DIENOGEST BY DR SHASHWAT JANI

1. Dr. Shashwat Jani.
M. S. ( Obs – Gyn )
Diploma in Advance Laparoscopy.
Consultant Assistant Professor,
Smt. N.H.L. Municipal Medical College.
Sheth V. S. General Hospital , Ahmedabad.
Mobile : 99099 44160.
E-mail : drshashwatjani@gmail.com

2. Progestins : Overview
 Used for  40 years in Rx of endometriosis
 Synthetic hormones with progesterone-like activity
 Show excellent activity through suppression of the
HPO axis, cause anovulation , reduced estrogen levels
and decidualization & atrophy of both ectopic and
eutopic endometriotic lesions
( ESHRE Capri Workshop Group 2001, Schweppe 2001 )
 Also inhibit angiogenesis, maintain the endometriotic
implants, restricts proliferation .
 Anti-inflammatory activity, reduces associated pain
 Excellent Rx to prevent recurrence and increase the
duration of symptom free period, post surgery
6/26/2017
Dr Shashwat Jani.
99099 44160.
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3. Progestins:
Advantages over other Rx options
 Exhibit excellent efficacy in the treatment of endometriosis
 Highly safe in comparison to GnRH agonists, Danazol etc.
 Lesser risk of androgenic and metabolic S/Es
 No significant loss of BMD; can be given to all age groups
 Extensive clinical data support
Progestins: Recommendations
• Progestins may be an appropriate alternative for
longer-term management of endometriosis due to
their safety, tolerability and cost
• ESHRE Capri Workshop Group 2001, Vercellini et al 2003
• Progestin may be considered as a ‘first line therapy’
• SOCG Clinical Practice Guidelines, July 2010
6/26/2017
Dr Shashwat Jani.
99099 44160.
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4. DIENOGEST
A new Hybrid, Designer progestin for
the treatment of endometriosis!

5. Dienogest – Global Status
- Available in combination with
ethinyl estradiol
- Indicated for contraception
- Natazia / Qlaira
- Available as Dienogest 25 mg
- Indicated for treatment in
Endometriosis
- Visanne
UNITED STATES OF
AMERICA
EUROPE
Dienogest was synthesized in 1979 in Jena, Germany
and first brand was Valette (contraceptive) in 1995
6/26/2017 5

6. Dienogest – Status in India
Dienogest is the first oral drug approved and
indicated for the treatment of Endometriosis
It was launched in 2014
More than
1,00,000 patients
treated with
Dienogest
INDIA
6/26/2017 6

7. Dienogest
• It’s a synthetic oral progestogen with
unique pharmacological properties
• Highly selective for the progesterone
receptor
6/26/2017
Dr Shashwat Jani.
99099 44160.
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8. Pharmacological effects
• Excellent anti-proliferative and anti-inflammatory
effects in the treatment of endometriotic lesions.
It also shows:
• Considerable anti-androgenic properties
• No glucocorticoid and no anti-mineralocorticoid
activity
• No anti-estrogenic activity
• No effect on metabolic and cardiovascular systems
• High efficacy and safety on long term use
• Less adverse effect profile
6/26/2017
Dr Shashwat Jani.
99099 44160.
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9. 6/26/2017
Dr Shashwat Jani.
99099 44160.
Dienogest:
Pharmacokinetics
9

10. 6/26/2017
Dr Shashwat Jani.
99099 44160.
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11. 6/26/2017
Dr Shashwat Jani.
99099 44160.
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12. Dose
• It appears that at a dose of 2 mg dienogest
per day, ovulation is inhibited but ovarian
hormone production is not completely
suppressed.
• Thus, compared to other endometriosis
treatments, estrogen-deficiency related side
effects are expected to be of low intensity
with 2 mg dienogest.
6/26/2017
Dr Shashwat Jani.
99099 44160.
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13. Dienogest - MOA
• Suppresses the HPO axis,
reduces GnRH secretion,
hypoestrogenic effect
• It binds to the progesterone
receptor with high specificity but
with relatively low affinity, at
10% that of progesterone.
• Shows pronounced
progestogenic effect attributed
to the high circulating levels of
the unbound molecule.
• Thus, it produces a progesterone
– rich environment, enhancing
the stability of the endometrium.
6/26/2017
Dr Shashwat Jani.
99099 44160.
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14. Dienogest: Effect on PGE2
PGE2
Increases
Aromatase
Increases
Estrogen
Increases
Fibroblast
Growth
factor – 9
(FGF-9)
Cell proliferation
Affects
Leukocyte
levels &
VEGF levels
Promotes
Angiogenesis &
Vasculogenesis
Inhibits
apoptosis
Cell proliferation
Macrophages and
Endometrial cells
Dienogest inhibits PGE2
production & Aromatase
Yamanaka et al, Fertil Steril, 2012; 97(2): 477 - 82
Prostaglandin E2 levels are
increased in endometriosis.
Lowers Estrogen
levels
Inhibits vascular
proliferation
Inhibits
angiogenesis
Promotes
Apootosis
Inhibition of PGE2 and Aromatase contributes to the therapeutic effects of
Dienogest in Endometriosis
6/26/2017 14

15. Progesterone resistance in
Endometriosis
• The endometrial dysfunction is due to diminished
response to Progesterone.
• It is seen that the Estrogen receptors’ levels increase and
the Progesterone receptors’ levels decrease.
• This leads to hyper-proliferative changes and anti-apoptotic
process.
• Dienogest improves the Progesterone resistance in endometrial
tissue.
• It significantly improved the expression of Progesterone
receptors, thus exhibiting clinical improvements in
endometriosis.
Hayashi et al. Journal of Ovarian Research 2012, 5:31
6/26/2017
Dr Shashwat Jani.
99099 44160.
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16. Main drawbacks of other drugs
• Combined Oral Contraceptives:
• Many women do not respond adequately, due to Progesterone resistance
• Thromboembolism
• GnRH agonists:
• Androgenic effects, Hypoestrogenic S/Es
• Use restricted to 6 months, in absence of add on HT
• Effects on BMD
• Danazol:
• Androgenic effects,
• Use restricted to 6 months, due to side effects
• Other Progestins:
• Androgenic effects, Breakthrough bleeding, thromboembolism
• Effects on metabolic systems and CVS
• Short term pain relief6/26/2017 16

17. DIENOGEST
Let us have a look at the CLINICAL DATA …
6/26/2017
Dr Shashwat Jani.
99099 44160.
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18. Dienogest vs. GnRH agonists
Comparative Recent trials
Author Drug and
Dose
N Duration
(Wks)
Results A/Es
Strowitzki T
et al (2010)
Leuprorelin
3.75 mg/4 wk
128 24 = improved VAS scores
Non Inferiority for DNG
Higher QoL – DNG
Mean BMD – 4% LA, + 0.25% DNG
No change in body weight
Headache
Hypoestrogenic S/Es
– LA
= Bleeding episodes
Harada T et
al (2009)
Buserelin 300
mcg tds
134 24 = change in subjective symptom
scores
Non inferiority for DNG
= % reduction in chocolate cysts
BMD : -2.6% BA, -1.0% DNG
Headache
Hypoestrogenic S/Es
– BA
Spotting – DNG
Cosson M et
al (2002)
Triptorelin
3.75 mg/4
wks
61 16 = Endometrial tissue scores
= No reappearance of endometrial
tissue in 25% in each group
Higher patient satisfaction – DNG
(86.2 %vs. 80%)
15 pts DNG vs. 12 pts T :
spontaneous pregnancies
Spotting – DNG (61.6
vs 25.4%)
Hot flushes (61.2 vs.
9.6%)
6/26/2017 18

19. Dienogest vs. GnRH agonists Safety
Jeng CJ et al, Expert Opin. Pharmacother, 2014; 15(6): 767-773
6/26/2017
Dr Shashwat Jani.
99099 44160.
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20. Dienogest vs Buserelin
Effect on size of chocolate cysts
Harada T et al, Jpn Pharmacol Ther, 2008
Harada T et al, Fertility ans Sterility, 2009
6/26/2017
Dr Shashwat Jani.
99099 44160.
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21. One important drawback with GnRH agonists is the
recommended duration of Rx… Not more than 6
months
Can Dienogest be
continued for a longer time
?
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22. Dienogest : Long term use
Long-term use of dienogest for the treatment of endometriosis
J Obstet Gynaecol Res. 2009 Dec;35(6):1069-76.
Momoeda M1, Harada T, Terakawa N, Aso T, Fukunaga M, Hagino H, Taketani Y.
Objective: To investigate the safety and efficacy of 52 weeks
of dienogest treatment in patients with endometriosis.
• 135 patients with endometriosis received 2 mg
of dienogest orally each day for 52 weeks
• Adverse drug reactions and bone density were evaluated every
4 weeks
• Global improvement was assessed based on the changes in
severity categories of five subjective symptoms during non-
menstruation
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23. Dienogest : Long term use Efficacy
Momoeda M, et al. J Obstet Gynecol Res 2009. 23

24. Dienogest : Long term use Efficacy
Momoeda M, et al. J Obstet Gynecol Res 2009. 24

25. Dienogest and Fertility
considerations
Most of the medical options cause anovulation
and amenorrhea in patients
What is the experience with Dienogest?25

26. Dienogest : Long term use
Resumption of menses
• Resumption of menses after the EOT was
confirmed in all 132 cases
• The number of days from the EOT to the first day
of menstruation was 29.9 ± 11.8 days
• Menstruation was confirmed within 2 months after
the EOT in 97.0% (128/132 cases) of the patients.
• It can be concluded from this study that Dienogest shows very
minimal effect on BMD, whereas the efficacy is cumulative.
• It can be used for long term (~ 52 weeks)
Momoeda M, et al. J Obstet Gynecol Res 2009. 26

27. Dienogest : Ovulation & Fertility
• Klipping C et al, 2011 evaluated 104 patients on 0.5 mg, 1 mg, 2 mg and 3
mg doses of Dienogest (DNG)
• Women with higher dose of DNG (2/3 mg) did NOT show
ovulation
• Follicle size varied as per the dose, highest for lowest dose (0.5 mg –
26.3mm)
Ovarian activity (Hoogland score) in
each dienogest dose group (%
participants)
Klipping C et al, J Clin Pharmacol, 2011 27

28. Dienogest : Ovulation & Fertility
• An LH surge in urine was
identified in 60 of 87 women
(69.0% overall, 2 mg- 80.0%),
occurring between days 1 and 43
after cessation of treatment.
• Only 2 women failed to ovulate
• Shows a prompt return to
fertility
• This is an unique feature of
DNG, not shared by any other
medication
• It was well tolerated during the
study.
• The intensity of bleeding/spotting
decreased during continued
treatment in all dose groups.
Klipping C et al, J Clin Pharmacol, 2011
Mean endometrial thickness at each visit during the
pretreatment (combined groups) and treatment
period (individual dose groups)
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29. Dienogest Vs. Norethisterone
• 17 women with rectovaginal endometriosis
• Persistent pain after Rx with NE
• DNG 2 mg/day for 6 months
• Primary end point - Patient satisfaction
• Secondary end point – Pain symptoms, A/Es
Results:
• Patient satisfaction improved at 3 and 6 months
• DNG decreased deep dyspareunia and pelvic pain (31.3 & 18.3 mm
resp, 24 week)
• Analgesic use reduced
• No A/Es reported
DNG may be the 1st choice progestin for treatment in endometriosis
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30. Dienogest : Key clinical benefits in Endometriosis
 Decreases the endometriosis associated pelvic pain
 Reduces symptoms, signs and severity
 As effective as GnRH agonists
 More safer side effects profile
 Not associated with clinically relevant androgenic A/Es
 No changes in BMD
 No alterations in lipid, metabolic or hematic parameters
 Long term efficacy evaluated (> 1 yr)
 Restores fertility post cessation (1 – 43 days)
 Newer applications established
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31. Dienogest
Post-0pertive Medical Treatment and Recurrence
The recurrence rate (pain or chocolate cysts) was compared between
patients with post-operative medical treatment (DNG or OC) (n= 134)
and patients without treatment (n= 234).
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32. New Clinical applications
Adenomyosis
Extragenital endometriosis (bladder, colon
etc)
Post-operative therapy
Pretreatment for hysteroscopy
Long term effect after discontinuation
Low-dose therapy (2mg/day to 1mg/day)
Infertility treatment Pre IVF
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33. Dienogest and Adenomyosis
Group Cases (n) Age
(median)
Rx
Duration
(m)
Chocolat
e cyst
(%)
Pain
Relief (%)
Side
effects
(%)
Continued 28 43 17.5 14.3 100 32.1
Shimada E. et al. presented at Kanto Society of Obstetrics and Gynecology 2011. [Pilot
study]
• Sasa H et al, 2014 showed DNG
equivalent to Danazol in adenomyosis
(n=20) in efficacy, with lower side effects
• Hirata T et al, 2014 showed that DNG
significantly reduced the adenomyosis
related pelvic pain in 17 patients
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34. Dienogest: Cyclic administration
• It has been seen that cyclic administration of Dienogest may
relieve:
• The intermittent uterine bleeding, a major side effect of Dienogest
• Equally reduce the associated menstrual pain in patients post surgery
• Yanase T et al, 2014
• Showed disappearance of intestinal endometriosis
• Marked reduction in lower abdominal pain
• Significant reduction in endometriotic cyst size
• Disappearance of endometriotic lesions (endoscopy)
• Tamura R et al, 2013
Week 1 Week 2 Week 3 Week 4
DNG 2 mg/day DNG 2 mg/day DNG 2 mg/day Withdrawn
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35. Thus, to summarize Dienogest proves to
be an excellent, safe and effective
treatment option in Endometriosis!

36. Dienogest – Summary
 Dienogest is an orally active, 19-nortestosterone
derivative
 Displays strong progestational effects
 Reduces signs, symptoms and severity of
endometriosis
 Decreased endometriosis-associated pelvic pain
 As effective as GnRH agonists, with better side
effect profile
 Well tolerated and safe for long term Rx (15 – 18
months)
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37. • Not associated with clinical relevant androgenic
adverse effects
• Does not exhibit any alterations in BMD
• No adverse effects on glucose metabolism, liver
and cardiovascular system
• Efficacy and tolerability sustained with long term
(>1yr) treatment
• Improved QOL of patients and lowers recurrence
rates.
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38. 26-Jun-17 38
Dr Shashwat Jani.
9909944160.