Endometriosis & INDIA A comprehensive update : Dr Sharda Jain

1. Endometriosis & INDIA
A comprehensive update
1
Dr. Sharda Jain

2. Katrina Kaif

3. •Diagnostic Dilemma
•Debilitating Disease
•Progressive Disease
•Disease with
“No Cure”
A Gynaecologist’s Dilemma

4. Endometriosis
remains a diagnostic
and therapeutic
challenge despite
decades of clinical
experience and
research
Multiple treatment
options for
endometriosis
indicate how
difficult to be
diagnosed and
effectively treat
with our current
understanding
?

5. Scope of Presentation
•Introduction
•Prevalence in INDIA
•Signs and Symptoms
•Sites of endometriosis
•Diagnosis
•Scoring system
Endometriosis:
Endometriosis and pain
Pathogenesis
Guidelines

6. ENDOMETRIOSIS
Endometriosis
“presence of
endometrial glands and
stroma outside the
uterine cavity,
predominantly in the
pelvic compartment”1
Estrogen dependent
Estrogen-dependent
chronic inflammatory
condition that is
associated with pelvic
pain and infertility1
Clinically
Symptomatic:
pelvic pain, severe
dysmenorrhea,
dyspareunia, and
infertility2
Sampson
• Coined the term “Endometriosis” in
19252
• The most common benign
gynecological proliferations in
premenopausal women3
1. Vercellini P, Viganò P, Somigliana E, Fedele L Nat Rev Endocrinol. 2014;10(5):261-275. doi:10.1038/nrendo.2013.255
2. T. Harada (ed.), Endometriosis: Pathogenesis and Treatment
3. Mehedintu C, Plotogea MN, Ionescu S, Antonovici M. J Med Life. 2014;7(3):349-357.
Asymptomatic:
incidentally discovered
at laparoscopic
surgery2
6

7. PREVALENCE

8. Prevalence
● Endometriosis affects roughly 10% of reproductive age
women and girls globally1
● Around 26 million in India are reported to have
endometriosis2
● The incidence of endometriosis range from 34% to
48%2
● In a Cohort study of endometriosis in south India, the
incidence of endometriosis was 55 % in the age group of
21-30 years of age group3
The prevalence
The prevalence of
endometriotic disease
seems to be ~5%, with a
peak between 25 years and
35 years of age
Age group affected
Frequent in adolescent
women with chronic
pelvic pain
1. https://www.who.int/news-room/fact-sheets/detail/endometriosis_accessed on 03.12.21
2. https://www.fogsi.org/wp-content/uploads/tog/KPP_Key_Practice_Points_on_Endometriosis_Final.pdf
3. Mohan M et al. Int J Reprod Contracept Obstet Gynecol. 2016 Nov;5(11):3883-88
8

9. Endometriosis- India prevalence in Infertility
● The frequency of
endometriosis1
○ highly observed between the age
group of 26-30 years old presenting
with an increase in primary infertility
● The prevalence of endometriosis
was 73.33% in infertile women2 24
21
15
11
21 23
20
30
35 34
52
44
24 23
13 15
0
10
20
30
40
50
60
20-25 26-30 31-35 36-40
%
of
women
with
endometriosis
Age group (years)
American fertility Score in 4
stages vs age of women1
Stage I Stage II Stage III Stage IV
Endometriosis predominantly affects the women
of reproductive age group and causes primary
infertility in majority of the patients1
1. Mohan M et al. Int J Reprod Contracept Obstet Gynecol. 2016 Nov;5(11):3883-88
2. Valson H et al. Int J Reprod Contracept Obstet Gynecol. 2016 ;5(2):514-519
9

10. SIGNS AND SYMPTOMS

11. 11

12. Association of clinical presentations of endometriosis with staging ( Indian Study )
1. Mishra VV, Gaddagi RA, Aggarwal R, Choudhary S, Sharma U, Patel U. J Clin Diagn Res. 2015;9(6):QC01-QC3.
Clinical signs and
symptoms
Stage 1 (of 119) Stage 2 (of 39) Stage 3 (of 11) Stage 4 (of 11) p-value
N(%) OR N(%) OR N(%) OR N(%) OR
Menstrual
Irregularity
25 (21.00%) 1.00 4 (10.25%) 0.43 1 (9.09%) 0.38 2 (18.18%) 0.84 0.40 (NS)
Heavy
Menstrual flow
12 (10.08%) 1.00 5 (12.82%) 1.31 2 (18.18%) 1.98 3 (27.27%) 3.34 0.36 (NS)
Scant
Menstrual flow
6 (5.04%) 1.00 3 (7.69%) 1.57 2 (18.18%) 4.19 1 (9.09%) 1.97 0.39 (NS)
Dysmenorrhea 40 (33.61%) 1.00 23 (58.97%) 2.83 6 (54.54%) 2.37 7 (63.63) 3.45 0.01 *
Dyspareunia 5 (4.20%) 1.00 4 (10.25%) 2.61 3 (27.27%) 8.55 5 (45.45%) 19 <0.01 *
Chronic Pelvic
pain
1 (0.84%) 1.00 1 (2.56%) 3.11 1 (9.09%) 11.8 5 (45.45%) 98.33 <0.01 *
Abdominal
mass
0 (0.00%) 1.00 0 (0.00%) N/A 0 (0.00%) N/A 0 (0.00%) N/A -
Tenderness 4 (3.36%) 1.00 4 (10.25%) 3.29 6 (54.54%) 34.5 11 (100%) N/A <0.01 *
Adnexal mass 1 (0.84%) 1.00 0 (0.00%) N/A 2 (18.18%) 26.22 6 (54.54%) 141.6 <0.01 *
Restricted
Mobility
1 (0.84%) 1.00 3 (7.69%) 9.83 4 (36.36%) 67.42 10 (90.90%) 1180 <0.01 *
OR represents Odds Ratios. p <0.05 considered to be statistically significant difference Here, NS represents Non-Significant difference between these groups
12

13. SITES OF ENDOMETRIOSIS

14. Sites of endometriosis
Pelvic (96.4%)
•Ovary with or without posterior cul-de-sac obliteration
Soft tissues (2.8%)
•Abdominal wall
•Uterine cervix and vagina
•Inguinal
•Vulva
Gastrointestinal (0.3%)
•Appendix
•Rectum
Urinary (0.2%)
•Bladder inside
•Ureter inside
Others (0.2%)
•Peritoneum and omentum
•Adrenal gland
Pelvic
97%
Soft tissues
3%
Gastrointestinal
0%
Urinary
0%
Others
0%
Sites of endometriosis
Pelvic Soft tissues Gastrointestinal Urinary Others
14

15. Location of soft tissue endometriosis
Abdominal wall
Previous cesarean scar site
Previous other surgery scar site
Surgery history unknown
Uterine cervix and vagina
Uterine cervix
Vagina
Inguinal area
Previous inguinal hernia scar site
Surgery history unknown
Vulvar area
Previous right episiotomy site
Previous median episiotomy site
1. Chapron C, Marcellin L, Borghese B, Santulli P. Nat Rev Endocrinol. 2019;15(11):666-682. doi:10.1038/s41574-019-0245-z
The heterogeneous characteristics of
endometriosis and adenomyosis
3 well-recognized phenotypes: superficial peritoneal lesions
(SUP), ovarian endometriomas (OMA) and deep infiltrating
endometriosis (DIE)
15

16. Multiple Manifestations of Endometriosis
1. Zondervan KT, Becker CM, Missmer SA. N Engl J Med. 2020;382(13):1244-1256.
Minimal endometriosis with four
peritoneal endometriotic lesions (white
arrows) on the right pelvic Side wall.
Extensive endometriosis with bowel
adhesions to the uterus and
obliteration of the posterior cul-de-
sac.
Superficial red peritoneal
endometriotic lesion and hyperemia
Endometrioma (“chocolate cyst”) in
the left ovary
Deep bladder nodule (black arrows) and
red, brown, and black peritoneal
endometriotic lesions (white arrows)
16

17. Endometriosis is a bigchallenge in diagnosis and requires
decision making at every stage by the clinician & the patient

18. DIAGNOSIS

19. The challenge of diagnosing endometriosis
● There are no pathognomonic features or biomarkers
necessary and sufficient to define endometriosis
● Diagnosis is delayed from 4 to 11 years
○ Delay from symptom onset to diagnosis
○ “normalization” of symptoms and misdiagnosis
● Gold standard:
○ laparoscopy with or without histologic
verification
○ But many Societies endorse the treatment of
symptoms before obtaining a definitive surgical
diagnosis
1. Agarwal SK, Chapron C, Giudice LC, et al. Am J Obstet Gynecol. 2019;220(4):354.e1-354.e12.
Empiric therapy prior to laparoscopy in the diagnostic and treatment
algorithm unless fertility is a priority
2017
The gold standard laparoscopy-
challenged!
20

20. Algorithm for a clinical
diagnosis of endometriosis
● The algorithm is intended
to make the diagnosis of
endometriosis more
accessible, reducing the
negative impact of
undiagnosed and
untreated endometriosis
on women’s lives.
● Practitioners should feel
empowered to clinically
diagnose this disease
early and without an
invasive procedure.
1. Agarwal SK, Chapron C, Giudice LC, et al. Am J Obstet Gynecol. 2019;220(4):354.e1-354.e12.
21

21. CLASSIFICATION

22. Endometriosis- classification
AFS and ASRM staging
system of endometriosis is
based on a points system
that takes into account
location, extent and depth
of disease in relation to
pelvic structures
Stage I (minimal, 1–5 points)
usually comprises few
superficial endometriotic spots
or adhesions
Stage II (mild, 6–15 points)
can be a few, deep peritoneal
lesions solely or in
combination with superficial
lesions and filmy adhesions
Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Viganò P. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9. Published 2018
Jul 19. doi:10.1038/s41572-018-0008-5 23

23. Endometriosis- classification
Stage III (moderate, 16–40
points) often includes an
endometrioma by itself or in
combination with superficial or
deep endometriosis and/or
dense adhesions.
Stage IV (severe, >40
points) is often characterized
by all of the above as well as
bilateral ovarian
endometrioma and/or dense
adhesions that can lead to a
partial or complete obliteration
of the lesser or true pelvis
Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Viganò P. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9. Published 2018 Jul 19. doi:10.1038/s41572-018-0008-5 24

24. RISK FACTORS

25. Risk factors for Endometriosis
1. Zondervan KT, Becker CM, Missmer SA. N Engl J Med. 2020;382(13):1244-1256.
Endometriosis across
the Life Course
Before a
definitive
diagnosis is
made, women
often endure
symptoms for
years while
negative
effects on well-
being and
quality of life,
in addition to
multisystemic
coexisting
conditions,
accumulate.
26

26. Risk factors for endometriosis
1. Shafrir AL, Farland LV, Shah DK, et al.. Best Pract Res Clin Obstet Gynaecol. 2018;51:1-15.
In-Utero and early life
Potential Increased Risk
↑Consistent
Lower birth weight
↑Inconsistent
Prematurity
↑Understudied
Maternal
diethylstilbesterol
Potential Decreased Risk
↓Consistent
↓ Inconsistent
Maternal/ paternal
smoking
↓ Understudied
Prenatal exposure to
diethylstilbestrol (DES), a
synthetic estrogen, has been
associated with a greater
risk of endometriosis (OR=1.3)
In utero DES exposure, which has
been linked to reproductive tract
structural abnormalities
A higher risk of endpometriosis
among women born with lower
birthweights compared to those
born with normal or high
birthweight
In-Utero and early life
27

27. Risk factors for endometriosis
1. Shafrir AL, Farland LV, Shah DK, et al.. Best Pract Res Clin Obstet Gynaecol. 2018;51:1-15.
Childhood and Adolescence
Potential Increased Risk
↑Consistent
Earlier age at menarche
Lower body mass index
↑Inconsistent
↑Understudied
Intense physical activity
Passive smoke
exposure
Skin sensitivity
Potential Decreased Risk
↓Consistent
↓ Inconsistent
↓ Understudied
Early age at menarche has been
consistently associated with an
higher risk of endometriosis
shorter menstrual cycles (<26
days) during late adolescence
(18-22 years) were associated
with a greater rate of
endometriosis
Inverse association between
childhood and adolescent body
size and the risk of endometriosis
Childhood and Adolescence
28

28. Risk factors for endometriosis
1. Shafrir AL, Farland LV, Shah DK, et al.. Best Pract Res Clin Obstet Gynaecol. 2018;51:1-15.
Adulthood
Potential Increased Risk
↑Consistent
Shorter menstrual cycle length
Lower body mass index
↑Inconsistent
Greater height
Alcohol use, Caffeine intake
PCB/dioxin exposure
Moles, Skin sensitivity
↑Understudied
Heavier menstrual volume
Lowe hip-waist ratio
Night shift work
Red meat/saturated fat, Trans fat
Potential Decreased Risk
↓Consistent
Greater parity
↓ Inconsistent
Cigarette smoking
Regular physical activity
↓ Understudied
Lactation
Fruits and vegetables
Fish and Omega-3 PUFA
Low-fat dairy products
Shorter menstrual cycles during
adulthood have been consistently
associated with a greater
endometriosis risk
Pregnancy is an important
detection window for
endometriosis, particularly among
asymptomatic women presenting
with infertility
a consistent inverse association
between adult BMI and
endometriosis has been observed
Adulthood
29

29. PATHOGENESIS

30. Pathogenesis
● Retrograde Menstruation
○ Most widely accepted theory
○ The reflux of menstrual debris with viable endometrial cells via the fallopian tubes into the pelvic cavity
● Viable endometrial fragments are driven through the fallopian tubes, possibly by a pressure
gradient originating from dys-synergic uterine contractions
● Upon reaching the peritoneal cavity, the fragments can implant, grow and invade onto pelvic
structures
● Influenced by :
○ Menstrual, reproductive or personal factor that would augment pelvic contamination by regurgitated endometrium
○ Early age at menarche
○ Long duration of menstrual flow,
○ Any alteration at the molecular level that favours the stepwise process of cell implantation and growth at ectopic locations
1. Vercellini P, Viganò P, Somigliana E, Fedele L. Nat Rev Endocrinol. 2014;10(5):261-275.
Endometriosis is a multifactorial disease, and its aetiology and pathogenesis are still ill-established.
31

31. Other theories on endometriosis pathogenesis
1. Vercellini P, Viganò P, Somigliana E, Fedele L. Nat Rev Endocrinol. 2014;10(5):261-275.
Endometrial stem
cell implantation
Endometrial epithelial progenitor
cells and mesenchymal stem-cell-
like cells together with their niche
cells are shed into the peritoneum
via retrograde menstruation
establishing ectopic implants.
Mostly suggested for
endometriosis infiltrating the cul-
de-sac and uterosacral ligaments.
Aberrant differentiation or
migration of the Müllerian ducts
could cause spreading of cells in
the migratory pathway of fetal
organogenesis across the
posterior pelvic floor.
Still supported for ovarian
endometriosis.
The coelomic epithelium covering
the ovary and the serosa of the
peritoneum could undergo a
metaplastic change
into endometrium.
Müllerian remnant
abnormalities
Coelomic
metaplasia
32

32. Pathogenesis- Other theories
Hormones
Steroid hormones should play a central
role in the aetiology of endometriosis
since it is a disease of women in
reproductive age and not usually seen in
postmenopausal women who are not on
hormonal treatment
Apoptosis Suppression
Evidence suggest upregulation of
antiapoptotic and prosurvival genes and
reciprocal downregulation of the genes
regulating the apoptosis pathway in
ectopic endometrial cells
Genetics
Endometriosis may be associated with
altering different gene clusters that
regulate specific cellular functional
aberrations.
Immune Dysfunction
Women with endometriosis have higher
expression of cytokines and vascular
endothelial growth factors in their
peritoneal fluid, which promote
proliferation of endometrial cells and
angiogenesis
1. Sourial S, Tempest N, Hapangama DK.. Int J Reprod Med. 2014;2014:179515. doi:10.1155/2014/179515 33

33. Coelomic metaplasia
● This theory postulates that endometriosis originates from
the metaplasia of specialised cells that are present in the
mesothelial lining of the visceral and abdominal
peritoneum
● Hormonal or immunological factors are thought to
stimulate the transformation of normal peritoneal
tissue/cells into endometrium-like tissue
● This theory may explain the occurrence of endometriosis
in prepubertal girls
○ The usual driving force for endometrial growth, oestrogen,
is not present in the pre-pubertal girls and therefore this
condition may be different from endometriosis that is
found in women of reproductive age.
1. Sourial S, Tempest N, Hapangama DK.. Int J Reprod Med. 2014;2014:179515. doi:10.1155/2014/179515
34

34. Oxidative Stress and Inflammation
Increased oxidation of
lipoproteins
ROS cause lipid
peroxidation
DNA damage in
endometrial cells
The presence of water
and electrolytes in the
increased peritoneal fluid
volume in patients with
endometriosis
source of ROS
Iron overload in their
peritoneal cavities
redox reactions
The release of the
proinflammatory heam
products
inflammation
recruitment of
lymphocytes and
activated
macrophages
cytokines induce
oxidizing of
enzymes and
promotes
endothelial growth
The excess production of
ROS
decreased level of
antioxidants that
usually eliminates
these molecules
1. Sourial S, Tempest N, Hapangama DK.. Int J Reprod Med. 2014;2014:179515. doi:10.1155/2014/179515
Accumulation of ROS may contribute to the propagation and maintenance of endometriosis and associated symptoms
35

35. Epidemiological factors and molecular mechanisms involved in endometriosis development
1. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261-275.
doi:10.1038/nrendo.2013.255
Menstrual and reproductive factors
• Parity ↓↓
• Age at menarche (early) ↑
• Menstrual cycle length (short) ↑
• Duration of flows ↑
Constitutional factors
• Family history ↑
• BMI ↓
• Freckles ↑
• Nevi ↑
Personal habits
• Alcohol drinking ↑
• Diet: inconsistent
• Smoking: no effect
• Regular exercise ↓
Epidemiological factors
Altered steroid biosynthesis and receptor response
• Increased ERβ expression
• Increased aromatase expression
• Perturbations in progesterone signal
intermediates: HOXA10, FOXO1, NF-κB, Hic-5,
NCoR2
• 17β-hydroxysteroid dehydrogenase-2 deficiency
Increased invasiveness and vascularization
• Upregulated MMP expression
• Increased peritoneal VEGF
• Overactive AKT
• Recruitment of Tie-2 expressing macrophages
Inflammatory response
• Production of chemokines: RANTES, MCP-1, IL-8
• Recruitment of alternatively activated
macrophages
• Increased peritoneal IL-6, TNF
• Engagement of NF-κB-dependent pathway
• Accumulation of iron and ROS production
Molecular and cellular alterations
36

36. Proposed interplay between the different factors reported in the pathogenesis of
superficial versus deep endometriosis
● The different initiating, propagating, and
predisposing factors are indicated through
different shapes, respectively.
● Retrograde menstruation may not explain the
pathogenesis of deep endometriosis, where no
deep endometrial lesions could be induced
● The arrows indicate the interplay between the
different factors.
● As indicated by the bold pink arrows, some of the
labelled propagating factors create a
microenvironment that impacts the differentiation
of stem cells and/or the transdifferentiation of
peritoneal cells into endometrial cells.
1. Sourial S, Tempest N, Hapangama DK.. Int J Reprod Med. 2014;2014:179515. doi:10.1155/2014/179515
37

37. New concept of etiology

38. Association with early neonatal bleeding
● Early onset endometriosis
● Neonatal Uterine Bleeding
Identified peritoneal reflux from neonatal uterine bleeding (NUB)
occurring in 3–5% of female neonates, as a biologically plausible
and likely cause of Early Onset Endometriosis
Giuseppe Benagiano; Progress In the diagnosis and management of adolescent endometriosis : an
opinion;Reproductive biomedicine online 36 2018

39. Long Cervix with
mucous plug
makes the blood
enter peritoneal
cavity easily

40. Stem cells and endometriosis

41. The endometrial basalis contains a small population of epithelial stem cells
and stromal stem cells, within the so-called endometrial niches.
(Gargett et sl., 2007)
In biology, the term is commonly used to describe an entity or a concept that is based on what is generally
accepted or inferred even without direct proof of it,

42. PAIN Overview

43. Endometriosis and Pain- An overview
7- to 10-fold increase in
endometriosis risk in women with a
first-degree relative with
endometriosis.
Women who have prolonged exposure
to estrogen with early menarche, shorter
cycles, lower parity, lack of lactation
periods appear to have increased risk of
developing endometriosis
71-87%
Suffer from
chronic pelvic
pain
Genetic predisposition Prolonged exposure to estrogen
Chronic inflammatory process
result in pain presence of increased density of
nerve fibers in peritoneal
endometriosis, with overexpression
of nerve growth factor leads to pain
Etiology of pain
Nerve growth factor
1. Kim JH, Han E. Endometriosis and Female Pelvic Pain. Semin Reprod Med. 2018;36(2):143-151. doi:10.1055/s-0038-1676103 44

44. Endometriosis Associated pain
Pain impulses sent to brain
• The pelvis is highly vascularized and enervated
Nerve growth factors that promote neurogenesis
• The ratio of sympathetic and sensory nerve fibers is
significantly altered within endometriotic tissue
• The nerve density within endometriotic nodules is increased
Cytokines and prostaglandins are attracted to ectopic
tissue
• Activate nerve fibers and can trigger nearby cells to
release inflammatory molecules
Endometriosis-induced neuroplastic changes
• Patients become highly sensitive to subsequent painful
stimuli
1. Nezhat C, Vang N, Tanaka PP, Nezhat C. Optimal Management of Endometriosis and Pain [published correction appears in Obstet Gynecol. 2020 May;135(5):1233]. Obstet
Gynecol. 2019;134(4):834-839. 45

45. Dilemmas of the pain in endometriosis

46. Nociceptive Pain Pain that arises from actual or
threatened damage to non-neuronal
tissue, and is due to activation of
peripheral nociceptors
Nociceptive pain refers to pain clearly associated with
tissue damage or inflammation

47. Chronic Pelvic
Pain
• Endometriosis
• Adenomyosis
• Adhesions
• Chronic PID
• Uterine fibroids
• Pelvic congestion
• Ovarian remnant
• Residual ovarian syndrome
No Brain, No
Pain

48. Guidelines of endometriosis So many !
14, 18, 21,22
ASRM

49. Summary of recommendations by guidlines till date
50
Category Recommendations Grade of
recommen
dation
Quality of
Evidence
CCP Clinicians should consider the diagnosis of endometriosis un the presence of
gynaecological symptoms such as : Dysmenorrhea non cyclical pelvic pain, deep
dyspareunia , infertility , fatigue of non – gynaecological cyclical symptoms
(dyschezia dysuria , hematuria , ractal bleeding , shoulder pain )
- -
EBR Recommended to perform Transvaginal sonography to diagnose or to exclude an
ovarian endometrioma and rectovaginal endometriosis.
A II
EBR RECOMMENDED NOT TO USE IMMUNOLOGICAL BIOMARKERS , INCLUDING CA -
125 , in plasma, urine orserum to diagnose endometriosis
A II
EBR For endometriosis – associated pain it is recommended to prescribe hormonal
treatment (hormonal contraceptives (level – B , progestagens (Level A), anti
progestagens (Level A), or GnRH analogues
A-B II

50. 51