Recent Advances in Endometriosis

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
womans time of the month.
3
STIGMA

• Beliefs that womens 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 ones
  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
Endometriosis
Hid a painful condition beneath all her charm
and personality. Had multiple miscarriages This
isnt part of being a woman, Had Fainting and
bleeding for years
5
Endometriosis
Endometriosis is
a
hormone-dependent disorder
by histological generated by the
Defined lesions growth tissue cavity
of endometrial-like out of the uterus
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
N o L o n g e r A c c e p t a b l e
Endometriosis Origin Old Theories Sampson
theory Angiogenic spread Lymphogenic
spread Metaplasia theory Only 10 of women
develop endometriosis although the phenomenon of
retrograde menstruation occurs in 7690 of
reproductive-age women
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
V I S I O N S O N

• PATHOGENESIS

10
1st- HYPOTHESIS-NUB
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Risk Factors for Early Onset Endometriosis
Neonatal Uterine Bleeding Low Birth Weightlt2.5
Kg Preeclampsia Post Maturity ABO incompatibility
5 of the neonates
Time and onset of mensturation and Cycle Length
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
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Epigenetic changes of key factors in immunology
induced by peritoneal fluid environment
inherited at
Resistance
birth, stress
and the oxidative of retrograde
toapoptosis
menstruation
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
INFECTION
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.
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
small lesions (1 to 3 mm), white vesicles, red
vesicles, or flame like
SUBTLE TYPICAL
0.5-4 cm superficial lesions. Black puckered
generally in a white sclerotic area. Found in
the pelvis diaphragm
CYSTIC
Ovarian endometriosis Chocolate cysts Mostly
3-4 cm in diameter, can be as large as 15 cm
DEEP
Solid tumours up to 5 by 6 cm in diameter mostly
in the frequentl
ENDOMpoucEh oTf Douglas.
RIOSIS
Your Text Here You can simply impress your
audience and add a unique zing and appeal to
your Presentations.
22
3 FORMS OF ENDOMETRIOSIS
SUPERFICIAL PERITONEAL ENDOMETRIOSIS
01
02
OVARIAN ENDOMETRIOSIS
03
DEEP ENDOMETRIOSIS
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
OVARIAN ENDOMETRIOSIS
PELVIC
DEEP INFILTERATING ENDOMETRIOSIS I II
PEVICEXTRA PELVIC
25
RISK FACTORS
AFFECTING PROGRESSION
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
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
Pilar García-Peñarrubia HR UPDATE 2020
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

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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
In a Casecontrol study with 60 women undergoing
gynaecological laparoscopic surgery.
HPV and Endometriosis
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
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 1.24.9).
Increased endometriosis risk with prematurity
(aOR 1.7, 95 CI 0.93.1) and maternal use of DES
PEVIC EXTRA PELVIC
DEEP INFILTERATING ENDOMETRIOSIS I II
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 2.853.2).

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-inflam
matory 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
SYMPTOMS omnipresent symptom is
pain. dysmenorrhea, chronic pelvic pain,
dyspareunia , dyschezia, and dysuria

• very very severe for deep endometriosis in 95

95
80

• 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
A. Red vesicular lesion
B. Powder Burn lesion
Painful palpation of the uterine-sacral ligaments.
Fornix fullness and palpation of cyst if large
D. Allen Masters Window
C. Fibrotic lesion
44
TVS
Accurate and reliable in the identification
Method of choice endometriosis
to diagnose
cystic
ovarian
and follow-up of deep endometriosis
infiltrating the bowel
Cannot diagnose superficial endometriosis
The sensitivity and specificity in diagnosis of
deep endometriosis remains reported to be gt85
and even close to 100
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 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
Women with pelvic adhesions and/or other pelvic
pathology, who might benefit from surgery to
improve their pelvic pain and/or subfertility
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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
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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.

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Adolescent Endometriosis
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RISK FACTORS FOR EARLY ONSET ENDOMETRIOSIS
Neonatal Uterine Bleeding Low Birth Weight
Preeclampsia Post Maturity ABO incompatibility Tim
e and onset of mensturation and Cycle Length
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THL-Transvaginal Hydro Laproscopy
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Post Operative adminstration of
Norethisterone acetate to manage pain and
bleeding in all stages of endometriosis
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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 forsevere 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
Reproductive, Obstetric and Perinatal outcomes of
women with Adenomyosis and Endometriosis A
Systematic Review and Meta Analysis Joanne
Horton, HR UPDATE 2019
ASRM Stage ( III and IV) influence all stages of
reproduction Ovarian endometriosis negatively
affects the oocyte yield
Women with these conditions should ideally
receive pre-natal counselling and should be
considered higher risk in pregnancy and at
delivery
Milder forms of endometriosis affect the
fertilization and earlier implantation processes
consistently reduced oocyte yield and a reduced
fertilization rate
Increased risk of miscarriage seen in both
adenomyosis endometriosis . Obstetric fetal
complications are increased - including preterm
delivery, C section neonatal unit admission
following delivery
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 1117 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.

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Endometriosis Management
67
Pain Management in Endometriosis
68
Factors to consider when planning treatment for
pain associated with Endometriosis Age Need to
preserve fertility Need for contraception Present
ing 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)
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
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MEDICAL VERSUS SURGERY FOR PAIN MANAGEMENT
Medical treatment to prevent recurrences after
surgery
Medical treatment to prevent progression
First line for symptomatic women not planning
conception is medical therapy
Medical therapy after surgery when surgery was
too delicate to be complete
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THREE-TIERED RISK STRATIFICATION
Stepwise Medical Treatments
ENDOMETRIOSIS
HIGH
INTERMEDIATE
LOW RISK
DIE/POST OP
SUPERFICIAL/POST OP
OMA / POST OP
NETA
COC
Similar Efficacy IFSIDE EFFECTS
Intolerable/CI
?DIENOGEST
NETA
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Points to consider
EP- Oc pills with 2nd - generation progestins
should be preferred Lowest possible EE
dose Healthy nonsmoking women gt40 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
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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 36 months for persistent or recurrent pain
after hysterectomy for endometriosis
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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

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RECURRENCE RISK FACTORS

• 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

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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 estrogenprogestins 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
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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
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Indications for Surgery In Endometriosis

• Complicated deep endometriosis (hydroureteronephro
  sis and sub-occlusive bowel stenosis)
• Symptomatic Endometriomagt3-4 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

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Factors to consider -Endometrioma Surgery
83
ENDOMETRIOMA
ASYMPTOMATIC
SYMPTOMATIC,SMALLlt3-4 CM
SIZE,AGE
MEDICAL THERAPIES
FAIL
gt40 YRS,BIG SIZE ?gt4cm
YOUNG,SMALL SIZE
SURGERY
SURGERY
YEARLY USG CA-125
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

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Surgery for peritoneal disease

• 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.

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
Superficial coagulation of bleeding vessels only
Avoiding excessive coagulation Especially
hilus- to avoid damage to the blood supply
Very small leisons - Draina -ge ablation
Correct cleavage plane
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 310 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

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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
Impact of Age on IVF Success Rate
45 40 35 30 25 20 15 10 5 0
LBR/CYCLE
LBR/CYCLE
lt35 35-37 38-40 41-42 gt42 , American Society for
Reproductive Medicine Society for Assisted
Reproductive Technology. 2010 assisted
reproductive technology fertility clinic success
rates report. Atlanta (GA)CDC 2012
98
A s y m p t o m a t i c E n d o m e t r i o s i s
PRE IVF/ ICSI
99
Removal of Small
ovarian endometriomas (diameter lt 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
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ESHRE GUIDELINES - ASYMPTOMATIC ENDOMETRIOMA
Expectant management if endometrioma lt 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 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. Women undergoing ovarian surgery
should be warned about the possible risk of
surgery on ovarian function.
103
A R T in Endometriosis
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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
Endometriosis - Infertility Mx

• ASRM guidelines
• 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
• 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.

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E n d o m e t r i o s i s 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 se
  vere (stage IIIIV) 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 endom
  etriosis 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 e
ndometriomas, 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
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Ideal number of Oocyte
Live birth rates peak with about 15 retrieved
oocytes in Fresh IVF cycles
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• 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 nonLactobacillus dominated (lt90) endometrial
  microbiota have adverse reproductive
  outcomesmeasured as implantation, pregnancy,
  ongoing pregnancy,

and miscarriage rateswhen compared with subjects
presenting a Lactobacillus-

• dominated (R90) endometrial microbiota
• Moreno 2016

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• 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

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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)

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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?
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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

1. Agonist or antagonist can be used but long long
   protocol yields BEST results
2. Endometrioma do not need to be removed unless
   indicated
3. Avoid PUNCTURING endometriomas at OPU to reduce
   risk of pelvic infection/abscess
4. 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).
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Endometriosis and IVF

• 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 freezethaw cycles
  are considered, cumulative fecundity rate will
  be higher in the agonist protocol
• 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 2139 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
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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

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Adenomyosis may adversely impact fertility by
its impact on myometrial contractility and/or
via altered molecular expressions in the
endometrium
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Strawberry endometrium
Irregular vascularization, small
subendometrial haemorrhagic cyst
Small haemorrhagic foci assuming a chocolate
brown colour
Irregular endometrial mucosa
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DIFFUSE
DIFFUSE
FOCAL
FOCAL
ADENOMYOMA
ADENOMYOMA
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• 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

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FAVOURS SURGERY
DIFFUSE VS FOCAL(FAVOURS)
MISCARRIAGE RATE
LBR
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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

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MECHANISM OF ACTION OF GnRH Agonist on
ADENOMYOSIS
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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-relea
sing intrauterine system on IVF and
vitrifiedwarmed 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
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ENDOMETRIOSIS
NEWER THERAPIES
136
NEWER THERAPIES
Valproic Acid Anti-platelet Therapy Selective
Progesterone Receptor Modulators Aromatase
Inhibitors GnRH Antagonists VEGF antagonists
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
hormoneantagonist a randomized clinical trial
Jacques Donnez,FERT STERT 2020

• Women aged 1845 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 lt1 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 1324), the
  patient reported continued alleviation of her
  symptoms.

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Thank You
Dr. Shivani Sachdev Gour MD DNB MRCOG (UK)
Dr. Nupur Garg MS, FNB Consultant Fertility
Consultant Fertility Specialist
Gynaecologist Director SCI IVF Centre New Delhi
Specialist Gynaecologist Director SCI IVF Centre
Noida
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