Invited Lecture delivered by Dr Sujoy Dasgupta in a CME, sponsored by Serum Institute of India Pvt Ltd in the Convocation Ceremony of Interns at Sagor Dutta Medical College
3. ENDOMETRIOSIS is a
chronic, estrogen-
dependent, inflammatory,
painful disorder in which
endometrial tissue grows
outside the uterus.
• Most commonly involves
ovaries, fallopian tubes and
tissue lining the pelvis as
well as bladder, bowel,
vagina or rectum.
• This endometrial tissue
thickens and bleeds, just as
normal endometrium does
during menstrual cycle.
4. • Occurs in 6–10% of women of reproductive age
• with a prevalence of 38% in infertile women,
and
• in 71–87% of women with chronic pelvic pain
• Improved recognition of endometriotic lesions
may have led to an increase in detection rate
• The Endometriosis Society of India estimates
that 25 million i.e about 35% Indian women
suffer from this condition.
5. 1. Endometriosis may be a diagnosis of
exclusion
2. A significant number of women with
endometriosis remain asymptomatic
Therefore, DIAGNOSIS of endometriosis in a
woman with pelvic pain is often delayed &
stretches over several years!
8. Diagnosis Of Endometriosis
Clinicians should consider the
diagnosis of endometriosis
in the presence of gynecological
symptoms-
Dysmenorrhea
non-cyclical pelvic pain
deep dyspareunia
Infertility
fatigue
in women of reproductive age with
non-gynecological cyclical symptoms
Dyschezia
rectal bleeding
Dysuria
Hematuria
shoulder pain
9. Quality of Life
• Work
• Education
• Relationships
• Social functioning
• Reduced work effectiveness
• Depressive symptoms
• Anxiety
As symptoms become more severe, quality of
life is reduced further.
10. There is NO permanent cure for
endometriosis
• As stated by ASRM, “Endometriosis should be viewed as a
chronic disease that requires a life-long management plan
with the goal of maximizing the use of medical treatment and
avoiding repeated surgical procedures”
• No single treatment is ideal for all patients, management
chosen should be directed to individual needs of each patient
• Combination therapy may be ideal; as it is a chronic disease,
we should consider not only efficacy but also long-term safety
and tolerability of treatment options.
• Long-term treatment / repeated courses owing to frequent
recurrence of pain within 6-12 months of completing
treatment course (within 5 years in about half of women)
11. Types of Endometriosis
• Peritoneal endometriosis
They are endometriotic implants on the surface of the surface of pelvic
peritoneum and ovaries.
• Endometriomas
They are ovarian cysts lined by endometrioid mucosa.
• Rectovaginal endometriotic nodules
It is a complex solid mass comprised of endometriotic tissue blended
with adipose and fibromuscular tissue, residing between the rectum and
the vagina.
•Adenomyosis (Endometriosis Interna)
Endometriosis in the myometrium (Musculature of the uterus)
•Extragenital endometriosis
Scar tissue, pleura, omentum, lungs, limbs
12. Complex interaction between aberrant
endometrial GENES expression & altered
HORMONAL response
Overproduction of
PROSTAGLANDINS
by an increased COX-2
activity
Overproduction of
ESTROGEN by
increased aromatase
activity
ENDOMETRIAL LESIONS proliferate release
macrophages and proinflammatory cytokines in peritoneal
fluid inflammation, adhesions, fibrosis, scarring,
anatomical distortions Pain & Infertility
1 2
13. Estradiol also specifically fuels these types of pain through its
effects on the endometriotic tissue
• Estradiol induces COX-2, which increases production
of prostaglandin E2 (PGE2)
• PGE2 directly causes pain and inflammation
• PGE2 in turn leads to increased aromatase, resulting in
increased local estradiol production
Positive feedback
loop is created.
15. NICE, 2017
• Do not exclude the possibility of
endometriosis if the abdominal or pelvic
examination, ultrasound or MRI are
normal. If clinical suspicion remains or
symptoms persist, consider referral for
further assessment and investigation.
16. Gold Standard
•The combination of laparoscopy and the histological verification of
endometrial glands and/or stroma
•In many cases the typical appearances of endometriotic implants in the
abdominal cavity are regarded as proof that endometriosis is present.
•Consider laparoscopy to diagnose endometriosis in women with
suspected endometriosis, even if the ultrasound was normal. (NICE,
2017)
•A negative diagnostic laparoscopy (i.e. a laparoscopy during which no
endometriosis is identified) seems to be highly accurate for excluding
endometriosis and is therefore of use to the clinician in aiding decision-
making. (ESHRE, 2013)
17. Standard procedure
A good quality laparoscopy should include systematic checking of
•1) the uterus and adnexa,
•2) the peritoneum of ovarian fossae, vesico-uterine fold, Douglas and
pararectal spaces,
•3) the rectum and sigmoid (isolated sigmoid nodules),
•4) the appendix and caecum and
•5) the diaphragm.
•6) speculum examination and palpation of the vagina and cervix under
laparoscopic control, to check for 'buried' nodules.
•A good quality laparoscopy can only be performed by using at least
one secondary port for a suitable grasper to clear the pelvis of obstruction
from bowel loops, or fluid suction to ensure the whole pouch of Douglas
is inspected.
•By a gynaecologist with training and skills in laparoscopic surgery for
endometriosis
18. Biopsy
to confirm the diagnosis of endometriosis
(be aware that a negative histological result
does not exclude endometriosis)
to exclude malignancy
1. if an endometrioma is treated but not excised
2. deep infiltrating disease
19. Stage 1: Lesions are
minimal & isolated
Stage 2: Lesions are mild -
may be several; adhesions
are possible.
Stage 3: Lesions are
moderate, deep or
superficial with clear
adhesions
Stage 4: Lesions are
multiple & severe, both
superficial & deep, with
prominent adhesions.
ASRM
classification of
endometriosis
20. Stage is based on location, amount,
depth & size of endometrial tissue
Limitations - not a good predictor of pregnancy,
does not correlate well with the symptoms of
pain and dyspareunia or infertility.
E.g. Woman in stage 1 tremendous pain,
while
Woman in stage 4 asymptomatic.
21. NICE, 2017
• Offer endometriosis treatment
according to the woman's symptoms,
preferences and priorities, rather than
the stage of the endometriosis.
22. Is Laparoscopy is a MUST?
•Empirical treatment can be started without a definitive diagnosis-
1. if signs of deep endometriosis or ovarian endometriosis are not
present in physical examination and imaging.
2. young adolescents or in women that decide not to have a
laparoscopy solely to know if the disease is there.
•Even if peritoneal disease is found it might not be the cause of pain
•Treatment of peritoneal disease does NOT influence the natural
course of the disease.
• If medical pain treatment relieves pain, many women will not be
interested whether or not their pain symptoms were due to
peritoneal endometriosis.
26. Subfertility
• About 1/3rd of women with endometriosis also suffer
from subfertility.
• Endometriosis does not equal infertility. It just implies that
some women may have a harder time becoming pregnant.
• Endometriosis causes adhesions and scar tissue which cause
the internal organs to get stuck to each other.
• Once the endometriosis is treated then women can usually
conceive naturally without any assisted reproductive
techniques.
27. Endometriosis and Infertility
• Dysparaeunia
• Distorted Pelvic Anatomy.
• Altered Peritoneal Function.
• Hormonal and Ovulatory Abnormalities.
• Impaired Implantation (challenged based on b-3
integrin research)
• Oocyte and Embryo Quality.
• Abnormal Uterotubal Transport.
28. Unexplained Infertility
• 10-20% of infertile couples
• Reflects an incomplete fertility evaluation
• Many cases represent undiagnosed endometriosis
• Can lead to empiric and costly therapies
29. French Study
63% Endometriosis
Eur J Obstet Gynecol Reprod Biol. 2012
Time to Treat
Undiagnosed Endometriosis
In
Unexplained Infertility
Leads to
Recurrent Implantation Failures
Belgium Study
47% endometriosis
Fertility & Sterility Vol. 92, 1, July 2009
30. Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Grade 4
Endometrio
sis
IVF
Grade 1-3 Enometriosis
OI/ IUI 4-6
cycles
No pregnancy within 6-12 months
after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF))
before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Laparoscopy
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo
transfer
Laparoscopy for
pain/ large cysts
Laparoscopy ONLY for
pain/ inaccessible ovaries
31. Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Grade 4
Endometrio
sis
IVF
Grade 1-3 Enometriosis
OI/ IUI 4-6
cycles
No pregnancy within 6-12 months
after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF))
before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Laparoscopy
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo
transfer
Laparoscopy for
pain/ large cysts
Laparoscopy ONLY for
pain/ inaccessible ovaries
32. Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Grade 4
Endometrio
sis
IVF
Grade 1-3 Enometriosis
OI/ IUI 4-6
cycles
No pregnancy within 6-12 months
after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF))
before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Laparoscopy
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo
transfer
Laparoscopy for
pain/ large cysts
Laparoscopy ONLY for
pain/ inaccessible ovaries
33. Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Grade 4
Endometrio
sis
IVF
Grade 1-3 Enometriosis
OI/ IUI 4-6
cycles
No pregnancy within 6-12 months
after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF))
before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Laparoscopy
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo
transfer
Laparoscopy for
pain/ large cysts
Laparoscopy ONLY for
pain/ inaccessible ovaries
34. Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Grade 4
Endometrio
sis
IVF
Grade 1-3 Enometriosis
OI/ IUI 4-6
cycles
No pregnancy within 6-12 months
after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF))
before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Laparoscopy
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo
transfer
Laparoscopy for
pain/ large cysts
Laparoscopy ONLY for
pain/ inaccessible ovaries
35. Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Grade 4
Endometrio
sis
IVF
Grade 1-3 Enometriosis
OI/ IUI 4-6
cycles
No pregnancy within 6-12 months
after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF))
before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Laparoscopy
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo
transfer
Laparoscopy for
pain/ large cysts
Laparoscopy ONLY for
pain/ inaccessible ovaries
36. Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Grade 4
Endometrio
sis
IVF
Grade 1-3 Enometriosis
OI/ IUI 4-6
cycles
No pregnancy within 6-12 months
after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF))
before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Laparoscopy
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo
transfer
Laparoscopy for
pain/ large cysts
Laparoscopy ONLY for
pain/ inaccessible ovaries
37. Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Grade 4
Endometrio
sis
IVF
Grade 1-3 Enometriosis
OI/ IUI 4-6
cycles
No pregnancy within 6-12 months
after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF))
before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Laparoscopy
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo
transfer
Laparoscopy for
pain/ large cysts
Laparoscopy ONLY for
pain/ inaccessible ovaries
38. Presented with Infertility
Fertility factors Evaluation (Ovarian reserve, tube, semen)
Natural conception is possible
Severe Pain
Laparoscopy
Grade 4
Endometrio
sis
IVF
Grade 1-3 Enometriosis
OI/ IUI 4-6
cycles
No pregnancy within 6-12 months
after Lap
IVF
Prev Surgery
High Age
Large cyst
Offer egg/ embryo
freezing (IVF))
before Lap
No Pain
Ovulation Induction (OI) 4-6 cycles
IUI 3-6 cycles
IVF
Laparoscopy
Needs IVF
(Male Factor, tubal factor, poor ovarian reserve)
IVF
Egg collection
Freeze all
GnRH Agonists- 3-6
Frozen embryo
transfer
Laparoscopy for
pain/ large cysts
Laparoscopy ONLY for
pain/ inaccessible ovaries
39. Case 1
• Mrs AB, P0+0, trying to conceive for one year. She
is having severe dysmenorrhoea not responding to
NSAID.
• Husband’s semen, HSG, AMH all are normal
39
41. Surgery for Peritoneal
Endometriosis
• Both ablation and excision improve the chance of
spontaneous conception in ASRM stage I/II
endometriosis (CO2 laser vaporization > monopolar
electrocoagulation)
• Complete surgical removal before ART- ?
42. Surgery for ovarian endometrioma
• Cystectomy improves the chance of spontaneous
conception, but NOT the success of ART
• controversial if cumulative pregnancy rate is more after
surgery but time to achieve the first pregnancy in
infertile patients was significantly shorter
• A small added risk of requiring an oophorectomy
• Management should be individualised
• clinicians counsel regarding the risks of reduced ovarian
function after surgery and the possible loss of the ovary.
The decision to proceed with surgery should be considered
carefully if the woman has had previous ovarian surgery.
43. Which Surgery
(RCOG 2017, NICE 2017)
Compared with drainage and coagulation,
Cystectomy is associated with
• an overall lower recurrence risk
• higher spontaneous postoperative pregnancy rate,
• particularly if the cyst is ≥3 cm in diameter. (OR
5.24, 95% CI 1.92–14.27; n = 88; two trials)
[Cochrane Database Syst Rev 2008;(2):CD004992]
43
44. Surgery for deep endometriosis
In women with infertility and severe pelvic pain who
are resistant to medical treatment or severe bowel
stenosis,
radical excision of endometriosis combined with
bowel segmental resection and anastomosis was
associated with a higher postoperative spontaneous
pregnancy rate
•Role before ART- ?
45. Risks associated with surgical
treatment
1. Complete excision of endometriotic tissue not
possible
2. Invasive procedure and chances of damaging the
surrounding organs increases.
3. Chances of damage to the reproductive organs
thus leading to infertility.
4. Preoperative Assessment of ovarian reserve
5. Needs skill
48. Hormonal therapies
•Pregnancy is not
possible/contraindicated
during hormonal therapy
•Hormonal treatment for
suppression of ovarian
function does not improve
the chance of natural
conception
•Only indicated- if wants to
delay Laparoscopy/ IVF
and the pain is severe
49. Case 1 (Contd.)
• Mrs AB underwent laparoscopy
• ovarian cystectomy (4 cm), adhesiolysis and
ablation of superficial peritoneal endometriosis
were done.
• Tubal patency was confirmed B/L.
49
53. Case 2
• Mrs PS, 28, trying for pregnancy for 15 months.
She had severe dysmenorrhoea, dyschezia and
dysuria.
• There was 5 cm unilateral endometrioma and MRI
scan suggested the possibility of rectosigmoid
endometriosis.
• AMH 2.3 ng/ml, husband’s semen normal, tubes not
checked
• She wanted to defer surgery for 4 months because
of professional commitments
54. Preoperative hormonal therapies
Clinicians should not prescribe preoperative hormonal treatment to improve the
outcome of surgery for pain in women with endometriosis
•In clinical practice, surgeons prescribe preoperative medical treatment with GnRH
analogues as this can facilitate surgery due to reduced inflammation,
vascularisation of endometriosis lesions and adhesions. However, there are no
controlled studies supporting this (ESHRE, 2013)
•Consider GnRH agonist x 3 cycles before surgery for deep infiltrating
endometriosis (NICE, 2017)
• From a patient perspective, medical treatment should be offered before surgery
to women with painful symptoms in the waiting period before the surgery
can be performed, with the purpose of reducing pain before, not after,
surgery.
55. Combined hormonal contraceptives
COC pills, vaginal contraceptive ring or a transdermal
(estrogen/progestin) patch-
-Reduce endometriosis-associated
1. Dyspareunia
2. dysmenorrhea (continuous use of a CHC)
3. non-menstrual pain
• The vaginal ring reduced dysmenorrhea significantly
more in patients with RV endometriosis compared to
women in the patch group.
56. Progesterone, Antiprogesterone
progestagens [medroxyprogesterone acetate (oral or
depot), norethisterone acetate, dienogest, cyproterone
acetate]
anti-progestagens (gestrinone, danazol)
• Danazol should not be used if any other medical
therapy is available. Recent studies indicate that
vaginal danazol may be better tolerated.
• LNG-IUS is particularly suited for deep RV
endometriosis
57. GnRH Agnosists
Evidence is limited regarding dosage or duration of treatment
Acts by downregulating the pituitary
Clinicians are recommended to prescribe hormonal add-back
therapy to coincide with the start of GnRH agonist therapy, to
prevent bone loss and hypoestrogenic symptoms during treatment.
This is NOT known to reduce the effect of treatment on pain
relief
careful consideration to the use of GnRH agonists in young
women and adolescents, since these women may not have reached
maximum bone density.
•GnRHa is more effective than placebo but inferior to the LNG-IUS
or oral danazol.
• No difference in effectiveness exists when GnRHa is administered
IM/ SC/ intranasally.
58. Aromatase Inhibitors
(Letrozole)
In women with pain from RV endometriosis refractory
to other medical or surgical treatment
consider prescribing aromatase inhibitors in
combination with COC, progestagens, or GnRH
analogues, as they reduce endometriosis-associated
pain
•The side effects are mostly hypoestrogenic in nature
•The evidence on the long-term effects is lacking.
59. G.A.J. Dunselman, N. Vermeulen, C. Becker, C. Calhaz-Jorge, T. D'Hooghe, B. De Bie,
O. Heikinheimo, A.W. Horne, L. Kiesel, A. Nap, A. Prentice, E. Saridogan, D. Soriano,
W. Nelen, ESHRE guideline: management of women with endometriosis , Human
Reproduction, Volume 29, Issue 3, March 2014, Pages 400–412
60. v/s placebo; 198 women aged 18–45 years
Optim
al dose
Leuprol
ide
Busere
lin
Triptor
elin
Extensi
on
PLACE
BO
64. Substantial reductions in VAS
score between baseline and
Week 24
Non-inferiority of dienogest
relative to LA - Absolute
reduction in VAS score was
47.5 mm with dienogest and
46.0 mm with LA (1.5 mm in
favour of dienogest)
65. Mean levels of serum
estradiol remained stable
in dienogest subgroup
(256.3 to 249.9 pmol/l)
and showed pronounced
decrease in LA subgroup
(from 299.0 to 68.5
pmol/l)
Estrogen threshold hypothesis
- estrogen levels are
suppressed sufficiently to
inhibit endometriotic lesion
growth, but are adequate to
prevent hypoestrogenic side
effects such as bone mineral
loss.
66. In LA group, mean number of days/week with hot flushes increased from
0.78 to 4.70.
Mean number of days/week with hot flushes was stable in dienogest
group
67. Mean lumbar BMD increased by 0.0022 g/cm2 in dienogest subgroup
and decreased by 0.0415 g/cm2 in LA subgroup
71. Results
• Increase in alkaline phosphatase in triptorelin group,
which may reflect an increased bone turnover; not
seen with Dienogest.
• Lipid profile (particularly HDL cholesterol) &
blood glucose levels were similar in both groups.
• Dienogest is a therapeutic alternative to GnRH
analogs in treatment of endometriosis.
• Postoperative treatment of endometriosis with
Dienogest was as efficient as triptorelin & had no
androgenic effects.
74. No cumulative decrease in BMD up to 52 weeks of
treatment.
Study on markers of bone metabolism revealed no change
in markers of bone metabolism, except a slight increase
only in serum osteocalcin, a marker of bone formation.
75. Key clinical benefits of
dienogest in endometriosis
• Decreases endometriosis-associated pelvic pain
• Reduces symptoms, signs and severity of endometriosis
• As effective as GnRH agonists
• Generally well tolerated
• Not associated with clinically relevant androgenic adverse
events
• Unlike GnRH agonists, not associated with clinically relevant
changes in BMD
• Efficacy and tolerability sustained with long-term (>1 year)
treatment
• Significantly prevents postoperative endometrioma
recurrence
76. Case 2 (Contd)
• Mrs PS’s laparoscopy suggested grade IV
endometriosis
• Adhesiolysis could not be done
• Tubal patency- negative both sides
76
81. Georgiou EX, Melo P, Baker PE, Sallam HN, Arici A, Garcia‐Velasco JA,
Abou‐Setta AM, Becker C, Granne IE. Long‐term GnRH agonist therapy before in
vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis.
Cochrane Database of Systematic Reviews 2019, Issue 11. Art. No.: CD013240. DOI:
10.1002/14651858.CD013240.pub2
• In light of the paucity and very low quality of existing
data, particularly for the primary outcomes examined,
further high‐quality trials are required to
definitively determine the impact of long‐term GnRH
agonist therapy on IVF/ICSI outcomes, not only
compared to no pretreatment, but also compared to
other proposed alternatives to endometriosis
management
83. Mechanism of action of GnRHA
• GnRHA have similar structure to native GnRH and a
great affinity to the GnRH receptors.
• Initially cause Gonadotrophin release (flare-up effect).
• After several days of continuous administration, this is
followed by a dramatic drop in the circulating
concentrations of FSH and LH, through a desensitization
mechanism.
• Presence of a different, yet unknown signaling pathway
activated in the ovary by GnRHA.
85. How to administer GnRH
Agonists
• Ultralong protocol
• Antagonist protocol → freeze embryos → give
GnRH agonist depot 3-6 → FET
• GnRH antagonist protocol may be not inferior to
GnRH agonist protocol in women with minimal
to mild endometriosis and endometrioma.
(ESHRE, 2015)
85
87. Safety profile of GnRHA
• Levels of serum estrogens and androgens decrease
significantly.
• The most common adverse effects of GnRH
agonists are hot flashes, vaginal dryness and
insomnia
• A decrease in bone mineral density has been
demonstrated in the LS spine. However, the bone
mineral density appears to recover completely 1 to 2
years after cessation of therapy.
88. Endometriosis and IVF Failure
• Repeated, unexplained IVF failure patients exist in most
practices
• IVF centers may not the inclination or skills to diagnose
endometriosis
• Studies have suggested endometrial receptivity defects
• Meta-analyses suggest IVF is affected by endometriosis
(Barnhart et al., F&S 2002)
• Brosens suggested aromatase expression is a marker of poor
IVF performance (Brosens et al., HR, 2004)
89. Ovarian hyperstimulation by gonadotropins
causes very high estrogen levels
E2 during the pre-implantation period (days
0–6)
Dr. Carlos Simone
ESHRE 1997
Fertility & Sterility
Vol. 70, No. 2, Aug. 1998
Window of uterine receptivity remains open for an
extended period at lower estrogen levels but
rapidly closes at higher levels
High estrogen levels provoke uterine non receptivity
90. Molecular expression - Implantation
• Aromatase present in Endometrium of women with
endometriosis. (Noble et al 1995)
• B-3 integrin expression is aberrant in endometrium of
women with endometriosis (Lessey et al 1996)
Implantation Requires Synchrony
• Delayed implantation - leads to miscarriage
• Miscarriage goes up with each day of delay
• Clinical evidence for the window of implantation
91. Implantation window
• The reception-ready phase of the endometrium of the uterus
is usually termed the "implantation window" and lasts about
4 days.
• The implantation window occurs around 6 days after the
peak in luteinizing hormone levels.
• days 6-10 postovulation
• 20th to the 23rd day after the last menstrual period
92. Human Reproduction, Volume 27,
Issue 3, 1 March 2012
Systems Biology in Reproductive
Medicine, Volume 60, 2014
Letrozole improves the
marker of Endometrial Receptivity
Letrozole improves
Integrin expression in IVF
Letrozole improves
Integrin, LIF & L- Selectin
expression in natural cycle
Window of uterine receptivity remains open for an extended period
at lower estrogen levels but rapidly closes at higher levels
PNAS March 4, 2003 100 (5) 2963-296
93. Case 3
• Mrs FR, 32 years, has been trying for pregnancy for
last 2 years. AMH, AFC, HSG all normal.
• Husband is having azoospermia. Donor sperm is no
acceptable.
• 6 cm right ovarian endometrioma, minimum
dysmenorrhoea
93
96. Surgical treatment prior to IVF
• A systematic review (five controlled studies; n = 655) [Hum
Reprod Update 2015]
• surgically-treated endometriomas compared to those with intact
endometriomas, both having IVF
• similar live birth (OR 0.9; 95% CI 0.63–1.28), clinical pregnancy
(OR 0.97; 95% CI 0.78–1.2) and miscarriage rates (OR 1.32; 95% CI
0.66–2.65)
• lower AFC
• required higher doses of gonadotrophins for ovarian stimulation.
• Women who had undergone surgical management for a unilateral
endometrioma had a lower number of oocytes retrieved from the
surgically-treated ovary (mean difference –2.59; 95% CI –4.13 to –
1.05) when compared with the contralateral normal ovary
96
98. Complications during and after OPU
(RCOG, 2017)
• Technical difficulties during oocyte retrieval is low,
• No data to suggest that surgery will prevent adhesion reformation and
facilitate oocyte retrieval effectively.
• Progression of pelvic endometriosis and ovarian endometriomas- ?
• Risks of infection from an endometrioma (0–1.9%)
• Follicular fluid contamination (2.8–6.1%)
• The risk of missing an occult malignancy in an endometrioma is
extremely low - The lifetime probability of Ca ovary increasing from 1% to
2% in the presence of an endometrioma.
• In the context of IVF treatment, delaying surgery for a few months or
years, until the treatment has been completed or following delivery, would
usually be a reasonable course of action unless there are other immediate
concerns.
98
99. Ultrasound-guided Aspiration
• Transvaginal USG-guided drainage without
surgery does not seem to be effective.
• a high recurrence rate
• To decrease recurrence rate, aspiration is
combined with in situ injection of
tetracycline/ethanol/methotrexate
• Disadvantages:
Complications: infection, abscess
formation, and pain
inability to rule out any malignancy
risk of pelvic adhesion
99
100. Case 4
• Mrs DH, 37 years old has been trying for pregnancy
for last 6 months. Husband’s semen normal, HSG
not done. AMH 0.5 ng/ml
• She underwent left ovarian cystectomy 6 years ago,
no documents are available for that.
• She is having severe dysmenorrhoea, TVS revealed
AFC 2 (right) plus 3 (left) and 5 cm chocolate cyst
in right ovary
101
102. RCOG Recommendations (2017)
Directly ART
• Asymptomatic women,
• women of advanced
reproductive age,
• those with reduced
ovarian reserve,
• bilateral endometriomas
• a history of prior ovarian
surgery
Surgery before IVF
• highly symptomatic
women,
• with an intact ovarian
reserve,
• unilateral and large cysts,
• cysts with suspicious
radiological and clinical
features.
103
103. Take Home
• Take into account overall fertility picture, age,
symptoms, previous surgery
• During Medical therapy pregnancy is NOT possible
• Medical therapy (ovarian suppression) does NOT
improve chance of natural conception
• Surgery improves the chance of natural conception
• Immediately after surgery- Best period to conceive
• Medical therapy will NOT compensate for inadequate
surgery
• Surgery does NOT improve the success rate of IVF
• Surgery improves pain, clarifies diagnosis
• GnRH Agonist improves the success rate of IVF
Notes de l'éditeur
Up to 20% of women with endometriosis have concurrent chronic pain conditions, including irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, fibromyalgia, and migraines
As I was telling you there is a years of gap between the onset of symptoms of pelvic pain and diagnosis of em
hypoestrogenic (GnRH agonist), hyperandrogenic (danazol, gestrinone) or hyperprogestogenic (oral contraceptives, medroxyprogesterone acetate) state that suppresses endometrial cell proliferation.
The complex interaction between aberrant expression of endometrial genes as well as altered hormonal response will predispose patients to the development of endometrial lesions. Key components in the development of endometriosis are local overproduction
of prostaglandins by an increase in cyclooxygenase-2 (COX-2) activity and overproduction of local estrogen by increased aromatase activity. Progesterone resistance dampens the antiestrogenic effect of progesterone and amplifies the local estrogenic effect. The resulting endometrial lesions can lead to a chronic inflammatory disorder with increased numbers of activated macrophages and proinflammatory cytokines in the peritoneal fluid that may cause pain and infertility.
The stage of endometriosis is based on the location, amount, depth and size of the endometrial tissue. Specific criteria include:
The extent of the spread of the tissue
The involvement of pelvic structures in the disease
The extent of pelvic adhesions
The blockage of the fallopian tubes
A serum estradiol concentration of 30–50 pg/mL is considered to fulfil the requirements of estrogen threshold hypothesis, by which estrogen levels are suppressed sufficiently to inhibit endometriotic lesion growth, but are adequate to prevent hypoestrogenic side effects such as bone mineral loss.