Postgraduate lecture

1. New Frontiers in Management of
Endometriosis
Salah Roshdy Ahmed,MD
Professor of Obstetrics & Gynecology
Sohag University, Egypt.2019

2. No conflict of interest

3. • Historically, endometriosis was first described in Egyptian
scrolls in the sixteenth century BC.
•The first scientific description of endometriosis was published
by Carl Freiherr von Rokitansky in 1860.
At this time, the concept of endometriosis as a disease entity
was not established and it was assumed to be an enigmatic
disease with an unknown pathology.

4. •Pain is the most debilitating complaint of patients with
endometriosis and it negatively affects quality of life, sexual
function, working efficiency and social life.
Ferrero et al.,2018
•Endometriosis can be defined as an estrogen-dependent
chronic inflammatory disease that causes a broad spectrum of
symptoms; however, the cardinal clinical features are
infertility and pelvic pain
Juares and Tomas, 2013

5. Prevalence of Endometriosis
176 million women with endometriosis
during the prime years of their lives…
1 in 10 women suffer from endometriosis
Rogers et al, Reprod Sci 2009;16:335-346
World Bank, Population Projection Tables by Country and Group, 2010
Most of whom have not been diagnosed & treated!!!
Adamson et al. J of Endometriosis 2010;2:3-6

6. •Hormonal, immunological, inflammatory,
genetic, environmental, and lifestyle factors are
implicated in the pathophysiology of the disease
The definitive pathogenesis of endometriosis
is unclear
•Several theories explaining different aspects and
locations of disease have been proposed
Uysal et al.,2015

8. Clinical Presentation
1. Severe dysmenorrhoea
2. Deep dyspareunia
3. Chronic pelvic pain
4. Ovulation pain
5. Perimenstural pain/bleed
6. Infertility
7. Chronic fatigue
8. Pain during defecation
Variable
Need high index
of suspicion
Usually delay of many years
b/w
Symptoms and Definitive diagnosis

9. Endometriosis is a challenging disease and requires decision making
at every stage by the clinician & the patient

10. Diagnosis of Endometriosis {NICE guidelines}
NICE 2017
U/S
MRI
Serum
CA125
Diagnostic
laparoscopy

12. Diagnosis of Endometriosis {NICE guidelines}
•Do not exclude the possibility of endometriosis if the abdominal
or pelvic examination, ultrasound or MRI are normal
•TVS to identify endometriomas and deep endometriosis involving
the bowel, bladder or ureter
•TVS to investigate suspected endometriosis even if the pelvic
and/or abdominal examination is normal
•If a TVS is not appropriate, consider a TAS scan of the pelvis
NICE 2017

13. Diagnosis of Endometriosis {NICE guidelines}
•Do not use serum CA125 to diagnose endometriosis.
•Consider pelvic MRI to assess the extent of deep endometriosis
involving the bowel, bladder or ureter.
•Do not use pelvic MRI as the primary investigation to diagnose
endometriosis in women with symptoms or signs suggestive of
endometriosis.
•Consider laparoscopy to diagnose endometriosis in women with
suspected endometriosis, even if the ultrasound was normal.
NICE 2017

14.  During a diagnostic laparoscopy, consider taking a biopsy of suspected
endometriosis {negative histological result does not exclude
endometriosis}
Diagnosis of Endometriosis {NICE guidelines}
 For women with suspected DIE, involving the bowel, bladder or
ureter, consider MRI before an operative laparoscopy
 A gynecologist with skills in laparoscopic surgery should perform a
systematic inspection of the pelvis
 If a systematic laparoscopy is normal, explain to the woman that she
does not have endometriosis, and offer alternative management
NICE 2017

15. Staging of Endometriosis
Endometriosis fertility index(EFI)

16. Staging of Endometriosis
Endometriosis fertility index(EFI)
The EFI score seems to be relevant for the prediction of the natural
conception rate in infertile women with endometriosis treated with
laparoscopic surgery
Zhang et al., 2018
Live births can accurately be predicted with the endometriosis fertility
index (EFI), with adnexal function being the most important factor to
predict non-assisted reproductive technology (non-ART) fertility or the
requirement for ART. Maheux-Lacroix et al., 2017

17. The management of women with endometriosis is always
challenging for healthcare professionals
Uysal et al.,2015
There is no absolute cure for
endometriosis

18. Modalities of treatment
Ferrero et al., 2018
MedicalSurgical
DefinitiveConservative CurrentInvestigational
 NSAIDS
 Estro-progestins
 Progestins
 GNRH agonists
 Danazol
 Aromatase inhibitors
 Anti-angiogenic drugs
 Antioxidants
 Immunomodulators
 SERM/SPRM
 GNRH antagonists
 Epigenetic agents
1st
line
2nd
line

19. Criteria for the ideal medication for endometriosis
• Curative rather than suppressive
• Treats pain and fertility at the same time
• Acceptable side effect profile
• Long-term use should be safe and affordable
• Non-contraceptive nature
• No interference with spontaneous ovulations and normal
implantation
• Bedaiwy. Future of endometriosis medical therapy. Fertil Steril 2017.

20. Criteria for the ideal medication for endometriosis
• Enhances spontaneous conception
• No teratogenic potential and safe to use periconceptionally
• Inhibits the growth of already existing lesions
• Aborts the development of new lesions
• Efficacious for all endometriosis phenotypes including superficial
disease, endometriomas, deep infiltrating endometriosis, and extrapelvic
endometriosis and adenomyosis
• Bedaiwy. Future of endometriosis medical therapy. Fertil Steril 2017.

21. Current medical treatment options for endometriosis (1st line)
NSAIDS ; D
Advantages
 First-line therapy
 Efficacious in improving moderate women pain
symptoms
 Not expensive
Disadvantages
 They only act on symptoms
 Does not block of ovulation
Indications
 Dysmenorrhea
 Dyspareunia
Types
 Tolfenamic acid (200x3)
 naproxen sodium (275x4)
Evidence
 Little evidence to support their use
in the treatment of
endometriosis
Adverse events
 gastrointestinal ulcers, cardiovascular
events, hypertension, and acute renal
failure
Brown et al., 2017

22. Current medical treatment options for endometriosis (1st line)
Estroprogestins ;A
Advantages
 First-line therapy
 Not expensive
 Low rates of AEs
 Multiple routes of administration available
Disadvantages
 One-fourth to one-third of patients treated
do not respond to them
Indications
 Dysmenorrhea
 Chronic pelvic pain
Types
 COCS
 Vaginal rings
 Transdermal patch
Recurrence
 Symptoms recur 6 months after the end of treatment
Protocols
 Continuous
 Sequential
 Contraception
 Safe
 Regular cycle
Leone et al.,2016

23. Current medical treatment options for endometriosis (1st line)
Progestins ;A
Advantages
 First-line therapy
 Not expensive
 Lower thrombotic risk
 Low rates of AEs and suitable for migraine patients
 Multiple route of administration available
Disadvantages
 Only two progestin approved for contraception purpose
(DSG, ENG-subdermal implant and LNG-IUS)
 Between one-fourth and one-third of patients treated do not
respond to them
Mechanism
 Frequency and amplitude of pulsatile (GnRH) in the
hypothalamus FSH & LH Anovulation &
hypoestrogenism Decidualization of ectopic and
eutopic endometrium
Types
 17-hydroxyprogesterone derivatives and 19 nortestosterone
derivatives (NETA, CPA, MPA, DSG, ETG, LNG and DNG)
Dienogest (2 mg/day)
 A new fourth-generation selective progestin with anti-
inflammatory proprieties, suitable for patients suffering
symptoms resistant to other progestins.
Adverse events
 Spotting, breakthrough bleeding, fluid retention, depression
and breast tenderness. Tafi et al.,2015

24. Current medical treatment options for endometriosis (2nd line)
Danazol ;A
Advantage
Inexpensive
Disadvantages
 Low popularity due to the androgenic AEs High
rate of AEs (estrogen-related)
 Danazol is a derivative of the synthetic steroid
ethisterone, which exhibits anti-gonadotropic,
hypoestrogenic, hyperandrogenic effects inducing
atrophy of the endometrium and of ectopic
endometriotic implants, which can alleviate the
symptoms of endometriosis. This drug was very
popular for the treatment of patients with
endometriosis during the 1970s and 1980s;
600 mg /day
vaginal
Adverse events
 Weight gain, acne, hirsutism and other androgenic
AEs;
Ferrero etal 2018

25. Current medical treatment options for endometriosis (2nd line)
Gonadotropin releasing hormone analogues;A
Advantages
 Secondary-line therapy (efficacious in treating patients who
did not respond to COCs or progestins)
Disadvantages
 Not oral administration (subcutaneous)
 Expensive
 High rate of AEs (estrogen-related)
Mechanism
 Downregulation of pituitary (GnRH) receptors FSH
& LH Anovulation & hypoestrogenism regression
of endometriotic lesions.
 Comparison between {intranasal, S.C or I.M} administration of
GnRH agonists no statistically significant difference for
pelvic pain, deep dyspareunia and dysmenorrhea
Evidence
 There is limited evidence in terms of optimal dosage,
duration of therapy and route of administration with GnRH
agonists.
Adverse events
 Alteration of lipid profile, depression, hot flushes, urogenital
atrophy and loss of body mineral density (BMD)
Abu Hashim, 2102

26. Investigational hormonal therapies
• 1. Aromatase inhibitors
• 2. Gonadotropin releasing hormone
antagonists
• 3. Selective estrogen receptor modulators
• 4. Selective progesterone receptor
modulators

27. Investigational non-hormonal therapies
• 1. Anti-angiogenetic drugs
• 2. Antioxidants
• 3. Immunomodulators
• 4. Epigenetic agents
• 5.Chinese methods
• 6.Green Tea
• 7.Stem Cells Therapy
• 8.Gene therapy

28. New medical treatment options for endometriosis
(Investigational)
Aromatase inhibitors;B
Advantage
 Not expensive
Disadvantage
 Low popularity due to the androgenic AEs
Mechanism
 Aromatase P450 is expressed in both the eutopic and
ectopic endometrium of patients with endometriosis while it
is not detectable in the eutopic endometrium obtained from
healthy women.
 Anastrazole and Letrozole
Evidence
 AIs are not licensed for the treatment of endometriosis and
they may only be considered in a research environment
when all other options have been exhausted.
Adverse events
 Hot flashes, weight gain, bone and joint pain, muscle
aches, and less frequently mood swings, headache, vaginal
spotting, fatigue, dizziness, depression, increase appetite,
insomnia, rash and decreased libido.Ferrero et al.,2009

29. New medical treatment options for endometriosis (Investigational)
Gonadotropin releasing hormone antagonists;B
Advantage
 GnRH-ants do not have initial flare-up effect.
 Effect is completely reversible
 No adverse effects of hypoestrogenism as mean estradiol
level oscillated around 50 pg /ml.
Mechanism
 GnRH-ants do not cause a flare-up effect because they immediately downregulate gonadotropin secretion by competing with
the endogenous GnRH for its pituitary receptors immediate decrease in the circulating levels of gonadal steroid hormones.
 A dose dependent suppression of pituitary and ovarian hormones regression of endometriotic lesions.
 Cetrorelix (S.C) and Elagolix, Relugolix (oral)
Adverse events
 Headache (20%), irregular bleeding (20%), insomnia, mood
swings and night sweats
Taniguchi et al.,2013

30. New medical treatment options for endometriosis (Investigational)
Selective estrogen receptor modulators (SERMs)
Advantage
 GnRH-ants do not have initial flare-up effect.
 Effect is completely reversible
 No adverse effects of hypoestrogenism as mean estradiol level
during treatment, oscillated around 50 pg /ml.
Mechanism
 Tissue-selective actions, acting as an ER agonist in some tissues and ER antagonist in others.
 Bazedoxifene (BZA) is a novel SERM used to treat osteoporosis in postmenopausal women with increased risk of fracture.
It effectively antagonizes estrogen-induced uterine endometrial stimulation without countering estrogenic effects in bone or in
the central nervous system
 SR-16234 seems to be a purer ER-α antagonist which may justify its evident effectiveness in the treatment of endometriosis.
 Bazedoxifene (BZA) and SR-16234
 Do not use Tamoxifen or Raloxifen because of potential
estrogenic effect that may exaggerate endometriosis.
Adverse events
 Headache (20%), irregular bleeding (20%), insomnia, mood
swings and night sweats
Kulak et al.,2011
Sakr et al.,2014

31. New medical treatment options for endometriosis (Investigational)
Selective progesterone receptor modulators (SPRMs)
Advantage
 Women had amenorrhea during treatment. Moreover,
mifepristone caused an improvement in pelvic pain in all
subjects without significant changes in the extent of the
disease as evaluated by laparoscopy.
Mechanism
 They bind to the progesterone receptor to block or modify downstream its signaling. They have pure agonist,
antagonist as well as mixed agonist/antagonist activity.
 Mifepristone and Gestrinone and Asoprisnil (Oral)
 Ulipristal acetate has been used in the treatment of uterine
fibroids but it has never been investigated for the treatment of
endometriosis.
Adverse events
 3.4% of the patients treated with mifepristone had a
significant increase in the transaminases.
Carbonell et al.,2016
Chwalisz et al.,2005

32. New medical treatment options for endometriosis (Investigational)
Anti-angiogenetic drugs
 Bevacizumab, a recombinant humanized monoclonal antibody
against VEGF, inhibited the development of endometriotic
lesions by decreasing cell proliferation and increasing apoptosis.
Mechanism
 Angiogenesis has an important role in the establishment and progression of endometriosis.
 (VEGF) is the most important angiogenetic factor in endometriosis
 Tyrosine kinase inhibitors (TKIs) inhibit the catalytic activity of the receptors of tyrosine kinases, such as vascular endothelial
growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs).
 Sorafenib and pazopanib and sunitinib
 Dopamine agonists have a critical role in the regulation of
VEGF mediated growth of implants.
Evidence
 No data on the use of these drugs in humans is available.
Laschke and Menger, 2018
Basu et al.,2004Ricci et al.,2011

33. New medical treatment options for endometriosis (Investigational)
Antioxidants
Mechanism
 Oxidative stress has an essential role in promoting the production of inflammatory mediators such as
cytokines, reactive oxygen species and prostaglandins (PGs) in endometriotic implants
 elocalcitol
 retinoic acid
 resveratrol
 green tea extract {Epigallocatechin-3-gallate
(EGCG)}
 Xanthohumol
Evidence
 Data on the use of these drugs is derived from human and animal studies
 omega-3
 N-acetylcysteine
 α-lipoic acid
 Statins
 Metformin
Parazzini et al.,2013
Augoulea et al.,2011
Rocha et al.,2012
Pinar et al.,2017
Dulak and Józkowicz,2005
Yilmaz et al.,2012

34. New medical treatment options for endometriosis (Investigational)
Immunomodulators
Mechanism
 All these studies showed a reduction in the expression of genes that regulate the production of inflammatory
cytokines, extracellular matrix metalloproteinases (MMPs), apoptosis inhibitors and VEGF.
Imiquimod [intraperitoneal administration]
Bentamapimod
V-Endo [derived from hydrolyzed, heat-
inactivated, pooled blood of women with
endometriosis]
Evidence
 Data on the use of these drugs is derived from human and animal studies.
etanercept
infliximab
thalidomide
human chorionic gonadotropin A (hCG-A)
Huber et al.,2007
Zhang et al.,2011
Zhang et al.,2010
Nenicu et al., 2014

35. New medical treatment options for endometriosis (Investigational)
Epigenetic agents
Mechanism
 These compounds act generally on histone deacetylases, a family of enzymes that modulate the acetylation
status of histones, critical for protein expression and, thus, for cell survival and proliferation
Valproic acid
Evidence
 Data on the use of these drugs is derived animal studies.
Trichostatin A
Hsiao et al .,2017Wu and Guo, 2007Wu and Guo, 2008

36. ESHRE Guidelines
Clinicians should take patient preferences, side effects, efficacy, costs and
availability into consideration when choosing hormonal treatment for
endometriosis-associated pain. (GPP)
Clinicians are recommended to prescribe hormonal treatment [hormonal
contraceptives (level B), progestagens (level A), anti-progestagens (level A),
or GnRH agonists (level A)] as one of the options, as it reduces
endometriosis-associated pain.

37. ESHRE Guidelines
Clinicians may consider the use of a vaginal contraceptive ring or a transdermal
(estrogen/progestin) patch to reduce endometriosis-associated dysmenorrhea,
dyspareunia and chronic pelvic pain (Level C).
Clinicians may consider the continuous use of a combined oral contraceptive pill in
women suffering from endometriosis-associated dysmenorrhea (Level C).

38. ESHRE Guidelines
Clinicians can consider prescribing a levonorgestrel-releasing intrauterine system
as one of the options to reduce endometriosis-associated pain (Level B).
Clinicians are recommended to use progestagens [medroxyprogesterone acetate (oral or
depot), dienogest, cyproterone acetate, norethisterone acetate or danazol] or anti-
progestagens (gestrinone) as one of the options, to reduce endometriosis-associated pain
(Level A)

39. ESHRE Guidelines
Clinicians are recommended to prescribe hormonal add-back therapy to coincide
with the start of GnRH agonist therapy, to prevent bone loss and hypoestrogenic
symptoms during treatment. This is not known to reduce the effect of treatment on
pain relief (Level A).
Clinicians are recommended to use GnRH agonists (nafarelin, leuprolide,
buserelin, goserelin or triptorelin), as one of the options for reducing
endometriosis-associated pain, although evidence is limited regarding dosage or
duration of treatment (Level A)

40. ESHRE Guidelines
The GDG recommends that clinicians should consider NSAIDs or other analgesics
to reduce endometriosis-associated pain (GPP).
In women with pain from rectovaginal endometriosis refractory to other medical or
surgical treatment, clinicians can consider prescribing aromatase inhibitors in
combination with oral contraceptive pills, progestagens, or GnRH analogues, as
they reduce endometriosis-associated pain (Level B).

41. ESHRE Guidelines
Clinicians may consider both ablation and excision of peritoneal endometriosis to
reduce endometriosis-associated pain (Level C).
When endometriosis is identified at laparoscopy, clinicians are recommended to
surgically treat endometriosis, as this is effective for reducing endometriosis-
associated pain i.e. ‘see and treat’ (Level A).

42. ESHRE Guidelines
Clinicians should be aware that presacral neurectomy (PSN) is effective as an
additional procedure to conservative surgery to reduce endometriosis-associated
midline pain, but it requires a high degree of skill and is a potentially hazardous
procedure (Level A).
Clinicians should not perform laparoscopic uterosacral nerve ablation (LUNA) as
an additional procedure to conservative surgery to reduce endometriosis-
associated pain (Level A).

43. ESHRE Guidelines
Clinicians can consider performing cystectomy rather than CO2 laser vaporization
in women with ovarian endometrioma, because of a lower recurrence rate of the
endometrioma (Level B).
When performing surgery in women with ovarian endometrioma, clinicians should
perform cystectomy instead of drainage and coagulation, as cystectomy reduces
endometriosis-associated pain (Level A).

44. ESHRE Guidelines
Clinicians should not prescribe preoperative hormonal treatment to improve the
outcome of surgery for pain in women with endometriosis (Level A).
Clinicians should refer women with suspected or diagnosed deep endometriosis to
a center of expertise that offers all available treatments in a multidisciplinary
context (GPP). .

45. ESHRE Guidelines
In women operated on for endometriosis, clinicians are recommended to
prescribe postoperative use of a (LNG-IUS) or a combined hormonal
contraceptive for at least (18–24) months, for the secondary prevention of
endometriosis-associated dysmenorrhea, but not for non-menstrual pelvic pain or
dyspareunia (Level A).
Clinicians should not prescribe adjunctive hormonal treatment in women with
endometriosis for endometriosis-associated pain after surgery, as it does not
improve the outcome of surgery for pain (Level A).
.

46. ESHRE Guidelines
In infertile women with AFS/ASRM stage I/II endometriosis, clinicians may
consider CO2 laser vaporization of endometriosis, instead of monopolar
electrocoagulation, since laser vaporisation is associated with higher cumulative
spontaneous pregnancy rates (Level C).
In infertile women with endometriosis, clinicians should not prescribe hormonal
treatment for suppression of ovarian function to improve fertility (Level A).
.

47. ESHRE Guidelines
In infertile women with endometriosis, clinicians may offer treatment with assisted
reproductive technologies after surgery, since cumulative endometriosis
recurrence rates are not increased after controlled ovarian stimulation for IVF/ICSI
(Level C).
The use of assisted reproductive technologies for infertility associated with
endometriosis is recommended, if tubal function is compromised or if there is male
factor infertility, and/or other treatments have failed (GPP)

48. ESHRE Guidelines
In women with endometrioma larger than 3 cm, the GDG recommends clinicians
only to consider cystectomy prior to assisted reproductive technologies to improve
endometriosis-associated pain or the accessibility of follicles (GPP).
In infertile women with endometrioma larger than 3 cm there is no evidence that
cystectomy prior to treatment with assisted reproductive technologies improves
pregnancy rates (Level A).

49. ESHRE Guidelines
Clinicians should counsel women with endometrioma regarding the risks of
reduced ovarian function after surgery and the possible loss of the ovary. The
decision to proceed with surgery should be considered carefully if the woman has
had previous ovarian surgery (GPP).

50. Conclusions
 Endometriosis is a benign chronic hormonal disease that requires a long-term
therapy balancing clinical efficacy and recurrence rate with an acceptable safety-
profile.
 The choice of treatment is based on patient age, preferences, reproductive plans,
intensity of pain, severity of disease and incidence of AEs.
 Currently available hormonal drugs for endometriosis are suppressive and not
curative and contraceptive ones are not suitable for young ladies who need kids.

51. Conclusions
 While COCs are considered the first-line treatment option for patients with
symptomatic endometriosis, the use of progestins as a monotherapy is progressively
increasing.
 Estroprogestins, which cause supraphysiologic levels of estrogen are responsible for
estrogen dominance in the presence of progesterone resistance, leading to
endometriosis progression under its use.
 Abnormal vaginal bleeding may be related to the ratio of estrogen to progestin
contained in COC formulations or in the absence of estrogen when progestins are
administered as a monotherapy.

52. Conclusions
 Breakthrough bleeding can be controlled by increasing dose of progestogen
[NETA to 5mg/day] or after long term use of dienogest, accompanied by an increase
in the amenorrhea rate.
 The long-term use of GnRH agonists is limited by the incidence of hypoestrogenism
related AEs (vaginal dryness, hot flashes and BMD loss). So, a treatment longer
than 6 months should be combined with add-back therapy with COCs or NETA.
 To date, studies on Aromatase inhibitors, included a small number of patients who
received these drugs for only 6 months. Neverthless, the reported AEs (hot flushing,
myalgia, arthralgia) seems to limit their long-term use in clinical practice

53. Conclusions
 Up to now, no SERM has been shown to be effective in the treatment of
endometriosis. However, future investigations should find new SERMs that act in the
modulation of lesions as an ER antagonist.
 GnRH-antagonists have been studied, for treating pain associated to endometriosis
they maintain sufficient circulating E2 levels in order to avoid vasomotor symptoms
or loss of BMD caused by estrogen deprivation. However, the most appropriate dose
of elagolix (150–200 mg once or twice daily) is unclear.

54. Conclusions
 The efficacy of several antioxidants to relieve endometriosis- associated pain and to
reduce endometriotic lesions has been assessed in several pre-clinical and some
clinical trials but only poor evidence exists to support their clinical application.
However, they are not expensive, largely available and with high safety-profile
 Among anti-inflammatory drugs, TNF-α blockers have shown to be efficacious in
animal studies. No trials in women with endometriosis has been performed, with the
exception of that on infliximab that lead to discouraging results.

55. Conclusions
In the absence of solid clinical data on new targets for
endometriosis therapy derived from large RCTs, the
introduction of new targeted drugs (except for GnRH-ant)
for the treatment of endometriosis is still far to be realized
and shouldn't be considered outside research level.

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