Recent advances in endometriosis

1. RECENT ADVANCES IN ENDOMETRIOSIS
Dr Nupur Gupta, Senior Consultant
Department of Obstetrics & Gynecology

2. BASICS

3. What is Endometriosis?
 It is a Chronic estrogen-dependent disease
(presence of endometrial-like tissue outside the uterus,
which induces a chronic, inflammatory reaction)
Symptoms - painful symptoms and/or infertility, or no
symptoms at all
2 to 10% in the general female population and up to 50% in
infertile women.

4. 1 in 10 women have endometriosis
during their reproductive years
Crosignani P et al. Hum Reprod Update 2006; 12(2): 179–189.

5. Endometriosis – Prevalence
Younger age at onset predicts more severe disease!
1. Ballweg ML et al. J Pediatr Adolesc Gynecol 2003; 2. Child TJ et al. Drugs 2001;
3. Cramer DW et al. Ann N Y Acad Sci 2002; 4. Bendigeri T et al. Indian Pract. 2015.
176 million women suffer from Endometriosis globally;
26 million in India alone!!

6. Endometriosis affects women during the
prime years of their lives
Nnoaham KE et al. Fertil Steril 2011; 96: 366–373.

7. Common Sites
ESHRE Guideline update 2013; Accessed at: http://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline.aspx

8. Peritoneal Endometriosis
• Superficial Lesions (black/brown spots, white
discoloration, red flame like streaks, small red
blisters or blue yellow patches)
• Cant be diagnosed on USG
• Only seen on laparoscopy

9. Ovarian Endometriosis
• Chocolate cyst or endometrioma
• As large as 15 cm
• Marker of extensive disease
• Cyst>3cm with pelvic pain should be excised

10. Deeply Infiltrating Endometriosis
• >5mm penetration under
endometrial surface
• Involves bladder, bowel,
vagina & uterosacrals
• Difficult surgery

11. 3 Ds
• Diffuse/chronic pelvic pain
• Dysmenorrhoea
• Dyspareunia
• Others – dysuria, dyschezia, lower abd or
back pain or GI upset

12. What causes endometriosis associated pain?
• Growth factors/cytokines
• Bleeding from endometriotic implants
• Nerve irritation by endometriotic implants

13. Diagnostic Delay in Endometriosis!
Average of 7 primary care visits before specialist referral!!!
Nnoaham KE et al. Fertil Steril 2011; 96(2): 366–373.
Arruda MS et al. Hum Reprod 2003; 18: 756–759.

14. Risk Factors
High Risk
• Increased exposure to
endometrial tissue (short
cycles, heavy or prolonged
bleeding, early menarche,
late menopause)
• Family history
• Low level of exercise
Low Risk
• High Parity
• Breastfeeding

15. Impacts Women & Society
• Impact on sexual life
• Impact on relationships & family
• Performance at school/university/work
Medical Cost
Surgical Cost
Caregiver cost
Absenteeism
Reduced productivity at work

16. Role of Estrogen in Endometriosis
Endometriotic Lesions have
• High levels of aromatase enzyme
• Decreased levels of 17Beta Hyroxysteroid
Dehydrogenase

17. Medical management Options
• First Line (CHCs, Progestin only)
• Second Line (GnRH agonist, LNG IUS)
• Others (Danazol, Aromatase inhibitors, NSAIDs)

18. Use of COCs in Endometriosis

19. Goals of Management
• Symptomatic treatment
• Avoid delay in diagnosis
• Reduce unnecessary surgeries & prevent resurgery

20. How does medical management help?
• Suppresses estrogen synthesis
• Interrupts the cycle of stimulation & bleeding
• Induces atrophy of ectopic endometriotic lesions
Ideal Treatment - relieves pain,
induces atrophy of endometriotic lesions
& not alter fertility

21. Are Progestins useful & how?
Lazzeri L et al. J Endometriosis 2010; 2: 169–181.
Kappou D et al. Minerva Ginecol 2010; 62: 415–432.
CrosignanI P et al. Hum Reprod Update 2006; 12: 179–189.
Reduction of serum
estrogen levels
Immunomodulatory
effect
Anti-inflammatory
effect
Decidualization + atrophy
of endometrial tissue
Inhibition of matrix
metalloproteinases
Anti-angiogenic effect
Progestins

22. Role of Estrogen in Endometriosis
Estrogens are responsible for proliferation of endometriotic tissue!

23. What is Dienogest?
19-nortestosterone derivatives
• Strong progestational effect
on endometrium
• Relatively short plasma half-
life of 9–11 hours
• High oral bioavailability >90%
Progesterone derivatives
• Good tolerability
• Anti-androgenic effects
• Relatively moderate
inhibition of Gn secretion
• Mainly peripheral action
Sasagawa S et al. Steroids 2008; 73: 222–231.
Ruan X et al. Maturitas 2012; 71: 337–344.

24. Dienogest vs other Progestins
Schindler AE, et al. Maturitas 2003; 46(Suppl 1): S7–S16.
Krattenmacher R. Contraception 2000; 62(1): 29–38.

25. How does dienogest act?
Hypothalamus
Pituitary gland
Gonadotropins
Estrogen and progesterone
Negative feedback
Uterus
Ovary
Estrogen
Progesterone
Endometrium
 Central effects (HPO Axis)
- Inhibition of Gn secretion: hypoestrogenic
-- Ovarian function: anovulation
 Local Effects (endometrium)
- Anti-Proliferative
- Anti-Inflammatory
- Anti-Angiogenenic

26. Pharmacokinetics
• Rapidly & completely absorbed after oral administration
• Peak at 1.5 hours (47 ng/ml)
• 91% bioavailability
• 9 to 10 hours half life
• Not related to food
• Does not bind to SHBG or CBG

27. ESHRE & WES Consensus
ESHRE 2013 guidelines;
Johnson NP et al. Hum Reprod 2013; 28: 1552–1568.
Clinicians are recommended to use
progestagens … as one of the options, to
reduce endometriosis-associated pain
Progestins with a proven effect in RCTs
and with a specific indication for the
treatment of endometriosis … can also
be considered as first-line treatments

28. Research Trials

29. Efficacy & safety of Dienogest for 65 weeks

30. Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010; 151: 193–198;
Petraglia F et al. Arch Gynecol Obstet 2012; 285: 167‒173.
Dienogest
2 mg/day
n=102
Placebo
n=96
Double-blind
placebo-controlled study
Week 12Week 0
12 weeks
Open-label extension
Treatment-free
follow-up
Week 65 Week 90
Dienogest
2 mg/day
n=168
53 weeks 24 weeks
n=34
Inclusion criteria:
Women aged 18–45 years with EAPP
Histologically proven endometriosis stages I to IV (rASRM)
Minimum VAS 30mm at baseline
Long-term DNG (pelvic pain) 2012

31. VAS(mm)
mean±SEM
DNG after 12 weeks: VAS score
Dienogest n=102; placebo n=96
Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010; 151: 193–198.
0
20
40
60
80
0 4 8 12
Dienogest 2 mg Placebo
Weeks of treatment
*
#
*
#p<0.0016
after 4 weeks
*p<0.0001
after 8
and 12 weeks
Change in VAS score:
–15.1mm
–27.4mm
–12.3mm

32. VAS score 2 years follow up
Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010; 151: 193–198;
Petraglia F et al. Arch Gynecol Obstet 2012; 285: 167‒173.
0
10
20
30
40
50
60
VAS(mm)mean±SEM
12 65 90
PLACEBO STUDY EXTENSION STUDY TREATMENT-FREE
Weeks of treatment
Placebo
DNG 2 mg/day
DNG 2 mg
(switched from placebo)
DNG 2 mg
(continued on DNG)
Efficacy shown over 15 months

33. Favourable safety profile@ 2yr follow up
 Adverse events were reported in 17/168 women (16.1%)
Breast discomfort (4.2%)
Nausea (3.0%)
Irritability (2.4%)
 SE were mild to moderate in most cases (92.5%), with low rates of
discontinuation (8.8%)
 Reduction in pelvic pain (decrease in size of endometriotic lesions) &
bleeding irregularities persisted for at least 24 weeks after treatment
cessation
Strowitzki T et al. Eur J Obstet Gynecol Reprod Biol 2010; 151: 193–198;
Petraglia F et al. Arch Gynecol Obstet 2012; 285:167‒173.

34. What should be the lowest effective
dose for Dienogest?
Kohler et al IJGO 2009

35. First laparoscopy
for
diagnosis/rASRM
score at wk 0
Week 24Week 0
Dienogest 1 mg/day*
n=4
Dienogest 2 mg/day
n=29
Dienogest 4 mg/day
n=35
R
Dose-ranging study
Köhler G et al. Int J Gynaecol Obstet 2010; 108: 21–25.
Inclusion criteria:
Women from menarche to menopause
Endometriosis stages I to III (rASRM) confirmed by laparoscopy & biopsy
Second laparoscopy
for rASRM score after
24 wks of treatment
(2mg vs 4 mg x 24 weeks)

36. Significant reduction in
mean VAS score by 7.8 at
Week 24
Köhler G et al. Int J Gynaecol Obstet 2010; 108: 21–25.
p<0.001;
Dienogest 2 mg group
11.4
3.6
0
5
10
15
Week 0 Week 24
MeanrASRMscore
VAS score

37. DNG 2mg: the lowest effective dose
 Alleviated endometriosis-related symptoms
(dyspareunia (51% to 7%), dysmenorrhea, diffuse
pelvic pain, and premenstrual pain)
 Adverse events were mostly mild to moderate in
intensity & associated with low rates of
discontinuation
 No notable effects on lipid, carbohydrate & liver
metabolism
Köhler G et al. Int J Gynaecol Obstet 2010; 108: 21–25.

38. Dienogest vs Leuprolide acetate
Strowitzki T

39. Dienogest vs leuprolide acetate
Strowitzki T et al. Hum Reprod 2010; 25: 633–641.
Week 24Week 0
Dienogest 2 mg
n=124
LA 3.75 mg IM/4 weeks
n=128
Randomization
Inclusion criteria:
Women aged 18–45 years with EAPP
With or without infertility
Histologically confirmed endometriosis stages I to IV
(rASRM)

40. Dienogest 2 mg vs leuprolide acetate
Dienogest n=124; leuprolide acetate n=128
Strowitzki T et al. Hum Reprod 2010; 25: 633–641
Strowitzki T et al. Int J Gynecol Obstet 2012; 117: 228–233.
Weeks of treatment
0
10
20
30
40
50
60
70
0 4 8 12 16 20 24
VAS(mm)mean±SEM
Endometriosis-related pain during study period
Non-inferiority of dienogest 2 mg
relative
to leuprolide acetate (p<0.0001)
~40% pain reduction was achieved in the first 4 weeks of treatment with dienogest 2 mg
24-week, open-label, randomized, multicenter study
Dienogest 2 mg
LA

41. Bone mineral density & hot flashes
Strowitzki T et al. Hum Reprod 2010; 25: 633–641
%changeinBMD*
-6
-5
-4
-3
-2
-1
0
1
P=0.0003
at 24 weeks
Weeks of treatment
0 24
0
1
2
3
4
5
6
7
1 4 8 12 16 20 24
Dienogest 2 mg
LA
Weeks of treatment
Hotflushes(daysperweek)*

42. Missing* None Moderate
Symptomatic relief
Dienogest 2 mg n=124; LA n=128;
Strowitzki T et al. Int J Gynecol Obstet 2012; 117: 228–233.
SevereMild
0%
20%
40%
60%
80%
100%
Screening Week 24 Screening Week 24
Severity(%patients)
Dienogest 2 mg LA
0%
20%
40%
60%
80%
100%
Screening Week 24 Screening Week 24
Severity(%patients)
Dienogest 2 mg LA
0%
20%
40%
60%
80%
100%
Screening Week 24 Screening Week 24
Severity(%patients)
Dienogest 2 mg LA
Dysmenorrhea Pelvic painDyspareunia
By Week 24 in both treatment arms, 53% of the women were free from total pelvic symptoms, no women
reported severe dysmenorrhea and 70% of women were free from dyspareunia

43. Specific quality-of-life measures @24 weeks
Strowitzki T et al. Int J Gynecol Obstet 2012; 117: 228–233.
0
20
40
60
80
100
Total Physical
functioning
scale
Role
physical
scale
Bodily
pain
scale
General
health
scale
Meanpercentage
improvementinSF-36
score
Physical Health Summary
0
5
10
15
20
25
30
35
Total Vitality
scale
Social
functioning
scale
Role-
emotional
scale
Mental
health
scale
Mental Health Summary
Dienogest 2 mg Leuprolide acetate

44.  No women had severe symptoms & only 5% had
moderate symptoms
 No clinically relevant impact on standard hematology,
blood chemistry, lipids & liver enzymes
 favourable safety profile
 Lower incidence of hypoestrogenic effects & limited
BMD changes compared with GnRH agonists
Endometriosis-related pain

45. DNG vs Goserelin
Takaesu Y et al JOGR 2016

46. DNG is as effective as GnRH agonist (Goserelin)
in reducing post-operative recurrence!
0
10
20
30
40
50
60
70
80
Dienogest Group (n
= 54)
Goserelin Group (n
= 51)
No Treatment
Group (n = 79)
Patients with Recurrence
Total number of Patients
Comparison of the recurrence rates in the dienogest, goserelin & non-treatment groups
* Recurrence rate between Dienogest group and No-treatment group: p < 0.05
Takaesu T et al. J. Obstet. Gynaecol. Res. Sept 2016; 42(9): 1152–58

47. Recurrence within 24 months
• 4 cases in the dienogest group (n = 54, 7.4%)
• 8 cases in the goserelin group (n = 51, 15.7%)
• 17 cases in the non-treatment group (n = 79, 21.5%)
No significant difference was observed in the postoperative recurrence
rate between the DNG & goserelin groups, the goserelin group & non-
treatment group; however, a significant difference was found in the
recurrence rate between the DNG group & the non-treatment group
(P = 0.027)

48. DNG after laparoscopic surgery
Adachi et al. Gynecological Endocrinology 2016

49. • To assess the effect of DNG on recurrence of ovarian endometriomas
(>2cm)and severity of pain after laparoscopic surgery
• Retrospective study of 81 patients, 6 months follow up
Adachi et al. Gynecological Endocrinology 2016
VAS Scores at baseline and 6, 12, 18 & 24 months
VAS Score

50. Recurrence (Pain & endometrioma)
DNG group – no recurrence
Expectant Group -16.5% at 12 months and
24.0% at 24 months

51. DNG prevents postoperative endometrioma
recurrence
Ota et al. Journal of Endometriosis & Pelvic Pain
Disorders 2015

52. DNG vs No Medicine
• N=568 (151 DNG) (417 no medicine)
• Retrospective cohort study; 5 years
• Ovarian endometrioma excision
• TVS every 6 months to check size
• Cumulative recurrence rate (4% in DNG Vs 69% in no
medication group)
• Reoperation (none in DNG & 3.6% in no medicine group)

53. Ota et al. JEPPD 2015; 7(2): 63-67
• No abnormality in serum lipid concentrations or liver
enzymes during the 5 years.
• Decrease in BMD > 4% was observed in 4.6% (7/151)
of the patients only (not clinically significant)
• Long-term administration reduces recurrence after
excision of endometrioma

54. Visanne Study to Assess Safety in Adolescents
(VISADO)

55. Week 0
Dienogest 2 mg/d
n=111
Open-label
enrolment:
Austria, Czech
Republic, France,
Finland, Germany
and Spain
52 weeks
EAPP assessed using VAS once every 4 weeks
BMD measurement in a
subgroup of patients with
decreased BMD at EoT
BMD measurement†
End of Treatment
BMD
measurement
Study design
Inclusion criteria:
Females aged 12–<18 years
Surgically confirmed or clinically suspected endometriosis
6-month follow up

56. Endometriosis associated pelvic pain
Ebert AD et al. J Pediatr Adolesc Gynecol. 2017, doi: 10.1016/j.jpag.2017.01.014..
64.3
36.8
25.9
23.6
19.3
16.7 15.5 18 16 16.5
11.9 10 9
12.1
0
10
20
30
40
50
60
70
80
90
100
4 8 12 16 20 24 28 32 36 40 44 48 52Base-
line
Weeks
Full analysis set = 111 patients*
VAS(mm)
mean±SEM
By week 4, the VAS score decreased to 36.8
mm and by week 48 to the lowest mean value

57. Asymptomatic patients increases from
baseline to end of treatment
Ebert AD et al. J Pediatr Adolesc Gynecol. 2017
9.1
3.6
9.1
71.2
78.8
23.1
0
20
40
60
80
100
Pelvic Pain Dysmenorrhea Dyspareunia*
Baseline
EoT
Percentageofpatients
52weeks/EoT)

58. Patient satisfaction score (VISADO)
•Patient assessment by Clinical Global Impression scale
Ebert AD et al. J Pediatr Adolesc Gynecol. 2017, doi: 10.1016/j.jpag.2017.01.014.
1 1.9 1.9
1.9 05.8
4.9
15.4
8.7
46.2
36.9
27.9
47.6
0%
20%
40%
60%
80%
100%
Week 12
(n=104)
Week 52/EoT
(n=103)
very much satisfied
much satisfied
minimally satisfied
Neither satisfied nor dissatisfied
minimally dissatisfied
Much dissatisfied
very much dissatisfied
Assessment
70%
84%
Percentofpatients

59. Conclusion (VISADO)
 Mean lumbar spine BMD decrease (L2–L4) of 1.2% in
adolescents after 1 year of treatment; partial recovery
after cessation of treatment
 Endometriosis-associated pain reduced in adolescents
from a baseline value of 64.3 mm to a mean value of 9.0
mm on the VAS after 48 weeks
Ebert AD et al. J Pediatr Adolesc Gynecol. 2017

60. Extragenital Endometriosis
Harada et al 2011 Gynecol Endocrinol
•Rectosigmoidal
•Bladder

61. Study Type Duration Sample size Endpoint Author
Open label
dose ranging
study
24 weeks 64 Lesion redn on
laparoscopy
Kohler 2010
Placebo
controlled
double blind
12 weeks 198 Pain relief Strowitzki 2010
Open Label
extension of
placebo
controlled
study
53 weeks 168 Pain relief Petralgia 2012
Open label
study DNG vs
LA
24 weeks 252 Pain relief Strowitzki
2010, 2012

62. Study Type Duration Sample size Endpoint Author
VISADO 52weeks 111 Pain relief &
BMD
Ebert 2017
Placebo
controlled
randomised
double blind
multicenter in
Chinese
(ViBriC)
Blinded phase
24 weeks,
Open label
phase 28
weeks
250 Pain relief Dong 2016

63. Bleeding pattern with DNG
• Initially – desynchronised bleeding pattern
• Later – progressive reduction in bleeding days
followed by amenorrhoea
Key to acceptance is appropriate
counseling

64. Adverse Events with DNG
Most common side effects %
Headache 9%
Breast discomfort 5.4%
Depressed mood 5.1%
Acne 5.1%

65. Return to fertility with DNG
Menses resume
• Within 4 to 6 weeks (Petralgia et al)
• From 29 days-2 months in 97% (Momeda et al)

66. The Estrogen Threshold Theory
pg/mL
Optimum
Range where
Endometriotic
lesion growth
and bone loss
are minimized
100
10
Maximalresponse(%)
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
Endometrial
lesion growth
Bone
turnover
Reduction in estradiol levels below this curve results in a
negative impact on bone turn-over – loss of bone mineral
density & risk of osteoporosis!
Increase in estradiol levels beyond this curve
promotes endometrial lesion growth
Mean estradiol levels with dienogest 2mg
were 39pg/mL1
Estradiol concentration (pg/mL)
Estradiol levels remain in the optimum range during treatment with Dienogest
Barbieri RL. J Reprod Med 1998; 43(3 Suppl): 287–292.
Klipping C et al. J Clin Pharmacol 2012; 52: 1704–1713.

67. Take Home Message
DNG 2mg is an effective & generally well tolerated
treatment option to
1. Reduce pain
2. Reduce lesions
3. Improve quality of life
4. Has an acceptable side effect profile, suitable for
long-term use

68. Thank you!