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Aboubakr Elnashar
Benha university hospital
Emerging treatment of endometriosis
Aboubakr Elnashar
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Introduction Endometriosis:
estrogen-dependent disorder
substantial morbidity:
pelvic pain
infertility.
Multiple operations
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Current treatment:
Ovarian suppressive agents.
Oral contraceptive
Progestins
GnRha
Androgenic agents
Surgery
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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.
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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
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LNG-IUD
GnRHan
Aromatase inhibitors
SERM
Progesterone antagonist
SPRM
Angiogenesis inhibitors
Immunomodulatory drugs.
Others
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Drugs Group
Mirena 1. LNG-IUD
Cetrorelix 2. GnRHan
Anastrazole (Arimidex),
Letrozole (Femara)
3. Aromatase
inhibitors
Tamoxifen, Raloxifene 4. SERM
Mifepristone, Onopristone 5. Progesterone
antagonist
Asoprisnil 6. 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
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I. Levonorgestrel-releasing
intrauterine device (LNG-IUD) Oral progestogens:
poor compliance
systemic SE.
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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
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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.
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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)
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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]
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5. Postoperative use of the LNG-IUD
reduces the recurrence of painful periods (Cochrane systematic review, 2006) .
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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.
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II. GnRH antagonists GnRHa:
↑LH & FSH: ↑E2: ↑pelvic pain: ↓quality of life (Miller , etal, 2000)
limited to the first 5 to 10 d.
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Mechanism of action:
GnRHan
immediately block GnRH effects
competing with endogenous GnRH for pituitary
binding sites
suppress LH secretion in a dose-dependent
manner.
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Uses
Endometriosis
Leiomyoma
Breast cancer
Premenstrual syndrome
PCOS
Superovulation in IVF
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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).
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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.
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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.
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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}
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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.
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Absorption & metabolism
• Letrozole:
Rapidly& completely absorbed from GIT.
Elimination half-life: 2 d
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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
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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.
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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).
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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)
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II. Premenopause:
AI alone may induce ovarian folliculogenesis:
AIs are combined with progestin,
COC, or
GnRHa
{prevent reflex increments in LH and FSH}
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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).
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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).
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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)
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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).
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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)
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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)
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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).
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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)
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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)
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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).
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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).
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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.
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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
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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
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Uses:
1. Prevention osteoporotic fractures in
postmenopause
2. Prevention of breast cancer.
3. Endometriosis (SERM directed towards β
subunits) {antiestrogenic effect on endometrial
tissue}.
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Studies:
In mice:
SERM directed towards the β –subunit: resolved
endometriosis in 40 – 75%
(Harris et al, 2005). In human:
No studies
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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
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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.
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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)
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Conclusion:
Further large RCT should be performed
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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
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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).
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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).
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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
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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}
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Rationale:
Inhibition of proangiogenic factors
e.g. VEGF and MMPs
Angiostatic drugs
TNP470
Endostatin
Anginex
Rapamycin
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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).
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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).
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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)
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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).
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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).
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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.
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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.
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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.
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VIII. Immunomodulators Rationale:
Altered immune function plays a crucial role in the
genesis and development of endometriosis.
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Mechanism of action:
Decreasing the inflammatory response to disease.
Includes
Loxoribine
IFN- α 2 β
TNF- α inhibitors.
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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).
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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).
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3. TNF-α inhibitors
Mechanism of action:
decreasing production or release of TNF- α from
macrophages:
preventing disease progression
regression of early stage disease.
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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).
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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
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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).
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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
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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).
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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
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2. Doxycycline (Dox)
Inhibition of matrix metalloproteinase (MMP)
activity.
In a rat:
Regression of endometriosis (Akkaya et al, 2009).
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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).
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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)
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