ENDOMETRIOSIS UPDATEFocus on Dienogest AGENDA Background What’s New in Endometriosis Clinical Discussions in Managing Endometriosis Newer Evidences on Dienogest

1. Dr. Sharda Jain
ENDOMETRIOSIS UPDATE
Focus on Dienogest
ISO 14001:2004 (EMS)
…Caring hearts, healing hands

2. Over 350 ppts are available on slideshare.net
***for use of public/Doctors
www.slideshare.net / Lifecarecentre

3. AGENDA
• Background
• What’s New in Endometriosis
• Clinical Discussions in Managing
Endometriosis
• Newer Evidences on Dienogest
• Bayer Holding 4:3 Template 2010 • July
2015

4. 1. Background
Endometriosis

5. WHAT IS ENDOMETRIOSIS?
 Endometriosis is defined as:
– Chronic estrogen-dependent disease
– Characterized by the presence of endometrial-like tissue
outside the uterus, which
– Induces a chronic, inflammatory reaction
 While some women with endometriosis experience painful
symptoms and/or infertility, others have no symptoms at all
 Exact prevalence unknown: estimates range from 2 to 10%
within the general female population and up to 50% in infertile
women.
Derived from ancient Greek: endo:‘inside’ and metra:‘womb’
* ESHRE guideline update 2013

6. 6
1 in 10 women have endometriosis
during their reproductive years
Crosignani P et al. Hum Reprod Update 2006; 12(2): 179–189.

7. Endometriosis – Prevalence
Page
7
Endometriosis is a prevalent condition!
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.
As per recent estimates, about 176 million women suffer from Endometriosis globally;
Of these, ~26 million women belong to India alone!! 4

8. Page 8

9. Endometriosis affects women during the
prime years of their lives
Nnoaham KE et al. Fertil Steril 2011; 96: 366–373.
World Endometriosis Research
Foundation prospective Global Study
of Women’s Health

10. Sites commonly affected in
Endometriosis
ESHRE Guideline update 2013; Accessed at: http://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline.aspx

11. Endometriosis:
The Lifelong Patient “Journey!
The lifelong patient journey: Juggling pain management & fertility desires!

12. 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.

13. An Introduction to Dienogest
1. Background

14. Rationale for using Progestins in treatment of
Endometriosis
* Image courtesy of Prof. Michael Mueller, Inselspital, Bern, Switzerland
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

15. What is Dienogest?
• Dienogest’s special chemical structure is responsible for it’s unique pharmacological profile
Page 15
Properties of 19-nortestosterone derivatives
• Strong progestational effect on endometrium
• Relatively short plasma half-life of 9–11 hours
• High oral bioavailability >90%
Properties of progesterone derivatives
• Good tolerability
• Anti-androgenic effects
• Relatively moderate inhibition of gonadotropin
secretion
• Mainly peripheral action
Additional double bond
(Strong affinity to progesterone
receptors)
Cyanomethyl instead of an ethinyl
group in the 17α position
(Low interaction with hepatic proteins e.g
Cytochrome P450)
Sasagawa S et al. Steroids 2008; 73: 222–231.
Ruan X et al. Maturitas 2012; 71: 337–344.

16. Dienogest: Comparison with other Progestins
Page 16
* 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*

17. Dienogest:
Mechanism of Action in Endometriosis
– Central effects (At level of hypothalamus & pituitary):
• Inhibition of gonadotropin secretion: hypoestrogenic,
hypergestrogenic endocrine environment1,2 with moderate
suppression of circulating estradiol3
• Ovarian function: anovulation (2mg dose)3
– Local effects (At level of endometrial tissue)
• Anti-Proliferative: inhibitory effect on proliferation of
endometrial-like tissue4–6
• Anti-Inflammatory: impact on endometriosis-related
inflammatory mediators7,8
• Anti-Angiogenenic: supressed angiogenesis in animal
models of endometriosis9–11
• Modulation of prostaglandin E2 expression12,13
Page 17
Hypothalamus
Pituitary gland
Gonadotropins
Estrogen and progesterone
Negative feedback
Uterus
Ovary
Estrogen
Progesterone
Endometrium
1. McCormack PL. Drugs 2010; 2. Sasagawa S et al. Steroids 2008; 3. Klipping C et al. J Clin Pharmacol 2012; 4. Katsuki Y et al. Eur J
Endocrinol 1998; 5. Fischer OM et al. Gynecol Obstet Invest 2011; 6. Shimizu Y et al. Steroids 2011; 7. Horie S et al. Fertil Steril 2005;
8. Mita S et al. Fertil Steril 2011; 9. May K and Becker CM. Minerva Ginecol 2008; 10. Katayama H et al. Hum Reprod 2010; 11. Nakamura
M et al. Eur J Pharmacol 1999; 12. Sacco K et al. Gynecol Endocrinol 2012; 13. Becker CM and D’Amato RJ. Microvasc Res 2007.
Growth of endometrial lesions inhibited via both, central and local effects

18. 2. What’s New in Endometriosis

19. 2. What’s New in Endometriosis
• Role of Estrogen in Endometriosis

20. Role of Estrogen in Endometriosis
Page 20
Estrogens are responsible for proliferation of endometriotic tissue!

21. Role of Estrogen in Endometriosis
Page 21
• Series of chemical reactions
convert cholesterol to
estradiol
• The final step involves
conversion of testosterone to
estradiol
• This is mediated by the
enzyme: estradiol synthase or
aromatase
• 17β-HSD2 then degrades
excess estradiol in to estrone
(inactive form)

22. Growth and survival of the endometriotic lesions is favored due to
the increased level of estrogen, locally
Page 22
Testosterone
Estradiol
Estrone
(weak, inactive
form)
Aromatase
17β-HSD2
Endometriosis
High levels of Aromatase in
endometriotic deposits
Low levels of 17β-HSD2 in
endometriotic deposits
Normal Pathway

23. The Estrogen Threshold Theory
Page 23
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
Figure adapted from Barbieri RL. J Reprod Med 1998; 43(3 Suppl): 287–292.
Klipping C et al. J Clin Pharmacol 2012; 52: 1704–1713.

24. Use of CoCs in Endometriosis:
But isn’t Endometriosis an estrogen-dependent, chronic
inflammatory disease??
Page 24* CoCs: Combined Oral Contraceptives

25. Progestin-only pills are better first-line treatment for
Endometriosis than CoCs!
Pain improvement with CoCs may be attributed to the reduction of
primary dysmenorrhea (PG-related), which may still occur in women
with endometriosis
Studies show lack of any beneficial effect of the OCP on non-
menstrual pelvic pain and dyspareunia in these endometriosis
patients
Dose of Estrogen in low-dose CoCs is equivalent to 4 to 6 times the
physiologic dose of estrogen
In evidence of ER and PR alterations in endometriosis
administering a high dose of estrogen and progestin in a CoC is
counterproductive, resulting in estrogen dominance in the presence
of progesterone resistance
Casper RF. Progestin-only pills may be a better first-line treatment
for endometriosis than combined estrogen-progestin contraceptive
Page
25
* ER: Estrogen Receptor; PR: Progesterone Receptor; CoCs: Combined Oral Contraceptives

26. 2. What’s New in Endometriosis
• Diagnosis &
• Management

27. Is surgical diagnosis of Endometriosis
always necessary?
Page 27

28. Goals of Management in Endometriosis
Page 28
Endometriosis should be viewed as a chronic disease that requires a life-long management plan with the
goal of maximizing the use of medical treatment and avoiding repeated surgical procedures
The Practice Committee of the American Society for Reproductive Medicine. Fertil Steril, 2014. 101(4): 927-35.

29. Role of progestins in Management of Endometriosis
ESHRE, European Society of Human Reproduction and Embryology; WES, World Endometriosis Society;
RCT, Randomly controlled trial
1. ESHRE 2013 guidelines; Accessed at: http://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline.aspx.
2. Johnson NP et al. Hum Reprod 2013; 28: 1552–1568.
ESHRE guidelines:
“Clinicians are recommended to use
progestagens … as one of the options,
to reduce endometriosis-associated
pain”1
WES consensus:
“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”2
Progestins are recommended, gaining popularity, and are efficacious in treating the symptoms of endometriosis
Newer progestins such as dienogest should be considered for use as first-line empirical medical treatment2

30. 2. What’s New in Endometriosis
• Dienogest – A Unique Progestin

31. Estradiol levels during Dienogest treatment remain within
suggested therapeutic window
Page 31
Klipping C et al. J Clin Pharmacol 2012; 52: 1704–1713.
Barbieri RL. J Reprod Med 1998; 43: 287–292.

32. Local effects of Dienogest:
Suggested effects on Progesterone resistance!
• Dienogest increased PR-B/PR-A ratio*
PR-B activates progesterone
genes/ PR-A represses PR-B
• Dienogest decreased ERβ/ERα ratio*
• Effects NOT seen with leuprolide
acetate (LA)
Hayashi A et al. J Ovarian Res 2012; 5(1): 31.
* Relative to control in endometrial tissue
ER= Estrogen receptor; PR= Progesterone receptor
PR-B PR-A ERβERα
Dienogest may help to improve
progesterone resistance in
endometriosis
The resistance of endometriotic tissue to progesterone can be explained by alterations in the distribution of
PR and ER isoforms
Decreased PR-B/PR-A and increased ERβ/ERαratios have been demonstrated in endometriosis

33. Anti-inflammatory effect of Dienogest
Shimizu Y et al. Steroids 2011; 76(1–2): 60–67.
Horie S et al. Fertil Steril 2005; 83(5): 1530–1535.
E2=estradiol; IL-8=interleukin-8; NF-κB=nuclear factor kappa B; TNFα=tumor necrosis factor α; DNG=dienogest.
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
TNFα
IL-8
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)

34. 3. Clinical Discussions in Managing
Endometriosis

35. 4. Newer Evidences on Dienogest
Long-term Use of Dienogest in Endometriosis

36. VISADO
(VISANNE STUDY TO ASSESS SAFETY IN ADOLESCENTS)
A CLINICAL INVESTIGATION WITH DIENOGEST 2 MG/DAY IN ADOLESCENT PATIENTS
Conclusion :
SAFE..IN 5 YEARS FOLLOW UP

37. Conclusion
– 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
• BMD: Bone mineral density, VAS: Visual analogue scale
• Ebert AD et al. J Pediatr Adolesc Gynecol. 2017, doi: 10.1016/j.jpag.2017.01.014.
In the adolescent endometriosis population the benefit-risk balance for Dienogest
(2mg/d), especially in the light of a lack of alternative treatment options with a better
benefit-risk profile, is considered favorable

38. International journal of women’s Health
SAFETY & TOLERABILITY OF DIENOGEST IN
ENDOMETRIOSIS :
pooled analysis from the
European clinical study program

39. CONCLUSION
of study
In this pooled analysis of 332 women with endometriosis ,
dienogest was well
Tolerated with a favorable safety profile extending over period of
up to 65 weeks.
There is a paucity of randomized trial evidence to support the use
of many treatment in endometriosis. These pooled analyses
from four clinical trials of dienogest 2mg represent a
contribution to evidence – based medicine in endometriosis,
providing outcome of potential relevance to daily practice.
• Bayer Holding 4:3 Template 2010 • July
2015

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