Non surgical interventions for endometriosis
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Transcript of Non surgical interventions for endometriosis
![Page 1: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/1.jpg)
Dr Mahmoud Abdel-Aleem
Assistant Professor of Obstetrics and Gynecology
Endometriosis
Non-surgical Interventions
Case study
A healthy 25-year-old woman presents with worsening
dysmenorrhea pain of recent onset in the LLQ
quadrant and dyspareunia She has regular menstrual
cycles and her last menstrual period was 3 weeks
before presentation
Why this subject
(I) Definitely A hot topic
Publications Growth Rate
Registered trials
80 Ongoing Clinical Trials
Sampson 1921
II The Basics are
Changing
38 differences
between the
endometrium and
the endometrial
tissue of
endometriosis
51 basic science
articles
III New insights into
pathogenesis
The newly discovered biomarkers opened the way
for newer and medical interventions for this
mysterious disease
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 2: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/2.jpg)
Case study
A healthy 25-year-old woman presents with worsening
dysmenorrhea pain of recent onset in the LLQ
quadrant and dyspareunia She has regular menstrual
cycles and her last menstrual period was 3 weeks
before presentation
Why this subject
(I) Definitely A hot topic
Publications Growth Rate
Registered trials
80 Ongoing Clinical Trials
Sampson 1921
II The Basics are
Changing
38 differences
between the
endometrium and
the endometrial
tissue of
endometriosis
51 basic science
articles
III New insights into
pathogenesis
The newly discovered biomarkers opened the way
for newer and medical interventions for this
mysterious disease
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 3: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/3.jpg)
Why this subject
(I) Definitely A hot topic
Publications Growth Rate
Registered trials
80 Ongoing Clinical Trials
Sampson 1921
II The Basics are
Changing
38 differences
between the
endometrium and
the endometrial
tissue of
endometriosis
51 basic science
articles
III New insights into
pathogenesis
The newly discovered biomarkers opened the way
for newer and medical interventions for this
mysterious disease
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 4: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/4.jpg)
(I) Definitely A hot topic
Publications Growth Rate
Registered trials
80 Ongoing Clinical Trials
Sampson 1921
II The Basics are
Changing
38 differences
between the
endometrium and
the endometrial
tissue of
endometriosis
51 basic science
articles
III New insights into
pathogenesis
The newly discovered biomarkers opened the way
for newer and medical interventions for this
mysterious disease
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 5: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/5.jpg)
Publications Growth Rate
Registered trials
80 Ongoing Clinical Trials
Sampson 1921
II The Basics are
Changing
38 differences
between the
endometrium and
the endometrial
tissue of
endometriosis
51 basic science
articles
III New insights into
pathogenesis
The newly discovered biomarkers opened the way
for newer and medical interventions for this
mysterious disease
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 6: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/6.jpg)
Registered trials
80 Ongoing Clinical Trials
Sampson 1921
II The Basics are
Changing
38 differences
between the
endometrium and
the endometrial
tissue of
endometriosis
51 basic science
articles
III New insights into
pathogenesis
The newly discovered biomarkers opened the way
for newer and medical interventions for this
mysterious disease
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 7: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/7.jpg)
80 Ongoing Clinical Trials
Sampson 1921
II The Basics are
Changing
38 differences
between the
endometrium and
the endometrial
tissue of
endometriosis
51 basic science
articles
III New insights into
pathogenesis
The newly discovered biomarkers opened the way
for newer and medical interventions for this
mysterious disease
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 8: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/8.jpg)
Sampson 1921
II The Basics are
Changing
38 differences
between the
endometrium and
the endometrial
tissue of
endometriosis
51 basic science
articles
III New insights into
pathogenesis
The newly discovered biomarkers opened the way
for newer and medical interventions for this
mysterious disease
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 9: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/9.jpg)
38 differences
between the
endometrium and
the endometrial
tissue of
endometriosis
51 basic science
articles
III New insights into
pathogenesis
The newly discovered biomarkers opened the way
for newer and medical interventions for this
mysterious disease
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 10: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/10.jpg)
III New insights into
pathogenesis
The newly discovered biomarkers opened the way
for newer and medical interventions for this
mysterious disease
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 11: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/11.jpg)
IV Different forms of the
disease
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 12: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/12.jpg)
Endometriotic
nodules implant
inside the ovary
It may then
extend to the
fallopian tubes or
the bowel
Endometriotic
nodules migrate
and implant
anywhere on the
peritoneal
surface
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 13: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/13.jpg)
(V) A Changing Paradigm
SURGERY MEDICAL
TREATMENT
ldquoEndometriosis is best viewed primarily as a medical disease withsurgical back-up Individuals with chronic superficial orpresumed disease should be treated medically reserving surgeryfor those having large endometriomas or palpable disease thatfails to respond to treatment ASRM_2014
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 14: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/14.jpg)
Why Changing Paradigm
Current thinkingDeep-rooted thinking
bull Preservation of OR is a
priority
bull Removal of lesions is a
priority
bull It is an inflammatory
syndrome
bull It is just a gynecological
lesion
bull Richness of databull Paucity of data
bull Recurrence means
persistent offending
factor
bull Recurrence means
incomplete 1ry surgery
bull ART is nowadays safer
and more effective
bull ART wasnrsquot that safe
effective
bull Endometriosis is the
nemesis of the eggs
bull No effect on the ovary
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 15: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/15.jpg)
The nemesis of eggs
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 16: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/16.jpg)
(VI) Assessment of medical Rx ASRM
2014
Assessing the success of medical treatment for endometriosis is difficult
RCTs comparing different agents are confounded by the side effects associated with the medications
Placebo effects in the range of 40ndash45 have been reported
Some drugs result in hypoestrogenic effects that interfere with efforts to perform a blinded study
No good quality studies have compared directly medical versus surgical treatment of endometriosis
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 17: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/17.jpg)
Cochrane of the Cochrane(s)
For women with pain GnRH-a (LNG-IUD) and danazol are beneficial interventions
The evidence on NSAIDs is inconclusive
There was no evidence of benefit with post-surgical medical treatment
There is no evidence that medical treatment
improves clinical pregnancy rates
In women with endometriosis undergoing ART 3
months of treatment with GnRH agonist improved
pregnancy ratesEvidence on harms was scanty but GnRH analogues
danazol and depot progestagens were associated with
higher rates than other interventions
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 18: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/18.jpg)
The concept of ldquoMe-toordquo drugs
Me-too drug A drug that is structurally very
similar to already known drugs with only minor
differences The term me-too carries a negative
connotation However me-too products may
create competition and drive prices down
There is a Deluge= طوفانof drugs that might help
patients with endometriosis
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 19: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/19.jpg)
The elephant in the room
Many studies
Poor quality
ldquoWith the steadily increasing volume
of endometriosis articles and titles and abstracts
readily available online there is a growing risk that
references are cited without the full articles having
been read by the author(s) or by referees Too often
the titles and statements in abstracts are not
supported by data in the published articlesrdquo
Koninckx PR1 Batt RE Hummelshoj L McVeigh E Ussia A Yeh JJ Minim
Invasive Gynecol 2010
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 20: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/20.jpg)
Clinical Recommendations
ESHRE 2013
ACOG
COCHRANE REVIEWS
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 21: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/21.jpg)
Principles of care
Look for the main presentation of your patient
Ovarian reserve should be assessed before
intervention
If fertility is a strong issue surgical treatment is
the first line treatment
Endometriosis surgery should be avoided in
women with diminished ovarian reserve who
should be offered art straightaway
Art is a strong option in recurrent cases and
cases with poor ovarian reserve
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 22: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/22.jpg)
Medical Treatment for
endometriosisndashassociated Pain
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
Adjunctive medical therapy after conservative
surgery1- COCs (continuous) 2- MPA 3-
GnRH agonists 4- Danazol
First line
1 NSAIDs
2 CoCs (cyclic)
Peritoneal
disease
Lesions lt3cm
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 23: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/23.jpg)
Medical Treatment for
endometriosisndashassociated
infertility
Third line
1 MIRENA
2 GnRH
agonists
3 AIs
4 Danazol
Failed line
2
Second line
1 CoCs
(continuous)
2 MPA
More
advanced
disease
NONESuper-ovulation AND IUI
IVF
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 24: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/24.jpg)
Established medications
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 25: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/25.jpg)
GnRH agonists Leuprolide
Common (in gt60 of patients) hot flashes
Less common (in 20ndash60 of patients) headache insomnia memory disorder substantial temporary loss of bone mineral density (if used for le6 mo)
Infrequent (2ndash19 of patients) substantial and persistent loss of bone mineral density anxiety dizziness asthenia depression vaginal dryness dyspareunia weight change arthralgias myalgias alopecia peripheral edema breast tenderness irritability and fatigue decreased skin elasticity decreased libido nausea altered bowel function irregular vaginal bleeding
Rare (lt2 of patients) vaginal hemorrhage allergic reaction
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 26: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/26.jpg)
Progestins
ESHRE 2013 use progestagens
MPA dienogest CA norethisterone
acetate or danazol or anti-
progestagens to reduce
endometriosis-associated pain
GRADE A
ESHRE 2013 recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain GPP
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 27: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/27.jpg)
Dienogest (Visanne)
A progestin that combines the properties of
both 19-nortestosterone derivatives and
progesterone derivatives
Mainly peripheral mode of action
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 28: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/28.jpg)
Dienogest (Visanne)
A progestogen with No estrogenic androgenic mineralocorticoid effect
Better safety profile
Comparable efficacy
Duration of use 24 months study
Easy intake
Free of pain after 3 months of use
Growth of lesions is reduced by is use (Anti-inflammatory and anti-angiogenic)
High oral bioavailability gt90
Irregular spotting is the main side effect
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 29: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/29.jpg)
The tricky point
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 30: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/30.jpg)
Comparable efficacy
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 31: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/31.jpg)
Prolonged medical treatment without a
positive diagnosis of endometriosis
Medical therapy as an alibi for incomplete
surgery
Unawareness of the anabolic side effects of
progestagen only therapy
Unawareness of the important placebo effect
for any type of medical therapy
Take Home Message
Pelvic pain
Infertility
![Page 32: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/32.jpg)
Take Home Message
Pelvic pain
Infertility
![Page 33: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/33.jpg)
Pelvic pain
Infertility
![Page 34: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/34.jpg)
Infertility
![Page 35: Non surgical interventions for endometriosis](https://reader036.fdocuments.net/reader036/viewer/2022062419/55a515891a28abe77f8b4599/html5/thumbnails/35.jpg)