Endometriosis: an invisible and neglected disease that affects 180 million women. Celebrities and famous women over the years have been known to be affected by this Queen Victoria to Marilyn Monroe to Katrina Kaif who had surgery for endometriosis. The old theories of Endometriosis such as Sampsons Theory Angiogenesis, Lymphogenesis theory are no longer acceptable. The Epigenetic/ Genetic theorey has been postulated. ROle of biomarkers in diagnosis Risk factrs affecting Endometriosis and Risk of Cancer is discussed

1. Endometriosis: an invisible and neglected
disease that affects 180 million women.
• Many women struggle in silence, not
even knowing they have it.
• Endometriosis can affect women of all
ages.
• Often labeled as ‘the
missed disease’
Endometriosis Association survey noted a 10-year delay
from symptoms to diagnosis, with 70% reporting
symptoms before age 20 and nearly 40% before age 15 .

2. Introduction
Menstruation is an experience shared by women across the
world yet is viewed differently depending on the culture and
community.
But what is one common theme spanning most cultures?
The stigma and embarrassment around discussing a
woman’s “time of the month.”

3. STIGMA
• Beliefs that women’s pain is “normal during menstruation” or that women who
complain about discomfort during sex or their periods are “hypochondriacs or
hysterics.”
• With the stigma and shame around discussing one’s period, girls and women often
remain silent through the pain rather than asking questions and seeking the medical
care needed.

4. It took 23 years for doctors to take this food writer,
actress, and model seriously and diagnose her with
endometriosis
“This isn’t part of being a woman,” Had Fainting and
bleeding for years
Hid a painful condition beneath all her
charm and personality. Had multiple
miscarriages
Endometriosis

5. Endometriosis
Endometriosis is a
hormone-dependent disorder
Defined by histological
lesions generated by the
growth of endometrial-like
tissue out of the uterus
cavity
Affects ~10% of women of reproductive age; Causes infertility in ~30% of affected women
At least 26 million women in India between 18 to 35 yrs afflicted (Das 2007 Endometriosis
Society of India Survey).

6. Only 10% of women develop endometriosis although the phenomenon of
retrograde menstruation occurs in 76%–90% of reproductive-age
women
Sampson theory
Angiogenic spread
Lymphogenic spread
Metaplasia theory
N o L o n g e r A c c e p t a b l e
Endometriosis Origin – Old Theories

7. U N E X P L A I N E D
F E A T U R E S
Endometriosis
- Variable macroscopic appearance
- Occurs also in women without endometrium and in men
- Poorly understood natural history.
- Hereditary and heterogeneous disease with many biochemical
changes in the lesions, which are clonal in origin.
- Associated with pain, infertility,
adenomyosis, changes in the junctional zone, placentation,
immunology, plasma, peritoneal fluid, and chronic inflammation
of the peritoneal cavity.

8. Bone marrow in the pathophysiology of endometriosis
Stem cells from bone marrow engraft normal endometrium and aid in the
repair of endometrium after injury. CXCL12 is a powerful chemoattractant
that leads to migration and engraftment of bone marrow cells
In endometriosis, estrogens stimulate the production and secretion of
CXCL12. It also attracts endothelial progenitor cells.
Endothelial progenitor cells are circulating cells that adhere to endothelium at
sites of hypoxia/ischemia and contribute to new vessel formation.
The incorporation of these stem cells is critical to blood vessel growth and the
propagation of endometriosis.

9. PATHOGENESIS
V I S I O N S O N

10. 1st- HYPOTHESIS-NUB

12. Risk Factors for Early Onset Endometriosis
Neonatal Uterine Bleeding
Low Birth Weight<2.5 Kg
Preeclampsia
Post Maturity
ABO incompatibility
Time and onset of mensturation and Cycle Length
5% of the neonates

13. NEW
THEORY
2nd
Hypothesis

14. The Genetic/Epigenetic theory - Explains It all
The origin of endometriosis can be an endometrial cell,
a stem cell, or a bone marrow cell.
These may have inherited genetic and epigenetic
defects.
After the implantation or metaplasia, the microscopic
lesions occur.
They either regress or progress into the typical, cystic
or deep penetrating lesions.
This theory is similar to multistep tumor development
and explains the vast variety of clinical features of
endometriosis.
All women are born with some genetic-epigenetic defects
predisposing to endometriosis(1st HIT) additional incidents
occur during life (2nd HIT)pollution, oxidative stress --
mainly retrograde menstruation, infection
Beyond a threshold of incidents endometriosis lesions
initiate. Each type of lesion has a different set of incidents
determine the evolution towards typical, cystic or deep
lesions

16. Epigenetic changes of key
factors in immunology
induced by peritoneal fluid
environment inherited at
birth, and the oxidative
stress of retrograde
menstruation
Resistance
toapoptosis

17. The Genetic/Epigenetic theory
Not a recurrent disease : if removed
completely there are no recurrences. New
lesions however can develop.
Not a progressive disease : in most
women
Is heterogeneous : depending on type of
genetic and epigenetic changes. In most
women endometriosis is no longer
progressive when the diagnosis is made.
However some endometriosis lesions
are different, and can remain fast
progressive or can react differently
to medical treatment

18. The peritoneal microbiome results from the uterine and upper-genital tract microbiome and the gut
microbiome. The peritoneal microbiome can cause endometriosis by inducing genetic epigenetic incidents
either directly or by increasing the oxidative stress.
INFECTION

19. SAMPSON THEORY GENETIC-EPIGENETIC THEORY
ENDOMETRIOSIS 1 DISEASE 3 diseases
Typical, Cystic and Deep Endometriosis
retrograde menstruation, implantation and
unavoidable progression.
starts with genetic or epigenetic changes as
occurs in benign tumors
progressive and recurrent NOT progressive NOR recurrent
subtle lesions are considered precursors
of severe lesions
typical, cystic and deep endometriosis are 3
different diseases
and subtle lesions are not precursors of
severe lesions
This leads to incomplete surgery since
recurreces are unavoidable.
Surgery thus should be complete

20. SAMPSON THEORY GENETIC-EPIGENETIC THEORY
80% of women with pain or infertility have
endometriosis,when subtle endometriosis is
considered erroneously as a disease.
40% have typical endometriosis
10% have cystic endometriosis
3% have deep endometriosis
endometriosis is a cause of pain and infertility Symptoms vary with the type of lesions
Subtle : no infertility not pain
Typical: infertility (?) pain (+ in 50%)
Cystic: infertility (++) severe pain (++ in 80%),
Deep: infertility (?) pain (+++ in 95%).
The rAFS classification
with mild (superficial), moderate and severe
(cystic) endometriosis
assumes progression
Subtle is not a disease.
Deep endometriosis should be classified
separately as the most severe lesions
whereas in the rAFS classification they are
mostly classified in class II

21. TYPE OF LESIONS
SUBTLE
TYPICAL
CYSTIC
Solid tumours up to 5 by 6 cm in diameter mostly in the frequentl
pouch of Douglas.
DEEP
ENDOMET –
RIOSIS
small lesions (1 to 3 mm), white vesicles, red vesicles, or flame like
0.5-4 cm superficial lesions. Black puckered generally in a white sclerotic area.
Found in the pelvis & diaphragm
Ovarian endometriosis: Chocolate cysts ; Mostly 3-4 cm in diameter, can be as
large as 15 cm
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22. 3 FORMS OF ENDOMETRIOSIS
SUPERFICIAL PERITONEAL
ENDOMETRIOSIS
01
OVARIAN ENDOMETRIOSIS02
DEEP ENDOMETRIOSIS03
4 stages based on extent and depth of leison
No co - relation between disease symptoms and
severity

23. •ASRM point system
•A score of 15 or less indicates
minimal or mild disease.
•A score of 16 or higher may
indicate moderate or severe
disease.
•Stage of the disease does not
necessarily reflect the level of
pain or presence of symptoms
USG Dx OF STAGE III & IV

24. SUPERFICIAL ENDOMETRIOSIS
DEEP INFILTERATING
ENDOMETRIOSIS I & II
OVARIAN ENDOMETRIOSIS
PELVIC
PEVIC+EXTRA
PELVIC

25. AFFECTING
PROGRESSION
RISK FACTORS

26. Risk for and consequences of endometriosis: A critical
epidemiologic review A.L.Shafrir 2018

27. Hypothetical roadmap towards endometriosis: prenatal endocrine-disrupting
chemical pollutant exposure, anogenital distance, gut-genital microbiota and
subclinical infections
Pilar García-Peñarrubia HR UPDATE 2020
Higher prenatal exposure to estrogen/ endocrine-disrupting compounds (phthalates, bisphenols, organochlorine pesticides) & a shorter anogenital
distance causes frequent postnatal faecal microbiota contamination of the vulva & vagina, producing cervicovaginal microbiota dysbiosis. This disrupts
local antimicrobial defences, induces a subclinical inflammatory response that could evolve into a sustained immune dysregulation, responsible for the development of
endometriosis

28. Modifiable Risk Factors for Endometriosis
1. Environmental Factors
2. Diet
3. Stress
4. HPV Infection
5. PID
6. Early life Factors

29. Environmental Factors
•The risk of developing endometriosis was
1.65 times higher in women exposed to
dioxins, 1.70 times higher for those exposed
to polychlorinated biphenyls (PCB), and
1.23 times higher for organochlorine
pesticides
•The level of evidence was judged to be
“moderate”
Human Epidemiological Evidence About the Associations Between
Exposure to Organochlorine Chemicals and Endometriosis: Systematic
Review and Meta-Analysis German Cano-Sancho Environ Int 2019

31. 31

32. Effect of Diet in
Endometriosis
NEGATIVE EFFECT
A diet high in trans fat.
Red meat consumption
Gluten
Coffee
Alcohol
POSITIVE EFFECT
Fibrous foods
Iron-rich foods
Foods rich in essential fatty acids
Antioxidant-rich foods

33. HPV and
Endometriosis
In a Case–control study with 60 women undergoing
gynaecological laparoscopic surgery.
Samples from the UGT and LGT were collected
and analysed by PCR for HPV and by multiplex
PCR for other sexually transmitted infections (STI).
Infertile patients were associated with high-risk
HPV (hrHPV) positivity in the UGT sites ( P
= 0.027).
The endometriosis group was associated with
hrHPV positivity in the LGT and UGT sites
( P = 0.0002 and P = 0.03, respectively).
Rodrigo M. Rocha RBMONLINE 2019

34. Effect of Stress on
Endometriosis
Exposure to chronic stress before and well after the induction of
endometriosis is reported to increase lesion sizes in rats
Chronic psychogenic stress induced epigenetic changes in the
hippocampus of mice with endometriosis, and activated the adrenergic
signalling in ectopic endometrium, resulting in increased angiogenesis
and accelerated growth of endometriotic lesions.
This raises the possibility that the use of anti-depressants in cases of
prolonged and intense stress might forestall the negative impact of stress
on the development of endometriosis.
Social psychogenic stress promotes the development of endometriosis in
mouse Sun-Wei GuoRBMONLINE 2016
DEEP INFILTERATING
ENDOMETRIOSIS I & II

35. DEEP INFILTERATING
ENDOMETRIOSIS I & II
Women who were regularly fed soy formula as infants had
more than twice the risk of endometriosis compared with
unexposed women (aOR 2.4, 95% CI 1.2–4.9).
Increased endometriosis risk with prematurity (aOR 1.7,
95% CI 0.9–3.1) and maternal use of DES
PEVIC+
EXTRA
PELVIC

36. • This nationwide retrospective
cohort study, involving a total of
141,460 patients, demonstrated
that patients with PID had a three-
fold increase in the risk of
developing endometriosis
• (HR = 3.02, 95% CI = 2.85–3.2).

37. Impact on Fertility

38. • Distorted Pelvic anatomy
• Reduced fecundity via mechanical
disruptions such as pelvic adhesions.
• Impaired oocyte release or pick-up
• Altered sperm motility
• Disordered myometrial contractions
• Impaired fertilization and embryo transport
• Mild disease - Inflammatory cytokines,
growth and angiogenic factors, and
aberrantly expressed genes are all
implicated
Erin M. Nesbitt-Hawes Endometriosis and Infertility
Reproductive Surgery in Assisted Conception pp 29-35

39. Decreased Ovarian Reserve
Women with endometriomas. All participants underwent serum (AMH)
testing twice, 6 months apart.
The median percent decline in serum AMH level was 26.4% in the
endometrioma group and 7.4% in the control groups
Progressive faster decline in serum AMH levels
FERT STERT 2018

40. Disturbances of the Female Reproductive
Tract Microbiota
Disturbance of the healthy genital tract microbiota has been linked to an increased risk of pelvic
infections and endometriosis
An altered upper reproductive tract microbiota and “bacterial contamination” of the uterine cavity and
the peritoneal fluid promotes the secretion of inflammatory cytokines and chemokines, thereby
facilitating the vascularization and implantation of endometrial tissue in other organs
Using 16s rRNA sequencing techniques, a study found evidence of subclinical infection in the
uterine cavity and also in ovarian endometriomas
Khan, K.N. Molecular detection of intrauterine microbial colonization in women with endometriosis.
Eur. J. Obstet. Gyneco 2016

41. Macrophages
Macrophages acquired from patients with endometriosis are more proinflammatory
Anti-inflammatory type 2 macrophages exhibit an enhanced proinflammatory phenotype in the patient
with endometriosis compared with controls
Altered microbiome in the eutopic endometrium of patients with endometriosis has been implicated in
this proinflammatory macrophage phenotype FERT STERT 2019

42. DIAGNOSIS
95%
80%
SYMPTOMS: omnipresent symptom is
pain.
dysmenorrhea, chronic pelvic pain,
dyspareunia , dyschezia, and dysuria
very very severe
for deep
endometriosis in 95%
very severe for cystic
ovarian endometriosis
in 80%
variable for typical
endometriosis
Infertility
Sexual Dysfunction

43. PELVIC EXAMINATION
Fixed uterine retroversion
Painful uterine mobilization
Painful Compression of the uterine
fundus
Painful palpation of the uterine-sacral
ligaments.
Fornix fullness and palpation of cyst if
large
A. Red vesicular
lesion
B. Powder Burn
lesion
C. Fibrotic lesion
D. Allen Masters
Window

44. TVS
Accurate and reliable in the identification
and follow-up of deep endometriosis
infiltrating the bowel
The sensitivity and specificity in diagnosis
of deep endometriosis remains reported to
be >85% and even close to 100%
Method of choice to diagnose cystic ovarian
endometriosis
Cannot diagnose superficial endometriosis
The diagnostic accuracy for larger deep endometriosis
nodules is high, but limited for smaller lesions
not useful for the diagnosis of sigmoid endometriosis

45. Soft Markers on TVS
Endometrioma (Ground Glass
Appearance)
Psuedo peritoneal cyst
Immobile and high up ovaries
POD obliteration
Restricted Cx and uterus mobility
RV & RF uterus
RV nodules or DIE
PROBE TENDERNESS IN FX
Symptoms + Clinical exam + Ultrasound =
Suspicion of endometriosis

46. Cat-scan, Colonoscopy MRI, Barium Enema In
Deep Endometriosis?
These exams are useful as preparation for surgery,
but limited for diagnosis
MRI in selected women with doubtful TVS
findings
Women with sub-occlusive symptoms, degree of
stenosis
 DCBE
 Multi-detector computerized tomography enema
 MRI with rectal contrast-degree of stenosis of
the rectosigmoid junction and sigma
IVP-ureteric occlusion

47. Follow-up serum CA-125
Ca 125, considered a
marker for endometriosis,
is helpful only in
postoperative follow-up.
It usually decreases after
surgery and rises when
the disease recurs or
progresses

48. Need for Biomarker
Women with endometriosis, who could
benefit from surgery to increase fertility and
decrease pain, could be identified.
Could aid in treatment or prevent the
progression of disease in particular for
women with minimal-mild disease
Laparoscopy is the gold standard for diagnosis of
endometriosis
Not appropriate for all women with endometriosis.
Biomarkers from blood, urine, or menstrual fluid -
surgical procedure could be avoided

49. Which Patients Should Be Targeted for a Clinical
Test of Endometriosis?
Women with pelvic adhesions and/or
other pelvic pathology, who might
benefit from surgery to improve their
pelvic pain and/or subfertility
Women with pelvic pain and/or subfertility with
normal ultrasound results.
All cases of minimal-to-mild endometriosis, some
cases of moderate to-severe endometriosis
without clearly visible ovarian
endometrioma

51. Epigenetic modifications OCCURS
through noncoding RNAs
Contribute to progesterone resistance
and heightened response to estrogen
Study of their distinctinctive profile in
endometriosis serves as an important
Biomarker

52. Epigenetic modifications OCCURS
through noncoding RNAs
Contribute to progesterone resistance
and heightened response to estrogen
Study of their distinctinctive profile in
endometriosis serves as an important
Biomarker

53. • Recent advance in the noninvasive diagnosis of
endometriosis
• Panel of 5 mi RNA found in plasma of affected
patients diagnosed using NGS

54. • Evidence from animal models (Boberg et al., 2013; ) and human
studies, have shown that maternal exposure to xenoestrogen
substances, i.e. Bisphenol A, phytoestrogens and monobutyl
phthalate, reduces AGD in newborn females (Huang et al., 2009).
• A case-control study , 114 participants
• The AGDAF, was associated with presence of endometriomas, DIE
• Optimal cut-off of the predicted probability of 20.9 mm.

55. Adolescent
Endometriosis

56. RISK FACTORS FOR EARLY
ONSET ENDOMETRIOSIS
Neonatal Uterine Bleeding
Low Birth Weight
Preeclampsia
Post Maturity
ABO incompatibility
Time and onset of mensturation and Cycle Length

58. THL-Transvaginal Hydro
Laproscopy

59. Post Operative
adminstration
of
Norethisterone
acetate to
manage pain
and bleeding in
all stages of
endometriosis

60. ENDOMETRIOSIS AND OBSTETRIC OUTCOME

61. • Spontaneous hemoperitoneum, cyst enlargement, abscess, and rupture of an endometrioma, uterine CV rupture, and
bowel perforation. early pregnancy (miscarriage), late pregnancy prematurity, placenta previa, placental abruption,
cesarean section, hemorrhages) and SGA
• All women with endometriosis should be informed about the risk associated with a future pregnancy, and those who are
affected by— or underwent surgery for—severe disease involving the bowel, bladder, or ureter should also be informed
about the potential technical difficulties in case of abdominal delivery.
• In a woman with endometriosis it is important, when nonspecific abdominal pain occurs during pregnancy, to suspect
possible intraperitoneal bleeding, infected or ruptured endometrioma, or uterine rupture, to undertake proper
management for achieving the best possible outcome for both mother & fetus

62. consistently reduced
oocyte yield and a
reduced fertilization
rate
Milder forms of
endometriosis affect the
fertilization and earlier
implantation processes
ASRM Stage ( III and IV)
influence all stages of
reproduction
Ovarian endometriosis
negatively affects the oocyte
yield
Increased risk of miscarriage seen in both
adenomyosis & endometriosis . Obstetric &
fetal complications are increased - including
preterm delivery, C section & neonatal unit
admission following delivery
Women with these conditions should
ideally receive pre-natal counselling and
should be considered higher risk in
pregnancy and at delivery
Reproductive, Obstetric and Perinatal outcomes of women with
Adenomyosis and Endometriosis: A Systematic Review and Meta –
Analysis Joanne Horton, HR UPDATE 2019

63. ENDOMETRIOSIS & CANCER RISK
• Ovarian cancer risk general female population -1-3%
• 2% in women with endometriosis.
• Although risk increased, lifetime risk is low and not substantially different from women
without endometriosis.
• According to recent estimates, 39% of women with harmful BRCA1 mutation and 11–17%
who inherit a harmful BRCA2 mutation develop ovarian cancer by 70 years of age.
• Woman in the general population, risks of breast (12%), lung (6%), and bowel (4%)
cancers are still higher than risk of developing ovarian cancer.
• Marina Kvaskoff, LANCET Informing women with endometriosis about ovarian cancer risk
2017

64. Epithelial Ovarian Cancer(EOC) with
Endometriosis-Features
 EOC is commonly detected at earlier stages
 Patients with EOC are younger Acién et al., (2015)
 Endometrioid and Clear cell- ovarian cancer more commonly associated
 More commonly unilateral
 Have better prognosis and improved survival rates compared to patients not associated
with endometriosis due to early diagnosis.
• Endometriosis and Ovarian Cancer: an Integrative Review (Endometriosis and Ovarian
Cancer)
• Aline Veras Morais BrilhanteAsian Pac J Cancer Prev. 2017

65. What to do to lower cancer risk?
• No clear evidence exists that TVS or serum CA-125 can detect ovarian cancers early
or risk-reducing surgery to remove the ovaries can save lives.
• Generally, to improve health and reduce the risk of cancer, a balanced diet with low
intake of alcohol,regular exercise, maintaining healthy weight, and avoid smoking.

66. Endometriosis
Management

67. Pain Management in Endometriosis

68. Age
Need to preserve fertility
Need for contraception
Presenting symptom (pain, infertility or
both)
Severity of pain and its impact on quality
of life
Type, extent and location of
endometriotic lesions
Involvement of other non-gynaecological
system (e.g. renal tract, bowel)
Factors to consider when planning treatment for pain associated with
Endometriosis

69. Lifestyle/Dietary interventions
Dietary intervention appears to be a suitable alternative to
hormonal treatment, that is associated with similar pelvic pain
reduction and quality of life improvement

71. MEDICAL VERSUS SURGERY
FOR PAIN MANAGEMENT
First line for
symptomatic women not
planning conception is
medical therapy
Medical therapy after surgery when
surgery was too delicate to be complete
Medical treatment to
prevent recurrences after
surgery
Medical treatment
to prevent
progression

73. THREE-TIERED RISK STRATIFICATION – Stepwise
Medical Treatments ENDOMETRIOSIS
DIE/POST OP
OMA / POST OPSUPERFICIAL/POST OP
NETA
NETA
COC
?DIENOGEST
Intolerable/CI
Similar Efficacy
IFSIDE EFFECTS
LOW RISK INTERMEDIATE HIGH

74. Points to consider
E+P- Oc pills with 2nd - generation progestins should be preferred
Lowest possible EE dose
Healthy nonsmoking women >40 years, not a contraindication
Protection against endometriosis associated ovarian cancer
Currently not recommended for primary prevention
P4-NETA preffered . Dienogest better tolerated but higher cost and bone lose on prolonged use

75. Other Progesterones
LNG-does not inhibit ovulation. Endometrioma recurrence rate of 25% at 5-year. Best
candidates - women not seeking pregnancy, main symptom dysmenorrhea, in their forties,
and who do not tolerate progestins used systemically
DMPA-prolonged action. transient and reversible decrease of bone mineral density that
has not been shown to reach the level of osteoporosis
Therefore, 150 mg DMPA intramuscular injections every 3–6 months for persistent or
recurrent pain after hysterectomy for endometriosis

76. Post surgery for ovarian endometriomas and
not seeking immediate conception
• Post surgery not seeking immediate conception recommended long-term treatment with estrogen–
progestins or progestins
• A cyst recurrence rate of ∼10% per year
• inhibition of ovulation decreases risk of recurrence
• no significant differences were detected between cyclic and continuous OC use in terms of cyst
recurrence rate (Muzii et al., 2011, 2016; Seracchioli et al., 2009, 2010).
• Better results were observed with continuous use when the considered outcome was dysmenorrhea
• Not indicated to replace incomplete surgery

77. • The reported recurrence rate is 21.5% at 2 years and 40-50% at 5 years
• 8% risk of endometrioma recurrence in long-term ‘‘always’’ OC users compared with a
34% risk in ‘‘never’’ OC users
RECURRENCE RISK FACTORS

78. Long Term Hormonal Medication
Do not prescribe drugs that cannot
be used for prolonged periods of time
because of safety or cost issues as
first-line medical treatment, unless
estrogen–progestins or progestins
have been proven ineffective, not
tolerated, or contraindicated
Among the available options,
hormonal contraceptives and
progestins demonstrated the
most favorable
safety/efficacy/
tolerability/- cost profile
(ACOG), 2010

80. SHIFT FROM SURGERY TO MEDICAL Rx
Only when its therapeutic benefit outweighs
the risks.
Patient-centered care
Prioritize pain reduction and improvement
of quality of life versus optimal
‘‘debulking’’ of disease

81. Indications for Surgery
In Endometriosis
• Complicated deep endometriosis (hydroureteronephrosis and sub-occlusive bowel stenosis)
• Symptomatic Endometrioma>3-4 cm
• Highly symptomatic women wishing a natural conception and declining IVF
• After failure of medical therapy
• Noncompliance with or intolerance to medical treatment
• Endometriosis emergencies: Rupture or torsion of endometrioma, obstructive uropathy, or bowel
obstruction

82. Factors to consider -Endometrioma Surgery

83. ENDOMETRIOMA
>40 YRS,BIG SIZE
?>4cm
SURGERY
SIZE,AGE
MEDICAL THERAPIES
ASYMPTOMATICSYMPTOMATIC,SMALL<3-4 CM
SURGERY
YOUNG,SMALL
SIZE
YEARLY USG &
CA-125
FAIL

84. Pre op Medical Rx – No Role
The lack of
estrogens
inactivates
endometriosis
lesions
Smaller
lesions might
be missed
Risk of
incompleteSur
gery
No
surgical
advantage
Should not be
given

85. • Options -- Excision
-- Ablation - Electrocoagulation
- Laser vapourisation
• Controversy - Ablation v/s excision
• peritoneal excision -ensure complete treatment because it is difficult to
determine the depth of the peritoneal implant.
• ablation therapy-claim that it is as effective as excision and has the
advantage of simplicity, less blood loss, and shorter operating time.
• Evidence from a small randomized trial has shown no difference in
effectiveness of excision vs. ablation.
Surgery for peritoneal disease

86. • Subtle lesions : vaporisation
• Typical lesions : Treatment of choice is excision or
vaporisation. Coagulation is not recommended since the
depth of a typical lesion is difficult to judge.

87. Surgery for endometriomas ESHRE 2014
• optimal surgery is controversial
• Drainage and ablation
Preserve ovarian reserve, but increased recurrence
• Cystectomy approach
minimizes the risk of recurrence risk of follicle loss, increased adhesions

88. Principles in Endometrioma Surgery
Correct
cleavage
plane
Avoiding excessive
coagulation
Especially – hilus- to
avoid damage to the
blood supply
Superficial
coagulation of
bleeding vessels only
Very small
leisons -
Draina -ge
& ablation

89. Deep endometriotic lesions?
• Do not remove uncomplicated deep endometriotic lesions in asymptomatic women, and also
• In symptomatic women not seeking conception when medical treatment is effective and well
tolerated
• Complications occur in 3–10% of patients undergoing deep endometriosis removal
• Deep invasive endometriosis does not progress in more than 9 out of 10 affected women
(Fedele et al., 2004).
• Surgery is mandatory in case of hydroureteronephrosis and sub-occlusive bowel stenosis
(complicated deep endometriosis) and in highly symptomatic women wishing a natural
conception and declining IVF
• Multidisciplinary approach including urologists and colorectal surgeons

92. SURGERY VERSUS IVF IN ENDOMETRIOSIS

93. ENDOMETRIOSIS AND INFERTILITY
• SURGERY VERSUS IVF?

94. Infertile patients with Stages I and II
Endometriosis-Laproscopy?
• Laparoscopy to detect and treat superficial peritoneal endometriosis in infertile women without pelvic
pain symptoms is not recommended (quality of the evidence, high; strong suggestion)
• NNT -12
• Prevalence of minimal or mild endometriosis among women with unexplained infertility is ≤50%
• Therefore NNT rises to more than 24
• Does not support routine laparoscopy for women with unexplained infertility

95. Surgery For Stage 3 or 4
• 44 - 63% of women conceive naturally within 2 - 3 years of
endometriosis surgery

96. Tool to determine if a woman will conceive naturally after
endometriosis surgery

97. 0
5
10
15
20
25
30
35
40
45
<35 35-37 38-40 41-42 >42
LBR/CYCLE
LBR/CYCLE
, American Society for Reproductive Medicine Society for Assisted Reproductive Technology.
2010 assisted reproductive technology: fertility clinic success rates report. Atlanta (GA):CDC;
2012
Impact of Age on IVF Success Rate

98. PRE – IVF/ ICSI
A s y m p t o m a t i c
Endometriosis

99. Removal of Small
ovarian endometriomas
(diameter < 4cm)
pre IVF?
Surgical excision of small endometriomas
before IVF is associated with a need for
higher amounts of gonadotrophins, lower
peripheral estrogens levels, reduced number
of follicles & oocytes retrieved
Ovarian responsiveness is crucial to IVF
success

100. Pregnancy outcomes in women with history of surgery for
endometriosis Marilena Farella, M.D Fert Stert 2019
• Retrospective study
• Total of 569 women with h/o surgery for endometriosis, postoperative conception,
and pregnancy evolution over 22 weeks of gestation
• Study found increased incidence of SGA, PT, Placenta previa
• In this series author confirms women with previous surgery for endometriosis are at
obstetrical complications despite complete healing endometriosis lesion before
pregnancy
Both presence of endometriosis during pregnancy and previous surgery are a risk factor
for pregnancy complications

102. ESHRE GUIDELINES -
ASYMPTOMATIC ENDOMETRIOMA
Expectant management if endometrioma < 4 cm and cases of recurrent endometrioma.
Women should be reassured that IVF does not influence the likelihood of endometriosis
recurrence (Benaglia et al., 2010) or growth of endometrioma (Benaglia et al., 2009).
Women undergoing ovarian surgery should be warned about the possible risk of surgery on
ovarian function.
Women who opt for surgical treatment of endometrioma prior to IVF should be offered ovarian
reserve tests before surgery and those with reduced ovarian reserve should be discouraged from
undergoing surgical treatment.

103. A R T
in Endometriosis

105. IUI in infertile women with endometriosis at
any stage?
COS and IUI to treat infertility associated with endometriosis at any stage not recommended
As per NICE guideline (2017), IUI is not cost-beneficial for the treatment of infertility
Meta-analysis conducted by Hughes (1997) suggest that IUI effectiveness is halved in women with early
endometriosis.
IVF but not IUI, overcome the detrimental effects of a pelvic inflammatory milieu.
First-cycle chance of pregnancy with IVF is significantly higher than the cumulative pregnancy rate after six
IUI cycles (Dmowski et al., 2002).
Risk of endometriosis recurrence appears to be increased by IUI (Van der Houwen et al., 2014) and was
reported to be higher than after IVF

106. Stage I/II endometriosis-associated infertility
younger patients- expectant management or superovulation/IUI after
laparoscopy
Women 35 years of age or older- SO/IUI or IVF-ET
Endometriosis - Infertility Mx
ASRM guidelines
Stage III/ IV endometriosis-associated infertility
conservative surgical therapy with laparoscopy and possible laparotomy
are indicated
If fail to conceive following conservative surgery or because of advancing
reproductive age, IVF-ET is an effective alternative.

107. Endometriosis
Impact on IVF

108. Multiple meta analysis – contradictory results
• Barnhart 2002- poor IR, FR, pregnancy rates
• Harb 2013(BJOG) - IRs and CPR are diminished in severe (stage III–IV)
endometriosis. Lower FR in stage I and II
• Hamdaan 2015(HR Update) - No effect on IVF outcome. Similar LBR compared to
control.
• Chun yang 2015 (RBM online) - similar IR, CPR, LBR compared to control group.
Lower oocytes retrieved, lower number of embryos formed

109. Endometriosis is associated with lower oocyte yield, lower IR & lower PR
Endometriosis, when associated with other alterations in the reproductive tract (poor
ovarain reserve, tubal factor) has the lowest chance of live birth.
In contrast, for the minority of women who have endometriosis in isolation, the LBR is
similar or slightly higher compared to other diagnostic groups

110. Conclusion:
Endometriosis Impact on IVF
• Increased gonadotropins needed & duration of
stimulation
• Reduced oocytes number & quality
• Cycle cancellation higher
• Reduced fertilization rates & IR
• Pregnancy outcome poorer in advanced disease
particularly with significant ovarian involvement
(endometrioma) or prior ovarian surgery

111. • Rate of aneuploidy was found similar between patients with endometriosis
and age-matched control patients in the IVF population.
• Retrospective cohort study.305 patients with endometriosis who produced
1,880 blastocysts.The mean age of the patients with endometriosis was 36.1 +-
3.9 years
• FERT STERT 2017

112. Reason for poor reproductive outcome
Smaller number of oocytes retrieved and reduced AMH levels in women with
severe endometriosis or endometriomas, even in the absence of previous
surgical intervention.
‘‘Burn-out’’ effect on the ovarian reserve
Excessive release of reactive oxygen species alters cellular function by
dysregulating protein activity and gene expression, resulting in harmful effects
Poor endometrial receptivity

113. Ideal number of Oocyte
Live birth rates peak with about 15 retrieved oocytes in Fresh
IVF cycles

114. The diagnosis of CE is more frequent in women with endometriosis.
• This study suggests that CE should be considered and if necessary ruled out in
women with endometriosis, particularly if they have abnormal uterine bleeding.
• Identification and appropriate treatment of CE may avoid unnecessary surgery.
Fertil Steril 2017

115. Upper Reproductive tract is not sterile(Baker 2018)
• Emerging evidence shows prescence of both Lactobacillus as well as non-
lactobacillus species
• TECHNIQUE-16S r RNAtargeted PCR(NGS)
• Cut off value of Lactobacillus relative abundance 90%;
• this cutoff -predict reproductive success.
• A non–Lactobacillus dominated (<90%) endometrial microbiota have adverse
reproductive outcomes—measured as implantation, pregnancy, ongoing pregnancy,
and miscarriage rates—when compared with subjects presenting a Lactobacillus-
dominated (R90%) endometrial microbiota
• Moreno 2016

116. • One of the hallmark changes seen in the endometrium of women with
endometriosis is an induction of p450 aromatase expression and
altered progesterone-to-estrogen activity
• Estrogen, produced locally inhibit key molecules in attachment of
embryos, including the avb3 integrin,L-selectin ligand
• LIF and HOXA 10 expression are reduced in patients of endometriosis
• Progesterone resistance- inadequate differentiation of the stroma, and
remodeling of the endometrium, all of which can lead to a nonreceptive
endometrium for embryo implantation

117. Progesterone Resistance
• Estrogen receptors not down-regulated
• Increase in cyclooxygenase,increase endometrial aromatase
expression with increased estrogen activity
• Increased SIRT-1 and Bcl-6 , mediators of progesterone
resistance(B)
• Anti-implantation effect
• Endometriosis and unexplained infertility
• Rx -medical suppression with the use of a GnRH agonist or
surgical treatment of endometriosis
• A-Normal in phase endometrium
• (Laura D Almiquist Fert Stert 2017)

118. Inflammatory Marker Test – Receptiva Dx
Evaluates endometrial sample for inflammatory marker specially in
ENDOMETRIOSIS
Immunohistochemical expression of B-cell CLL/BCL6
Collected from LH6 to LH10 in a natural cycle or P5 to P10 in a stimulated
cycle
Abnormal (increased) BCL6 expression and found a significant decrease in
pregnancy and live birth rates
(Endometrial BCL6 testing for the prediction of in vitro fertilization
outcomes: a cohort study Laura D. Almquist,Fert Stert 2017

119. Maximising ART
O u t c o m e
To suppress or not to
suppress?

120. IVF - Special Considerations
1. Counselling:
• a) May need to do multiple cycles for egg/embryo pooling + FET as number of oocytes retrieved might be reduced
especially if advanced disease or multiple previous surgeries
• b) Risk of cycle cancellation
2) Increased dosage of gonadotropins
3) Agonist or antagonist can be used but long long protocol yields BEST results
4) Endometrioma do not need to be removed unless indicated
5) Avoid PUNCTURING endometriomas at OPU to reduce risk of pelvic infection/abscess
6) Consider prolonged down regulation before FET especially in advanced disease or previous failed cycle due to
implantation failure(Bourdon 2018)
7) Frozen embryo transfer
8) In women with endometrioma, antibiotic prophylaxis at the time of oocyte retrieval, although the risk of ovarian abscess
following follicle aspiration is low (Benaglia, et al., 2008).

121. • COH with both GnRH-a and GnRH
antagonist protocols has similar IVF
outcomes in patients with mild-to-
moderate endometriosis
• However, agonist protocol have a
significantly higher number of MII oocytes
& embryos that can be cryopreserved
compared to antagonist protocol. When
the subsequent freeze–thaw cycles are
considered, cumulative fecundity rate will
be higher in the agonist protocol
Endometriosis and IVF
Recai Pabuccu, M.D Fertility SterilIty, 2007 Oct

122. A comparison of two months pretreatment with GnRH agonists with or without
an aromatase inhibitor in women with ultrasound-diagnosed ovarian
endometriomas undergoing IVF
Arielle Cantor RBMONLINE 2018
• Retrospective study , 126 women aged 21–39 years who failed a previous IVF cycle and
endometriomas.
• Women were non-randomly assigned to either 3.75 mg intramuscular depo-leuprolide
treatment alone or in combination with 5 mg of oral letrozole daily for 60 days prior to
undergoing a fresh IVF cycle.
LETROZOLE NON LETROZOLE
AFC 10.3 6.4
ENDOMETRIOMA cm 1.8 3.2
Gn dose 2079 3716
MII 9.1 4
CPR 50% 22%
LBR 40% 17%

123. Normalising Eutopic Endometrium
• In a randomized trial, a 3-month ovarian suppression with the
use of GnRHa before ART significantly improved outcome
• OC for 6– 9 weeks before ART normalized implantation rates
(IRs) in severe endometriosis compared with control subjects
of the same age, whereas IRs were lower in non suppressed
women

125. Adenomyosis may
adversely impact
fertility by its impact
on myometrial
contractility and/or
via altered molecular
expressions in the
endometrium

126. Strawberry
endometrium
Irregular
vascularization,
small
subendometrial
haemorrhagic
cyst
Small
haemorrhagic
foci assuming a
chocolate
brown colour
Irregular
endometrial
mucosa

127. DIFFUSE
FOCAL
ADENOMYOMA
FOCAL
ADENOMYOMA
DIFFUSE

128. • The rates of implantation, clinical pregnancy per cycle, clinical pregnancy
per embryo transfer, ongoing pregnancy, and live birth among women
with adenomyosis were significantly lower than in those without
adenomyosis.
• The miscarriage rate in women with adenomyosis was higher than in
those without adenomyosis.
• Surgical treatment or treatment with GnRHa increases the spontaneous
pregnancy rate in women with adenomyosis
• Adenomyosis has a detrimental effect on IVF clinical outcomes..
Fertil Steril 2017

129. FAVOURS SURGERY
MISCARRIAGE RATELBR
DIFFUSE VS FOCAL(FAVOURS)

131. Long-term Pituitary Downregulation Before Frozen
Embryo Transfer Could Improve Pregnancy
Outcomes in Women With Adenomyosis
2013 Zhihong Niu
• 339 patients with adenomyosis were included in this retrospective study, 194 received
long-term GnRH agonist plus HRT (down-regulation + HRT) and 145 received HRT
• Rates of clinical pregnancy (51% vs. 25%)
• Implantation (33% vs. 16%)
• Ongoing pregnancy (49% vs.21%)
• were higher after long-term suppression in frozen embryo cycles

132. MECHANISM OF ACTION OF GnRH Agonist
on ADENOMYOSIS

133. A controlled trial on uterine adenomyosis treatment comparing
Aromatase inhibitor plus Gnrh analogue versus Dienogest in women
undergoing IVF
M. Sbracia FERT STERT 2018
• The combined treatment for uterine adenomyosis with Anastrazole plus
GnRH analog showed better results than dienogest treatment with a higher
reduction of symptoms and a higher pregnancy rate.
• The combined treatment seems to be the treatment of choice in these women.
These data should be confirmed in larger study.

134. Effect of Pretreatment with a Levonorgestrel-releasing intrauterine
system on IVF and vitrified–warmed embryo transfer outcomes in
women with adenomyosis Zhou Liang RBMONLINE 2019
Retrospective study included 358 women with Adenomyosis
undergoing IVF
CONTROL LNG
OPR 29.5% 41.8%
IR 32% 22%
CPR 44% 33%

135. NEWER
THERAPIES
ENDOMETRIOSIS

136. Valproic Acid
Anti-platelet Therapy
Selective
Progesterone
Receptor Modulators
Aromatase Inhibitors
GnRH Antagonists
VEGF antagonists
NEWER
THERAPIES

137. The role of new technologies: the example of
high-intensity focused ultrasound
• In Lyon, teams of research clinicians led by Prof. Gil Dubernard
(Hospices Civils de Lyon and Inserm unit 1032 LabTAU) have
developed an ultrasound-based treatment for bowel endometriosis.
• A phase I clinical trial carried out in 11 patients in 2017
demonstrated that high-intensity focused ultrasound may be a
useful alternative to surgery.
• An ultrasound probe inserted into the rectal passage is able to
“desensitize” the lesions within a few minutes

138. • Elagolix is a novel, orally available nonpeptide GnRH antagonist.
• Dose 200-300 mg twice daily
• They can rapidly and reversibly suppress pituitary gonadotropin secretion
• Dose can be titrated to the desired degree of suppression.
• Can replace GnRH agonists for suppression of estrogen-dependent diseases
• Attractive alternative to ocpill for both contraceptive and noncontraceptive purposes.
Elagolix for Fertility Enhancement Clinical Trial (EFFECT TRIAL)underway
for suppression of suspected endometriosis prior to ET. Outcomes will include pregnancy rate,
miscarriage rate and ongoing and live birth rate following treatment.

139. Treatment of endometriosis-associated pain with linzagolix, an oral
gonadotropin-releasing hormone–antagonist: a randomized clinical trial
Jacques Donnez,FERT STERT 2020
• Women aged 18–45 years with surgically confirmed endometriosis and moderate-to-severe EAP.
• The interventions were 50, 75, 100, or 200 mg linzagolix (or matching placebo) administered once daily for 24
week
• Compared with placebo, doses ≥ 75 mg resulted in a significantly greater proportion of responders for overall
pelvic pain at 12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively).
• A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or
increased at 24 weeks. Serum estradiol was suppressed, QoL improved, and the rate of amenorrhea increased in a
dose-dependent fashion.
• Mean BMD loss (spine) at 24 weeks was <1% at doses of 50 and 75 mg and increased in a dose-dependent fashion
up to 2.6% for 200 mg. BMD of femoral neck and total hip showed a similar pattern.

140. Gonadotropin-releasing hormone antagonist
(linzagolix): a new therapy for uterine adenomyosis
Olivier Donnez, M.D FERT STERT 2020
• To compare the efficacy of a selective progesterone receptor modulator, ulipristal acetate, and a
gonadotropin-releasing hormone antagonist, linzagolix, in a case of severe uterine adenomyosis
• During treatment with UPA, the symptoms (pelvic pain, dysmenorrhea, bulk symptoms)
worsened and MRI revealed aggravation of the adenomyotic lesions.
• During the 12-week course of once-daily 200 mg linzagolix, the patient remained in amenorrhea
and noted a very significant improvement in symptoms. On MRI, the uterine volume had fallen
from 875 cm3 to 290 cm3, and the adenomyotic lesions had significantly regressed. During the
100-mg linzagolix course (weeks 13–24), the patient reported continued alleviation of her
symptoms.

141. S c i e n c e T e c h n o l o g y E n g i n e e r i n g A r t s M a t h e m a t i c s
Thank You
Dr. Shivani Sachdev Gour
MD DNB MRCOG (UK)
Consultant Fertility Specialist
Gynaecologist
Director
SCI IVF Centre New Delhi
Dr. Nupur Garg
MS, FNB
Consultant Fertility
Specialist Gynaecologist
Director
SCI IVF Centre Noida