2. INTRODUCTION
Presence of endometrial tissue constituting of both stroma & glands outside uterus is known as
endometriosis.
This tissue responds to ovarian hormones i.e. estrogen & progesterone like the normal endometrial tissue &
breaks down causing internal bleeding, which is absorbed by surrounding tissue. Over time implants grow
and form destructive scar tissue and adhesions.
Collection of blood called sac or cyst.
It is a common but poorly understood condition
It is an estrogen dependent condition
2
ENDO – METRI – OSIS
Within Womb
Or
Uterus
Condition
3. Endometriosis is defined as the presence of endometrial
tissue (glands and stroma) outside the uterus which
induces a chronic inflammatory reaction.
Predominantly found in women of reproductive age
group.
Most frequent sites are pelvic viscera and peritoneum.
Can affect any organ except spleen
The extent of disease varies from a few small lesions to
large ovarian endo-metriotic cysts (endometrioma) or
extensive fibrosis and adhesion formation causing
marked distortion of pelvic anatomy.
3
4. RISK FACTORS
• Mostly women in their reproductive age group are affected (25-
35 yrs). However adolescent girls & post menopausal women
receiving hormone replacement therapy have been reported to
have the disease.
• Early menarche
• Short cycles
• Menorrhagia
• Tall, thin women with low body mass index.
• Delaying pregnancy until older age.
• Racial predisposition
• White > Asian > black
• Alcohol or caffeine use
4
5. PROTECTIVE FACTORS
• Term pregnancy
• Exercise
• Smoking
SOME ASSOCIATIONS
• Endometriosis and SLE
• Endometriosis and dysplastic naevi
• Endometriosis and h/o melanoma in reproductive age
5
6. SITES
6
COMMON SITES
Ovary (most common site)
Anterior & posterior cul-de-sac
Posterior uterus
Uterosacral ligaments
Posterior broad ligament
Fallopian tube & other pelvic organ
Surgical scars
Intestine – rectosigmoid (10%)
Less common sites
•CNS, Lungs, pleura, diaphragm, skin etc.
7.
8. APPEARANCE
• MACROSCOPIC : Varies in appearance from a few minimal lesions on
otherwise intact pelvic organs to massive ovarian endometriotic cysts
disrupting pelvic anatomy with extensive adhesions involving bowel, bladder
& ureter.
• To the naked eye may appear dark blue / powder burn black / Red / brown /
yellow / white i.e. clear or atypical.
• Varies in size and shape
• MICROSCOPIC / Histologic appearance shows stroma, epithelium & glands
with haemosiderin deposit as residual.
8
10. 10
Endoscopic image of endometriotic lesions in the Pouch of Douglas
and on the right sacrouterine ligament.
11.
12.
13.
14.
15.
16. 16
Micrograph of the wall of an endometrioma. All features of endometriosis
are present (endometrial glands, endometrial stroma and hemosiderin-
laden macrophages.
17. AETIOLOGY - THEORIES
1. Retrograde menstruation/ transtubal migration / transplantation theory
– SAMPSON’S THEORY
SUPPORTS OF SAMPSON’S THEORY
a) Detection of blood & endometrium in peritoneal cavity during
menses in 75-90% of women by laparoscopy.
b) The viable endometrial cells thus obtained from peritoneal cavity
can be grown on cell culture and can attach and penetrate
peritoneum.
c) Increased incidence of endometriosis in women with lower genital
tract obstruction.
17
18. 18
AETIOLOGY - THEORIES
2. Coelomic Metaplasia – MEYER & IVANOFF’S THEORY
Spontaneous transformation of coelomic epithelium into endometrial tissue.
Occurs through activation of k-ras.
Facts in support of coelomic metaplasia
Endometriosis in premenarcheal girls
Endometriosis in thorax
Endometriosis in extremities like thumb, thigh & knee
Rare cases of endometriosis in men treated with high doses of estrogen
Ovarian surface epithelium cells cultured with estradiol form endometrial gland
and stroma on collagen gel lattice.
(Contd.)
19. AETIOLOGY - THEORIES
2. Induction theory– Merill’s Theory : An extension of coelomic metaplasia.
Endogenous factor induces metaplasia in undifferentiated peritoneal cells.
3. Vascular or lymphatic transport of endometrial cells (Halban theory) –
Explains endometriosis in distant organs.
4. Direct implantation – Explains endometriosis in scars.
20. PATHOGENESIS
• Despite of extensive research pathogenesis is poorly understood.
• Pathogenesis interfaces four areas
1. Genetics
2. Environmental factors
3. Cancer biology
4. Immunology
GENETICS
• Endometriosis is a multifactorial disease & results from interaction between
multiple genes & environment.
• No clear Mendelian pattern of inheritance has been observed.
20
21. PATHOGENESIS
GENETICS:
Endometriosis is 7 times more prevalent in first degree relatives of women with
disease.
: Two genetic associations with endometriosis have been recognized
• Polymorphism in galactose – 1 – phosphate uridyl transferase
(GALT)
• Nullmutation in glutathione-s-transferase M1. (GSTM1)
Enzymes of glutathione-s-transferase family are involved in toxification
of dioxin.
21
22. PATHOGENESIS
GENETICS
normal expression of aromatase
Androgen Aromatase Estrogen
22
Endometriotic implants exhibit ed level of aromatase
resulting in in estrogen
Estrogen COX-2
PGE2
Aromatase
+
+
+
Positive feedback loop for continuous estrogen
production resulting in absent 17- hydroxysteroid
dehydrogenase (17- HSD) type 2 with normal 17-
HSD type 1
23. PATHOGENESIS
GENETICS
23
There are 2 isoform of progesterone receptor, PR-A, PR-
B, PR-B mediates action of progesterone.
In endometriosis PR-B absent resulting in no -HSD type2
resulting in local estrogen.
Loss of heterozygosity of chromosome 16P P53 GALT,
APOA2, 11q, 22q.
Aneuploidy of some chromosome
Estrone Estradiol
17 HSD type 1
17 HSD type 2
24. PATHOGENESIS
IMMUNOLOGY
• There occurs in immune cell number but altered function in
endometriosis.
Altered macrophage function in endometriosis
• ↓ in phagocytic activity of macrophages & secretion of substances
that act as growth factor, restrict natural killer (NKcells) activity,
angiogenesis, fibrosis, proliferation.
• There occurs failure of fertilization, embryodevelopment and
implantation causing infertility.
24
25. PATHOGENESIS
IMMUNOLOGY…
2. Paracrine changes in peritoneal environment in endometriosis.
• level of IL-8,
• level of IL -1
• level of TNF
• level of MCP – 1 (monocyte chemotactic protein)
• level of VEGF
• level of RANTES
All the substances are derived from cells of immune system like
macrophages, T – lymphocytes, NK cells & are proliferation,
angiogenesis, fibrosis enhancing.
25
26. CONCLUSION
• Genetic susceptibility, environmental factors & immunology
interfere with each other creating a circle responsible for
development and progression of disease.
26
Genetic susceptibility Environmental factors
Immunology
Retrograde
menstruation
Endometrium
27. DIAGNOSIS
• Diagnosis is usually delayed
• Often takes 5 to 8 years for a women to be diagnosed with
endometriosis.
1. CLINICAL DIAGNOSIS : Diagnosis is suspected from symptoms,
finding of physical examination.
SYMPTOMS
• Pain Infertility
Dysmenorrhea
Dyspareunia
Pain during ovulation
Pain during bowel movement & urination,
Chronic lower abdominal pain.
Pain during examination by doctor
Chest pain – Lung endometriosis
Headache : Brain endometriosis 27
Strongly associated
with endometriosis
28. SYMPTOMS
A large group of women are symptomless
Presentation variable ---considerable overlap with irritable bowel syndrome
(IBS) & pelvic inflammatory disease (PID) → delay in diagnosis.
Severe dysmenorrhoea esp – after years of pain free menses.
Chronic pelvic pain,Dyspareunia,dyschesia,dysuria
Ovulation pain
Cyclical or peri-menstrual symptoms with or without abnormal bleeding
Infertility or subfertility
Chronic fatigue.
28
29. 29
DIAGNOSIS
1. CLINICAL DIAGNOSIS
Causes of pain : Pain associated with endometriosis has 3 primary
mechanisms.
• Action of inflammatory cytokines in peritoneal cavity
• Direct & indirect effects of focal bleeding from implants.
• Irritation or direct infiltration of nerves in pelvic floor
Deep infiltration with tissue damage, adhesion formation, fibrotic
thickening, collection of blood in implant causing traction with
movement of tissue causes pain.
No relationship between stage, site or morphologic characteristic
of pelvic endometriosis and pain.
30. 30
DIAGNOSIS
1. CLINICAL DIAGNOSIS
Causes of infertility : three primary mechanisms
• Distorted adnexal anatomy inhibits ovum capture after ovulation.
• Interference with oocyte development or early embryogenesis
• Reduced endometrial receptivity
Other manifestation include diarrhoea or constipation, nausea,
vomitting, menorrhagia, cyclical haematuria, cyclical haemoptysis,
cyclical swelling & bleeding of scar, seizures, fatigue etc.
SIGNS : Many women have no abnormality
• Nodularity in uterosacral ligament, cul-de-sac
• Lateral or cervical displacement by scarring
• Painful swelling of rectovaginal septum
• Unilateral ovarian cystic enlargement
• Fixed retroversion of uterus in severe cases.
31. DIAGNOSIS
2. BLOOD TESTS
• CA125 – It is a glycoprotein found in cell surface of coelomic epithelium & is
increased in moderate and severe endometriosis.
• Due to poor specificity it is not useful for diagnosis..
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32. DIAGNOSIS
3. TVS & MRI
• Useful for ovarian endometrioma
• Can’t detect peritoneal adhesions and small peritoneal lesions.
4. For accurate diagnosis, visual inspection of inside of abdomen and pelvis
as well as tissue biopsy is important.
• Only accurate way of diagnosis is at time of surgery, either laparotomy
or laparoscopy.
• Laparoscopy is the most common surgical procedure for diagnosis and
performed under GA or LA as an outpatient procedure.
• Biopsy should be performed for diagnosis.
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33. Till now laparoscopy is considered as the gold
standard & biopsy is essential for diagnosis.
33
36. EMPIRICAL TREATMENT
• Treatment of pain symptoms suggestive of endometriosis in absence of a
definitive diagnosis.
• Empirical treatment includes : Counselling
Analgesia
Nutritional therapy
Progestins
Oral contraceptive pill
• Generally women suffering from dysmenorrhoea are treated with NSAIDS.
36
37. HORMONAL MEDICAL
TREATMENT
• As oestrogen is known to stimulate growth of endometriosis – hormonal
therapy has been designed to suppress estrogen synthesis.
Progestagens
• Cause initial decidualisation of endometrial tissue followed by atrophy
• In high doses it can cause amenorrhoea
• Can be considered as first choice : Low cost
Fewer side effects
• Commonly used drug is medroxy progesterone acetate.
• Another progestogen such as desogestrel is now being looked as an
alternative to MPA.
37
38. HORMONAL MEDICAL
TREATMENT
Side Effects-
• Nausea, Weight gain, Fluid retention, breast tenderness
• Break through bleeding, depression
• Levonorgestrel (LNG) containing IUD resulted significant reduction in
dysmenorrhoea, pelvic pain and dyspareunia particularly in rectovaginal
endometriosis.
• Depo preparation of MPA is as effective as GnRH agonists.
38
40. COMBINED OC PILL (COCP)
Even today COCP are the most commonly prescribed treatment for the
disease.
Continuous administration used to induce pseudo-pregnancy i.e. a high
oestrogen and high progesterone environment.
These are continued for 6-12 months
Cyclical administration may provide prophylaxis against either the
development or recurrence of endometriosis as frequent menstrual
bleeding is a known risk factor for endometriosis.
40
41. GESTRINONE
19 nortestosterone derivative having properties
-Androgenic - free testosterone and reduce sex hormone binding protein
-Anti progestinic
-Anti oestrogenic - ↓ serum oestradiol level
-Anti gonadotrophic - ↓ mean LH level, obliterate LH & FSH surge.
Causes cellular inactivation and degeneration of endometriotic implants.
Resumption of menses occur 33 day after discontinuing medication
Long half life (28 hrs) – twice weekly dose of 2.5 mg for 6m
41
42. DANAZOL
Isoxazol derivative of 17-ethinyltestosterone with the following properties
Suppression of GnRH
Direct inhibition of steroidogenesis
Inhibitis midcycle LH surge and induce a chronic anovulation state.
This effects produce a high androgen and low oestrogen environment
Inhibits growth and new seeding of implants of endometriosis
Immunologic effects
↓ Sr. immunoglobins ↓ Sr. C3 ,autoantibodies
↓ Sr. CA 125 levels inhibitis IL-I & TNF- production by
Monocytes
42
43. DANAZOL
• Dose: start 200 mg twice daily and increase the dose to achieve amenorrhoea and relieve of
symptoms.
S/E: Related to androgenic and hypoestrogenic properties
• Wt. gain
• Fluid retention
• Acne, oily skin
• Hirsutism
• Hot flushes
• Atrophic vaginitis
• Reduced breast size
• Loss of libido
• Deepening of voice
• Adverse changes in lipid profile
43
44. DANAZOL
Contraindication
• Liver disease
• Hypertension
• Pregnancy
• CCF
• Impaired renal function
• Local application : because of many side effects local application of danazol
as vaginal ring (1500 mg) tried → pilot study (limited data available)
44
45. PROGESTERONE ANTAGONISTS
45
They act by their antiproliferative effects on endometrium
without the risk of hypo-estrogenism or bone loss.
Mifepristone: Also has got antiglucocorticoid antibody -25-100
mg/d reduced pelvic pain and induced 55% regression of
lesions.
Onapristone – causes remission in 40-60% pt
46. GnRH AGONISTS
• Bind to pituitary GnRH receptors and stimulate LH & FSH synthesis & release
however they have a longer half life (3-8hrs).
↓
• Results in continuous exposure of GnRH receptors to GnRH agonists.
• There will be a initial ‘flare’ followed by loss of pituitary receptors and down
regulation of GnRH activity
↓
• Low FSH & LH levels
• Decrease the activity of plasminogen activators and matrix MMPs and
increased the activity of their inhibitors. Suggesting potential GnRH regulated
mechanisms for reducing adhesion formation.
46
47. VARIOUS AGENTS INCLUDE
• Leuprolide
• Buserelin
• Nafarelin
• Histrelin
• Goserelin
• Deslorenin
• These drugs are inactive orally- administered IM,SC or IN
• Results with GnRH agonists are similar to those with Danazole or progestin therapy
• These drugs does not have adverse effect on serum lipids
S/E : Due to hypoestrogenism like hot flushes, reduced libido, osteoporosis (6 – 8%)
To prevent these effects : ADD-BACK THERAPY is added
Goal: Treat endometriosis and endometriosis associated pain while preventing vasomotor
symptoms & bone loss.
47
48. ADD BACK THERAPY …..
• Achieved by progesterone : Nor-ethisterone 1.2mg
Nor-ethindrone 5 mg
• Can also be achieved by :
• Tibolone 2.5 mg/d
• E-P Combination (Congugated estrogen 0.625 mg + MPA 2.5)
• Raloxifene 60mg/day
• But bone mineral density reduction occurred with long term GnRH agonist
use was not fully recovered even after 6 years.
• Hence should not be prescribed to girls who have not attaining their maximal
BMD.
48
49. • Anastrozole 1mg/d with elemental calcium 1.5gm/d resulted in
hypoestrogenism, pain relief in 2 m and after 9m a 10 fold reduction in size of
endometriosis.
• It inhibits oestrogen production in peripheral tissue, endometrial tissues as
well as ovary however randomized controlled trials are needed to confirm.
Selective Estrogen Receptor Modulator (SERM):
Raloxifen resulted in regression of endometriosis.
• It acts as estrogen antagonist on endometrium (attenuates growth) and is an
agonist on bone.
49
AROMATASE INHIBITORS
50. EFFICIENCY OF MEDICAL
TREATMENT
PAIN
• MPA, gestrinone, danazole, GnRH agonists all have similar efficacy in
resolution of the laparoscopically documented disease and pain alleviation.
• Post operative medical therapy may be required for incomplete surgical
resection and persistent pain. Treatment should continue for 3-6 months.
• Pain releif may be of short duration because endometriosis recurs.
SUBFERTILITY
• Pregnancy is either impossible or contraindicated during medical treatment
of endometriosis.
50
51. SURGICAL TREATMENT
• Depending on severity of the disease diagnosis and removal of endometriosis
should be performed simultaneously at the time of surgery.
• Goal: Excise all visible endometrial lesions and associated adhesions,
peritoneal lesions, ovarian cysts, deep rectovaginal endometriosis and to
restore normal anatomy.
• In most women, laparoscopy can be used as this technique decreases
morbidity and possibility of recurrence of adhesions post operatively.
• Laparotomy reserved for :
• Advanced disease who can’t undergo laparoscopy
• Fertility conservation not necessary
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52. SURGICAL TREATMENT
PREOPERATIVE HORMONAL TREATMENT
• In severe endometriosis it has been recommended that surgical treatment be
preceded by a 3 month course of medical treatment to reduce vascularisation
and nodular size.
• However a recent randomized study with 3m GnRH agonists failed to show
any significant difference in ease of surgery.
PERITONEAL ENDOMETRIOSIS
• Can be removed during laparoscopy by surgical excision with scissors, bipolar
coagulation or laser methods (CO2 laser, potassium-titany-phosphate laser or
argon laser).
• CO2 laser is superior as it causes minimal thermal damage.
52
53. SURGICAL TREATMENT
OVARIAN ENDOMETRIOSIS
Superficial lesions can be vaporized
Small ovarian endometrioma (<3 cm) can be aspirated, irrigated & inspected
with ovarian cystoscopy for intracystic lesions, their internal wall must be
vaporized to destroy mucosal lining
Large endometrioma (> 3 cm) can be aspirated followed by excision and
removal of the cyst wall to prevent recurrence.
Normal ovarian tissue is preserved.
There is increasingly concern that ovarian cystectomy may reduce ovarian
volume and reserve and diminish fertility.
53
54. SURGICAL TREATMENT
ADHESIOLYSIS
• Removal of endometriosis related adhesion performed carefully
• Reactive use of pharmacologic agents to prevent post operative adhesion not
recommended
54
56. SURGICAL TREATMENT…..
RECTOVAGINAL OR RECTOSIGMOID ENDOMETRIOSIS
• Surgical excision is difficult and can be associated with major complications
• Bowel perforation & peritonitis can occurs.
• Essential pre-operative investigations like USG, IVP (to exclude ureteral
endometriosis) and colon contrast radiography (to exclude intramural
rectosigmoidal endometriosis)
• To allow complete excision bowel wall resection may be needed hence pre-op
full bowel preparation required .
OOPHORECTOMY & HYSTERECTOMY
• Indicated in severe situation more commonly perfomed by laparotomy.
56
59. RECURRENCE
• Tends to recur unless definitive surgery is performed.
• Recurrence rate is about 5-20% per year.
59
60. ASSISTED REPRODUCTION AND
ENDOMETRIOSIS
• The treatment of endometriosis related infertility is dependent on
• Age of the women
• Duration of infertility
• Stage of endometriosis
• Involvement of ovaries tubes or both
• Previous therapy
• Associated pain symptoms
• Cost of treatment
• Assisted reproduction including controlled ovarian hyperstimulation with IUI,
IVF and GIFT may be options for infertility treatment
• IVF is the method of choice when distortion of the tubo ovarian is present.
60
61. INTRAUTERINE INSEMINATION
(IUI)
• Infertility can be successfully treated with intrauterine insemination in
combination with ovarian stimulation.
• In one study a significantly higher live birth rate per cycle was reported (11%) than
the control group (2%)
• There is clear evidence that pregnancy rate in an insemination programme is
lower than in women with unexplained infertility.
IN VITRO FERTILIZATION (IVF )
• Pregnancy rate after IVF is lower in women with endometriosis than women
without this disease.
• There is normal fertilization rate but a reduced implantation rate per embryo
transferred because of increased IL-6 levels in follicular fluid.
• use of Danazole gestrinone or GnRH agonist before IVF improve pregnancy rate.
61
63. Definition
• Adenomyosis is the condition where
there is ingrowth of the
endometrium, both the glandular and
stromal components, directly into the
myometrium.
64. • Exact cause is not known
• It may be related to repeated childbirths, vigrous
curettage or excess of estrogen effect
• Pelvic endometriosis co-exists in about 40 percent
CAUSES
65. • Histologically , it is characterized by the extension of endometrial glands
and stroma beneath the endometrial-myometerial interface (EMI)
• It forms nests, deep within myometrium
• Subsequently, there is myometrial hyperplasia around the endometriotic
foci
• It is thought that the disturbance of normal junctional zone predisposes to
secondary infiltration of endometrial glands and stroma to inner
myometrial zone
• This disturbance may be due to endometrial factors, genetic predisposition
or alteres immune response
• Trauma to the deeper endometrium (repeated curretage), causing
breakdown of EMI is also taken as etiological factor
Pathogenesis
66. • The growth and tissue reaction in the endometrium depend on the
response of ectopic endometrial tissues to the ovarian hormones
• If basal layer is only present, tissue reaction is much less
• But if functional zone is present which is responsive to hormones, the
tissue reaction surrounding endometrium is marked
• There is hyperplasia of the myometrium producing diffuse enlargement of
uterus, sometimes symmetriacally but at times more on posterior wall
• The growth may be localised or may invade a polyp
Pathology
67.
68. • Diffuse symmetrical enlargement of the uterus
• Posterior wall is more often thickened than the anterior wall
• Size usually doesnot increase more than 12-14 weeks uterus size
• On cut section, there is thickening of uterine wall
• Cut section presents characteristic trabeculated appearance
• Unlike fibroid, there is no capsule surrounding the growth
• There may be visible blood spot at places
GROSS APPEARANCE
69.
70. • Histological examination :
• Glandular tissue like that of endometrium surrounded by stromal cells in the
myometrium
71. Clinical features
• About 1/3rd remains asymptomatic, being discovered on histological
examination
• Patients are usually parous with age usually above 40
72. Symptoms
• Menorrhagia (70%)
Excessive bleeding is due to increased uterine cavity, associated
endometrial hyperplasia and inadequate uterine contraction
• Dysmenorrhoea (30%)
Progressively increased colicky pain during period is due to retrograde
pattern of uterine contractions
It also depends on the number and depth of adenomyotic foci in
myometrium
When depth of penetration is >= 80% of the myometrium, the pain is
severe
Other causes of pain are – local tissue and prostaglandins
73. • Due to enlarged and tender uterus
Dyspareunia or frequency of urination
• Higher incidence of infertility and miscarriage
• The reasons are
• Abnormal function of subendometrial myometrium
• Retrograde myometrial contractions
• Interference in sperm transport and blastocyst implantation
• Abnormal endometrial immune response and nitric oxide level
Infertility
74. Signs
Abdominal examination may reveal a
hypogastrium mass arising out of pelvis
Size usually doesnot exceed 12- 14 weeks
uterus size
Pelvic examination reveals uniform
enlargement of the uterus
75. Ultrasound and colour doppler
• Myometrium normally has three distint zones of different echogenicity
• The inner layer is hypoechoic relative to middle and outer layer. This
subendometrial halo is charactersitic of adenomyosis
76. • Other features are-
i. Hetrogenous echogenicity
ii. Hypoechoic myometrium with multiple small cysts in the myometrium
(honeycomb appearance)
iii. Increased vascularity within the myometrium
77. Treatment
• The treatment is surgical
• There is little place for hormone therapy
• Levonoergestrol releasing IUD: improve menorrhagia and
dysmennorhoea
• Danazol loaded (300-400mg) IUD also improve symptoms of
menorrhagia and dysmenorrhoea
• Surgical management :
A. Conservative surgery –
• Adenomyomectomy
• Uterine mass reduction
B. Hysterectomy (parous and aged women).