Managing Endometriosis

1. MANAGING
ENDOMETRIOSIS
Dr. Teh Beng Hock
Obstetrician & Gynaecologist
Gynaecological Oncologist
Department Of O&G
Sarawak General Hospital.
FMS Update
9th September
2017

2. MANAGING ENDOMETRIOSIS
– FROM A PRIMARY HEALTHCARE PERSPECTIVE
• INTRODUCTION ✓
• PATHOGENESIS & THEORIES ✘
• CLINICAL MANIFESTATIONS & STAGING ✘
• INVESTIGATIONS ✘
• MANAGEMENT ✓

3. DEFINITION
A MEDICAL CONDITION IN WHICH TISSUE SIMILAR
TO NORMAL ENDOMETRIUM IN STRUCTURE AND
FUNCTION IS FOUND IN LOCATIONS OTHER THAN
THE ENDOMETRIAL LINING

4. CLINICAL SYMPTOMS
Endometriosis
Dysmenorrhoea /
Chronic Pelvic pain
Infertility
Bladder
symptoms
Bowel
symptoms
Dyspareunia
Menstrual
Irregularities

5. MANAGEMENT
- Live well with
Endometriosis

6. Management
strategies
• Infertility
•Dysmenorrhoea
• Pelvic Pain
• Dyspareunia
• Menstrual irregularities
• Bowel complaints
• Bladder complaints
•

7. TREATMENT CLASSIFICATION OF
ENDOMETRIOSIS
Symptomatic Medical Surgical
Prostaglandin
inhibitors
Paracetamol
Opioids
Anti-depressants
Combined OCP
Progestogens
LNG-IUS
GnRH-a +/- ‘add-back
therapy’
Danazol
Gestrinone
Diathermy
Laser vaporization
Excision
Ovarian cystectomy
Presacral
neurectomy
TAHBSO

8. TREATMENT CLASSIFICATION OF
ENDOMETRIOSIS
Symptomatic Medical Surgical
Prostaglandin
inhibitors
Paracetamol
Opioids
Anti-depressants
Combined OCP
Progestogens
LNG-IUS
GnRH-a +/- ‘add-back
therapy’
Danazol
Gestrinone
Diathermy
Laser vaporization
Excision
Ovarian cystectomy
Presacral
neurectomy
TAHBSO

9. SYMPTOMATIC
TREATMENT
• ONLY TREAT SYMPTOMS (PAIN)
• PG SYNTHETASE INHIBITORS , PARACETAMOL , OPIOIDS , ANTI-
DEPRESSANTS

10. PG SYNTHETASE INHIBITORS
 ENDOMETRIOSIS MAY BE RELATED TO PG PRODUCTION
 PG SYNTHETASE INHIBITORS ACT BY INHIBITING THE
PRODUCTION OF PG’S
EG : NSAIDS (MEFENAMIC ACID, NAPROXEN, IBUPROFEN ETC)
COX 2 INHIBITOR (CELECOXIB, ARCOXIA)
 SIDE EFFECTS – TO BE EATEN WITH MEAL
 TAKE BEFORE ONSET OF PAIN !! ***

11. TREATMENT CLASSIFICATION OF
ENDOMETRIOSIS
Symptomatic Medical Surgical
Prostaglandin
inhibitors
Paracetamol
Opioids
Anti-depressants
Combined OCP
Progestogens
LNG-IUS
GnRH-a +/- ‘add-back
therapy’
Danazol
Gestrinone
Diathermy
Laser vaporization
Excision
Ovarian cystectomy
Presacral
neurectomy
TAHBSO

12. MEDICAL TREATMENT OF
ENDOMETRIOSIS
Medical Rx
of Endometriosis
(Hormone Suppression)
Oestrogens or
Androgens
Oestrogens &
progestogens
Progestogens
onlyDanazol
Gestrinone
GnRH analogue
LNG-IUS

13. AIM
 TO INDUCE ATROPHY IN THE ECTOPIC ENDOMETRIAL TISSUE
WITH THE USE OF HORMONES
 CHOICE OF MEDICAL TREATMENT :
ADVERSE EFFECTS
COST OF THERAPY
EXPECTED PATIENT COMPLIANCE
 CLINICAL EFFECTIVENESS ARE SIMILAR AMONG ALL HORMONAL
THERAPIES ( RELIEF OF SYMPTOMS AND RECURRENCE RATE ) –
[IB]

14. HORMONE SUPPRESSION THERAPY
 ENDOMETRIOSIS REQUIRE HORMONE/OVARIAN STEROIDS FOR
GROWTH AND DEVELOPMENT
 ENDOMETRIOTIC IMPLANTS POSSESS OESTROGEN, PROGESTOGEN
AND ANDROGEN RECEPTORS
 AIM - SUPPRESS CYCLICAL HORMONE CHANGES FROM THE
OVARY AND PITUITARY --- HYPO-OESTROGENIC STATE
 THE SUCCESS OF TREATMENT DEPENDS ON THE LOCALIZATION
AND DEPTH OF THE IMPLANT

15. RECURRENCE RATE
 IN GENERAL, SUPPRESSES SYMPTOM AND PREVENTS
PROGRESSION BUT DOES NOT PROVIDE LONG LASTING CURE
OF DISEASE
First year 5 - 15 %
5 years 40 - 50%
Minimal disease 35%
Severe disease 75%

16. 1) COMBINED ESTROGEN &
PROGESTOGENS
 FIRST-LINE TREATMENT
 REDUCE OR COMPLETE RELIEVE OF PAIN IN 42% OF PATIENTS
 MAY CONSIDER GIVING CONTINUOUS OCs WITHOUT 7-DAY
BREAK FOR 3 MONTHS

17. 2) PROGESTOGENS (ORAL/DEPOT)
 USED EITHER CONTINUOUSLY OR CYCLICALLY.
 BOTH PROGESTERONE (MPA, DYDROGESTERONE) AND 19-
NORTESTOSTERONE DERIVATIVES (NORETHISTERONE, NORGESTROL,
DIENOGEST) CAN BE USED.
 CAUSES - DECIDUALIZATION AND ATROPHY OF THE TISSUE BY
SUPPRESSING OVARIAN ACTIVITY.
 MOST COMMONLY USED IS MPA EITHER IN THE ORAL (10-30 MG
DAILY) OR INJECTABLE (150 MG MONTHLY).
 EFFECTIVE IN RELIEVING SYMPTOMS IN ABOUT 80% OF CASES.

18. DIENOGEST - A PROGESTIN WITH A SPECIAL CHEMICAL
STRUCTURE, RESPONSIBLE FOR ITS UNIQUE
PHARMACOLOGICAL PROFILE
• SASAGAWA S ET AL. STEROIDS 2008; 73: 222–231.
• RUAN X ET AL. MATURITAS 2012; 71: 337–344
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)
DIENOGEST (VISANNE)

19. Hypothalamus
Pituitary gland
Gonadotropins
Estrogen and progesterone
Negative feed-back
Uterus
Ovary
Estrogen
Progesterone
Endometrium
DIENOGEST: MODE OF ACTION
•CENTRAL EFFECTS
• INHIBITION OF GONADOTROPIN SECRETION:
• MODERATE
• SUPPRESSION OF CIRCULATING ESTRADIOL
• OVARIAN FUNCTION:
• ANOVULATION (2 MG DOSE)
•LOCAL EFFECTS
• ANTI-PROLIFERATIVE
• ANTI-INFLAMMATORY
• ANTI-ANGIOGENIC
•1. KLIPPING C ET AL. J CLIN PHARMACOL 2012; 52: 1704–1713. MCCORMACK PL. DRUGS 2010; 70: 2073–2088.
SASAGAWA S ET AL. STEROIDS 2008; 73: 222–231. SHIMIZU Y ET AL. STEROIDS 2011; 76: 60–67. KATAYAMA H ET
AL. HUM REPROD 2010; 25: 2851–2858.
19

20. ESTRADIOL LEVELS DURING DIENOGEST 2
MG TREATMENT REMAIN WITHIN
SUGGESTED THERAPEUTIC WINDOW
• KLIPPING C ET AL. J CLIN PHARMACOL 2012; 52: 1704–1713. BARBIERI RL. J REPROD MED 1998; 43: 287–292.
0
0
25
50
75
100
125
150
10 20 30 0 10 20 30 40 50 60 70 80
0
91.8
183.5
275.3
367.1
458.9
550.6
Estradiol(pg/ml)
Pre-treatment (days) Treatment (days)
Estradiol(pmol/L)
Pre-
treatment
Treatment with Dienogest 2
mg
20

21. VAS(mm)
mean±SEM
DIENOGEST 2 MG DEMONSTRATES A
SIGNIFICANT REDUCTION IN PAIN VS
PLACEBO
•
• DIENOGEST N=102; PLACEBO N=96,
• SEM: STANDARD ERROR OF THE MEAN. VAS: VISUAL ANALOGUE SCALE
• STROWITZKI T ET AL. EUR J OBSTET GYNECOL REPROD BIOL 2010; 151:193–198.
0
20
40
60
80
0 4 8 12
Dienogest 2mg
Placebo
Weeks of treatment
*
#
*
#p<0.0016
after 4 weeks
*p<0.0001
after 8
and 12 weeks
Change in VAS score:
-15.1mm
-27.4mm
-12.3mm
21
PAIN

22. SUSTAINED PAIN RELIEF UP TO 6 MONTHS
AFTER STOPPING TREATMENT
• N=168 (EXTENSION STUDY, ALL DIENOGEST); FOLLOW-UP TREATMENT FREE: N=34
• SEM: STANDARD ERROR OF THE MEAN. DNG: DIENOGEST, VAS: VISUAL ANALOGUE SCALE
• FIGURE ADAPTED FROM: STROWITZKI T ET AL. EUR J OBSTET GYNECOL REPROD BIOL 2010; 151:193–198. PETRAGLIA F ET AL. ARCH GYNECOL OBSTET 2012; 285(1):167‒173.
0
10
20
30
40
50
60
VAS(mm)mean±SEM
12 65 90
PLACEBO STUDY EXTENSION STUDY TREATMENT-FREE
Weeks of treatment
Placebo
DNG 2 mg/day
DNG 2 mg
(switched from placebo)
DNG 2 mg
(continued on DNG)
Efficacy shown over 15 months
22

23. DIENOGEST 2 MG SIGNIFICANTLY REDUCES
ENDOMETRIOTIC LESIONS
• DIENOGEST 2 MG N=29 (WOMEN FROM MENARCHE TO MENOPAUSE WITH ENDOMETRIOSIS STAGES I TO III (RAFS) CONFIRMED BY LAPAROSCOPY AND BIOPSY)
• FIGURE ADAPTED FROM KÖHLER G ET AL. INT J GYNAECOL OBSTET 2010;108: 21–25.
0%
20%
40%
60%
80%
100%
Baseline 24 weeks
Patients(%)
None
Stage I (minimal)
Stage II (mild)
Stage III (moderate)
At 24 Weeks:
In >80% of patients
no / minimal endometriosis detectable
n=29, treated with Dienogest 2 mg
23ENDOMETRIOTIC
LESIONS

24. SAFETY AND TOLERABILITY ASPECTS
24
1) DURATION OF TREATMENT?
2) ADVERSE EFFECTS
- PV SPOTTING
- ↓ BMD

25. FREQUENCY OF ADVERSE DRUG REACTIONS
(ADRS) DURING TREATMENT WITH
DIENOGEST 2 MG (POOLED ANALYSIS)
•REPORTED ADRS OVER UP TO 15 MONTHS OF DIENOGEST 2 MG TREATMENT:
GENERALLY MILD TO MODERATE IN INTENSITY
USUALLY SUBSIDED WITHIN THE FIRST 3 MONTHS
• STROWITZKI T ET AL. INT J WOMENS HEALTH 2015;7: 393–401.
Most frequently reported ADRs
Total population (n=332)
% of Patients
Headache 9.0
Breast discomfort 5.4
Depressed mood 5.1
Acne 5.1
25

26. 3) LNG-IUS (MIRENA)
 CAUSES ATROPHY OF THE ENDOMETRIUM AND AMENORRHOEA
(BUT NO EFFECT ON OVULATION)
 MAY BE USEFUL IN PAIN CONTROL
 LONG TERM USE POSSIBLE : NO EFFECT ON BMD

27. 4) GNRH AGONISTS
LEUPROLIDE ACETATE (LUCRIN)
GOSERELIN ACETATE (ZOLADEX)
TRIPTORELIN (DIPHERELINE) ***
NAFARELIN ACETATE (SYNAREL)

28.  ↓ REGULATE & DESENSITIZATION OF THE PITUITARY GLAND
→ EXTREMELY LOW LEVELS OF OESTROGEN → AMENORRHOEA
 ↓ IN SERUM OESTRONE, OESTRADIOL, TESTOSTERONE AND
ANDROSTENEDIONE
 75% -90% : SYMPTOMS DISAPPEAR
 OVARIAN FUNCTION WILL RETURN TO NORMAL IN 6 - 12 WEEKS
AFTER 6 MONTHS OF GNRH AGONIST THERAPY

29. 29
Structure formula
Chemical name
D-trp-6-LHRH
Int. generic name (DCI)
Triptorelin
1. Data on file
Diphereline (Triptorelin)

30. Closest analogue to native GnRH-a
• Triptorelin, differs from native GnRH by only one
amino acid while other GnRH agonists have two amino
acid substitutions
1. Data on file

31. GREATEST BINDING AFFINITY
• SPECIFIC, SATURABLE AND REVERSIBLE BINDING TO GNRH
RECEPTORS2,3
• RECEPTOR AFFINITY THAT IS 100 TIMES GREATER THAN
NATIVE GNRH2,3
2. Heyns CF. Am J Cancer 2005;4:169–183. 3. Ipsen Pharma. Triptorelin SR: Summary of product characteristics. 2011.

32. LONGEST HALF-LIFE
• ENHANCED RESISTANCE TO ENZYME DEGRADATION2,3
• LONG HALF-LIFE OF 7.5 HOURS2,3
2. Heyns CF. Am J Cancer 2005;4:169–183; 3. Ipsen Pharma. Triptorelin SR: Summary of product characteristics. 2011.

33. Drug sustained-releasing mechanism
Illustration of sustained-release
microsphere
Active ingredients
(2%) and Polymer (98%)
Continuous
polypeptide releasing
over 28 days
1. Data on file

34. Prolonged half-life:
From natural GnRH 3mins to 7.5hrs
Less vulnerable to peptidase
Stronger affinity to specified receptors:
100 times stronger than natural GnRH
Diphereline® offers more sustained ovarian
suppression.
An Ideal GnRHa

35. STRENGTH OF DIPHERELINE® PR
• DIPHERELINE® PR 3.75 MG: 28-DAY SUSTAINED-RELEASE
FORMULATION
• DIPHERELINE® PR 11.25 MG: 3-MONTH SUSTAINED-RELEASE
FORMULATION
Triptorelin
Acetate
•
Triptorelin
Pamoate
4. Diphereline package insert

37. GNRH AGONISTS & ADD-BACK THERAPY
 A 6 MONTH COURSE OF THERAPY WITH GNRH-A, REDUCES THE
TRABECULAR BONE DENSITY OF LUMBAR SPINE BY 5-6% WHILE A
2-3% REDUCTION IS NOTED AT THE FEMORAL NECK
COMPLETELY RECOVER AFTER 12 TO 24 MONTHS OF DISCONTINUING THERAPY
 ~30 PG/ML OESTRADIOL IS ENOUGH TO PROTECT THE BODY
FROM SUBSTANTIAL BONE LOSS AND NOT HIGH ENOUGH TO
INTERFERE WITH THE INHIBITION OF GROWTH OF
ENDOMETRIOSIS
 REDUCE OR ELIMINATE ADVERSE CLINICAL AND METABOLIC SIDE
EFFECTS ASSOCIATED WITH HYPOOESTROGENISM
 ALSO FACILITATE SAFE AND EFFECTIVE PROLONGATION OF
GNRH AGONISTS THERAPY FOR UP TO 12 MONTHS.

38. VARIOUS 'ADD-BACK‘ THERAPIES FOR GNRH-A :
ESTROGEN
 CONJUGATED EQUINE ESTROGEN (PREMARIN 0.625MG OD)
 PROGYNOVA (1MG/2MG OD)
PROGESTOGENS
 NORETHISTERONE (5MG OD)
 MPA (20-30MG/DAY OR 100MG OD)
ORGANIC BIPHOSPHONATES (± PROGESTOGENS)
 SODIUM ETIDRONATE
OTHERS
TIBOLONE (FIRST CHOICE) (2.5MG OD)
 CALCITONIN

39. DANAZOL
 ATTENUATED ANDROGEN
 SYNTHETIC STEROID – ISOXAZOLE DERIVATIVE OF
ETHISTERONE ( 17- ALPHA-ETHINYLTESTOSTERONE)
 HYPO-OESTROGENIC AND HYPERANDROGENIC ON
STEROID SENSITIVE END ORGANS
 ANDROGENIC AND ANABOLIC
 SIDE EFFECTS: HIRSUTISM, DEEPENING OF VOICE

40. OESTROGENS AND ANDROGENS
 OESTROGENS (STILBOESTROL) AND ANDROGENS
(METHYLTESTOSTERONE).
 ABLE TO RELIEVE PAIN SYMPTOMS BUT HAD SERIOUS SIDE EFFECTS SUCH
AS THROMBOEMBOLISM, ENDOMETRIAL HYPERPLASIA, NAUSEA AND
VOMITING, WHILE METHYLTESTOSTERONE WAS ASSOCIATED WITH ACNE,
DEEPENING OF VOICE AND HIRSUTISM.
 NO ROLE IN MODERN ENDOMETRIOSIS TREATMENT.

41. GESTRINONE
 SYNTHETIC TRIENIC 19-NORSTEROID DERIVATIVE
 MILD ANDROGENIC AND ANTIGONADOTROPHIC PROPERTIES.
 BIND TO PROGESTERONE AND ANDROGEN RECEPTOR BUT NOT TO OESTROGEN
RECEPTOR
 ABOLISHED MID CYCLE GONADOTROPHIN SURGE
 INIHIBITION OF OVARIAN STEROIDOGENESIS
 REDUCTION OF SEX HORMON BINDING GLOBULIN
 2.5 – 5.0 MG ORALLY TWICE WEEKLY FOR 6-9 MONTHS
 INDUCES ENDOMETRIAL ATROPHY AND IN 85-90% PATIENTS BECOME AMNORRHOEIC
WITHIN 2 MONTHS
 S/E: WEIGHT GAIN, BREAKTHROUGH BLEEDING, REDUCED BREAST SIZE, MUSCLE
CRAMPS, UNCOMMONLY HIRSUTISM, VOICE CHANGE AND HOARSENESS

42. AROMATASE INHIBITORS
 POSTULATED THAT ENDOMETRIOTIC LESIONS EXPRESS
AROMATASE AND HENCE ABLE TO PRODUCE OWN
ESTROGEN IN THE ABSENCE OF GONADOTROPHIN
INFLUENCE
 EXPERIMENTAL ?
 AS A LAST RESORT (BAD SIDE EFFECTS)

43. SIDE EFFECTS OF MEDICAL THERAPY
a) HYPO-OESTROGENIC
. FLUSHES . BREAST ATROPHY
. VAGINAL DRYNESS . NIGHT SWEATS
. INSOMNIA
b) PROGESTOGENIC
. IRREGULAR BLEEDING . NAUSEA
. MOOD CHANGES . FLUID RETENTION
c) ANDROGENIC
. WEIGHT GAIN . VIRILIZATION
. ACNE . VOICE CHANGES
. HIRSUTISM
d) METABOLIC
. LIPID . HEPATIC
. SKELETAL

44. TREATMENT CLASSIFICATION OF
ENDOMETRIOSIS
Symptomatic Medical Surgical
Prostaglandin
inhibitors
Paracetamol
Opioids
Anti-depressants
Combined OCP
Progestogens
LNG-IUS
GnRH-a +/- ‘add-back
therapy’
Danazol
Gestrinone
Diathermy
Laser vaporization
Excision
Ovarian cystectomy
Presacral
neurectomy
TAHBSO

45. Surgical Management of Endometriosis
When is Surgery Indicated ?
•Inadequate pain control by medical
methods
•Endometriomas
•Rectovaginal septum endometriosis
•Urinary or bowel symptoms
•Infertility

46. • What types of surgery ?
• Ablative surgery
• Excisional surgery
• THBSO
• Laparoscopy v.
laparotomy

47. • Ovarian
Endometrioma
• Ovarian cystectomy
• Ovarian drainage ✘
• Adnexalectomy
• THBSO

48. SURGICAL TREATMENT OF
ENDOMETRIOSIS
Surgical Rx
of Endometriosis
Laparoscopy /
Laparotomy
-Adhesiolysis
-Ablation
- Excision
-Cystectomy / SO
- TAHBSO
Bladder, Bowel,
Ureteric surgery
Pelvic exenteration
Presacral
neurectomy

49. GENERAL GUIDE IN TREATING
ENDOMETRIOSIS
• SUSPECTED ENDOMETRIOSIS – TRIAL OF MEDICAL TREATMENT FIRST BEFORE SURGERY
• TREATMENT SHOULD BE TAILORED ACCORDING TO:
• AGE
• FERTILITY OR CONTRACEPTIVE WISHES
• SEVERITY AND EXTENT OF THE DISEASE
• AVOID REPEATED SURGERIES IF POSSIBLE
• AVOID GNRH-A IN ADOLESCENTS
• SURGERY IS THE FIRST-LINE OPTION IN MANAGING POSTMENOPAUSAL ENDOMETRIOSIS
• ALWAYS CONSIDER COMBINED HRT OR TIBOLONE IN WOMEN WHO HAVE HAD TAHBSO
FOR ENDOMETRIOSIS