ENDOMETRIOSIS Panel Disscussion March

ENDOMETRIOSIS & ROLE OF
DYDROGESTERONE
ENDOMETRIOSIS IS THE…..
 Presence of endometrial-like tissue (lesions) outside uterine

cavity
 Diagnosis is often delayed after the onset of symptoms and

mistaken because of its nonspecific complaints
 Asymptomatic endometriotic lesions can be detected in

nearly half of the women seeking infertility treatment
CHEN LH, LO WC, HUANG HY, WU HM. A LIFELONG IMPACT ON ENDOMETRIOSIS: PATHOPHYSIOLOGY AND PHARMACOLOGICAL TREATMENT. INT J MOL SCI. 2023 APR 19;24(8):7503. DOI:
10.3390/IJMS24087503. PMID: 37108664; PMCID: PMC10139092.
CHEN LH, LO WC, HUANG HY, WU HM. A LIFELONG IMPACT ON ENDOMETRIOSIS: PATHOPHYSIOLOGY AND PHARMACOLOGICAL TREATMENT. INT J MOL SCI. 2023 APR 19;24(8):7503. DOI: 10.3390/IJMS24087503.
PMID: 37108664; PMCID: PMC10139092.
ENDOMETRIOSIS AND INFERTILITY
Avoiding sexual intercourse - dyspareunia & chronic pelvic pain

limits feasibility of natural conception
Pelvic adhesion  anatomical distortion interrupting conception

process including oocyte release from ovaries, ovum pickup, and
transport through fallopian tubes
Oxidative stress in endometrioma causes damage to adjacent
healthy ovarian cortex - reducing ovarian reserve
Alterations of intrafollicular microenvironment and aberrant

steroidogenesis impair folliculogenesis and oocyte competence
Dysregulation of immune and inflammatory profiles plays an

essential role in recurrent implantation failure and early pregnancy
loss
10.3390/IJMS24087503.
10.3390/IJMS24087503.
PRESENTATION
 Endometriosis of the diaphragm and pleura has been associated with chest and shoulder
pain
 Neurological changes and chronic inflammation in endometriosis enhance pain perception,

anxiety, fatigue, and depression
CHEN LH, LO WC, HUANG HY, WU HM. A LIFELONG IMPACT ON ENDOMETRIOSIS: PATHOPHYSIOLOGY AND PHARMACOLOGICAL TREATMENT. INT J MOL SCI. 2023 APR 19;24(8):7503. DOI: 10.3390/IJMS24087503.
QUESTIONS
 How often do you see patients of endometriosis in your practice?
 Which age group patients usually come with symptoms of endometriosis in your clinic?
 What % of endometriosis patient present in your clinic with difficulty in conceiving?
 What are the most major concerns of the endometriosis patients that you have come across
 What is the most common symptoms that endometriosis patients present with in your practice?
 Which is the most atypical presentation of endometriosis patient you have seen?
 What is the maximum duration that a patient has had symptoms of endometriosis and has not approached a doctor for the
same?
DIAGNOSIS
Clinical TVS MRI

examination
CA – 125 Laparoscopy
QUESTIONS
 How often is one able to diagnose the condition with patient history and examination
according to your experience?
 What is the most preferred diagnostic test to confirm the case of endometriosis?
 How often is endometriosis diagnosed accidentally?
 When doing laparoscopy is removal also done at the same time?
 How often is CA 125 analysis done for the diagnosis of endometriosis?

M
A
N
A
G
E
M
E
NT
MANAGEMENT
HORMONAL MANIPULATION
Targets on presumed altered steroidogenesis in

endometriosis
Act by suppressing fluctuations in gonadotropic

and ovarian hormones
Resulting in the inhibition of ovulation and the

reduction of menstrual bleeding
CHEN LH, LO WC, HUANG HY, WU HM. A LIFELONG IMPACT ON ENDOMETRIOSIS: PATHOPHYSIOLOGY AND
PHARMACOLOGICAL TREATMENT. INT J MOL SCI. 2023 APR 19;24(8):7503. DOI: 10.3390/IJMS24087503.
SOME POINTS TO PONDER ON
 What is the most preferred method for management of endometriosis?
 What are the consideration or points that are to be noted while choosing a specific
management method?
 What are the most preferred drugs for the management of endometriosis?
 How often is fertility a consideration while choosing a particular management mode?
 For patients wanting to achieve fertility what is the most preferred treatment?
DYDROGESTERONE
 Retro progesterone derived from progesterone that is similar in structure and pharmacology
to endogenous progesterone
 Acts as a selective progesterone receptor agonist and has better oral bioavailability
compared with oral micronized progesterone
 Since the 1960s and is used as postmenopausal hormone-replacement as well as for

treatment of menstrual disorders and endometriosis
PENG C, HUANG Y, ZHOU Y. DYDROGESTERONE IN THE TREATMENT OF ENDOMETRIOSIS: EVIDENCE MAPPING AND META-ANALYSIS. ARCH GYNECOL OBSTET. 2021 JUL;304(1):231-252. DOI:
10.1007/S00404-020-05900-Z. EPUB 2021 JAN 4. PMID: 33398505; PMCID: PMC8164626
DYDROGESTERONE
 Has additional double bond between C6 and C7
 Highly selective progestin and less in its androgenic, anti-androgenic, glucocorticoid and anti-
glucocorticoid effects
 Binds exclusively to PR – B
 Selectivity results in minimal or no unwanted side-effects
ABDUL KARIM, A. K., SHAFIEE, M. N., ABD AZIZ, N. H., OMAR, M. H., ABDUL GHANI, N. A., LIM, P. MOKHTAR, N. (2018). REVIEWING THE ROLE OF PROGESTERONE THERAPY IN ENDOMETRIOSIS.
GYNECOLOGICAL ENDOCRINOLOGY, 1–7. DOI:10.1080/09513590.2018.1490404
DYDROGESTERONE - ACTION
These effects are less

pronounced in dienogest
compared to dydrogesterone
DYDROGESTERONE ACTION ON ENDOMETRIOSIS
 Dydrogesterone has been shown to relieve symptoms of endometriosis, regress lesions, and
improve pregnancy rates in patients with infertility
Proposed mechanism underlying the pharmacological action of

progestogens involves initial decidualization of endometrial tissue and
eventual atrophy
Dydrogesterone causes atrophy of ectopic endometrium without

suppressing normal endometrium and simultaneously inhibits
development of new endometriotic lesions
Does not inhibit ovulation and regular menstruation and does not
induce weight gain and edema
PENG C, HUANG Y, ZHOU Y. DYDROGESTERONE IN THE TREATMENT OF ENDOMETRIOSIS: EVIDENCE MAPPING AND META-ANALYSIS. ARCH GYNECOL OBSTET. 2021 JUL;304(1):231-252. DOI: 10.1007/S00404-
020-05900-Z. EPUB 2021 JAN 4. PMID: 33398505; PMCID: PMC8164626
Meta analysis –Evidence mapping
of Dydrogesterone in
endometriosis treatment
EVIDENCE MAPPING
 9 RCTs, 4 CCTs and 1 cohort study that compared the effect of various dosages of
dydrogesterone with non-dydrogesterone therapies
 Evidence mapping included 1709 female participants
 Dydrogesterone was found to be more effective than gestrinone in relieving dysmenorrhea

and achieving a higher pregnancy rate and was associated with a lower risk
 Compared with GnRH-a, dydrogesterone was also associated with a lower risk of
endometriosis recurrence and elevated transaminase levels
Overall 74% patients rated Dydrogesterone use as excellent to good and
70% doctors rated the same in the study
ADVANTAGES OF DYDROGESTERONE
Relatively low
Does not suppress Most of available antagonistic
normal evidence indicates activity at
endometrium or - dydrogesterone Patients are able glucocorticoid &
alter natural does not inhibit to conceive while mineralocorticoid
progression of ovulation and on receptors
endometriosis regular dydrogesterone if compared with
while causing menstruation at they desire progesterone –
atrophy of ectopic usual therapeutic weight gain &
endometrium dosages edema not
observed
PROLONGED CYCLICAL AND CONTINUOUS REGIMENS OF DYDROGESTERONE ARE EFFECTIVE FOR REDUCING CHRONIC PELVIC PAIN IN WOMEN
WITH ENDOMETRIOSIS: RESULTS OF ORCHIDEA STUDY
SUKHIKH G,ADAMYAN L,DUBROVINA S, PROLONGED CYCLICAL AND CONTINUOUS REGIMENS OF DYDROGESTERONE ARE EFFECTIVE FOR REDUCING CHRONIC PELVIC PAIN IN WOMEN WITH
ENDOMETRIOSIS: RESULTS OF THE ORCHIDEA STUDY, FERTILITY AND STERILITY,,2021,HTTPS://DOI.ORG/10.1016/J.FERTNSTERT.2021.07.1194.
ORCHIDEA STUDY
 350 women between 18 – 45 age group
 Compared cyclical and continuous regimen of Dydrogesterone 10 mg 2-3 times a day
 Cyclical was between 5 – 25 days and for both the cut off was use till 6 months
ORCHIDEA - RESULTS
PRIMARY OUTCOMES
After 6 months mean change in chronic
pelvic pain intensity score was –3.3 (2.2;
P<0.0001) in continuous regimen
89.9% & 81.8% patients in prolonged

cyclical & continuous groups experienced
any reduction in pain intensity
In dydrogesterone 20 mg daily use there

was significant in intensity of chronic
pelvic pain
SECONDARY OUTCOMES
Significant In intensity of chronic pelvic
pain, number of days analgesics were
required and severity of dysmenorrhea
ORCHIDEA STUDY - RESULTS
Significant decreases In intensity of

chronic pelvic pain number of days in
which analgesics were required and
severity of dysmenorrhea
Improvements in sexual well-being and

in measures of HR-QoL including
perceived health status, mental health,
pain and physical and social
functioning
No significant differences
DYDROGESTERONE USE IN STUDIES SHOWED
 Studies have used between 10 and 60 mg/day for various duration per cycle over one to six months
 Majority of women became symptom-free or experienced a significant reduction in the

number/severity of symptoms
 Dydrogesterone has also been used in doses of 5 to 10 mg in combination with estradiol valerate as
add-back therapy for postoperative GnRH analog in moderate to severe endometriosis
 Combination of 0.1 mg estradiol valerate/5 mg dydrogesterone can reliably relieve pain symptoms,
reduce bone mass loss, alleviate menopausal symptoms, improve quality of life, minimize overall
adverse effects, improve patient compliance and prolong GnRH agonist treatment duration
ABDUL KARIM, A. K., SHAFIEE, M. N., ABD AZIZ, N. H., OMAR, M. H., ABDUL GHANI, N. A., LIM, P. S., … MOKHTAR, N. (2018). REVIEWING THE ROLE OF PROGESTERONE THERAPY IN ENDOMETRIOSIS.
GYNECOLOGICAL ENDOCRINOLOGY, 1–7. DOI:10.1080/09513590.2018.1490404
CLINICAL STUDY
PMS in 15 sites in Japan
10 mg BD  5-25 day of cycle in

women aged 20 – 49
RESULTS
• Endometrioma volume reduction

seen in 50%, unchanged in 25%
and increase in 25%
• Significantly reduce
dysmenorrhea scores, severity of
dysmenorrhea pain VAS
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
SOME MORE POINTS TO PONDER ON
 How often do you prescribe Dydrogesterone for the management of endometriosis?
 What are the aspects taken into consideration before starting a patient on
Dydrogesterone?
 What is the maximum duration the patients are prescribed Dydrogesterone or any
hormonal therapy?
 What % of endometriosis patient present with recurrence in your practice?
 What is the most preferred drug in case of recurrent patients?
 Are hormonal therapies usually prescribed in patients who undergo surgery for
endometriosis?
BIOAVAILABILITY STUDY OF DYDROGESTERONE 30 MG
 Randomized, open label, balanced, two treatment, two period, two sequence, two-way,
crossover, single oral dose, comparative bioavailability study of Dydrogesterone Extended
Release Tablets 30 mg With Duphaston10 mg TID in healthy adult female subjects under
fasting conditions
Investigational
Objectives
Products
Pharmacokinetic: To assess Safety: To monitor the

Reference product (R): the comparative bioavailability safety and tolerability
Duphaston® (Dydrogesterone) between Test product (T), of a single oral dose of
Tablets I.P. 10 mg (Thrice a day) Dydrogesterone Extended- Dydrogesterone
Release Tablets 30 mg with Extended-Release
Test product (T): Reference product (R), Tablets 30 mg in
Dydrogesterone Extended- Duphaston® (Dydrogesterone) healthy adult female
Release Tablets 30 mg Tablets I.P. 10 mg (Thrice a day) subjects.
Primary parameters: AUC0-t and AUC0-inf

Secondary Parameters: AUCExtrapolated%,
AUCRatio%, Tmax, Kel and t1/2
90% Confidence Interval of geometric mean ratio (i.e. Test / Reference) of test (T) and reference (R)
products falls within the range of 80.00% to 125.00% for pharmacokinetic parameters AUC 0-t and
AUC
28 healthy 25 subjects completed
female both periods in the study
subjects (18 to and were considered for
45 yrs.) analysis
Sampling Time Points

1. Screened for Test Product: pre-dose and and 00.25, 00.50, 00.75, 01.00,
gynecological disorder 01.25, 01.50, 01.75, 02.00, 02.25, 02.50, 02.75, 03.00,
2. Hb level more than 03.50, 04.00, 04.50, 05.00, 05.50, 06.00, 06.50, 07.00,
12g/dl 07.50, 08.00, 08.50, 10.00, 12.00, 16.00, 24.00, 48.00* and
3. Dosing was given within 72.00* hr post-dose
10 days of LMP Reference Product: pre-dose 00.17, 00.33, 00.50, 00.75,
01.00, 02.00, 02.25, 02.50, 02.75, 03.00, 03.50, 04.00,
07.00, 07.50, 08.17, 08.50, 09.00, 09.50, 10.00, 11.00,
12.00, 14.00, 15.00, 16.17, 16.50, 16.75, 17.00, 17.50,
18.00, 20.00, 22.00, 24.00, 48.00* and 72.00* hr post-dose
Washout Period: at least 35 days

PHARMACOKINETIC RESULTS
C0-t and AUC0-inf of Dihydrodydrogesterone (N = 25)

Geometric Mean Ratio
Geometric LSM (90% Confidence Interval)
Intra-
(%)
subject
Parameter Power (%)
variability
Test Reference Test vs Ref (%)
AUC
UC0-t and (pg*hrof/mL)
0-tAUC 37267.360
Dydrogesterone (N =34618.076
25) 107.65 (96.68 - 119.87) 22.28 96.10
0-inf
AUC0-inf (pg*hr /mL) 42382.857 38772.925 109.31 (96.53

Geometric - 123.78)
Mean Ratio 25.88 90.68
Geometric LSM (90% Confidence Interval)
Intra-
(%)
subject
Parameter Power (%)
variability
Test Reference T vs R (%)
90% CIs for both the parameters is within the acceptable range of 80% to
SAFETY
There were no abnormalities reported in vital signs and systemic

examination in any subject
Safety Results:
No clinically significant alterations in laboratory parameters were reported

in any subject
No serious adverse event was reported in any subject
Two subjects administered the reference product in Period II reported

dizziness & headache and 3 in test group. Both these events were mild,
probably related to the study drug, and resolved within 6 hours without any
supportive medication
36
Overall, both the study drugs were found to be well

tolerated in the study
CONCLUSION
 90% confidence intervals of the ratio of geometric least squares means for the Ln-transformed
pharmacokinetic parameters AUC 0-t and AUC0-inf of Dydrogesterone are within the bioequivalence
acceptance limits of 80.00 - 125.00%
 Results conclude that the Test product, Dydrogesterone Extended-Release Tablets 30mg of M/s.
Zydus Healthcare Limited, India is comparatively bioavailable to the Reference product,
Duphaston® (Dydrogesterone) Tablets I.P. 10mg (thrice a day) of M/s. Abbott India Limited, India in
terms of rate and extent of absorption under fasting conditions
37
PHASE III STUDY OF DYDROGESTERONE 30 MG
A Prospective, Randomized, Double-Blind, Single-Dummy, Two-Arm, Active-Controlled, Parallel,

Multicentre, Phase III Clinical Trial to Assess the Efficacy and Safety of Dydrogesterone
Extended Release Tablets 30 mg as Compared to Dydrogesterone Tablets 10 mg for Treatment
of Endometriosis in Women
Study Flow Chart

DISPOSITION OF SUBJECTS
39
Inclusion Criteria
Female patients of age 18-45 years (both inclusive)
Patients diagnosed with endometriosis based on USG
Patients with an endometriosis-associated pain score of at least 30mm on a 100mm

visual analog scale
Patients willing to give written informed consent and comply with the study
procedures
Dosing Regimen
Study Endpoints
Secondary Endpoint
Efficacy
PRIMARY ENDPOINT  Consumption of rescue pain medication for endometriosis-
associated pelvic pain during the study period in the two groups.
 Change in size of Endometrioma from baseline to end of study
Change in
Endometriosis as assessed by USG
Associated Pelvic Pain  Change in serum VEGF levels from baseline to the end of the
(EAPP) from baseline study in the two groups
to end of study as  Changes from baseline in the health-related quality of life using
assessed on 100mm the HRQoL-4 questionnaire in the two groups at the end of the
VAS scale study
Safety
 Adverse events reported during the study
 Serious adverse events reported during the study
Primary Endpoint: Endometriosis Associated Pelvic
Pain (EAPP)
Test group Reference group
VAS Score
(N = 115) (N = 113)
Visit 2 / Day 0 62.13 (11.58) 61.05 (10.62)
Visit 3 / Day 30 47.20 (12.15) 47.14 (11.23)
Visit 4 / Day 60 34.05 (13.41) 34.71 (12.62)
Visit 5 / Day 90 22.69 (14.12) 23.42 (14.26)
Data presented as mean (SD)

SECONDARY ENDPOINT: CHANGE IN SIZE OF ENDOMETRIOMA AS ASSESSED BY
USG
Size of Reference
Test group
endometriom Group P value#
(N =115)
a (N=113)
Visit 1 /
16.63
Baseline 16.46 (7.54) ---
(cm2) (9.08)
Visit 5 / Day
6.86 (6.06) 6.72 (5.80) ---
90 (cm2)
Percentage 62.36
61.68 (28.68) 0.13
Reduction (%)* (24.43)
*Data presented as mean (SD)
#
P value calculated using 2-sample t-test
44
SECONDARY ENDPOINT: RESCUE PAIN MEDICATION FOR
ENDOMETRIOSIS-ASSOCIATED PELVIC PAIN
Reference
Rescue medication Test group P
group
use (N = 115) value#
(N = 113)
Visit 2 to 3 (Day 0-
8.18 (4.74) 8.33 (5.12) 0.82
30)*
5.63 (4.00) 5.05 (3.96) 0.28
60)*
2.49 (2.55) 2.70 (2.65) 0.54
90)*
*Data presented for Number of tablets consumed as mean (SD)
#
SECONDARY ENDPOINT: CHANGE IN SERUM VEGF LEVELS
Reference P
Serum VEGF Test group
Group value
levels (mIU/ml) (N =115)
(N=113) #
Visit 1 / 311.45 331.74

---
Baseline (99.64) (125.74)
Visit 5 / Day 153.05 176.12
---
90 (87.71) (104.52)
-158.40 -155.62
Mean change* 0.81
(81.97) (89.59)
*Data presented as mean (SD)
#
SECONDARY ENDPOINT: HRQOL-4 QUESTIONNAIRE SCORE FROM BASELINE TO END OF STUDY

HRQoL-4 Score
(N = 115) (N = 113)
Visit 2 / Day 0 22.40 (13.22) 22.29 (12.59)
Visit 3/ Day 30 17.23 (8.47) 16.96 (7.68)
Visit 4 / Day 60 12.05 (4.59) 12.13 (4.64)
Visit 5 / Day 90 8.93 (3.57) 9.19 (3.74)
Data presented as mean (SD)
47
SAFETY ENDPOINTS
Incidence of Adverse Events

SOC Term Preferred Term
(N = 115) (N = 113)
Nausea 2 (1.7%) 3 (2.7%)
Gastrointestinal disorders Vomiting 2 (1.7%) 0 (0.0%)
Abdominal pain 0 (0.0%) 3 (2.7%)
Bloating 0 (0.0%) 2 (1.8%)
General disorders and
administration site Fever 3 (2.6%) 2 (1.8%)
conditions
Musculoskeletal and
connective tissue Back pain 1 (0.9%) 1 (0.9%)
disorders
Headache 2 (1.7%) 3 (2.7%)
Nervous system disorders
Dizziness 1 (0.9%) 0 (0.0%)
48
Reproductive system and
Breast tenderness 2 (1.7%) 2 (1.8%)
breast disorders
Data presented as n(%); % calculated from No. of subjects analyzed for safety
CONCLUSION
 The results of this prospective, randomized, double-blind, single-dummy, two-arm,

active-controlled, parallel, multicentre, phase III clinical trial suggest that the efficacy of
Dydrogesterone Extended-Release Tablets 30mg given once daily is non-inferior to
Dydrogesterone Tablets 10mg given thrice daily for management of endometriosis
 Dydrogesterone Extended Release Tablets 30mg was well tolerated and its safety
profile is also similar to Dydrogesterone 10mg tablets in patients with endometriosis.
49

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ENDOMETRIOSIS & ROLE OF

 Presence of endometrial-like tissue (lesions) outside uterine

 Diagnosis is often delayed after the onset of symptoms and

 Asymptomatic endometriotic lesions can be detected in

Avoiding sexual intercourse - dyspareunia & chronic pelvic pain

Pelvic adhesion  anatomical distortion interrupting conception

Alterations of intrafollicular microenvironment and aberrant

Dysregulation of immune and inflammatory profiles plays an

 Neurological changes and chronic inflammation in endometriosis enhance pain perception,

 How often do you see patients of endometriosis in your practice?

 What % of endometriosis patient present in your clinic with difficulty in conceiving?

Clinical TVS MRI

 How often is endometriosis diagnosed accidentally?

 When doing laparoscopy is removal also done at the same time?

 How often is CA 125 analysis done for the diagnosis of endometriosis?

Targets on presumed altered steroidogenesis in

Act by suppressing fluctuations in gonadotropic

Resulting in the inhibition of ovulation and the

 What is the most preferred method for management of endometriosis?

 How often is fertility a consideration while choosing a particular management mode?

 Since the 1960s and is used as postmenopausal hormone-replacement as well as for

 Has additional double bond between C6 and C7

 Selectivity results in minimal or no unwanted side-effects

These effects are less

Proposed mechanism underlying the pharmacological action of

Dydrogesterone causes atrophy of ectopic endometrium without

 Evidence mapping included 1709 female participants

 Dydrogesterone was found to be more effective than gestrinone in relieving dysmenorrhea

 350 women between 18 – 45 age group

 Compared cyclical and continuous regimen of Dydrogesterone 10 mg 2-3 times a day

89.9% & 81.8% patients in prolonged

In dydrogesterone 20 mg daily use there

Significant decreases In intensity of

Improvements in sexual well-being and

 Majority of women became symptom-free or experienced a significant reduction in the

PMS in 15 sites in Japan

10 mg BD  5-25 day of cycle in

• Endometrioma volume reduction

 What % of endometriosis patient present with recurrence in your practice?

 What is the most preferred drug in case of recurrent patients?

Pharmacokinetic: To assess Safety: To monitor the

Primary parameters: AUC0-t and AUC0-inf

Sampling Time Points

Washout Period: at least 35 days

C0-t and AUC0-inf of Dihydrodydrogesterone (N = 25)

AUC0-inf (pg*hr /mL) 42382.857 38772.925 109.31 (96.53

There were no abnormalities reported in vital signs and systemic

No clinically significant alterations in laboratory parameters were reported

No serious adverse event was reported in any subject

Two subjects administered the reference product in Period II reported

Overall, both the study drugs were found to be well

A Prospective, Randomized, Double-Blind, Single-Dummy, Two-Arm, Active-Controlled, Parallel,

Study Flow Chart

Female patients of age 18-45 years (both inclusive)

Patients diagnosed with endometriosis based on USG

Patients with an endometriosis-associated pain score of at least 30mm on a 100mm

Visit 3 / Day 30 47.20 (12.15) 47.14 (11.23)

Visit 4 / Day 60 34.05 (13.41) 34.71 (12.62)

Visit 5 / Day 90 22.69 (14.12) 23.42 (14.26)

Data presented as mean (SD)