Aboubakr Elnashar

Benha university hospital

Emerging treatment of endometriosis

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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

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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Thank you

elnashar53@hotmail.com Aboubakr Elnashar