Dydrogesterone: The NEW AVTAR for Treatment of Endometriosis

1. Dydrogesterone: The NEW
AVTAR for Treatment of
Endometriosis
Dr Jyoti Agarwal
Dr Sharda Jain

2. Causes
progesterone
resistance in the
endometrium
Repetitive retrograde endometrial
shedding exacerbates
progesterone resistance
Endometriotic lesions and surrounding
peritoneal fluid are rich in reactive oxygen
species
Chronic inflammation
Oxidative stress
Dydrogesterone effectively
tackles chronic inflammation
Increasing progesterone
receptor expression
Decreasing proinflammatory
cytokines
Dydrogesterone exerts
endothelial anti-
inflammatory actions via a
decrease in expression of
leukocyte adhesion
molecules.
Progesterone Action is Crucial to Decrease
Inflammation In The Endometrium

3. Dydrogesterone Effectively Tackles Chronic Inflammation
Associated With Endometriosis
Reduces TNF-α-induced
NF-κ-activation and
suppresses proliferation of
endometriotic stroma
cells.
Suppresses IL-8 production
in lymphocytes.
Increases NO production
that plays an anti-
inflammatory role.
IL-8
TNF-α
Lymphocyte
Stromal cell in
endometriotic implant
TNF-α-induced
NF-Кβ activation
induces proliferation
Growth factors
Neoangiogenesis
DYD
Acts on
Proliferation
DYD
TNF-α-induced
upregulation
DYD reduces
Influence of dydrogesterone on TNF-α and IL-8–induced inflammatory
reactions in lymphocytes and proliferation of endometriotic stromal cells

4. Dydrogesterone Enhances Quality of Life and Reproductive
Health as it leads to
Endometriosis therapy should enhance quality of life and
reproductive health
No inhibition of
ovulation
Reduction in
pain symptoms/
size of
endometriosis
lesions
Improvement in
quality of life
parameters
Improved
pregnancy
outcomes

5. Clinical Evidence for
Dydrogesterone in the
Management of Endometriosis

6. Clinical Evidence:
Reduction of Endometriosis-
Related Pain and Improvement
of Quality of Life

7. Cyclic application
(days 5–25 of cycle)
10–20 mg for 4
months provides
symptomatic relief to
women with
dysmenorrhea
Fewer days of bleeding
60% decrease in abdominal
cramping and pain
Reduction in severity of headache
and nausea/vomiting
Dydrogesterone
Was first reported to be effective in endometriosis in the 1960s
The overall success rate is around 90%
reduction in the number/severity of symptoms
Laparoscopic examination in several of the studies supports its usage

8. Baseline After therapy
Mean laparoscopic scoring of severity 14.5±8.6 2.1±3.4
15%
improvement
75%
elimination
Laparoscopic examination
of endometriosis
Kaiser E, Wagner ThA. TW Gynäkologie.1989;2:386–388.
Dydrogesterone: 10 mg per day from
5th to 15th day; 20 mg per day from
16th to 25th day of each cycle.
20 patients
Duration of treatment:
6–9 months
4 cases
15 out of 20
Laparoscopic examination confirmed elimination of endometriosis in 15 out of
20 (75%) cases and improvement of endometriosis in another 4 cases (15%)

9. Dydrogesterone inhibit development of
new endometriotic lesions
Dydrogesterone
Reduced
CYR61 and VEGFA
gene expression1
Reductions in:1
• neoangiogenesis
• blood vessel density
Reduced proliferation
of endometriotic
stromal cells1,2
Dydrogesterone can reduce the expression of transcription factors and growth factors
involved with the establishment and maintenance of endometriotic lesions
Reduced
development of
endometriotic
lesions
Reduced MMP
gene expression1
Reduced extracellular degradation
of the peritoneal mesothelium1
Reduced growth and
implantation of
endometriotic tissue1
Reduced
TNF-α-induced
activation of NF-κβ2
Reduced expression
of growth-promoting
cytokines (including IL-8)

10. Dydrogesterone Induces Atrophy In
Ectopic Endometrial Tissue
Study involved 15 sites in Japan.
• Dydrogesterone 10 mg twice daily orally was
administered for 21 days (day 5-25 of each cycle) for 4
cycles.
• The study group comprised women with an
endometrioma aged 20 to 49 (47.4% cases aged ≥40
years).
• Endometrioma volume was reduced in 50% (26/52),
unchanged in 25% (13/52) of women from baseline to
the end of cycle 5
• Dydrogesterone significantly reduced total
dysmenorrhea scores and severity of dysmenorrhea
pain
Kitawaki J, Koga K, Kanzo T, Momoeda M. An assessment of the efficacy and safety of dydrogesterone in women with ovarian
endometrioma: An open-label multicenter clinical study. Reprod Med Biol. 2021 Jun 4;20(3):345-351
Mean (+SD) volume of ovarian endometriomas from
before treatment initiation to end of Cycle 5
Dydrogesterone inhibits the formation
of de novo endometriotic tissue while
leaving the endometrium unaffected

11. Post-Laparoscopic Treatment of Endometriosis With
Dydrogesterone : very effective
98 pts
10 mg/day or 20 mg/day ( severe
cases) days 5 to 25 of each cycle
• Trivedi et al. designed an open, prospective, multicenter study to assess the efficacy and safety of
dydrogesterone in the post-laparoscopic treatment of endometriosis in Indian patients
• Ninety-eight patients with minimal, mild, moderate, or severe endometriosis, with or without infertility, who had
undergone laparoscopy, were treated with dydrogesterone
• Pelvic pain, dysmenorrhea, and dyspareunia improved significantly (by 29%, 32%, and 38%, respectively, p<0.05)
after the first cycle of treatment
• By the end of the sixth cycle, the reduction in pelvic pain, dysmenorrhea, and dyspareunia was 95%, 87%, and 85%,
respectively
Trivedi P, Selvaraj K, Mahapatra PD, et al
Gynecol Endocrinol 2007;23(Suppl 1):73–76.
Recurrence rate of
endometriosis is high after
surgery

12. Effective Post-Laparoscopic Treatment of
Endometriosis With Dydrogesterone
Trivedi P, et al. Gynecol Endocrinol 2007;23(Suppl 1):73–76.
0
0.5
1
1.5
2
0 1 2 3 4 5 6
Assessment of endometriosis symptoms for 6 months
Pelvic pain score
Dysmenorrhoea score
Dyspareunia score
Month of treatment
Pain
score
*
*
*
**
98 patients
10 mg/day dydrogesterone or 20 mg/day (in
severe cases) on days 5 to 25 of each cycle
3–6 months
Overall, 21.1% of patients were considered cured and 66.7% showed improvement.

13. High Satisfaction With Dydrogesterone Therapy for
Endometriosis
22.2
52.2
20
5.6
13.3
56.7
25.6
4.4
0
10
20
30
40
50
60
Excellent Good Satisfactory Bad
Proportion
of
patients
(%)
Global assessment of treatment
Patient Doctor
74.4%
rated
good/excellent
Patient
5.6%
rated poor
70.0%
rated
good/excellent
Doctor
4.4%
rated poor
Dydrogesterone is an effective and safe post-laparoscopic treatment for endometriosis.
Trivedi P, et al. Gynecol Endocrinol 2007;23(Suppl 1):73–76.
No adverse events were reported by any of the patients

14. Clinical Evidence:
Avoids Inhibition of Ovulation
& Improves Pregnancy Outcomes
Management of infertility in women
with endometriosis is a complex issue

15. Current medical therapies both hormonal and non-hormonal have been fairy
successful to provide symptomatic relief but Inhibit Ovulation and Delay
Conception
01
02
03
04
No evidence that
medical therapy alone
or in combination with
surgery improves
fertility.1
Suppress
ovulation;
cannot be used
in women
desiring
fertility.1
Delay in
conception
Do not
provide fertile
benefit after
treatment
There is a requirement of a therapy that can avoid unwanted side effects
and specifically target the lesions without affecting the ovarian function
1. Rafique S, et al. Clin Obstet Gynaecol. 2017;60(3):485. 2. Elnashar A. Middle East Fertil Soc J. 2015;20(2):61–9.

16. Does not cause anovulation
unlike other gestagens
Does not affect serum
estradiol levels
Induces decidual transformation
and necrosis & resorption of
endometrial implant
Continuous application of dydrogesterone
Dydrogesterone Does Not Inhibit Ovulation
Since dydrogesterone therapy does
not cause a hypoestrogenic state,
estrogen add-back therapy not
needed

17. Progesterone receptor activation
Upregulation of progesterone-induced blocking
factor (PIBF)
PIBF increases production of regulatory cytokines and
blocks pro-inflammatory cytokines.
Prerequisite to successful treatment of endometriosis-
associated infertility
Dydrogesterone
induces PIBF
production
Dydrogesterone Improves Pregnancy Outcomes By
Reducing Levels of Inflammatory Markers

18. Metabolite of Dydrogesterone Improves Endometrial
Receptivity and Pregnancy Outcomes
Metabolite Dihydrodydrogesterone retains immunomodulatory effects of
dydrogesterone
Induces
nitric oxide
synthesis
Improves uterine and
subendometrial blood
flow
Increases utero–
placental
circulation
Improves
endometrial
receptivity
and
pregnancy
outcomes

19. Dydrogesterone Has a Favorable Safety Profile for Women
Wanting to Conceive
No estrogen-
associated side
effects
No intrauterine
deaths, congenital
abnormalities, or
pregnancy-related
complications
Improved quality
of life
High selectivity for
progesterone
receptors; minimizes
activation of other
receptors and
unwanted effects

20. Makhmudova GM, et al. Akush Ginekol (Sofiia). 2003;42(4):42–46.
Efficacy of Dydrogesterone Treatment in Women With Endometriosis After
Reconstructive Surgery
Total, 300 infertile patients with endometriosis undergoing laparoscopy were divided in five groups & advised
follow-up 12 months after end of treatment
50% pregnancy rate with dydrogesterone
63.3% pregnancy rate with danazol
• Depo-medroxyprogesterone acetate (MPA), 50 mg each week for 3 months
• Dydrogesterone 10 mg OD on days 5 to 25 of each cycle for 6 months
• Norethisterone 10 mg OD for 6 months
• Danazol 400 mg BID for 6 months
• Coagulation of lesions, no medical treatment
0% 25% 50% 75%
No medical treatment
Danazol
Norethisterone
Dydrogesterone
Depot-MPA
Pregnancy rate after 6 months of therapy
20% during therapy, 30%
immediately after
7.6±1.2 months after the product was
stopped
BID: Twice daily; MPA: Medroxyprogesterone acetate; OD: Once daily.

21. 1. Orazov MR, et al. Int J Pharm Res. 2019;11(3):1001–1006. 2. Prescribing information of Duphaston®. Available at: https://data.health.gov.il/drugs/alonim/Duphaston_dr_1410193172635.pdf.
3. Seibel MM, et al. Fertil Steril. 1982;38(5):534–7. 4. Dmowski WP. Prog Clin Biol Res. 1982;112:167. 5. Makhmudova GM, et al. Akush Ginekol (Sofiia). 2003;42(4):42–46.
Dydrogesterone does not inhibit
ovulation and can be used before
and during pregnancy Danazol induces a state of
pseudomenopause and delays
conception by at least 6 months
Recommendation
Dydrogesterone
Most effective therapy and
most preferable drug
Hormonomodulative therapy after
surgical treatment of endometriosis

22. Latest Updates on Use of
Dydrogesterone in Treatment
of Endometriosis

23. 3 months (cycles)
of treatment
6 months (cycles)
of treatment
Follow-up period
Study aim
To study the efficacy of
dydrogesterone in laparoscopy-
confirmed cases of endometriosis
Patient population
Women 18–45 years of age with
endometriosis and chronic pelvic
pain with or without
dysmenorrhea (N=350)
N=350
Prolonged cyclical
treatment group
(n=273)
Continuous treatment
regimen group (n=77)
aIn the overall study population; bbetween days 5 and 25 of the menstrual cycle
HR-QoL, health-related quality of life; ITT, intent-to-treat
Sukhikh GT, et al. 2021. Submitted manuscript
Visit 1 Visit 2 Visit 3
Baseline
ITT population
Primary
endpoint
To compare the change in intensity of chronic pelvic
pain from baseline to Month 6 between patients
receiving prolonged cyclical or continuous treatment
regimens of dydrogesterone
Secondary
endpoints
To determine changes from baseline to Month 6 in:a
• Intensity of chronic pelvic pain
• The number of days per menstrual cycle when
analgesics were taken
• Severity of dysmenorrhea
• Duration of menstrual cycles
• Patient-reported sexual well-being
• HR-QoL
ORCHIDEA is a large, multicenter clinical trial
(10 mg, 2–3 times /day)

24. 5.7
***
2.5
5.8
***
2.8
0
1
2
3
4
5
6
7
Baseline Month 6
Mean
intensity
of
chronic
pelvic
pain,
NRS
Prolonged cyclical regimen (n=198) Continuous regimen (n=66)
–3.3
(56% reduction)
–3.0
(52%
reduction)
***p<0.0001 vs baseline; aAnalysis population comprised patients who were selected by propensity score matching
NRS, numerical rating scale
Sukhikh GT, et al. 2021. Submitted manuscript
The difference
between the two
treatment regimens
was not statistically
significant
Pelvic pain intensity at baseline and Month 6 (n=264a)
ORCHIDEA primary efficacy endpoint demonstrated
Significant reduction (52%) in chronic pelvic pain
Both prolonged cyclical and continuous treatment regimens with dydrogesterone led to
similar, significant improvements in chronic pelvic pain during the ORCHIDEA study
(assessed using the 11-point numerical rating scale)

25. There was a reduction in the number of days with
analgesics during the study
1.1
*
0.7
*
0.5
*
0.3
*
0.2
*
0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6
Mean
number
of
days
with
analgesics
(per
cycle)
Cycles of treatment with dydrogesterone
–0.9
(82% reduction)
*p<0.05 vs Cycle 1
1. Sukhikh GT, et al. 2020. Submitted manuscript; 2. Abbott data on file. ORCHIDEA clinical study report. 2020
Patients experienced significant decreases in the
number of days on which analgesics were required
Analgesic use during treatment (N=350)1
The overall
reduction in use
of analgesics
(80%)
was statistically
significant

26. 5.4
***
3.4
***
2.4
6.0
***
3.7
***
2.6
0
1
2
3
4
5
6
7
Baseline Month 3 Month 6
Mean
intensity
of
chronic
pelvic
pain
and
dysmenorrhea,
NRS
Chronic pelvic pain Dysmenorrhea
ORCHIDEA secondary endpoints demonstrated
improved symptoms of endometriosis
3
***
3.5
***
3.8
0
1
2
3
4
5
6
7
Baseline Month 3 Month 6
Mean
sexual
well-being,
Likert
scale
0.8
(27% increase)
–3.0
(56% reduction)
–3.4
(57% reduction)
***p<0.0001 vs baseline; aData from both treatment regimens
NRS, numerical rating scale
Sukhikh GT, et al. 2021. Submitted manuscript
Treatment with dydrogesterone during the ORCHIDEA study led to significant
improvements in chronic pelvic pain, dysmenorrhea, and sexual well-being
Chronic pelvic pain and dysmenorrhea intensity
during treatmenta (N=350)
Sexual well-being
during treatmenta (N=350)

27. Multiple measures of HR-QoL improved
during the study
41.7
53.1
55.8
73.1
56.2
66.4
54.4
66.4
41.2
85.5 83.5
80.2
***
61.7
***
71.9
***
27.3
***
93.0
***
94.2 ***
86.6
0
20
40
60
80
100
Perceived health
status
Mental health Pain Physical functioning Role functioning Social functioning
Mean
SF-20
score
Baseline Month 3 Month 6
19.9b
(48% increase)
18.8b
(35% increase)
–28.4b
(51% decrease)
20.1b
(27% increase)
38.5b
(68% increase) 20.0b
(30% increase)
Treatment with dydrogesterone led to significant
improvements in multiple measures of HR-QoL during the
ORCHIDEA study
HR-QoL scores during treatmenta (N=350)

28. Dydrogesterone Improves Quality of Life at All Stages
of Endometriosis
● Visit 1 (Baseline) ● Visit 3 (after 6 months of dydrogesterone therapy) *p<.0001
I
Stages of endometriosis (R-AFS) II III IV
Health perception*
Pain*
Psychic health*
Physical functioning*
Role functioning*
Social functioning*
43
55
55
72
66
68
64
71
29
94
98
91
0 50 100
+50%
+34%
+30%
-47%
+29%
+49%
42
54
55
75
58
67
61
72
29
91
94
85
0 50 100
+62%
+27%
+21%
-47%
+34%
+45%
43
54
54
74
60
69
65
74
24
94
96
89
0 50 100
+61%
+29%
+28%
-57%
+36%
+53%
35
46
62
69
29
56
50
68
32
92
84
79
0 50 100
+189%
+41%
+34%
-48%
+49%
+42%
SF-20 score
Dydrogesterone improves the quality of life during all the
four stages of endometriosis

29. Dydrogesterone in Endometriosis: Recommended
Regimen
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Prolonged cyclical regimen
Continuous regimen
Dydrogesterone is the only gestagen of choice
Dydrogesterone
20–30 mg per day
for 6 months or
longer

30. Endometriosis
affects 10% of
women during
their reproductive
age, of which up to
50% women suffer
from infertility.
01
Delayed
diagnosis is a
major problem
leading to
increased distress
among patients.
02
Infertile women are
6 to 8 times more
likely to have
endometriosis than
fertile women.
03
Medical treatment
should regress
endometrioid
lesions, pain, and
menstrual disorders
while preserving
ovarian reserve and
fertility during long-
term use.
04
Key Messages

31. 01 02
Blocks proliferation
and facilitates
apoptosis of
endometriotic
lesions
03
Does not suppress
ovarian function
when given at
therapeutic doses
and preserves
fecundity
04
01 02
Demonstrates anti-
angiogenic and anti-
inflammatory effects
Effectively relieves
endometriosis-
associated pain
with minimal
adverse events
Compensates luteal
phase insufficiency
05
Dydrogesterone is an effective choice for management of endometriosis-
associated infertility

32. Thank You