Andon Hes)antoro, MD,REI

Date of Birth : 27 November 1960

Birth place : Medan

Chairman of Yasmin IVF Clinic, Jakarta
Chairman of Indonesia ReproducHve Endocrinology and FerHlity
AssociaHon (HIFERI)
Chairman of Indonesian ReproducHve Medicine Research and Training
Center (INA-Repromed)
ExecuHve Board Member of Asia Pacic IniHaHve on ReproducHon
ScienHc CommiVee of Indonesia Obstetric and Gynaecology Society
Lecturer of ReproducHve Immunoendocrinology Division, Departement of
Obstetric and Gynecology, Universitas Indonesia, Jakarta

Pain Management in Endometriosis

Andon HesHantoro

ReproducHve Immunoendocrinology Division

Department of Obstetrics and Gynecology
Faculty of Medicine, Universitas Indonesia
Dr. Cipto Mangunkusumo, JAKARTA

Endometriosis is an inammatory condiHon characterized by

lesions of endometrial-like Hssue outside of the uterus and is
associated with pelvic pain and inferHlity (Giudice, 2010)

Sharpe-Timms K. FerHl Steril

2005;84:35-7
Giudice LC. N Engl J Med
2010;362:2389-2398

u Aects about 6-10% of the female populaHon

u Found predominantly in women of reproducHve age

Crosignani P, et al. Hum Reprod Update 2006;12:179-189

Kennedy S, et al. Hum Reprod 2005;20:2698-2704

Pathogenesis of endometriosis

Giudice LC, et al. The Lancet 2004; 364(9447): 1789-1799

Grade
Supercial
peritoneal
Endometrioma
DIE

Type of lesion

Minimal
Mild
Moderate
Severe

Dysmenorrhea
Dyspareunia
Non cyclic pain
Dyschesia
Dysuria
Musculo-
skeletal pain

Type of pain

Endometriosis can aect physical and mental health

Fourquet J, et al. Fertil Steril 2011;96:107112;

EndometrioHc site of lesion that cause of pain

Unmyelinated nerve ber type C in menstrual blood endometriosis paHents

B
!

McKinnon, B., FerHl Steril 2012; 97(2): 373-380

Cakra MA, HesHantoro A. in preparaHon for publicaHon

Biologic mechanism of visceral

pain
1. NocicepHve pain
2. Inammatory-related pain
3. Neuropathic-related pain
4. Psychogenic-related pain

SensiHzaHon for pain

1. Peripheral sensiHzaHon
2. Central sensiHzaHon
3. Estradiol modulaHon on
pain

Surgical Therapy
Aimed at removing endometrial implants and
restoring anatomy
Ecacy reects the skill of the surgeon
Surgical technique to minimize tissue damage
Technique or agents to prevent postoperative adhesion

Recurrence is common: 4050% at 5 years1,2

Presacral neurectomy
DeniHve surgery3
Hysterectomy alone
Hysterectomy with BSO
1. Mounsey AL, Wilgus A, Slawson DC. Am Fam Phys 2006;74:594600
2. Guo SW. Hum Reprod Update 2009;15:441461.
3. Shakiba K et al., Obstet Gynecol 2008;111:1285-92

Recurrence of pain symptoms

Remodeling of CNS
Role of reproducHve tract in reacHvaHng pain
Adhesion
InammaHon
Bleeding

Incomplete removal (that may also increase pain), due to :

Poor technical skill because of dicult lesion locaHons
Lack of recogniHon of variable appearance of lesions
Recurrence of lesions

Several treatment modality in endometriosis

Therapy

Medicinal

Surgical

Aim of therapy

Kind of
medica)on

Side efect

Pain reducer

NSAID

Not cured

Pseudo
pregnancy

ProgesHn
COC

Not cured

Pseudo
menopause

GnRH

Osteoporosis
Hot ushes
Vaginal dryness

Lesion removal

Cut and burn

Early Menopause

Recurrent rate of endometriosis =

a. 8-15 % at rst year
b. 40-50% within 5 years

E2

InammaHon

Growth

StAR = steroidogenic acute regulatory protein

EpigeneHc Changes in EndometrioHc Hssue

ParHal PR resistance in endometrioHc lesion

Tariverdian N, et al. Semin Immunopathol 2007;29:193-210

TherapeuHc window for endometriosis management

Barbieri RL: Hormone treatment of endometriosis: The estrogen

threshold hypothesis. Am J Obstet Gynecol 166:740, 1992

Working site of medicinal treatment

Zeitoun K, Bulun SE. Fertil steril 1999, 72(6): 961-969

ER-beta modulator, Phaleria macrocarpa, DLBS 1442

Wiweko B, et al . Medicinus
2013;26(2):35-38

Dienogest A Unique ProgesHn

OH
Additional
double bond

CH2CN

Cyanomethyl
instead of an
ethinyl group
in the 17
position

O
DNG is a 19-nortestosterone derivative with selective binding to the PR
DNG has properties of 17 hydroxyprogesterone derivatives.

DNG is a progestin that combines the properties of both

19-nortestosterone derivatives and progesterone derivatives
Oettel M, Carol W, Elger W et al. Drugs Today 1995;31:517536.

EndometrioHc Lesion Changes with

Dienogest
Endometriotic lesion in the Douglas pouch from one of the first
patients treated with dienogest 2 mg/day for 24 weeks*

At time of menstruation prior to

dienogest therapy
*Copyright Prof. G. Khler
Note: The vessels indicated by the short arrows are for orientation
rAFS = Revised Classification of the American Fertility Society

Following 24 weeks of
dienogest therapy

Anti-angiogenic Effects in Animal Experiments

" Endometrial autogram model (rat): transplantaHon of endometrial fragments into
dorsal skinfold chamber
" Signicant suppression of angiogenesis of endometrial autogra@s
" Reduced size of microvascular networks
" Reduced microvessel density
" Signicant reducHon in the level of perivascular a-smooth muscle acHn within endometrial
autograms
control
DNG
ovx

Katayama H et al 2010

Anti-inflammatory Effects in Experimental Endometriosis

Katsuki Y et al. Eur J Endocrinol 1998.

0.4
Interleukin-1 (pg/ml)

Experimental endometriosis
induced by auto-transplantation in
rats
Peritoneal fluid:
Amelioration of implant-induced
alterations of immune system
Increased natural killer cell
activity
Decreased macrophage
activity:
reduction of interleukin-1
production in macrophages
(figure)
Effects NOT seen with danazol
and buserelin

*
0.3
0.2

**

0.1
0.0
Intact

Control

Dienogest

*P<0.01 versus intact; **P<0.01 versus control

22

Kadar estradiol selama terapi dienogest

2mg dienogest kept estradiol levels within the suggested therapeuHc
window for endometriosis treatment

Estradiol (pg/ml)

Estradiol (pmol/L)

Pre-treatment
Dienogest 2 mg

Suggested estradiol
therapeutic window2

Pre-treatment (days)
Klipping C, et al. J Clin Pharmacol 2012; 52: 17041713
Barbieri RL. J Reprod Med 1998;43:287292

Treatment (days)

Dienogest 2 mg vs. Leuprolide Acetate:

Efficacy in Reduction of Pain by VAS
70
Dienogest 2 mg

VAS (mm) mean SEM

60

Leuprolide acetate

50
40
30
20
Non-inferior versus
leuprolide acetate (P<0.0001)

10
0

12

16

20

24

Weeks of treatment

Strowitzki T et al. Hum Reprod 2010.

VAS, visual analogue scale.

Dienogest 2 mg Long-term Extension Study: Uterine bleeding paHern

" Maximal bleeding intensity: 90-day periods 1 vs. 4
" Decrease in heavy bleeding and substantial increase in no bleeding

90-day period 1
(n = 164)

Heavy
Normal
Light
Spotting
No bleeding

90-day period 4
(n = 136)

20

40

60

80

100

Proportions of patients (%)

Petraglia F et al. Arch Gynecol Obstet 2012.

Menstrual Period return to normal within

4-6 weeks

Dienogest 2 mg Long-term Extension Study

60

VAS (mm, mean SEM)

50

Placebo

40
Prior-placebo
30

DNG 2 mg/day
Combined group mean

20
Prior-DNG
10
0
Placebo study

Extension study all women DNG 2mg/day

12
Weeks of treatment

Petraglia F et al. Arch Gynecol Obstet 2012.

Treatment-free
65

DNG, dienogest;
EAPP, endometriosis-associated pelvic pain;
VAS, visual analogue scale

90

Dienogest Pooled Data:

Most Commonly Reported Adverse Drug Reactions

MedDRA
Preferred Term

Dienogest 2 mg
n=332 (100%)

Placebo
n=96 (100%)

Leuprolide acetate
n=128 (100%)

Dienogest 4 mg
n=34 (100%)

Events

n (%)

Events

n (%)

Events

n (%)

Events

n (%)

Headache

51

30 (9.0%)

3 (3.1%)

32

27 (21.1%)

32

16 (47.1%)

Acne

32

17 (5.1%)

0 (0.0%)

6 (4.7%)

17

10 (29.4%)

Nausea

14

14 (4.2%)

1 (1.0%)

3 (2.3%)

0 (0.0%)

Weight increased

13

12 (3.6%)

0 (0.0%)

6 (4.7%)

1 (2.9%)

Breast discomfort

15

11 (3.3%)

1 (1.0%)

0 (0.0%)

3 (8.8%)

Depressed mood

17

10 (3.0%)

0 (0.0%)

3 (2.3%)

6 (17.6%)

Flatulence

15

10 (3.0%)

0 (0.0%)

1 (0.8%)

26

13 (38.2%)

Maximum treatment
duration (weeks)

65

12

24

24

Note: Menstrual bleeding paHerns were assessed systemaHcally using paHent diaries. Based on diary data, changes in menstrual bleeding
paVerns were common, but were only occasionally reported as adverse event by the paHents
Khler G et al. Int J Gynaecol Obstet 2010;
Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010;
Strowitzki T et al. Hum Reprod 2010;
Petraglia F et al. Arch Gynecol Obstet 2012.

MedDRA, Medical DicHonary for Regulatory AcHviHes.

GnRH agonist and add-back therapy

Surrey ES, et al. Fertil Steril 1999; 71(3): 420-424

Zou S, et al. Int J Clin Exp Med 2013;6(1):67-73

The frequencies of hot ashes and uterine bleeding with Hme. (A) Hot ashes. (B) Uterine bleeding. PaHents received daily add-back therapy beginning at the same
Hme as the second GnRHa injecHon (second month). The frequency of hot ashes was high in the rst month amer the iniHaHon of add-back therapy, but decreased
markedly in the second month in both groups. The incidence of hot ashes each month was not signicantly dierent between the two groups. The incidence of
uterine bleeding decreased with Hme and was less common in group B than group A paHents from the second month amer the start of add-back therapy; however, this
dierence was not staHsHcally signicant.

The ecacy and tolerability of short-term low-dose estrogen-only add-back therapy during post-operaHve GnRH agonist treatment for endometriosis
Kim, Na Young, European Journal of Obstetrics & Gynecology and ReproducHve Biology, Volume 154, Issue 1, 85-89

Copyright 2010 Elsevier Ireland Ltd

First line empirical

therapy :
1. Dienogest
2. GnRH agonist
3. Etonogestrel
implant

Konsensus tatalaksana nyeri pada endometriosis. HIFERI 2013

Conclusion
Endometriosis is a chronic inammatory disease
Estrogen play role in pathogenesis and symptom
associated endometriosis
De-methylaHon of ER-beta and PR resistance are
associated with pain and recurrence of
endometriosis
Treatment modality for endometriosis should be
focused on ER-beta and aromatase modulaHon