1. The document discusses emerging treatments for endometriosis, including levonorgestrel-releasing intrauterine devices (LNG-IUD), gonadotropin-releasing hormone antagonists (GnRHan), aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and progesterone antagonists. 2. It finds that LNG-IUD is effective for pain control and reduction in endometriosis lesions. GnRHan provide immediate hormone suppression with fewer side effects than agonists. AIs reduce estrogen levels through multiple pathways and show promise when combined with other drugs, though require further research. SERMs and progesterone antagonists aim to block estrogen and progesterone's

1. Aboubakr Elnashar
Benha university hospital
Emerging treatment of endometriosis
Aboubakr Elnashar

2. Introduction
Endometriosis:
estrogen-dependent disorder
substantial morbidity:
pelvic pain
infertility.
Multiple operations
Aboubakr Elnashar

3. Current treatment:
Ovarian suppressive agents.
Oral contraceptive
Progestins
GnRha
Androgenic agents
Surgery
Aboubakr Elnashar

4. Outcome of current TT:
1. Pain relief: Only half of patients
2. Fertility:
No benefit
Delayed conception
3. Disease:
No eradication
Recurrence (disease, symptoms): quite common.
4. SE: Unwanted {hypoestrogenic state}: limit the
long-term use.
Aboubakr Elnashar

5. For these reasons, new drugs that aim new targets
are required
An ideal treatment for endometriosis:
Regression of the disease & symptoms
No adverse hypoestrogenic effects
Literature review in last 5 y
Aboubakr Elnashar

6. LNG-IUD
GnRHan
Aromatase inhibitors
SERM
Progesterone antagonist
SPRM
Angiogenesis inhibitors
Immunomodulatory drugs.
Others
Aboubakr Elnashar

7. DrugsGroup
Mirena1. LNG-IUD
Cetrorelix2. GnRHan
Anastrazole (Arimidex),
Letrozole (Femara)
3. Aromatase
inhibitors
Tamoxifen, Raloxifene4. SERM
Mifepristone, Onopristone5. Progesterone
antagonist
Asoprisnil6. SPRM
TNP470, Endostatin, Anginex,
Rapamycin
7. Angiogenesis
inhibitors
Loxoribine, IFN- α 2 β, TNF- α
inhibitors.
8. Immunomodulatory
drugs.
Matrix metalprotease, Doxycycline,
5-fluorouracil, Thiazolidinediones
9. Others
Aboubakr Elnashar

8. I. Levonorgestrel-releasing
intrauterine device (LNG-IUD)
Oral progestogens:
poor compliance
systemic SE.
Aboubakr Elnashar

9. LNG-IUD
T-shaped
Release rate of LNG:
20 μg/24 h during 1st y
slowly ↓ throughout the 5 y of use.
: Endometrial atrophy
Ovulation: usually not suppressed.
Contraception
Hypomenorrhea or
amenorrhea
Reduced dysmenorrhea
Aboubakr Elnashar

10. Mechanism of action:
Unclear
LNGIUD delivers significant amounts of LNG into
the peritoneal fluid: clearing up the local effect on
the endometriotic implants
mediated through estrogen& progesterone
receptors: decidualization.
{peritoneal fluid levels of LNG were closely related
to the levels in serum}: hematogenous mechanism
by which LNG reaches the peritoneal cavity.
Aboubakr Elnashar

11. Studies:
1. Peritoneal as well as rectovaginal endometriosis:
Great improvement in pain control
Reduction in size
(Vercellini et al, 1999; Fedele et al,2001).
2. Minimal to moderate endometriosis:
Significant reduction of pain as well as stage
Continuation rate: 68% after 6 ms
Adhesions: as expected, not altered
(Lockhat et al, 2004)
Aboubakr Elnashar

12. 3. Symptomatic endometriosis
12 ms after surgery dysmenorrhea scores were
significantly lower
[Crosignani, 2003].
4. Stage I–IV endometriosis
LNG-IUS & GnRHa were effective in TT of chronic
pelvic pain -associated endometriosis
No differences between the two treatments
[Petta et al, 2007]
Aboubakr Elnashar

13. 5. Postoperative use of the LNG-IUD
reduces the recurrence of painful periods
(Cochrane systematic review, 2006) .
Aboubakr Elnashar

14. Conclusion
LNG-IUD
Treatment of choice for CPP-associated
endometriosis in women who do not wish to
conceive.
{1. Effective for at least 5 ys
2. Can be reapplied every 5 ys.
3. No modifications in estrogen levels
4. In the long term it is a low-cost therapy
5. Fewer SE than other progestogenic agents.
Aboubakr Elnashar

15. II. GnRH antagonists
GnRHa:
↑LH & FSH: ↑E2: ↑pelvic pain: ↓quality of life
(Miller , etal, 2000)
limited to the first 5 to 10 d.
Aboubakr Elnashar

16. Mechanism of action:
GnRHan
immediately block GnRH effects
competing with endogenous GnRH for pituitary
binding sites
suppress LH secretion in a dose-dependent
manner.
Aboubakr Elnashar

17. Uses
Endometriosis
Leiomyoma
Breast cancer
Premenstrual syndrome
PCOS
Superovulation in IVF
Aboubakr Elnashar

18. Studies:
3 mg of cetrorelix/w for 8 w
E2: suppressed to 50 pg/ml.
100%: symptom-free period during GnRH TT
50%: Regression
2nd look laparoscopy: Degree of endometriosis
declined to a mild stage
(Kupker et al, 2002).
Aboubakr Elnashar

19. Conclusion:
GnRHan
1. useful in TT of endometriosis in most cases.
2. Fewer SE e.g. postmenopausal symptoms
3. No estradiol add-back is needed.
4. Superior to GnRHa
{immediate suppression of LH and FSH secretion:
avoid the agonist phase of GnRHa}.
 In the future: oral GnRHan: improve patients’
comfort &compliance.
Aboubakr Elnashar

20. III. Aromatase inhibitors (AIs)
Aromatase enzyme
•Responsible for:
Conversion of androgens to estrogens (E1& E2).
•Localized primarily in:
1.Ovarian granulosa cells in premenopausal
women
2. Other tissues: liver, brain.
3. After menopause: adipose tissue is the principle
source of estrogens.
Aboubakr Elnashar

21. 4. In Normal endometrium:
No detectable levels of aromatase activity
In endometriosis:
An increased expression of cytochrome P450
aromatase in endometrial tissue
{inflammatory mediator prostaglandin E2: increase
local estrogen production}
Aboubakr Elnashar

22. 3rd generation AIs
Potent, specific & better tolerability than the former
compounds.
Types:
i-Steroidal derivatives: Exemestane (Aromasin)
approved in USA.
ii-Non-Steroidal imidazole derivatives: Fadrozole.
iii-Non-Steroidal triazole derivatives:
Anastrazole (Arimidex)
Letrozole (Femara)
Both are approved in USA for the treatment of breast
cancer.
Aboubakr Elnashar

23. Absorption & metabolism
• Letrozole:
Rapidly& completely absorbed from GIT.
Elimination half-life: 2 d
Aboubakr Elnashar

24. Uses of AIs
1. Breast cancer (FDA approved)
2. Endometrial carcinoma & endometrial stromal
sarcoma
3. Endometriosis
4. Induction of ovulation
5. Unexplained infertility
6. Poor responders
Aboubakr Elnashar

25. Mechanism of action in endometriosis
Estrogen is produced by 3 pathways
1. Hypothalamic-pituitary-ovarian pathway
2. Peripheral conversion
3. Locally within endometriosis.
 GnRHa stops only 1st pathway
 AI stop all 3 pathways
•Decreasing aromatase in the brain: decrease LH&
FSH: decrease estrogen
•Suppress ovarian & peripheral (e.g. adipose tissue)
estrogen production.
Aboubakr Elnashar

26. Mechanism in induction of ovulation
1. Initial response to AI:
↓estrogen levels: ↑FSH and LH: directly stimulates
the ovary: ↑number of mature follicles
(Mitwally & Casper, 2001).
2. locally in the ovary: ↑ follicular sensitivity to FSH
(Vendola et al,1998).
Aboubakr Elnashar

27. Studies
I. Postmenopause:
1. Severe recurrent endometriosis
Anastrozole: complete relief of pain after 2 ms
(Bulun et al,1999).
2. Endometriosis-associated pain
Letrozole was effective
(Mousa et al,2007)
3. Large recurrent abdominal wall endometrioma:
AI plus progestin & serial cyst aspiration:
successful TT
(Sasson et al, 2009)
Aboubakr Elnashar

28. II. Premenopause:
AI alone may induce ovarian folliculogenesis:
AIs are combined with progestin,
COC, or
GnRHa
{prevent reflex increments in LH and FSH}
Aboubakr Elnashar

29. 1. laparoscopically visible endometriotic lesions:
letrozole (2.5 mg/day), norethindrone acetate (2.5
mg/day), calcium & vit D for 6 ms:
Effective in reducing pelvic pain scores
(Ailawadi et al,2004).
Aboubakr Elnashar

30. 2. Endometriosis failed to respond to COC&
GnRHa:
Anastrozole (1mg/d) with progestin (200 mg/d) for 6
ms:
Rapid reduction in symptoms
Remission of symptoms & absence of
endometriotic lesions for >2 ys
Pregnancy in both cases after 2 ys.
SE: minimal
(Shippen& West 2004).
Aboubakr Elnashar

31. 3. Endometriosis with severe pelvic pain
Anstrazole (1mg daily) Vs Goserelin (3.6 mg, SC)
for 6 mo:
SE & relapse after 1y: similar
(Muderris, 2002)
Aboubakr Elnashar

32. 4. Bladder endometriosis
letrozole (2.5 mg/day), norethisterone acetate (2.5
mg/day), calcium &vit D3 for 6 ms:
Both patients:
improved pain & urinary symptoms
One patient:
myalgia & severe arthralgia; pain & urinary
symptoms recurred few months after the
interruption of the 6-m: laparoscopic partial
cystectomy.
These agents should be administered only to
patients who refuse surgery & fail to respond to
other therapies.
(Ferrero, 2010).
Aboubakr Elnashar

33. 5. Refractory pain from endometriosis who failed to
other therapies
Anastrozole 1 mg for 6 ms & COC continuous:
Decrease in pain scores
(Amsterdam et al, 2005)
Aboubakr Elnashar

34. 6. Recurrent endometriotic cysts
Letrozole (2.5 mg), COC, calcium (1,200 mg), & vit
D3 (800 IU) daily for 6 ms:
Complete regression of the cyst
Pain relief in all cases
No significant change in bone density
(Seal et al, 2011)
Aboubakr Elnashar

35. 7. Post operative surgery for severe endometriosis
Anastrozole (1 mg/day) & goserelin Vs goserelin
alone for 6 mo:
↑ pain-free interval
↓symptom recurrence rates
(Soysal et al, 2004).
Aboubakr Elnashar

36. 8. Class IV endometriosis
GnRHa ( Goserelin, 3.6 mg SC/4w) plus Anastazole
(1 mg daily) for 6 ms Vs GnRHa alone
SE: similar
In anstrazole-agonist group:
Relapse is less (10% Vs 38%)
Pregnancy rate is higher (47% Vs 17%)
(Scarpellini & Sbracia, 2000)
Aboubakr Elnashar

37. 9. Severe endometriosis
Anstrazole (1 mg/d from the start of the agonist to
the beginning of HMG) in the long protocol of COH,
for IVF,.
•In letrozole-agonist group:
PR: higher (21.7 & 23.8 % Vs 3.6% & 4.3%).
{The lowest E2 just before HMG administration}.
(Krasnopol & Kaluina, 2002)
Aboubakr Elnashar

38. AI for ovulation induction.
Pain: continuously
Ov induction: cyclically
Not FDA approved
Black box warning regarding using in pregnancy
Chromosomal anomalies as well as major
congenital malformations: the same in the CC and
letrozole group
(Tulandi et al,2006).
Aboubakr Elnashar

39. Side effects: Rare
Headache (6.9%) Nausea (6.3%),
Peripheral edema (6.2%) Fatigue (5.2%),
Hot flushes (5.2%) Bone&back pain(4.8%)
Hair thinning and rash (3.4%)
Osteoporosis {decrease E in local tissues}:
Controversial
No change in BMD at 6 ms after use of an AI with
COC
Decrease in BMD with the use of AI with a GnRH
agonist after 6 ms
(Soysal et al, 2004).
Aboubakr Elnashar

40. Conclusion
1. All 3 combinations decrease pain in patients with
refractory endometriosis.
2. Combinations of an AI with a progestin or COCs
will become more popular than combinations of an
AI with a GnRHa {cheaper, fewer side effects}
3. No severe SE
4. AIs should be offered to women who have
severe pain despite previous surgical& hormonal
therapies.
4. Further research is required before
recommending the routine use of these agents.
Aboubakr Elnashar

41. Conclusion
1. LNG-IUD
Treatment of choice for CPP-associated
endometriosis in women who do not wish to conceive.
2. GnRHan
useful in TT of endometriosis in most cases and
superior to GnRHa
3. AIs
should be offered to women who have severe pain
despite previous surgical& hormonal therapies.
should be combined with a progestin or COCs
Aboubakr Elnashar

42. IV. Selective estrogen receptor
modulators (SERMs)
SERM:
Can act as either estrogen agonists or antagonists
depending on the target tissue
Can be directed towards the αor βsubunits of Ers
1st generation: Tamoxifen
2nd generation: Raloxifene
Aboubakr Elnashar

43. Uses:
1. Prevention osteoporotic fractures in
postmenopause
2. Prevention of breast cancer.
3. Endometriosis (SERM directed towards β
subunits) {antiestrogenic effect on endometrial
tissue}.
Aboubakr Elnashar

44. Studies:
In mice:
SERM directed towards the β –subunit: resolved
endometriosis in 40 – 75%
(Harris et al, 2005).
In human:
No studies
Aboubakr Elnashar

45. V. Progesterone antagonist
An oral active progesterone antagonist at the
receptor level.
High affinity for progesterone and glucocorticoid II
receptors.
Mifepristone (RU-486)
Onopristone
use in medical abortions
Aboubakr Elnashar

46. Mechanism of action:
1. Antiprogesterone effect: prevents progesterone
from exerting its action.
2. Direct inhibitory effect on human endometrial cells
3. Modulate the estrogen and progesterone receptor
expression in both eutopic and ectopic
endometrium.
Aboubakr Elnashar

47. Studies:
1. In Rodent:
promising effects
(Tjaden et al, 1993; Stoeckermann, 1995).
2. In human:
50 mg mifepristone for 6 ms:
Significant regression in visible endometriotic
Decrease in clinical symptoms.
SE with doses of ≥ 200 mg
{antangonistic affinity of the drug to glucocorticoid
receptors causing a hypoadrenal state}.
(Kettel et al, 1998)
Aboubakr Elnashar

48. Conclusion:
Further large RCT should be performed
Aboubakr Elnashar

49. VI. Selective Progesterone receptor
modulators (SPRM)
SPRM:
agonist/antagonist effects based on the target
tissue, dose and presence or absence of
progesterone.
progesterone receptor ligands with a high degree
of endometrial selectivity
Asoprisnil
Aboubakr Elnashar

50. Rationale for the treatment of endometriosis.
1. Induce reversible amenorrhea {selective
inhibition of endometrial proliferation, a direct
effect on endometrial blood vessels}
2. Suppress endometrial prostaglandin production
in a tissue-specific manner without the systemic
effects of estrogen deprivation
Asoprisnil: suppress both the menstrual cycle and
endometrial growth
(DeManno et al, 2003).
Aboubakr Elnashar

51. Studies:
1. Endometriosis with moderate or severe pelvic
pain
asoprisnil (5, 10 and 25 mg/day) for 12 w:
Reduced pelvic pain as well as dysmenorrhea;
Effect on bleeding pattern was dose-dependent
(Chwalisz et al, 2004).
2. 5 mg is the minimum effective dose for pain relief
(Chwalisz et al, 2005).
Aboubakr Elnashar

52. Benefits.
1. In relationship to antiprogesterones, they are
more specific for the progesterone receptors: not
inhibiting the glucocorticoid receptors
2. No serious SE
3. No signs of estrogen deprivation
Aboubakr Elnashar

53. VII. Angiogenesis inhibitors
Angiogenesis is a prerequisite for endometriosis
development.
{Retrograde menstruation: peritoneal endometriotic
lesions.
Endometrial tissue requires the establishment of a
new blood supply in order to survive in the
peritoneal cavity.
The endometrium has angiogenic potential, and
endometriotic lesions grow in areas with a rich
vascularization}
Aboubakr Elnashar

54. Rationale:
Inhibition of proangiogenic factors
e.g. VEGF and MMPs
Angiostatic drugs
TNP470
Endostatin
Anginex
Rapamycin
Aboubakr Elnashar

55. Studies
1. In mouse:
Angiostatic compounds: effective in reducing the
growth of endometriotic
(Nap et al, 2004).
2. In human:
Thalidomide
{angiostatic & immunomodulatory} effective in
women with relapsing endometriosis
(Scarpellini et al, 2002).
Aboubakr Elnashar

56. 3. Statin:
a. TT of heart disease and prolong life expectancy
{lower blood cholesterol}
b. reducing the risks of diabetes, dementia and
osteoporosis.
c. inhibit the growth of human endometrial stromal
cells in vitro
(Piotrowski et al, 2006).
Aboubakr Elnashar

57. 4. Rapamycin
a. antifungal, immunosuppressant and
antiangiogenic effects.
b. Regression of endometriotic lesions
{inhibiting neovascularization and cell proliferation}.
Inhibition of VEGF-mediated angiogenesis
(Laschke et al, 2006)
Aboubakr Elnashar

58. 5. Dopamine agonists
a. Cabergoline (Cb2)
In experimental endometriosis
Cb2 treatment in has an anti-angiogenic effect
acting through VEGFR-2 activation.
A significant decrease in endometriotic lesions and
cellular proliferation index
(Novella-Maestre et al, 2009).
Aboubakr Elnashar

59. b. Quinagolide
Endometriosis-associated hyperprolactinemia
70% reduction in the size of the lesions
35% vanishing completely.
{interfering with angiogenesis, enhancing
fibrinolysis, and reducing inflammation}
quinagolide reduces or eliminates peritoneal
endometriotic lesions
(Gomez et al, 2011).
Aboubakr Elnashar

60. Limitations and challenges (Langendonckt et al,
2008).
1. Antiangiogenic treatments may alter reproductive
function by impairing physiological angiogenesis,
the greatest concern being the potential risk of
teratogenicity.
2. The initial promise of vascular therapy has not yet
been fulfilled {limited selectivity}.
3. Combining angiostatic agents and VDAs with
medical and surgical therapies in an adjuvant
setting may be the quickest and most efficient
way of enhancing current treatment modalities.
Aboubakr Elnashar

61. Conclusion
1. Vasculature is a promising target because of its
genetic stability, easy access via the circulation
and amplifying action during treatment.
2. Antiangiogenic drugs reduce the establishment,
maintenance and progression of endometriotic
lesions in different laboratory and animal models
3. The role of antiangiogenic compounds in the
treatment of endometriosis remains to be defined
4. Further investigations are required before clinical
trials can be planned in humans.
Aboubakr Elnashar

62. 5. It is unlikely that antiangiogenic drugs may cure
the symptoms caused by large endometriotic
nodules that are mainly composed by
fibromuscular tissue; on the contrary, these
agents may have a role in the postoperative
treatment of endometriosis to increase the pain
free interval and decrease the recurrence of the
disease.
Aboubakr Elnashar

63. VIII. Immunomodulators
Rationale:
Altered immune function plays a crucial role in the
genesis and development of endometriosis.
Aboubakr Elnashar

64. Mechanism of action:
Decreasing the inflammatory response to disease.
Includes
Loxoribine
IFN- α 2 β
TNF- α inhibitors.
Aboubakr Elnashar

65. Studies:
1. Loxoribine:
Stimulate natural killer cells, which then do not allow
endometrial cells to implant in ectopic tissues.
In rat:
significant reduction in amount of disease
(Keenan , 1999).
Aboubakr Elnashar

66. 2. IFN- α 2 β
intraperitoneal or by SC
In animal models and in tissue cultures:
decrease endometriosis
(Ferrero, 2005).
In human:
intraperitoneal during surgery with a GnRHa
postoperatively:
increased recurrence risk after surgery
(Acien & Quereda, 2002).
Aboubakr Elnashar

67. 3. TNF-α inhibitors
Mechanism of action:
decreasing production or release of TNF- α from
macrophages:
preventing disease progression
regression of early stage disease.
Aboubakr Elnashar

68. a. Etanercept
 Used: rheumatoid and autoimmune diseases.
In the rodent and baboon model
inhibit the development of endometriosis and
endometriosis-related adhesions.
(D’Antonio et al, 2000; D’Hooghe et al, 2001)
In humans:
Evidence is not so promising.
No improvement of infertility or endometriosis
(Shakiba et al, 2006).
Aboubakr Elnashar

69. b. Infliximab
Severe pain and a rectovaginal nodule
5 mg/kg
No effect for any of the outcome measures.
(Koninckx et al, 2008)
Conclusion
No enough evidence to support the use of anti-TNF-
alpha drugs in the management of endometriosis for
the relief of pelvic pain
Aboubakr Elnashar

70. 4. Cytokines
Interleukin-12 (IL-12) and IL-18: regulation of the
adaptive immune response
IL-12 induces other cytokines, particularly interferon-
γ (IFN-γ)
In a murine model:
Intraperitoneal injection of IL-12 of endometriosis:
significant reduction
(Somigliana et al, 1999).
Aboubakr Elnashar

71. 5. Pentoxifylline
Mechanism of action:
1. inhibits phagocytosis and generation of toxic
oxygen species and proteolytic enzymes by
macrophages and granulocytes
2. inhibits both TNF-a production by macrophages,
and the proinflammatory action of TNF-a and IL-1 on
granulocytes
Aboubakr Elnashar

72. 1. Minimal or mild endometriosis
800 mg/day oral for 12 ms
No benefit for fertility
(Balasch et al, 1997).
2. No significant effect on reduction of pain
No evidence of an increase in clinical pregnancy
events
(Cochrane systematic review, 2009).
Aboubakr Elnashar

73. IX. Others
1. Matrix metalprotease (MMP)
Capable of degrading components of the
extracellular matrix.
Regulated by:
tissue inhibitors of matrix metalloproteinase (TIMPs)
Important in:
1. embryo implantation
2. cyclic endometrial breakdown
3. endometriosis
Suppressing the action of secreted MMPs from
human ectopic endometrium with TIMP-1significantly
inhibited the establishment of endometriosis lesions
in a nude mice model (Bruner et al, 1997).
Aboubakr Elnashar

74. 2. Doxycycline (Dox)
Inhibition of matrix metalloproteinase (MMP)
activity.
In a rat:
Regression of endometriosis
(Akkaya et al, 2009).
Aboubakr Elnashar

75. 3. 5-fluorouracil [5-FU]).
Rational:
Common features between endometriotic cells and
tumor cells
Significantly decreased the proliferation of
endometriotic cells in vitro
controlled the growth of both cells from ovarian
endometrioma and deep infiltrating endometriosis.
(Ngô et al, 2010).
Aboubakr Elnashar

76. 4. Thiazolidinediones: (TZDs)
In animal models
reduce endometriotic lesions.
In human:
Endometriosis-related pain.
Rosiglitazone, 4 mg daily, for 6 ms:
improvement in severity of symptoms and pain
Rosiglitazone was well tolerated without impeding
ovulation and without the need for add-back therapy.
(Moravek et al, 2009)
Aboubakr Elnashar

77. Thank you
elnashar53@hotmail.comAboubakr Elnashar