PANEL DISCUSSION ON ENDOMETRIOSIS IN ADOLESCENTS (2018 ) MODERATOR DR SHARDA JAIN DR ILA GUPTA DR DIPTI NABH panelist UMA RAI RAJ BOKARIA JYOTI AGARWAL JYOTI BHASKER RENU CHAWLA DIPTI NABH VANDANA GUPTA

1. PANEL DISCUSSION ON
ENDOMETRIOSIS IN
ADOLESCENTS
(2018 )
MODERATOR
DR SHARDA JAIN
DR ILA GUPTA
DR DIPTI NABH

2. PANNELISTS
• UMA RAI
• RAJ BOKARIA
• JYOTI AGARWAL
• JYOTI BHASKER
• RENU CHAWLA
• DIPTI NABH
• VANDANA GUPTA
9TH
AUGUST
2018

3. introduction
• ENDOMETRIOSIS..ENIGMA
• OUR PROBLEM..RR /OR
• AVAILBLE TREAMENT
• 4 cases
• DNG...WONDER DRUG
• ALL ABOUT DRUG
• EDGE OF DNG OVER GnRh a.
• PROGESTOGENS
• SIDE EFFECTS
• CONTRAINDICATIONS

4. Endometriosis-an enigma
• Endometriosis is defined as the presence of
endometrial-like tissue outside the uterus,
which induces a chronic, inflammatory
reaction (Kennedy, et al., 2005). Its USP..can be
summed up in 4 lines.
• DIAGNOSTIC DELEMMA…Takes 5 to 7 yrs
• DEBILITATING Disease
• PROGRESSIVE Disease
• NO CURE Today

5. PREVALANCE
• The exact prevalence of endometriosis is
unknown but estimates are that around 10%
of the general female population & up to 50%
in infertile women (Eskenazi and Warner,
1997;, Meuleman, et al., 2009) have
Endometriosis.

6. ASRM has stated that,
“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.”
Fertil & Steril, 2008
Why :recurrence-high/
decrease in ovarian reserve

7. CURRENTLY AVAILABE TREATMENT
MEDICAL
• Danazol
• GnRh a
• OCP
• Progestogens
• DIENOGEST
• SURGERY
• Diag.Laparoscopy
• Open surgery
• Operative LAP for
Deep infiltrative
Endometriosis
Big chocolate cyst
IUI / IVF /ICSI /SURROGACY

8. TYPE OF CASES IN ADOLESCENTS
• BIG CHOCOLATE CYST..BABY HEAD SIZE
• CHOCOLATE CYST—LESS THAN 5 CMS
• SEVERE DYSMENORROEA
EARLIER THE DISEASE PRESENTS—
WORSE IS PRESENTATION

9. ADOLESCENT GIRL..CASE I
• 20 yrs young unmarried female presenting
with progressive dysmenorrhoea, periodic
bloating, diarrhea or constipation for last few
years
• Clinical examination was normal
• Per vaginal - not done/ ..P/R ..NORMAL
• USG -- lower abdomen revealed nothing
abnormal

10. TRANS RECTAL SONOGRAPHY ??
CA 125—NOT FOR DIAGNOSIS ..
MRI --NOT NEEDED
LAPAROSCOPY: NOT NEEDED FOR
PROVISIONAL DIAGNOSIS IN THIS CASES

11. ESHRE--2003
• CLINICIANS SHOULD BE AWARE THAT THE
USEFULNESS OF MAGNETIC RESONANCE
IMAGING (MRI) TO DIAGNOSE PERITONEAL
ENDOMETRIOSIS IS NOT WELL ESTABLISHED
(STRATTON, ET AL., 2003.
• NOT NEEDED for further MANGEMENT

12. ESHRE--2010
• CLINICIANS ARE RECOMMENDED NOT
TO USE IMMUNOLOGICAL
BIOMARKERS, INCLUDING CA-125, IN
PLASMA, URINE OR SERUM TO
DIAGNOSE ENDOMETRIOSIS
(MAY, ET AL., 2010, MOL, ET AL., 1998).

13. ESHRE –2010
GUIDELINES FOR
DEEP INFILTRATIVE DISEASE
• THE GDG RECOMMENDS THAT CLINICIANS
SHOULD ASSESS URETER, BLADDER, AND
BOWEL INVOLVEMENT BY ADDITIONAL
IMAGING IF THERE IS A SUSPICION BASED ON
HISTORY OR PHYSICAL EXAMINATION OF DEEP
ENDOMETRIOSIS, IN PREPARATION FOR
FURTHER MANAGEMENT
GDG – Guideline Development Group NHS

14. HOW TO TREAT ?
• ANALGESICS
• ORAL CONTRACEPTIVES
• DINOGEST/PROGESTOGENS
• GNRH ANALOGUE

15. THE PANEL RECOMMENDS
In this case
• Clinicians to counsel GIRL & HER PARENTS -That
symptoms are presumed to be due to
endometriosis
• Tell them it is Life long Disease and needs
Lifelong planning of Treatment
• Surgery to be avoided just to diagnose
Endometriosis
• At present to empirically treat her for 60 days with
adequate analgesics, combined hormonal
contraceptives or Progestagens or DIENOGEST—for
diagnosis& relief of Symptoms –if symptom of PAIN
disappears..it confirms the diagnosis

16. ???
Why your choice is DIENOGEST in
endometriosis associated pelvic
pain ?
Is Dienogest effective in adolescent
endometriosis?

17. • DIENOGEST is recent entry for the
treatment of endometriosis
• Dienogest at a dose of 2 mg daily for 12
weeks was significantly more effective
than placebo or other Drugs for
reducing endometriosis associated pain

18. Dienogest (2mg/d) substantially decreases endometriosis
associated pelvic pain. By week 4, the VAS score decreased to
36.8 mm and by week 48 to the lowest mean value of 9.0 mm
18
• *Standard Error of the mean is shown; EOT: End of treatment ; VAS: Visual Analogue Scale
• Figure adapted to data in 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 17.5 16.1 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

19. 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
Pag
e 19
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

20. Rationale for using Progestins-Dienogest in
treatment of Endometriosis
Page
20
* 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

21. Changes in Bone Mineral Density (BMD)
• The use of Dienogest in adolescents (12 to 18 years) over a
treatment period of 12 months was associated with a mean decrease
in bone mineral density (BMD) in the lumbar spine of 1.2%. After
cessation of treatment, BMD increased again in these patients.
• Loss of BMD is of particular concern during adolescence and early
adulthood, a critical period of bone accretion. It is unknown if BMD
decrease in this population will reduce peak bone mass
• Therefore, the treating physician should weigh the benefits of
Dienogest against the possible risks of use in each individual
adolescent patient also taking into account the presence of
• significant risk factors for osteoporosis. Adequate intake of calcium
and Vitamin D, whether from the diet or from supplements, is
important for bone health in women of all ages.

22. CONCLUSION of panel
– 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
22

23. CASE II
19 yrs old girl is having rt sided endometrioma
of 5 cm ,she had h/o laparoscopic
Appendicectomy.
HOW YOU ARE GOING TO MANAGE HER ??

24. • The PANEL recommends that clinicians
counsel the girl & her parents with
endometrioma regarding the risks of reduced
ovarian function after surgery and may be
the possible loss of the ovary.
• The decision to proceed with surgery should
not be considered if the woman has had
previous LAPAROSCOPIC surgery.

25. • In GIRL with endometrioma less than 5 cm,
the PANEL recommends clinicians only to use
Medical Treatment with DIENOGEST for 12
weeks..
• If symptoms go away..one can stop it.
• SURGERY—ONLY For ENDOMETRIOSIS-
ASSOCIATED severe PAIN. PAIN…Signify
infiltrative disease.

26. CASE III
• CASE OF ENDOMETRIMA..3 CMS IN 20 YRS
YEARS OLD GIRL JUST MARRIED BUT STUDYING
–NOT WANTING TO HAVE CHILD.
• CA 125 45
• REST NORMAL.
• TREATMENT--DIENOGEST IS THE
CHOICE OF PANELISTS
• WHY ?

27. Long term DNG treatment beyond one year as first-line
treatment for endometriosis proved to be effective and safe
Ovarian chocolate cysts markedly reduced by short-term use of
DNG
• Aim: To evaluate the efficacy and adverse effects of Dienogest (DNG) over at least 53 weeks for the
treatment of endometriosis
• Study Design: Retrospective examinations of medical records of 75 patients over a minimum period of
53 weeks
Average reduction rate of endometriotic cyst
• Ovarian endometriotic cysts were
reduced satisfactorily until 15 months.
• At 18 months, ovarian endometriotic
cysts increased slightly, because of a short
cessation of dienogest in some cases
(patients considered they no longer
required DNG)
Average Duration: 87 weeks (~ 1 year 7 months)
Longest follow-up: 120 weeks (~ 2 years 3 months)
Sugimoto et al. Use of dienogest over 53 weeks for the treatment of endometriosis. J. Obstet. Gynaecol. Res. 2015

28. CASE 4
WOMEN aged 18 has chocolate cyst
of 10 cm--.went to emergency at
night.
• CA 125 58
• Any role of Dienogest in this case
of endometrioma ?
• SURGERY..If so why ?

29. SURGERY..OVARIAN CYSTECTOMY
TO PREVENT RECURRENCE OF DISEASE.
• GIVE HER DIENOGEST
• Dose of Dienogest already discussed.—
• Dienogest could be taken safely for one year
or more without recurrence of disease.

30. No recurrence was observed in Dienogest group during treatment
Recurrence rate in Expectant Management Group was 16.5% at 12 months and 24.0% at 24
months
• Aim: To assess the effect of dienogest on recurrence of ovarian endometriomas and
severity of pain after laparoscopic surgery
• Study Design & Type: Retrospective study of 81 patients was performed at three
institutions in Osaka, Japan
Adachi et al. Postoperative administration of dienogest for suppressing recurrence of disease and relieving pain in subjects with ovarian endometriomas.
GynecologicalEndocrinology, DOI: 10.3109/09513590.2016.1147547
VAS Scores at baseline and 6, 12, 18 & 24 months Recurrence-free survival (Kaplan–Meier method)
Dienogest Group
Expectant Management Group
Dienogest is effective in preventing recurrence of ovarian endometrioma and
relieving pelvic pain after laparoscopic surgery

31. Common side effects of Dienogest

32. Frequency of most common drug related adverse
events comparable with that in adult population
•
• 1. Ebert AD et al. J Pediatr Adolesc Gynecol. 2017, doi: 10.1016/j.jpag.2017.01.014. 2. Strowitzki T et al. Int J Womens Health 2015: 7 393–401.
Common drug-related Adverse
Events Adolescents
Pooled safety data in adults2,
(n=332)
N (%) N (%)
Headache 10 (9.0) 30 (9.0)
Breast discomfort 8 (7.2) 18 (5.4)
Depressed mood 1 (0.9) 17 (5.2)
Acne 2 (1.8) 17 (5.2)
Nausea 3 (2.7) 14 (4.2)
Weight increased 7 (6,3) 12 (3.6)
Abdominal pain 6 (5.4) 12 (3.6)
Asthenic conditions 1 (0.9) 10 (3.0)
Flatulence 0 (0) 10 (3.0)
Ovarian cyst 1 (0.9) 10 (3.0)
Vomiting 4 (3,6) 4 (1.2)
32

33. Long term use of Dienogest

34. Long term efficacy and safety of Dienogest
Dienogest is the most effective to reduce the recurrence of endometrioma and
therefore the necessity of re-operation for a prolonged period
34
• Ota et al. Long-term administration of dienogest reduces recurrence after excision of endometrioma . Journal of Endometriosis and Pelvic Pain Disorders 2015; 7(2): 63-67
Study Duration: 5 years
Other Key Findings:
1. No abnormality in serum lipid
concentrations or liver enzymes
during the 5 years.
2. Decrease in the bone mineral
density of more than 4% was
observed in 4.6% (7/151) of the
patients only. It was not
clinically significant
Significant reduction in post surgical recurrence with Dienogest;
2.6% (4/151) recurrence of ovarian endometriomas as compared to
22% in the no-postoperative-medication.

35. Dinogest: Long-term administration
Effect on Endometriosis Recurrence Post-Laparoscopic Resection
• Retrospective analysis: 126 patients
• Post-laparoscopic resection of Uterosacral ligaments
(USLs) with deep infiltrating endometriosis
• Treatment Groups: DNG and no medication
• To evaluate the effect of dienogest (DNG) in preventing
the occurrence of pain and endometriomas after
laparoscopic resection
• Average duration of Dienogest administration: 31 + 17.6
months
• There were three (5.0%) cases of endometrioma in 59
patients from the DNG group and 21 (31.3%) cases in 67
patients from the no medication group (p= 0.0002)
• Pain returned to preoperative levels in eight (11.9%)
cases in the no medication group. No recurrence of pain
occurred in the DNG group (p = 0.0061).
Prevalence of pain at the same level as preoperatively,
in no medication group
Yamanaka A, Hada T, Matsumoto T et al. Effect of dienogest on pain and ovarian endometrioma occurrence after laparoscopic resection of uterosacral ligaments with deep infiltrating endometriosis.
European Journal of Obstetrics & Gynecology and Reproductive Biology. 2017; 216: 51–55
Recurrence of endometrimas in no medication and
dienogest groups

36. Comparison of Dienogest with
GNRH analogue

37. • A 24-week, randomized, multicentre, head-to-head
comparison of dienogest and LA in women with
histologically proven endometriosis demonstrated that
dienogest 2 mg/day orally is as effective as i.m. LA for
relieving endometriosis-associated pelvic pain.
• This finding is of high clinical relevance, as pelvic pain is one
of the most important symptoms of endometriosis and
because agents in the GnRH agonist class are widely
considered a reference standard treatment for improving
these symptoms (Dlugi et al., 1990;Ling, 1999; Prentice et
al., 2000; Crosignani et al., 2006; Schlaffet al., 2006).

38. Contraindications of Dienogest
• Active venous thromboembolic disorder
• Arterial and cardiovascular disease, present or in history
(e.g. myocardial infarction, cerebrovascular accident,
ischemic heart disease)
• Diabetes mellitus with vascular involvement
• Presence or history of severe hepatic disease as long as
liver function values have not returned to normal
• Presence or history of liver tumors (benign or malignant)
• Known or suspected sex hormone-dependent malignancies
• Undiagnosed vaginal bleeding
• Hypersensitivity to the active substance or to any of the
excipients

39. Comparison with GNRH Analogue

40. Take Home Message
• A presumptive Diagnosis of Endometriosis based on
symptoms and clinical assessment is enough.
• Diagnostic laproscopy once considered the gold
standard to diagnose endometriosis is no longer
considered so.
• CA 125 has no role in conforming the diagnosis of
endometriosis.
• In adolescents unless there is severe pain indicating
deep infiltrative endometriosis or the size of
endometrioma is more than 5cm and is associated with
severe pain, operative / diagnostic laproscopy is not
needed.

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