we need to update our knowledge regarding management of endometriosis. Which is better: medications or surgery? let's see what can this talk tell us about

1. 1
Update on endometriosis management

2. 2
Epidemiology
• Endometriosis is a prevalent condition:
5–10% of the female population1,2
Estimated to affect ~176 million worldwide3
Affects women during reproductive years
Younger age at onset predicts more severe disease4
Endometriosis is found in:
50% of women with dysmenorrhea
75% of women with pelvic pain
25% of infertile/subfertile women5,6
1. Mounsey AL et al. Am Fam Phys 2006; 74: 594–600.
2. Eskenazi B and Warner ML. Obstet Gynecol Clin North Am 1997; 24(2): 235–258.
3. Adamson GD et al. J Endometriosis 2010; 2(1): 3–6.
4. Ballweg ML. J Pediatr Adolesc Gynecol 2003; 16(3 Suppl): S21–S26.
5. Child TJ and Tan SL. Drugs 2001; 61(12): 1735–1750.
6. Cramer DW and Missmer SA. Ann N Y Acad Sci 2002; 955: 11–22.

3. 3
Image courtesy of Dr Mauricio S Abrao, Sao Paulo University, Brazil.
DeCherney AH et al. Current Diagnosis & Treatment: Obstetrics & Gynecology. Chapter 56. The McGraw-Hill Companies, Inc. 2013.
Streuli I et al. Expert Opin Emerg Drugs. 2012; 17(1): 83–104.
Streuli I et al. Expert Opin Pharmacother. 2013; 14(3): 291–305.
Types of endometriosis
• Chocolate cysts containing
blood and debris
• May reduce fertility by
reducing number of follicles
and causing local
inflammation
• Superficial endometrial
implants on peritoneal
surface
• Usually detected only with
laparoscopy
• Penetrates peritoneal
surface deeply (>5mm)
Ovarian
endometriosis
Deep infiltrating
endometriosis
Peritoneal
endometriosis

4. 4
Ovary
Bladder
Sites commonly affected in endometriosis
“Endometriosis has been found in almost every tissue type in the body. Symptoms
depend on the site of the disease.”
ESHRE guideline update 2013
Bowel
Ureter
Vagina
Bladder
Ovary
Peritoneum
Pouch of Douglas
Uterosacral ligament
Rare sites:
• Lungs
• Brain
ESHRE Guideline update 2013; Accessed at: http://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline.aspx

5. 5
Pain
• Dysmenorrhea
Most commonly reported symptom
Severe dysmenorrhea is highly suggestive of
endometriosis2
• Dyspareunia
Commonly found in peritoneal (88%) and rectovaginal
(100%) disease3
• Chronic pelvic pain
• No clear relationship exists between pain severity
and extent of disease1
*Figure adapted from Sinaii et al, 2008.
1. Sinaii N et al. Fertil Steril 2008; 89(3): 538–545.
2. Mahmood TA and Templeton A. Hum Reprod 1991; 6(4): 544–549.
3. Gruppo Italiano per lo Studio dell’Endometriosi. Hum Reprod 2001; 16(12): 2668–2671.
Symptoms that led to
diagnosis1*
Percentage*
Dysmenorrhoea 78.7
Pelvic pain 69.4
Dyspareunia 44.9
Bowel upset 36.4
Bowel pain 29.0
Infertility 26.2
Ovarian mass/tumour 19.5
Dysuria 9.9
Other urinary problems 6.2

6. 6
Impact of endometriosis on sexual life is the main factor affecting
quality of life (QoL)
Bernuit D et al. Journal of Endometriosis 2011; 2: 73–85.

7. 7
Diagnostic delay in endometriosis
Average of 7 primary care visits before specialist referral
1. Nnoaham KE et al. Fertil Steril 2011; 96(2): 366–373.
2. Arruda MS et al. Hum Reprod 2003; 18: 756–759.
Average delay ~ 7 years1,2

8. 9
Is surgical diagnosis always necessary?
Is surgical diagnosis always necessary?
Vercellini P et al. Endometriosis: current and future medical therapies.
Best Pract Res Clin Obstet Gynaecol 2008; 22(2): 275–306.
Luciano DE and Luciano AA. Management of endometriosis-related pain: an update.
Womens Health (Lond Engl) 2011; 7(5): 585–590.
“The common belief that a preliminary laparoscopy must always be
performed in order to definitely diagnose the disease should be
challenged, as the nonsurgical diagnosis of endometriosis has been
demonstrated to be highly reliable”
“Although definitive diagnosis of endometriosis requires a
laparoscopy, empiric medical treatment has been advocated to not
only treat symptoms but also to make a presumptive diagnosis of
endometriosis”

9. 10
The goals of endometriosis management
Treat the symptoms
If the symptom is pain, alleviate the pain
If the symptom is infertility, assist fertility
Reduce risk of disease progression
Preserve fertility
Prevent the progression to chronic pain
Keep surgeries to a minimum
Identify patients who will really benefit, and find the best time for surgery
Importance of post-surgical maintenance
SOGC Clinical Practice Guideline. J Obstet Gynecol Can 2010; 32(7 Suppl 2): S1– S32.

10. 11
Medical treatment of endometriosis
The ideal treatment should relieve pain, induce regression of endometriotic lesions, even
in the severe forms, and allow conception3
1. Kappou D et al. Minerva Ginecol 2010; 62(5): 415–432.
2. JOCG guidelines; Accessed at http://sogc.org/wp-
content/uploads/2013/01/gui244CPG1007E.pdf
3. Soares SR et al. Fertil Steril 2012; 98(3): 529–555.
4. Vercellini P et al. Hum Reprod Update 2003; 9(4): 387–396.
Advantages Disadvantages
Cornerstone of endometriosis treatment
Current hormonal options do not allow pregnancy whilst on
treatment4
Suppression of pain symptoms (dysmenorrhea,
dyspareunia and chronic pelvic pain) is part of the lifelong
treatment plan2
Need to be taken long term as recurrence can be expected when
treatment is stopped5
Oral contraceptives and progestins are suggested to
constitute the first-line of medical treatment1
Few treatments are specific for endometriosis and are supported
by few RCTs6
Multiple options exist3
Among currently available treatments a range of undesirable
effects must be taken into consideration such as headaches,4,7
effects on BMD,7 hot flushes,7 androgenic side effects,7 irregular
bleeding patterns,6,7 vaginal dryness4 and delayed return to
fertility8
5. Johnson NP et al. Hum Reprod 2013; 28(6): 1552–1568.
6. Davis L et al. Cochrane Database Syst Rev 2007; 18(3): CD001019.
7. McCormack P et al. Drugs 2010; 70(16): 2073-2088.
8. Klipping C et al. j clin Pharmacol 2012; 52: 1704-1713.
COC, combined oral contraceptive; RCT, randomized control trial; BMD, Bone mineral density
The main concept behind current medical modalities for endometriosis: Suppress estrogen synthesis, interrupt
the cycle of stimulation & bleeding and induce atrophy of ectopic endometrial lesions1

11. Dienogest’s mechanism of action in endometriosis
Growth of endometriotic lesions inhibited via:
Central effects
Inhibition of gonadotropin secretion: hypoestrogenic, hypergestrogenic endocrine environment1,2 with
moderate suppression of circulating estradiol3
Ovarian function: anovulation (2mg dose)3
Local effects (specific activities)
Proliferation: inhibitory effect on proliferation of endometrial-like tissue4–6
Inflammation: impact on endometriosis-related inflammatory mediators7,8
Angiogenesis: supressed angiogenesis in animal models of endometriosis9–11
Modulation of prostaglandin E2 expression12,13
E2, estradiol
1. McCormack PL. Drugs 2010; 70(16): 2073–2088.
2. Sasagawa S et al. Steroids 2008.
3. Klipping C et al. J Clin Pharmacol 2012; 52: 1704–1713.
4. Katsuki Y et al. Eur J Endocrinol 1998; 138: 216–226.
5. Fischer OM et al. Gynecol Obstet Invest 2011; 72: 145–151.
6. Shimizu Y et al. Steroids 2011; 76: 60–67.
7. Horie S et al. Fertil Steril 2005; 83(5): 1530–1535.
8. Mita S et al. Fertil Steril 2011; 96: 1485–1489.
9. May K and Becker CM. Minerva Ginecol 2008; 60: 245–254.
10. Katayama H et al. Hum Reprod 2010; 25: 2851–2858.
11. Nakamura M et al. Eur J Pharmacol 1999; 386: 33–40.
12. Sacco K et al. Gynecol Endocrinol 2012; 28: 134–138.
13. Becker CM and D’Amato RJ. Microvasc Res 2007; 74: 121–130.
12

12. Dienogest effects on ovarian activity
Rapid return of ovulation following treatment cessation (LH peak detected in 69% of
women during follow-up)
Ovulation
Luteinized
unruptured follicle
Active follicle-like
structure
Potential activity
No activity
Observational period 1 (days 1‒36) Observational period 2 (days 37‒72)
0.5mg 1mg 2mg 3mg 0.5mg 1mg 2mg 3mg
100
80
60
40
20
0
Klipping C et al. J Clin Pharmacol 2012; 52: 1704–1713.
Complete inhibition of ovulation
with dienogest 2mg
Percentage
of
women
(%)
n=87
13

13. pg/mL
Endometriotic
lesion growth
and bone loss
are minimized
100
10
Maximal
response
(%)
80
60
40
20
0
0 20 30 40 50 60 70 80 90 100
Atrophy of endometrial lesions Stimulation of endometrial lesions
Substantial bone loss Minimal bone loss
Estradiol concentration (pg/mL)
Endometrial
lesion growth
Bone
turnover
Relevance of estradiol levels in endometriosis
Figure adapted from Barbieri RL. J Reprod Med 1998; 43(3 Suppl): 287–292.
1. Klipping C et al. J Clin Pharmacol 2012; 52: 1704–1713.
Mean estradiol levels with dienogest 2mg
were 39pg/mL1
14
367.1
Postmenopausal women Women of reproductive age (30–400 pg/mL)
Estradiol concentration pmol/L
36.7 73.4 146.8 183.5 220.3 293.7
256.9 330.4
110.1

14. Local effects of dienogest – anti-proliferative effects
• Dienogest reduces endometrial implant volume1,2
1. Katsuki Y et al. Eur J Endocrinol 1998; 138: 216–226.
2. Fischer OM et al. Gynecol Obstet Invest 2011; 72: 145–151.
Control rat at proestrus
stage
Rat given dienogest
Reduction of endometrial implants (cyst walls) in:
Volume
of
endometrial
implants
(mm
3
)
*P<0.05 versus control
(1mg/kg per
day)
Control Dienogest
Volume
of
endometrial
implants
(mm
3
)
15

15. Dienogest group
Control group Ovariectomized group
Local effects of dienogest – anti-angiogenic effects
• Endometrial autograft model (rat): transplantation of endometrial fragments into dorsal skinfold
chamber
• Angiogenesis is an important process supporting the proliferation of endometrium-like tissue in
endometriosis
Katayama H et al. Hum Reprod 2010; 25: 2851–2858.
Dienogest significantly suppressed angiogenesis of
endometrial autografts in rats
0 4 10 14
7
Time (days)
0
100
200
300
400
Microvessel
density
(cm/cm
2
)
Control
Dienogest (1mg/kg/day,
from day of autograft)
P<0.05 for
dienogest
versus
control, at
Control group Ovariectomized group Dienogest group
16

16. Suggested positive feedback cycle in endometriotic lesions
Cyclooxygenase-2 (COX-2)*
Prostaglandin E2 (PGE2) Aromatase
Local Estradiol
Microsomal PGE2 synthase -1
(mPGES-1)*
NF-B
PGE2 synthases
* Abundant expression in human endometrial epithelial cells
Shimizu Y et al. Steroids 2011; 76(1–2): 60–67.
Horie S et al. Fertil Steril 2005; 83(5): 1530–1535.
TNFα
IL-8
E2=estradiol; IL-8=interleukin-8; NF-κB=nuclear factor kappa B; TNFα=tumor necrosis factor α; DNG=dienogest.
Endometriosis
proliferation
Inflammation
DNG directly blocks the proliferation pathway
in two ways:
1. Direct inhibition of NF-κB
2. Direct inhibition of estradiol in the ovary
DNG
DNG
DNG
DNG
Prostaglandin E2 (PGE2)
17

17. *relative to other progestins
Schindler AE, et al. Maturitas 2003; 46(Suppl 1): S7–S16.
Krattenmacher R. Contraception 2000; 62(1): 29–38.
Dienogest has properties that make it particularly suitable in
endometriosis treatment*
18

18. 19
Where is the evidence for efficacy?
Study type Study
duration
Sample size
(n)
Main efficacy
end-points
Publication
Open-label dose-range
finding
24-week 64
Lesion reduction
rAFS score with 2nd look
laparoscopy
Köhler et al. (2010)
Placebo-controlled double-
blind
12-week 198
Pain relief: VAS
Strowitzki et al. (2010)
Open-label extension of
placebo-controlled study
53-week 168 Petraglia et al. (2012)
Open-label leuprolide
acetate- controlled
24-week 186
Strowitzki et al. (2010)
Strowitzki et al. (2012)
rAFS=revised American Fertility Society; VAS=visual analog scale.
Köhler G et al. Int J Gynaecol Obstet 2010; 108: 21–25.
Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010;151:193–198.
Petraglia F et al. Arch Gynecol Obstet 2012; 285(1):167‒173.
Strowitzki T et al. Hum Reprod 2010; 25: 633–641.
Strowitzki T et al. Int J Gynecol Obstet 2012; 117: 228–233.

19. Dienogest 2mg, n=29.
Figure adapted from Köhler G et al. Int J Gynaecol Obstet 2010; 108: 21–25.
Dose-range study: effect on endometriotic lesions
In >80% of patients, no
or only minimal
endometriosis was
detectable at 24 weeks
None
Stage I (minimal)
Stage II (mild)
Stage III (moderate)
Patients
(%)
40
80
100
0
Visanne®
Baseline 24 weeks
20
60
20

20. Dose-range study: effect on endometriotic lesions
Mean
rAFS
score
rAFS, revised American Fertility Society.
Error bars represent mean ±SEM.
Figure adapted from Köhler G et al. Int J Gynaecol Obstet. 2010; 108: 21–25.
11.4
3.6
p<0.001; Visanne® group
Visanne® significantly
reduced mean lesion score
by 7.8 at week 24
Week 0 Week 24
21

21. VAS
(mm)
mean
±
SEM
Weeks of treatment
Placebo
Visanne®
SEM=standard error of the mean, VAS=visual analogue scale.
Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010; 151: 193–198.
Change in VAS score:
-15.1mm
-27.4mm
*
#
*
#p<0.0016
after 4 weeks
*p<0.0001
after 8 and 12
weeks
-12.3mm
Visanne® vs placebo: effect on pain
Visanne® demonstrated superiority over placebo at reducing pain in
endometriosis patients
22

22. 0 8 12 24
16 20
4
10
20
50
70
30
60
40
0
VAS
(mm)
mean
±
SEM
Weeks of treatment Visanne®
LA
Visanne® vs leuprolide acetate: equivalent pain
reduction
VAS, visual analogue scale.
Figure adapted from Strowitzki et al. Hum Reprod 2010; 25(3): 633–641.
Strowitzki et al. Int J Gynecol Obstet 2012; 117(3): 228–233.
• Visanne® has been shown to
be as effective as LA in pain
reduction
• 40% of the total pain reduction
is in the first 4 weeks of
treatment (p<0.0001)
23
Change in VAS score:
Visanne®: -47.5mm
LA: -46.0mm
-1.5mm

23. Dysmenorrhea
24
Visanne® was associated with symptom improvements,
comparable to those observed with LA
*missing, not performed, unknown or inapplicable
Description of severity by % of patients according to Biberoglu & Behrman scoring at screening and after week 24.
Figures adapted from Strowitzki T et al. Int J Gynecol Obstet 2012; 117: 228–233.
Individual
pelvic
symptom
severity
(%
patients)
Week 24
Individual
pelvic
symptom
severity
(%
patients)
100
80
60
40
20
LA
Pelvic pain
Visanne®
Week 24
0
Screening Screening
Individual
pelvic
symptom
severity
(%
patients)
100
80
60
40
20
0
LA
Visanne®
Screening Week 24 Screening Week 24
-72.2%
LA
Dyspareunia
Visanne®
Week 24 Week 24
100
80
60
40
20
0
Screening Screening
-25.6%
-47.9%
-65.6%
-20.8%
-55.5%
Missing* None Moderate Severe
Mild n=186

24. Visanne® vs leuprolide acetate: proportion of
responders after 24 weeks
Absolute change in VAS score Proportional change in VAS score
VAS, visual analogue scale.
p<0.004 for all comparisons.
Strowitzki T et al. Int J Gynecol Obstet 2012; 117: 228–233.
Decreasing strictness of
response threshold
Decreasing strictness of
response threshold
25

25. Visanne® vs leuprolide acetate: QoL improvement
Visanne® was associated with pronounced improvements in specific quality of life
measures
QoL, quality of life; SF-36, health survey.
Strowitzki T et al. Int J Gynecol Obstet 2012; 117: 228–233.
Physical Health Summary Mental Health Summary
26

26. Visanne® adverse event profile
Most frequent adverse drug reactions (ADRs) recorded in Visanne® clinical trials (pooled
analysis)1–4
ADRs were low in frequency, generally mild to moderate in intensity1–4 and usually
subsided within the first 3 months of dienogest treatment1
Adverse event profile is acceptable in light of symptom improvement during treatment
Although weight gain and acne, were reported in some studies, Visanne® was not
generally associated with clinically relevant androgenic effects and has no negative
impact on lipid levels1–5
1. Köhler G et al. Int J Gynaecol Obstet 2010; 108: 21–25.
2. Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010; 151: 193–198.
3. Strowitzki T et al. Hum Reprod 2010; 25: 633–641.
4. Petraglia F et al. Arch Gynecol Obstet 2012; 285(1): 167‒173.
5. Strowitzki T et al. Int J Obstet Gnecol 2012; 117: 228–233.
Patients (%) Patients (%)
Headache 9.0 Depressed mood 5.1
Breast discomfort 5.4 Acne 5.1
27

27. Bleeding patterns with Visanne®: key to acceptance is
appropriate counselling
Bleeding irregularities:
Greater in first 3 months
Become less irregular, frequent and prolonged during longer-term treatment
with dienogest
By 6 months: ~30% amenorrhea
Most patients accept the bleeding, with significant improvement in pain scores
In trials, less than 1% discontinuation due to irregular bleeding
Similar counseling to LNG IUS required
Petraglia F et al. Arch Gynecol Obstet 2012; 285: 167‒173
Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010; 151: 193–198
Strowitzki T et al. Hum Reprod 2010; 25: 633–641.
29

28. Weeks of treatment
%
change
in
BMD
Hypoestrogenic side effects: bone mineral density
Strowitzki T et al. Hum Reprod 2010;25:633–641.
Visanne®
31
Bone mineral density did not decrease during 24 weeks of treatment with Visanne®

29. 35
International consensus on endometriosis
• The World Endometriosis Society brought
together experts from national and international
endometriosis societies
• The views of women with endometriosis were
also represented
Advocates early, proactive management of pelvic
pain
Supports the use of both empirical and adjuvant
medical therapy
Johnson NP et al. Hum Reprod 2013; 28(6): 1552–1568.
Positions Visanne® (dienogest 2mg) as first-
line medical treatment for endometriosis as
well as an adjunct to surgery

30. Japan: long-term dienogest therapy for endometriosis
Recent data from Japan on long-term use of dienogest 2mg in patients
treated up to 36 months
21 patients (endometriosis=13; adenomyosis=8) at the Department of Ob/Gyn, Kanazawa Medical University
Hospital between April 2008 and September 2011
Treated with oral dienogest 2mg/day* for >12 months and up to 36 months
Alleviation of pelvic pain in all patients
Size reduction of ovarian endometrioma (9/10)
Irregular bleeding main side effect
No abnormal changes in the main serum biochemistry
Estradiol remained within the range 43.1~61.2pg/mL
No decrease in bone density
*1mg dienogest twice daily (approved regimen of Dinagest®, manufactured by Mochida Pharmaceutical Co., Ltd.)
Takagi H et al. Kanazawa Medical University. 2012 (Abstract from FIGO, Italy 2012).
36