
ADHESIONS
421R Filmy
1684Dense
421L Filmy
1684Dense
421R Filmy
168º4ºDense
421L Filmy
168º4ºDense Aboubakr Elnashar

Revised AFS (1985)
• Stage I (minimal) 1 – 5.
• Stage II (mild) 6 – 15.
• Stage III (moderate) 16 – 40.
• Stage IV (severe) > 40.
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ASRM classification (1996)
The only difference between the 1985 rAFS
classification & 1996 ASRM classification is that the
latter includes information on the morphologic
appearance of the disease.
•Red: red, red-pink & clear lesions
•White: white, yellow-brown, peritoneal defects,
subovarian adhesion
•Black: black & blue lesions.
•Denote percent of total described as R ….%, W ….%
and B ….%. Total should equal 100%.
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Atypical
Typical
Red Red yellow Clear
White Defect White
Black Blue
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CLINICAL PICTURE
Common symptoms:
•Infertility.
•Pain
Pelvic pain.
Dysmenorrhea (Crescendo=progressive)
Dysparunia.
Dyschasia.
Dysuria
Less common symptoms:
Heamaturia, rectal pain,
urgency, heamoptysis,
coetaneous nodules, hyperprolactinaemia.
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Infertility:
E should be suspected in
infertile females.
Suspicion is heightened when
there are also dysmenorrhea
&
dysparunia.
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Mechanism of infertility (Prentice, 2001)
I- Advanced disease:
Mechanical interference with
ovulation, ovum pick up,
Tubo-ovarian adhesion,
Severe pelvic adhesions &
Distorted tubal anatomy.
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II- Minimal & mild disease:
1. Coital problems: dysparunia.
2. Altered peritoneal environment:
increase volume of peritoneal fluid,
increase proportion of activated macrophages
(phagocytosis of sperms, decreased sperm motility &
embyotoxicty).
3. Altered foliccular maturation:
lutenized unruptured follicle,
anovulation,
luteolysis caused by prostaglandin F2
No evidence that they are more common in E.
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Chronic Pain:
The severity of pain is not
correlated to the extent of E but to
the site & the depth (Demco, 1998)
Midline disease is more painful
than lateral disease (Konickx, 1994)
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 Acute Abdominal Pain
 {Rupture of an endometrioma, usually at
menstruation}.
 Differential Diagnosis:
1. Disturbed ectopic
2. PID
3. Acute appendicitis.
 Careful analysis of past and present history
suggests the diagnosis of endometriosis.
Laparoscopy is usually needed to reach the
diagnosis.
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Dyschasia
Pain during defecation occurs
when there is involvement of the
rectovaginal septum
It is particularly noticeable during
menstruation.
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Dysmenorrhea
 E should be considered in women who develop
dysmenorrhea after years of pain-free cycles.
 Pain
1. May be diffuse in the pelvis
localized to one side or
felt in the rectum.
2. Comes on gradually for few days before the
period, but is more severe during menstruation
(Crescendo).
3. Later on it may persist during most of the cycle.
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Deep-seated dyspareunia:
Douglas pouch.
Uterosacral ligament .
Rectovaginal 'septum
Fixed retroversion flexion.
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Sings:
Pelvic tenderness,
Nodules in the cul-de-sac,
Adnexal mass,
Uterine fixity,
Nodules along the uterosacral ligament.
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Adolescent Endometriosis
(Reese et al's 1996)
%Symptoms
95Pelvic pain.
94Dysmenorrhea.
25Irregular menses.
29Deep dyspareunia
43Abdominal pain &
nausea
3Constipation and
diarrhea
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A history of E in the family should prompt further
questioning & raise the index of suspicion (Attaran
and Gidwani, 2003)
Laparoscopic evaluation of the pelvis commonly
reveals atypical, endometriotic lesions.
Microlaparoscopic evaluation may be
recommended in those cases
(Nazhate et al 2000)
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Diagnosis is very difficult (Taylor ,2003):
 Most women become accustomed to
painful menstrual cycles at an early age.
 Even with extensive E, it is possible to
have minimal symptoms or none at all.
 The presentation is so variable and there
is considerable overlap with other
conditions such as irritable bowel
syndrome and pelvic inflammatory disease
(RCOG 1999)
 Physicians have few diagnostic-usually
invasive- tools. Aboubakr Elnashar

Diagnosis is usually delayed:
• It takes a average of 4 years from the
time a woman has her first symptom,
to the time she discusses it with her
doctor.
• It takes average of 9 years from the time
she first experiences symptoms, until a
diagnosis of E is finally made.
Aboubakr Elnashar

Methods of diagnosis:
 Invasive diagnosis
I. Laparoscopy
II. Microlaparoscopy.
 Non invasive diagnosis.
I. Therapeutic .
II. Imaging: U/S, MRI
III. Endometrial nerve fibers
IV. CA 125
V. Other.
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Laparoscopy
 Gold standard' diagnostic test
 Advantages
(RCOG Grade B evidence lll)
1. Excludes other conditions e.g. ovarian
cancer
2. Treatment of E.
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 Disadvantages.
1. Requirement for surgery and anesthesia.
2. Risk of major complications
(e.g. bowel perforation)
Diagnostic laparoscopy: 0.06%
operative laparoscopy: 1.3% in (Harkki-Siren et al, 1999)
3. Visual inspection might
not prove to be E on histological analysis.
not detect deep E.
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Technique:
•2 port approach
•Inspection of D pouch, us lig, pelvic side walls,
anterior surface of the ovary (adhesions) To ensure
complete evaluation, inspection of the pelvis in a
clockwise or counterclockwise fashion.
•Biopsy if there is doubt. It is not a routine
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 Findings:
 Peritoneal
Typical E: black-blue, powder-burn appearance.
Diagnosis in most cases is simple, without the need
for a biopsy.
Atypical (Subtle = Non-pigmented) E: E lesions that
lack the typical black-blue, powder-burn
appearance
Diagnosis: more difficult with standard laparoscopy
Other laparoscopic procedures or
biopsy may be necessary to confirm diagnosis
(Martin,1999)
 Endometrioma Aboubakr Elnashar

1-Near-contact: magnifies the peritoneal area
(Redwin,1987)
2-Peritoneal blood painting: flowing erythrocytes
outline surface irregularities
(Redwin,1987)
3-Examined from different angles and at different
degrees of illumination to see vesicles or whitish
lesions.
4-Direct vision:
Although the resolution of cameras has improved, it
is still not comparable to that of direct vision
(Nezhate et al, 2000)
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5. Laparoscopic visualization through lactated Ringer
or normal saline
(Laufer,1997) .
Vesicular lesions are no longer falsely interpreted as
light reflection .
6. Bubble test:
The posterior cul de sac is irrigated with short bursts
of saline under controlled pressure. Development
of dense soap like bubbles for at least 5 s
indicates a positive test. {increased level of
triglycerides in peritoneal fluid}
(Amer A & Omar M., 2002)
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Accuracy
Visual diagnosis of endometriosis is unreliable.
54–67% of suspected endometriotic lesions are
confirmed histologically
18% of patients clinically suspected to have
endometriosis have no evidence of endometriosis
on pathology
(Walter et al, 2001)
a positive finding on laparoscopy will be incorrect
in half of the cases
(Wakes et al, 2004)
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In these circumstances, peritoneal lesions±
inflammatory changes,
hemangiomas,
foreign body reaction,
mesothelial hyperplasia
hemosiderin deposits
Biopsy of normal-appearing peritoneum has
revealed endometriosis in
6% of women with no visible lesions and
25% of asymptomatic infertile women
(Balasch et al, 1999).
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Directed biopsy (Brosen, 1994)
•E in
90% of typical &
40% of atypical cases.
•Endometrioma:
The appearance most commonly associated
with positive histology:
irregular brown or red mottling on the surface
of white capsule.
•old hemorrhagic corpus luteum:
uniform brown appearance
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Laparoscopic visualization of peritoneal lesions
alone is of limited accuracy, and if a diagnostic
laparoscopy is performed, confirmatory biopsies of
peritoneal lesions, even atypical ones, will be of
value (SOGC, 2010).
The lesions most likely to be histologically
confirmed as endometriosis are
generally large
mixed-color lesions
in the culde sac or on the uterosacral ligaments
(Stegmann et al, 2008)
On histopathology, the diagnosis requires the presence of two or more
of these histologic features:
endometrial epithelium
endometrial glands
endometrial stroma
hemosiderin-laden macrophages (ACOG, 1999)
Aboubakr Elnashar

Is laparoscopy required before medical
management of pelvic pain?
(SOGC, 2010)
not always necessary .
{1. Management of the pain is required whether or
not endometriosis is the cause.
2. All the management strategies for E are relatively
general strategies to decrease inflammatory
conditions in the pelvis}
Aboubakr Elnashar

E can be strongly suspected
severe dysmenorrhea unresponsive to NSAID
with pelvic tenderness and nodularity on palpation
of the uterosacral ligaments and rectovaginal
septum, or
US: endometrioma.
: In these situations, laparoscopy for diagnosis is
not necessary before medical treatment.
Laparoscopy should be performed only if the
surgeon is prepared to vaporize or excise lesions if
endometriosis is discovered {surgical management
provides long-term pain relief for up to 50%}
(Abbott et al, 2003)
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• Less invasive
II. Microlaparoscopy
Out patient procedure
Local anesthesia
Pain mapping.
For adolescent E.
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Non Invasive Diagnosis
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I. Diagnosis by therapeutic trials:
1. Pain suggestive of E +
Woman not trying to conceive +
No pelvic mass
• Therapeutic trial of
COCs (monthly or tricycling) or
Progestogen without performing a diagnostic
laparoscopy
(RCOG 1999)
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2. Chronic pelvic pain
{Moderate to severe
at least 6 m,
unrelated to menstruation
unrelieved by NSAI & antibiotics} +
Clinically suspected E +
• Clinical response to GnRha (Depot leuprolide
acetate 3.75 mg monthly for 3 m)
Can diagnose E (Ling, 1999).
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• GnRH agonist is an appropriate therapy of
chronic pelvic pain, even in the absence of
surgical confirmation of E, provided that a
detailed initial evaluation fails to demonstrate
some other cause of pelvic pain
(ACOG Recommendations Grade (B)
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II. Imaging
1. Transvaginal ultrasound
• first-line investigational tool for suspected E
• help diagnose endometriomas, bladder lesions,
and deep nodules such as those in the
rectovaginal septum.
• Findings:
1. Anechoic to echogenic cysts
2. Masses containing multiple septations & solid
tissue (Morane &Older, 1996)
3. Cysts with low-level echoes: The commonest
finding (95%)
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Cysts with low-level echoes
(Patel et al, 1999)
Endometrioma 95%
Hemorrhagic cyst 50%
Teratoma 18%
Malignant neoplasm 12%
Benign neoplasm 6%
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No Wall
Nodularity
Unilocular Adnexal mass with diffuse
low-level internal echoes (Patel et al,1999)
6 w Follow-
up US MRI or Doppler
Wall Nodularity
regional
bright
echo =
Teratoma
hyperechoic
wall foci =
Endometrioma
No
characteristic
feature.
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Hyperechoic
wall foci
No neoplastic
features
Multilocular Adnexal mass with diffuse
low-level internal echoes (Patel et al,1999)
= Endometrioma
No hyperechoic
wall foci
Neoplastic
features
MRI or Doppler
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2. Transrectal ultrasound
Detect
rectal involvement in E
depth of infiltration by E,
lesions on the posterior bladder wall
but it has not been shown to be superior
to transvaginal ultrasound.
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3. CT:
has been replaced by MRI
poor specificity
high radiation dose
An important role for the CT scan with contrast is to
detect ureteral involvement and possible renal
insufficiency.
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 MRI
Indications: (Funt et al, 2002):
1. Indeterminate
2. Poorly visualized
3. Inadequately localized lesions
Relies on:
Detection of pigmented hgic lesions: signal
characteristics vary according to the age of
hge.
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MR And Endometriosis
Advantages:
1. Greater sensitivity. Detect 75% of mild disease
(Stratton et al, 2003).
2. Evaluation of deep lesions
3. superior to ultrasound in diagnosing rectosigmoid
lesions and endometriosis of the bladder.
Disadvantages:
Not readily available
Expensive.
Aboubakr Elnashar

III. Endometrial nerve fibers
Appropriate marker (Fatheima et al, 2011)
an increased number of nerve fibers in the
endometrium of women with endometriosis
compared to women without endometriosis.
These nerve fibers are reported to be primarily
small unmyelinated sensory C fibers in the
functional layer of endometrium, which
are identified by their staining with PGP9.5, VIP,
and substance P, but not with neurofilament.
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(A) Absence of nerve fibres in the functional layer of
endometrium in adenomyosis but no endometriosis.
(B) Small unmyelinated C nerve fibres (black arrows) in the
functional layer of endometrium in a woman with peritoneal
endometriosis (immunohistoclinical staining with protein
gene product 9.5 and fast red chromogen.Aboubakr Elnashar

IV. Serum markers:
• limited value as a screening test as well as a
diagnostic test.
• Useful marker for monitoring treatment
• no individual serum marker has been found
to specifically correlate with the symptoms of
endometriosis, and many of them are
present in other conditions.
Aboubakr Elnashar

V. Other:
1. Cystoscopy (for bladder endometriosis)
2. sigmoidoscopy or colonoscopy (for transmural
bowel lesions),
3. ultrasound-guided fine needle aspiration
(FNA: for endometriosis in the rectosigmoid,
rectovaginal septum, or in abdominal scars).
4. IVP, barium study
Aboubakr Elnashar

D.D.
1. Ovarian cysts*.
2. Pelvic inflammatory disease .
3. Other causes of nodularity in Douglas pouch:
tuberculous peritonitis
metastases of ovarian cancer.
4. Causes of haematuria,
bleeding per rectum and
acute abdominal pain
if the patient is presented by one of these
symptoms.
5. Asymmetrical enlarged uterus.
Aboubakr Elnashar

• Endometrioma
Hyperechoic wall foci (in 35%)
• Hemorrhagic cyst :
Lacelike internal echoes (in 40%)
• Teratoma
Regional bright echoes ( in 97% )
*Cysts With Low-level Echoes +
Characteristic Features
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*Endometrioma Vs Malignancy
(Brown et al 1998)
Suggestive of malignancy:
1. Mural thickening
2. Wall nodularity
3. Septations > 3 mm
4. Papillary projections
The most significant predictor of malignancy:
Solid component within an ovarian mass
Aboubakr Elnashar

Medical treatment
of endometriosis
Prof Aboubakr Elnashar
Benha university hospital
elnashar53@hotmail.com
Aboubakr Elnashar

Contents
Lines of treatment and treatment
strategy
Non hormonal
Hormonal
New treatments
Evidence based recommendations
Aboubakr Elnashar

Depend on:
1. Age
2. Presenting symptoms
3. Reproductive status
4. Fertility demands
5. Stage
6. Previous response to
treatment. Aboubakr Elnashar

Lines of treatment
A- Symptomatic:
PG inhibitors
ART
Psychotherapy.
Aboubakr Elnashar

B- Hormone (Medical) suppression:
Conventional
New drugs
C. Surgical:
Conservative:
Diathermy, laser vaporization,
excision,
Ov cystectomy, presacral
neurectomy
Radical:
Hysterectomy & ovarian removal.
Aboubakr Elnashar

Treatment strategy
1. Endometriosis & pain (RCOG,2000) :
a. Medical:
NSAID: may be effective.
COC, progestagens, danazol & GnRHa:
equal in relieve pain associated with E.
Prescribe the safest & cheapest.
b. Surgical:
Effective for many women.
Some women fail to respond
{incomplete excision or
post-operative disease recurrence}.Aboubakr Elnashar

(SOGC, 2010)
Aboubakr Elnashar

2. Endometriosis & infertility:
Medical:
No value.
{results in 6 mo. of contraception which further
delays pregnancy.}
Minimal or mild E:
Ovarian stimulation & IUI is more effective than
either no treatment or IUI alone
Surgical:
Minimal or mild:
Laparoscopy: destruction or ablation of the E
implants & lysis of adhesions
Moderate to Severe:
Surgical treatment may improve fertility but RCTAboubakr Elnashar

I. Non hormonal
NSAIDs
Conventional:
COC
Progestagens,
GnRHa
Danazol
New
LNG-IUD
GnRHan
Aromatase inhibitors
SERM
Progesterone antagonist
SPRM
Angiogenesis inhibitors
Immunomodulatory drugs.
Medical treatment
II. Hormonal
Aboubakr Elnashar

I. NSAIDs
 Useful in women trying to conceive
 ibuprofen (Sapofen)
naproxen (Naprosyn).
Mefenamic acid (Ponstan)
Start 2 d before menstruation
Similar efficacy
Gastric irritation.
Aboubakr Elnashar

 Cyclooxygenase-2 (COX-2).
 Celebrex
 Vioxx
Not more effective (than naproxen or ibuprofen)
lower risk of gastric ulceration
high cost
(Mahutte & Arici, 2003)
Aboubakr Elnashar

II. Hormonal
Conventional
Rationale:
E. Implants:
estrogen, progesterone & androgen receptors
at a lower concentration than eutopic endometrium.
Aboubakr Elnashar

Is laparoscopy required
before medical management
of pelvic pain?
(SOGC, 2010)
Not always necessary .
{1. Management of the pain is
required whether or not E is
the cause.
2. All managements aim to
decrease inflammatory
conditions in the pelvis}
Aboubakr Elnashar

E can be strongly
suspected
Severe dysmenorrhea
unresponsive to NSAID+
on palpation of the uterosacral
ligs and rectovaginal septum:
tenderness and nodularity OR
US: endometrioma.
: In these situations,
laparoscopy for diagnosis is
not necessary before medical
treatment.
Aboubakr Elnashar

Laparoscopy should be
performed only if the surgeon
is prepared to
 vaporize or
excise lesions
{: long-term pain relief for up
to 50%}
(Abbott et al, 2003)
Aboubakr Elnashar

Diagnosis by therapeutic
trials:
1. Pain suggestive of E +
Woman not trying to conceive +
No pelvic mass
 COCs (monthly or tricycling) or
Progestogen for 3 cycles
(RCOG 1999)
Clinical response
can diagnose E
Aboubakr Elnashar

2. Chronic pelvic pain
{Moderate to severe
at least 6 m,
unrelated to menstruation
unrelieved by NSAI & antibiotics}
+
Clinically suspected E +
 GnRha (monthly for 3 m)
Clinical response
can diagnose E (Ling, 1999).
Aboubakr Elnashar

GnRHa
An appropriate therapy of
CPP, even in the absence
of laparoscopic
confirmation of E,
provided that a detailed
evaluation fails to
demonstrate other cause
(ACOG Recommendations Grade (B)
Aboubakr Elnashar

Indications of medical treatment
.
Suspected endometriosis
Confirmed endometriosis
.
1. Dysmenorrhea, dysparunia & pelvic pain
associated E.
2. Temporary relief of pain in women awaiting for IVF
3. After surgical treatment who need long-term
management.
Aboubakr Elnashar

Indications of long term medical therapy
1. Severe symptoms with little palpable findings
2. Recurrence after conservative surgery.
Aboubakr Elnashar

 Results:
1. Volume of the disease: similar for
all forms
2. Pain: equally effective
3. Subsequent pregnancy rates:
similar for all forms
4. Recurrence rates: similar
5. Infertility: no improvement
 The various agents: are
comparable in terms of efficacy
 Choice is determined by cost & side
effects.
Aboubakr Elnashar

 Aim:
(A) Pseudopregnancy :
1. Combined contraceptive pills
2. Progestins {avoid oestrogen's
side effects}
(B) Pseudomenopause (induction
of amenorrhoea)
1. Danazol.
2. Gn RH analogues.
Aboubakr Elnashar

1. Combined oral contraceptives
Mechanism of action:
pseudopregnancy
Decidual transformation of both normal & ectopic
endometrium followed by gradual necrosis &
absorption of the decidual cells.
Dose:
Initially, a trial of continuous or cyclic for 3 months.
With pain relief, continue for 6-18 months.
Aboubakr Elnashar

Continuous administration:
more beneficial in terms of pain relief.
{preventing withdrawal bleeding prevent retrograde
menstruation}
Aboubakr Elnashar

Side effects:
BTB:
More common with continuous than with cyclic tt
Treated with conjugated estrogen 1.25 mg or
estradiol 2mg for 1 w.
Other estrogen induced side effects:
Nausea & vomiting
weight gain
DVT.
Aboubakr Elnashar

Efficacy:
OCP Vs GnRHa (Cochrane library, 2005).
No significant difference in the relief
of dyspareunia or non-menstrual
pain
With OCP:
More Headaches and wt gain
Less Hot flushes, insomnia &
vaginal dryness
Aboubakr Elnashar

OCP is first line therapy in the management of E.
1. Effective as GnRHa
2. With E: an increased risk of epithelial ovarian
cancer: COCPs protect against this.
3. Can be taken indefinitely
(SOGC, 2010)
Aboubakr Elnashar

2. PROGESTAGNES
 Mechanism of action:
decedualization & subsequent atrophy of the
endometrial tissue.
Suppression of the ovarian activity.
Aboubakr Elnashar

Dose:
Continuously:
Progestagens given in the luteal phase are not
effective
DoseNamePreparation
30mg/dProveraMPA
150mg/1- 3 mo, IM.Depo proveraDMPA
10-20 mg/d.Primoult norNoreethisterone acetate
20 mg/dDuphastonDydrogestrone
2mg/dVisanneDienogest
Aboubakr Elnashar

Side effects:
Irregular bleeding:
Common
Treated with estrogen for 7d
Wt gain
Fluid retention,
Depression.
Adverse effect on lipoprotein High doses
Aboubakr Elnashar

Efficacy:
Norethindrone acetate
effective in most patients for relieving
dysmenorrhea and chronic pelvic pain.
positive effect on calcium metabolism: relatively
good maintenance of BMD.
BTB: 50%
Negative effects on serum levels of high-density
lipoprotein cholesterol.
Aboubakr Elnashar

MPA:
like danazol can relieve the symptoms of E
effective in the treatment of painful symptoms
(Cochrane library, 2005).
First choice for medical T.T. of E.
{more cost effective & fewer side effects}.
Aboubakr Elnashar

DMPA
equivalent to leuprolide acetate in relieving pain.
effective in relieving pelvic pain in up to 75%
Very economical alternative
Aboubakr Elnashar

loss of BMD but not as much as leuprolide acetate
without addback.
Long-term use:±detrimental to BMD.
Prolonged delay in resumption of ovulation (6-12 mo)
:not be given if pregnancy is aimed in the near future.
BTB: may be prolonged, heavy, and difficult to
correct {progestin effect can not be reversed quickly}.
An ideal indication: residual E after hysterectomy
with or without BSO when future conception and
irregular uterine bleeding are not issues.
Aboubakr Elnashar

Dienogest: Visanne
selective 19-nortestosterone and progesterone
activity. {strong progestational and moderate antigonadotrophic effects, but
no androgenic, glucocorticoid or mineralocorticoid
Activity}.
Effective as GnRHa (triptorelin 3.75 mg/4w)
Quality of life: slightly improved compared with
leuprolide acetate
Effective long-term treatment option
 less hypoestrogenic side effects and little
changes in BMD: advantages in safety and
tolerability
 Higher incidence of abnormal menstrual bleeding
patterns
Aboubakr Elnashar

Vercellini et al, 2011
For pain relief, OCs used continuously is a worthy
option in women with peritoneal and ovarian
lesions
NETA appears to be the preferable compound in
patients with rectovaginal disease.
For prevention of endometrioma recurrence, OCs
are extremely effective whether used continuously
or cyclically, as the mechanism of action seems to
be ovulation inhibition.
Aboubakr Elnashar

3. GNRH AGONISTS
Produced by
Modification of the native GnRH decapeptide at 6 &
10 positions
Glp-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
LHRH
Glp-His-Trp-Ser-Tyr-Ser(But)-Leu-Arg-Pro-Azgly-NH2
Goserelin
100 times more potent than natural LHRH
Aboubakr Elnashar

Mechanism:
After initial agonistic action (flare response),
down-regulation & desensitization of the
pituitary: hypogonadotrophic, hypogonadal
state.
Aboubakr Elnashar

Indications
GnRHa with HT addback
should be considered as 2nd
line treatment:
No response to CHCs or
progestins
Recurrence of symptoms
after initial improvement
(SOGC, 2010)
Aboubakr Elnashar

Types
PriceEPcompanyDoseRouteNamePreparation
530Astrazenica3.6 mg/4w
11.8mg/12w
SCZoladexGoserelin
605
266(7syr)
FerringCR: 3.75mg,
0.1mg then 0.05 mg
IM, SCDecapeptylTriptolerin
750
1550
540
Abbot3.75 mg/4w
11.25 mg/12 w
2.8 ml, 1 ml daily
IM, SC
IM, SC
Lupron
Lucrin
Leuprorelin
Sanofi0.5 mg then 0.2 mgNasal, SCsuperfactBuserelin
Pfaizer0.2 mg bidnasalSynarelNafarelin
Aboubakr Elnashar

 Site of injection:
anterior abdominal wall
• Best route of absorption
and steady dissolution of
depot
• The trunk area is less
sensitive than the thighs:
negligible pain on injection
Aboubakr Elnashar

Side effects:
GnRHa alone: symptoms of estrogen
deficiency
hot flushes
insomnia
Loss of libido,
vaginal dryness,
emotional instability, depression, headache.
loss of BMD, which is not always reversible.
Aboubakr Elnashar

Add-back therapy:
Aim:
To prevent demineralization of bone
& menopausal symptoms.
When:
•GnRha should not be given as a
single agent for >6 ms.
•GnRHa should not be used for any
length of time in the absence of HT
addback
(SOGC, 2010).
Aboubakr Elnashar

Rationale:
There is a threshold serum estrogen concentration that
is low enough that endometriosis is not stimulated but
high enough that hypoestrogenic symptoms are
prevented (Barbieri,1992).
Addback
GnRHa
Oestradiol
Endometriosis symptoms
Menopausal symptoms
This concentration is the same as that achieved with
physiologic HT for menopausal women.Aboubakr Elnashar

•Estrogen-progestagen combination.
Tibilone (livial): 2.5 mg/d.
Bisphosphonates: Etidronate.

Aboubakr Elnashar

Efficacy:
GnRHa: Pain relief 85-100%
persisting for 6-12 months
after cessation of tt.
(Winkel et al,2005 )
GnRHa Vs other hormonal tt:
No difference with respect to pain
relief or reduction in E deposits
(Cochrane library, 2005).
Aboubakr Elnashar

4. DANAZOL(Danocrine, Danol).
isoxazzole derivative of 17 α ethinyltestosterone
It is an oral “impeded” or weak androgen
The golden age for danazol has passed:
No more effective than the other medications
Side effects
Expensive
Aboubakr Elnashar

Inhibition of pituitary Gnt.
Inhibition of steriodogenesis in C. luteum.
It is metabolized to at least 60 products.
The multiple effects of these products is
high-androgen, low-estrogen environment that does
not support the growth of endometriosis &
amenorrhea prevents new seeding from the uterus
into peritoneal cavity.
Aboubakr Elnashar

Side effects:
Androgenic
Wt gain
fluid retention
Fatigue
decreased breast size
acne, oily skin, growth of facial
hair
Hepatocellular damage
{metabolized in liver}
increased cholesterol & LDLP
& decreased HDLP.
Hypoestrogenic
atrophic vaginitis
hot flushes
muscle cramps
emotional liability.
small study raised the concern of
an increased risk of ovarian cancer
The significant side effects limit its use
(Cochrane Reviews 2003)
Aboubakr Elnashar

Contraindications:
Liver disease.
Severe hypertension
congestive heart failure
impaired renal function.
Dose:
200mg 4 times daily for 6 mo.
< 800 mg daily is less effective.
low-dose regimens or vaginal administration
have been described.
Aboubakr Elnashar

Efficacy:
Recurrence in 1/3 of cases.
Success is greatest in cases of
peritoneal E.
Endometriomas > 1cm are less likely
to respond.
Effective in treating symptoms and
signs of E.
Useful to relieve pain & prevent
progress of the disease.
Aboubakr Elnashar

New drugs
An ideal treatment:
Regression of the disease & symptoms
No adverse hypoestrogenic effects
Aboubakr Elnashar

DrugsGroup
Mirena1. LNG-IUD
Cetrorelix2. GnRHan
Anastrazole (Arimidex),
Letrozole (Femara)
3. Aromatase
inhibitors
Tamoxifen, Raloxifene4. SERM
Mifepristone, Onopristone5. Progesterone
antagonist
Asoprisnil6. SPRM
TNP470, Endostatin, Anginex,
Rapamycin
7. Angiogenesis
inhibitors
Loxoribine, IFN- α 2 β, TNF- α
inhibitors.
8. Immunomodulatory
drugs.
Matrix metalprotease, Doxycycline, 5-
fluorouracil, Thiazolidinediones
9. Others
Aboubakr Elnashar

1. levonorgestrel (IUD):
Unclear
LNGIUD delivers significant amounts of
LNG into the peritoneal fluid: clearing up
the local effect on the endometriotic
implants
Aboubakr Elnashar

LNG-IUD
T-shaped
Release rate of LNG:
20 μg/24 h during 1st y
slowly ↓ throughout the 5 y of use.
: Endometrial atrophy
Ovulation: usually not suppressed.
Contraception
Hypomenorrhea or
amenorrhea
Reduced dysmenorrhea
Aboubakr Elnashar

LNG-IUD
Treatment of choice for CPP-associated E in
women who do not wish to conceive.
1. Effective for at least 5 ys
2. Can be reapplied every 5 ys.
3. No modifications in estrogen levels
4. In the long term it is a low-cost therapy
5. Fewer SE than other progestogenic agents.
Aboubakr Elnashar

II. GnRH antagonists
Aboubakr Elnashar

GnRHan
immediately block GnRH
effects
competing with endogenous
GnRH for pituitary binding
sites
suppress LH secretion in a
dose-dependent manner.
Aboubakr Elnashar

Studies:
3 mg of cetrorelix/w for 8 w
 E2: suppressed to 50 pg/ml.
 100%: symptom-free period during GnRH TT
 50%: Regression
 2nd look laparoscopy: Degree of E declined to a
mild stage
(Kupker et al, 2002).
Aboubakr Elnashar

3. Armoatase inhibitors
Anastrazole (Arimidex): 1mg/d
Letrozole (Femara): 2.5 mg/d
Both are approved in USA for tt of breast cancer.
Aboubakr Elnashar

Mechanism of action in endometriosis
Estrogen is produced by 3 pathways
1. Hypothalamic-pituitary-ovarian pathway
2. Peripheral conversion
3. Locally within endometriosis.
 GnRHa stops only 1st pathway
 AI stop all 3 pathways
•Decreasing aromatase in the brain: decrease LH&
FSH: decrease estrogen
•Suppress ovarian & peripheral (e.g. adipose tissue)
estrogen production.
Aboubakr Elnashar

AIs:
1. Should be combined with a progestin or COCs or
GnRHa
2. Combinations of an AI with a progestin or COCs
is more popular {cheaper, fewer side effects}
3. No severe SE
4. AIs should be offered with severe pain despite
previous surgical& hormonal therapies.
4. Further research is required before
recommending the routine use of these agents.
Aboubakr Elnashar

Evidence based
Recommendations
Aboubakr Elnashar

1. Combined hormonal contraceptives, ideally
administered continuously, should be
considered as 1st line agents. (I-A)
2. Administration of progestin alone orally,IM, or
SC may also be considered as 1st line therapy.
(I-A)
3. A GnRHa with HT addback, or the LNG-IUS,
should be considered 2nd line therapeutic
option. (I-A)
Aboubakr Elnashar

4. A GnRHa should be combined with HT
addback therapy from commencement of
therapy and may be considered for longer-term
use (> 6 months). (I-A)
5. While awaiting resolution of symptoms from
the directed medical or surgical treatments for
endometriosis, NSAIDs can be tried. (III-A)
Aboubakr Elnashar

4. SERM: Raloxifene has
Estrogen antagonist on the endometrium
(attenuates the growth)
Estrogen agonist on bone (preserve bone
mineral), but
Vasomotor symptoms limits its use
Aboubakr Elnashar

5. SPRM (asoprisnil):
Mixed agonistic & antagonistic.
It inhibits endometrial growth without
producing systemic progestational
effects
Aboubakr Elnashar

6. Pentoxifylline:
Multi-site immunomodulating drug
7. Mifepristone:
It has antiprogesterone & antiglucocorticoid
actions.
8. Endostatin (Becker et al, 2005)
angiogenesis inhibitor
suppressed the growth of endometriotic in
mice without any apparent negative effects
on fertility or reproduction,
Aboubakr Elnashar

Endometriosis & miscarriage
RCT: miscarriage rate was in the normal range in
women with E who were not treated.
Implantation failure & early abortion: E does not
result in a higher rate of early pregnancy loss.
Endometriosis & ovulation
The frequency of anovulation & luteal phase defects
is similar in women with & without E.
Aboubakr Elnashar

Endometriosis & IVF
• The presence of E does not generally impair
the results of IVF but it increases the risk of
infection.
• It is preferable not to cauterize ovarian
endometrioma if IVF or ICSI is indicated for fear
of destruction of ovarian tissues.
Aboubakr Elnashar

A- Conservative:
Aim :
•Restore normal anatomical relationships
•Excise or destroy as much of the E as possible
•Prevent or delay recurrence
Even 1/10 of an ovary can be enough to preserve
function & fertility (Speroff, 1999).
Aboubakr Elnashar

Routes: Laparoscopy or laparotomy
Laparoscopy
•Advantages:
Better visualization
Less tissue trauma & desiccation
Smaller incision, speedier postoperative
recovery.
Postoperative adhesions & complications
may be less than laparotomy
Results are equivalent or better than
laparotomy (Admson & Pasta, 1994)
Aboubakr Elnashar

Disadvantages:
In advanced E it may be extremely hazardous.
For gynecologist without level III training
laparotomy will be more appropriate.
Strict adherence to microsurgical principles:
Magnification
Minimal tissue trauma
Minimal exposed sutures
Meticulous hemostasis
Aboubakr Elnashar

Procedures:
1. Peritoneal implants:
Ablation (with unipolar or bipolar electrosurgery or
laser) or
Excision by sharp dissection.
Superiority of one method over another are not
substantiated (Sperof & Fritz, 2005)
2. Adhesions:
Excision is preferable to simple lysis because
adhesions will frequently contain disease.Aboubakr Elnashar

3. Ovarian endometrioma:
Wedge resection,
stripping,
drainage with & without ablation of the internal cyst wall.
The best is cystectomy or fenestration with ablation of the internal
cyst wall (Sperof & Fritz, 2005)
1. Residual deep ovarian disease is less likely than after
drainage alone
2. Reoperation rates are lower after drainage without ablation
3. Wedge resection is associated with marked postoperative
adhesions
4. Fenestration & ablation may preserve more functional ovarian
tissue
Aboubakr Elnashar

4. Dysmenorrhea & central pelvic pain:
Presacral neurectomy (PSN) &
Laparoscopic uterosacral nerve ablation (LUNA)
PSN= interrupting the sympathetic innervations of the
uterus at the level of the superior epigastric plexus.
LUNA= transecting the mid-portion of ut sac lig.
Risks:
injury to the ureters or bowel
bladder dysfunction.
RCT
These procedures add no significant benefit to
conservative surgery (Daniell et al 1995).
Aboubakr Elnashar

5. Deeply infiltrating rectovaginal E:
Extensive surgery
By the most skilled & experienced surgeons.
Often, a portion of the posterior
vagina must be excised, &
sometimes, a short segment of
rectum must be resected, followed
by anastomosisAboubakr Elnashar

Results of surgery:
Pain
Mild E:
effectiveness is comparable to that of medical tt.
Endometriomas or deeply infiltrating disease:
Surgical tt offers better long term results.
The combined surgical approach (of laparoscopic laser
ablation, adhesiolysis and uterine nerve ablation) is
beneficial for pelvic pain associated with minimal, mild
and moderate endometriosis (Cochrane library, 2005)
Aboubakr Elnashar

Infertility:
Moderate to severe E: Surgical treatment
improves fertility
Minimal & mild: improvement to a modest
extent
Aboubakr Elnashar

Preoperative medical treatment:
No proven value except in deep disease
involving the cul-de sac or rectovaginal
septum.
Aboubakr Elnashar

Postoperative medical treatment:
Infertility:
It does not increase PR (Vercellini et al, 1998).
The highest PR following conservative surgery occur
in the first year & most doctors not use it.
Pain:
It delays recurrence (6 mo) of the disease &
symptoms & warrants consideration in extensive or
residual disease (Hrnestein, 1997)
Aboubakr Elnashar

Recurrence of E after surgery
E. tend to recur unless definitive surgery (TAH &
BSO) is performed.
Recurrence rate: 10-20% per year
Reasons of recurrence:
Microscopic E escaped detection
Incomplete treatment,
Reestablishment of primary disease.
Aboubakr Elnashar

B- Radical:
Indications:
Failure of hormonal tt &
conservative surgery is unnecessary or
unsuccessful
Hysterectomy& usually bilateral salpingo-
oophrectomy.
Aboubakr Elnashar

HRT after radical surgery
•Estrogen & progestagen replacement therapy at
usual doses can be started immediately after
surgery with negliable risk of recurrence.
Aboubakr Elnashar

Thank you
Benha University Hospital, Egypt
Email:elnashar53@hotmail.com
Aboubakr Elnashar

Pharmacological therapy for endometriosis is
inevitably a compromise.
Not all women using progestins will be relieved
from pain, not all will be satisfied with their
treatment, not all will continue it and not all will
avoid surgery. But at least two-thirds of them could
substantially ameliorate their health-related quality
of life, controlling the disease with marginal
associated morbidity. This appears to be a major
medical achievement, and as such should be
regarded.
Aboubakr Elnashar

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