MANAGEMENT OF REFRACTORY ENDOMETRIOSISfile.lookus.net/tajev/sunumlar/Serdar Bulun.pdf · (339)...

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Serdar Bulun, MD JJ Sciarra Professor and Chair Department of Ob/Gyn Northwestern University (339) MANAGEMENT OF REFRACTORY ENDOMETRIOSIS

Transcript of MANAGEMENT OF REFRACTORY ENDOMETRIOSISfile.lookus.net/tajev/sunumlar/Serdar Bulun.pdf · (339)...

Page 1: MANAGEMENT OF REFRACTORY ENDOMETRIOSISfile.lookus.net/tajev/sunumlar/Serdar Bulun.pdf · (339) MANAGEMENT OF REFRACTORY ENDOMETRIOSIS ENDOMETRIOSIS Teenager: severe dysmenorrhea often

Serdar Bulun, MD

JJ Sciarra Professor and Chair

Department of Ob/Gyn

Northwestern University

(339) MANAGEMENT OF

REFRACTORY ENDOMETRIOSIS

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ENDOMETRIOSIS Teenager: severe dysmenorrhea often starting at menarche

20s: chronic pelvic pain (between periods)

Late 20s, early 30s: first laparoscopy and diagnosis, commonly stage 1-2

30s-40s: multiple and usually ineffective follow-up laparoscopies,

experimental medications

OCs

OCs, Depot Progestin, Depot GnRH agonist

Depot GnRH agonist

TH-BSO

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PERITONEAL ENDOMETRIOSIS

OVARIAN ENDOMETRIOMA RECTOVAGINAL NODULE

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HYPOTHALAMUS

PITUITARY

OVARY - OVULATION

E2 P

GnRH

FSH LHE2P

+-

+-

ENDOMETRIUM ENDOMETRIOSIS

GnRH analogue

Oral Contraceptive

High-dose progestin

menses

ERb

PR

E2 Chol

survival

growth

inflammation

PAINinflammation

Aromatase

InhibitorPERITONEUM

nociceptor

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Current Surgery: Laparoscopic

Resection/Ablation

• Allows assessment of extent of disease

• Should be performed by an experienced surgeon

• Resection is superior to vaporization or fulguration

• En bloc stripping of cul-de-sac peritoneum may reveal microscopic disease

• Rectovaginal dissection should be considered especially for dyspareunia

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Current Medical Treatment Options

• Oral contraceptives (OCs); continuous use

• Progestins (Depot-MPA; oral NEA)

• IUD - levonorgestrel

• GnRH agonists (monthly injections) only (up to 3 months)

• GnRH agonist + NEA (2.5 mg or 5 mg daily; >3 months)

• Danazol

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Response Rates for Pain Relief

• In the absence of a RV nodule or endometrioma,

response rates to laparoscopic surgery and medical

treatment in treatment-naïve patients are similar : 90-

100%. Pain recurs in ~90% of patients within 2 to 5

year after discontinuation.

• Response rate to surgery or medication decreases in

previously treated patient population. Average

response rate: ~50%. Pain recurs in most patients

within 6 months to 2 years after discontinuation.

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Refractory Endometriosis

• Endometriosis previously diagnosed by

laparoscopy

• Pain not responding to recent medical and

surgical treatment attempts (ovarian

suppression by OC, progestin or GnRHa and

laparoscopic ablation)

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Treatment Options for Refractory Pain

1. Medical Treatment

2. Laparoscopic resection/ablation

3. TH-BSO

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Ineffective Treatments for Refractory Endometriosis

• Endometrial ablation

• Hysterectomy without oophorectomy

• LUNA

• Progestin IUDs??

• Presacral neurectomy

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Experimental Treatments

• Aromatase inhibitors (letrozole 2.5mg/d or anastrozole 1mg/d)

• AI only in post menopausal women

• AI + OC or AI + NEA in premenopausal women

• RU486 5mg/d, ulipristal acetate 5 or 10 mg/d

• Other selective progesterone receptor modulators (SPRMs) or antiprogestins

• Oral GnRH antagonists

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Hypothalamus

Pituitary FSHLH

Postmenopausal on AI

Ovary

Peripheral Tissues

Endometriosis

Aromatase

PeripheralAromatase

No FollicularAromatase

AI

Aromatase

Premenopausal on AI

Aromatase

Follicle Development

FSHLH

AromataseE2

PeripheralAromatase

AI

Aromatase

Takayama et al, Fertil Steril, 1998; Ailawadi et al, Fertil Steril, 2004; Soysal et al, Human Reproduction, 2004; Amsterdam et al, Fertil Steril, 2005; Abushahin et al, Ferti Steril, 2011

Premenopausal on AI

+ OC or P

Aromatase

FSHLH

Aromatase

PeripheralAromatase

AI

OC P

GnRHa

AromataseE2

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Pre- and Post-treatment Pain Scores (n=10)

0

5

10

0

5

10

Baseline post-treatmentp=0.0028

PREMENOPAUSAL WOMEN TREATED WITH LETROZOLE AND NORETHINDRONE ACETATE

Ailawadi, et al, Fertil Steril, 2004

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Anastrozole and Alesse® for Refractory Endometriosis and Chronic Pelvic Pain

Months

Amsterdam, LA, et. al. Fertil Steril 2005;84:300-4.

N=15

Pain

Sco

re

Baseline 1 2 3 4 5 6

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Soysal et al, Human Reprod, 2004

0 6 12 18 24

Time to recurrence (months)

10

20

30

40

50

60

70

80

90

100%

rec

urr

ence

-fre

ep

atie

nts

GnRHa+anastrozole

GnRHa only

54.7%

10.4%

randomized trial, n=80

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PROGESTERONE RECEPTOR MODULATORS

AGONIST ANTAGONIST

mixedagonist/antagonists

J867

CDB4124 (UPA)RU486

CDB2924MPA

R5020PROGESTERONE

NEA

PROGESTINS(ProgesteroneAgonists)

progestogenic activity

ZK98299

ProgesteroneAntagonists

ANTIPROGESTINS

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ANTIPROGESTINS

• Amenorrhea in majority of patients (anovulation and

direct endometrial effects)

• Pain relief possibly better than progestins

• Cystic glandular dilatation often associated with both

admixed estrogen (mitotic) and progestin (secretory)

epithelial effects

• Endometrial thickness is related to cystic glandular

dilatation Hawkins-Bressler, et al, JRM, 2018

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UNDIAGNOSED ENDOMETRIOSIS(dysmenorrhea, dyspareunia, chronic pain)

Pelvic Exam

Vaginal Ultrasound

Endometrioma

Rectovaginal nodule

Laparoscopic resection

by an experienced surgeon

No endometrioma

or RV nodule

Diagnostic laparoscopy

resection by an experienced

surgeon

Challenge by

Continuous OC

Long-term continuous OC

Unsatisfactory

response

Long-term continuous OC

Add Aromatase Inhibitor to OC

Repeat Surgery or Lupron depot or UPA

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ESTABLISHED ENDOMETRIOSIS(RECURRENT SYMPTOMS)

Pelvic Exam

Vaginal Ultrasound

Endometrioma

Rectovaginal nodule

Laparoscopic resection

by an experienced surgeon

No endometrioma

or RV nodule

Continuous OC

Long-term continuous OC

Unsatisfactory

response

Add Aromatase Inhibitor to OC

Repeat Surgery or Lupron depot or UPA

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SPECULATIONS

The symptomatology of endometriosis represents a spectrum of a broad

chronic disease involving a basic pathology in pelvic tissues including the

endometrium.

Sampson’s hypothesis explains the majority of the cases of peritoneal

endometriosis, rectovaginal nodule and ovarian endometrioma.

The disease becomes initially manifest with the so-called primary

dysmenorrhea in teenage years and advances to laparoscopically visible

endometriosis.

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MORE SPECULATIONS

In epigenetically susceptible women, the risk of development of

endometriosis or its symptoms increases in direct proportion with the

number of ovulatory menses.

Long-term suppression of menses with OCs in young women with primary

dysmenorrhea should decrease the risk of symptomatic endometriosis.

It would be clinically beneficial to view pelvic symptoms associated with

endometriosis as a spectrum and broaden its definition to a “systemic

disease characterized with estrogen-induced inflammation, pelvic pain

responsive to hormonal suppression or surgical resection of endometriotic

tissue.”

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UNMET NEEDS: ENDOMETRIOSIS

In patients with chronic pelvic pain and endometriosis, a useful diagnostic

test geared towards response to a specific treatment is needed. On the

other hand, a test that will simply replace laparoscopic visualization will

not likely be clinically useful because this phenotype is extremely

prevalent and nonspecific.

Endometriosis-associated infertility is poorly understood, and there are no

specific medical treatments.

The key challenge is to treat endometriosis-associated pelvic pain not

responding to currently available modalities. At least half of the patients

with a diagnosis of endometriosis are not satisfied with the available

treatments.

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Retrograde Menstruation

Altered Nuclear Receptor and Co-

activators

Inflammatory Stress

MethylationDefects

Elevated cytokines, IL-1B,

TNFα, IL-8, COX-2 and PGE2

Increased macrophage

recruitment to lesions.

Elevated ERβ, SF1, decreased

ERα, PR, RARs, SRC-1.

HOXA10, ERβ, SF1, PR, AROM

How do inflammatory

signals and nuclear

receptor alterations

contribute to disease in

endometriosis?

Molecular Aberrations in

Endometriosis