Presentation given in 2018 on Endometriosis - management in the infertility setting. When are assisted reproductive technologies used and what are the medications used for dealing with this condition?

1. Dr. Anuradha Katragadda
ANU TEST TUBE BABY CENTER

2. Endometriosis
Common, chronic and often progressive
inflammatory condition of pelvis
Estimated prevalence in general female population
2 – 10 %
25 – 50 % of infertile women have endometriosis &
30 – 50 % of women with endometriosis are
infertile

3. Endometriosis - Dilemma
Why a dilemma :
Varied presentations
Different age groups
Different problems
Pain
infertiltiy
Occasionally asymptomatic
& incidental finding
What treatment
No cure / only
suppression
Treatment of
symptoms and
effects

4. Endometriosis drugs - Dilemma
To use or not to use ; when and what
Adolescent age group
Infertility
Empirical treatment for pain
Pre-operative and post-operative
Menopausal age
prevention

5. Endometriosis -
Pathophysiology
Systemic & reversible inflammatory condition that
alters endometrial function
Estrogen dominance & progesterone resistance
Progesterone resistant disease
(progesterone plays a role in decreasing
inflammation)
Increased cell proliferation & survival
elevated levels of Estrogen receptors
Affecting Estrogen driven mechanism &
differentiation capacity of tissue

6. Medical Treatment
Available Options
• Non Hormonal
• Hormonal
Aim -
to suppress ovarian function leading to
amenorrhoea

7. Non-
Hormonal
• Non-steroidal anti-
inflammatory
• Others
Immunomodulators
Antiangiogenic agents
Vit D
Matrix –
metalloproteinase
inhibitors Requires further research
and not yet licensed

8. Hormonal
Estrogen-progestin contraceptives (COC)
Progestins & anti-progestins
Gestrinone
Danazol
Levo-Norgestrel intrauterine system (Ln-IUS)
GnRh agonists / antagonists
Dienogest (newer progestin)

9. Danazol

10. Danazol
Side effects
Acne
Edema
Vaginal spotting, weight gain
Muscle cramps
Oral danazol has been withdrawn from the
market in some countries due to its side
effect profile,
Recent studies indicate that vaginal danazol may
be better tolerated
What is
worse
Cats or
Rats

11. NSAIDS - Endometriosis
Pain is a cardinal symptom
Elevated prostaglandin levels in peritoneal
fluid and endometriotic tissue
Side-effects –
Inhibition of ovulation
Gastric ulceration
Cardiovascular disease
Effectiveness – not well established
Recommendation (ESHRE GDG)

12. Gestrinone
Non-estrogenic contraceptive
Weak progestin with strong antiprogesterone properties
Orally – 1.25 mg. twice a wk
Efficacy equivalent to Danazol
Androgenic side effects
Most develop at least one adverse event
Gestrinone & Danazol
Embryotoxic &
May canse masculanization of female fetus
To avoid when possibility of pregnancy
Use contraception

13. GnRH antagonists
Direct pituitary Gonadotrophin suppression
hypoestrogenism
Suppression of LH/FSH secretion
Avoids lag seen with GnRHa
More effective & faster improvement of symptoms
Fewer side effects
Injectables (Gonirelix, Cetrorelix)
3 mg/wk. over 8 wk
Safe & efficient
Oral non-peptide forms
(Elagolix, Abarelix, Ozarelix, TAK 385)

14. Elagolix
Elagolix, Approved by FDA, 2018
Costs around $10,000/ year
Welcome addition to treatment paradigm;
Improved tolerability
Minimal impact on BMD
Oral administration – 150 mg/d
Increased control over dosing & allows immediate
cessation of therapy (short ½ life 6 hrs)
Long term safety and efficacy data, yet to be known

15. Aromatase Inhibitors
Letrozole – 2.5 mg/d
2nd generation AI
Anastrozole – 1 mg/d
Reversible inhibitors of enzyme aromatase
competing with androgens for aromatase
binding sites
Side-effects;
Hypoestrogenic –
vaginal dryness, hot flushes and
diminished bone mineral density

16. AI – Premenopausal women
Progestin or CHC – added to prevent
Ovarian stimulation
Cyst formation
Some data support use of AI for
Refractory or
Recurrent endometriosis

17. COC (Estrogen + Progestin)
Mechanism : Acts by ovarian suppression
Continous or cyclic administration
Continous with out a 7 day break to avoid
withdrawal bleeding; more beneficial in
terms of pain
Considered 1st line treatment for pelvic pain
OCP may not be universally effective (relates to
status of Estrogen & Progesterone receptors in
ectopic endometriosis implants)
Est. receptors are normal but progesterone
isoforms (PRA & PRB) are reduced or absent

18. Oral
Medroxy progesterone
acetate
10 – 20 mg/d
continuously
Norethindrone acetate
5 – 20 mg/d
ed 100 mg/d – 6m.
- complete
remission in some
Megesterol acetate
40 mg/d
Decidualization &
atrophy of
endometrium
Available as
Oral
Injectables
IUS
Progestins

19. Advantage
Positive effect on Ca. metabolism relatively
good maintenance of BMD
Continuous use approved by USFDA
Disadvantage
Breakthrough bleeding in ½ the patients
Neg. effect on HDL cholesterol
Newer progesterone – ‘Dienogest”
Progestins

20. Injectable progestins
Depot medroxy progesterones
150 mg IM every 3 m.
Very economical
Do not increase significantly thrombotic risk
- Can be adopted in women with cardiovascular or
metabolic contraindication to estrogen – progest.
However, prolonged delay in resumption of ovulation
- Not suggested for women desiring preg. in near
future
Break through bleeding may be prolonged, heavy –
difficult to correct since progestin effect can not
be quickly reversed
- Long term use may be detrimental to BMD

22. Etonogestrel implant
Inserted intradermally in the arm
Offers contraceptive benefit for 3 yrs
Marketed as implanon & Nexplanon
Equally effective when compared to DMPA
Does not reduce BMD & hence can be used in
young women, who have not achieved their
peak bone mass

23. Intrauterine Progestin –
releasing system (LNG-IUS)

24. Disadvantages :
Expulsion rate of 5%
Risk of pelvic infection – 1.5%
Since ovulation not inhibited
Risk of ovarian endometrioma is increased
Long term effect on BMD is not known
Effective therapy for
Recto-vaginal endometriosis
Dysmenorrhoea, non-menstrual pelvic pain,
dysparennia & dyschezia
(LNG-IUS)

25. Gonadotrophin releasing hormone
agonists - Endometriosis
GnRH – agonists derived from native GnRh
Administration of GnRH agonist causes
An initial flare effect
Followed by downregulation of receptors
Low FSH / LH
Causes hypogonadal state
Induces hypoestrogenism inactivate pelvic lesions
Can be administered IM, SC or intranasally
All are equally effective
75 % women reach hypogonadal state in 4 wks

26. GnRH-a in
Endometriosis
Indications:
Women not responding
COC / Progestins
Or have recurrence of
symptoms after
initial inprovement

27. GnRH agonists

28. GnRH-
agonists &
Endometriosis
Side effects:
Related to Estrogen
deficiency
Hot flushes
Insomnia
Vaginal dryness
Loss of libido &
Loss of BMD

29. GnRH-a & Loss of BMD
Significant with 6 m. GnRH-a therapy
Bone loss occurs in both
Lumbar spine (Trabekular) &
Femoral neck (cortical bone)
Can approach or even exceed 1% / month

30. GnRH-a +
Add back
therapy
• Provides
maintenance
of BMD &
• Absence of
hypoestrogenic
symptoms
Estrogen
 0.625 mg (conjugated),
 2 mg estradiol valerate or
 0.05mg transdermal
estradiol
And progestins
 5-10 mg MPA or
 1 mg norethisterone
acetate

31. GnRH-agonist therapy -
Endometriosis
Accentuation of pain in 1st cycle because of intial
flare effect
Appropriate to provide analgesia
NSAIDs / Opiods
To make patient comfortable until primary
medical management becomes effective

33. Dienogest – Newer Progesterone
Synthetic oral progestin
With selective 19 – Nortestosterone and progesterone
activity
No androgenic, glucocorticoid, or mineralocorticoid activity
Mechanism of action :
High selectivity for progesterone receptors
Strong progestogenic effect on endometrium
Creates hypoestrogenic and hyperprogestogenic
environment
Causes decidualization of ectopic endometrial tissue
atrophy of lesions

34. Beneficial antiandrogenic properties and cause
minimal changes in lipid and carbohydrate
metabolism
Moderate Estrogen and GnRH suppression
Antiinflammatory, Antiangiogenic and
Antiproliferative effect
Dosage :
2 mg/d continous administration
Can be started on any day of menstrual cycle
Continued irrespective of vaginal bleeding
Dienogest

35. Dienogest -
Advantages
Prolonged pain relief even
after return of
normal cycles
(because of reduction in
endometriotic lesions)
Inhibits ovulation
Improvement in quality of
life

36. Dienogest – side effects
Although near to being ideal candidate;
Irregular PV bleeding,
Headache, acne, nausea
Weight gain,
Depressed mood
Contraindication:
Active venous thromboembolic disease
History of cardiovascular disease
History of Hepatic disease
Dienogest is as effective as GnRH – agonist therapy and may be
an effective long term Treatment option for endometriosis
associated pain, post-operatively and adenomyosis

37. Pain associated with Endometriosis –
Medical Treatment
Treatments offer partial relief of pain
symptoms, but symptoms often recur
after discontinuation of therapy
(All drugs are equally effective with
different side-effects profile)

39. Empiric treatment for pain
In women suffering from pelvic pain with a high
suspicion of endometriosis use
Empirical analgesics
Hormonal medication
- COC
- or progestogens
With out prior definitive Lap. diagnosis

40. Medical Therapy
Effective
for-pain relief and
To prevent p-o recurrence
But, ineffective for recovery of fecundity
Inhibits ovarian function by suppressing ovulation
Endometriosis - associated Infertility

41. Minimal – Mild Endometriosis
Suppression of ovarian function by means of
Danazol, GnRH – analogues or OCP to improve
fertility is not effective and should not be
offered for this indication alone

42. GnRH – agonists & IVF
Administration of GnRH-a for a period of
3-6 m. prior to IVF/ICSI –
increases odds of clinical preg.

43. Combination therapy –
Medical & Surgical
Pre-operative or
Post-operative medical therapy
May unnecessarily delay further fertility therapy

44. Pre-operative Medical therapy
GnRH-analogues prescribed in clinical
practice reported to -
- Reduce pelvic vascularity and size of
endometriotic implants
- reducing intraoperative blood loss &
- decreasing amount of surgical –
resection needed
More difficult to identify & treat lesions at
time of surgery

45. Post Operative
Hormonal Therapy
To improve outcome of surgery for pain
Secondary prevention;

47. Adolescents –
Endometriosis
(Medical management)
Unresponsive to medications,
require early referral for
further investigations
Potential for bone loss with GnRH-a
& depot progestin
Step-Wise approach-
COC therapy – extended or
continuous
Empiric GnRH-a with add-
back – over 18 yrs
In 16 yr. old adolescents with
persistent problematic pelvic
pain
- continuous COC
- GnRH-a + Add back therapy
• Empiric treatment
with
• NSAIDS &
• COC
Is appropriate

48. Adolescents
Medical therapy
Congenital anomalies of
reproductive tract –
11% of adolescents
Intra – Op. appearance –
Differ from classic
‘powder – burn’
lesions
Subtle atypical lesions
• General advise
about bone health
maintenance
• Supplemental
calcium & Vit D
• Monitoring of
BMD

49. Menopausal women Endometriosis
(Medical Therapy)
• Malignant transformation-
surgery/radiation/chemo
therapy
- Drugs-progestin therapy
- Aromatase inhibitors
• Residual endometriosis after
hysterectomy with or
without bilateral salpingo-
ophorectomy
- Injectable progestins-
• Typically regarded as
pre-menopausal
disease
• Recurrence and
malignant
transformation
can occur
• HRT may re-activate
endometriosis

50. Current endometriosis
treatments - Limitations
Suppressive rather than curative
Contraceptive rather than fertility-promoting
Endometrioma:
Medical treatment not effective
DIE & exptra pelvic disease –
Limited medical options

51. ENDOMETRIOSIS
Prevention & Awareness
OCP - Current use has protective
effect against development of
endometriosis; not observed in
past users
High level activity –
slight reduction in incidence

52. Complexity Simplified
Adolescents
COC
Etonogestrel implant - ? Expensive
LNG-IUS
Menopausal
AI
Progestins - ? Injectables
Recto-vaginal endometriosis
AI
LNG-IUS

53. Drugs
COC
1st line drug
Empirical treatment
Adolescents
GnRH-a
Convenient
Monthly or every 3m.
Pre-op & post-op
Before IVF
Combine with add-back
therapy
Progestins
Economical
Good maintenance of BMD
BUT
-ve effect on Lipoproteins
Breakthrough bleeding
Injectables
Convenient
Delay in resumption of ovulation /
cycles
Long term detrimental to BMD

54. Recent drugs
LNG-IUS
Effective for long term
Risk of in ov. Endometrioma
systemic side-effects
Reversible
Dienogest
Oral
Minimal change in lipid metabolism
ed quality of life

55. Practice Recommendations
1. While awaiting resolution of symptoms from the
directed medical or surgical treatments for
endometriosis, practitioners should use clinical
judgement in prescribing analgesics ranging from
NSAIDs to opioids. (III-A)
2. Combined hormonal contraceptives, ideally
administered continuously, should be considered as
first-line agents. (I-A)
3. Administration of progestin alone-orally,
intramuscularly or subcutaneously-may also be
considered as first-line therapy.(I-A)

56. 4. A GnRH agonist with HT addback, or the LNG-IUS,
should be considered a second-line therapeutic
option. (I-A)
5. A GnRH agonist should be combined with HT addback
therapy from the commencement of therapy and
may be considered for longer-term use
(> 6 months).(I-A)
6. GnRH-a therapy ‘has no adverse effects on serum
lipids and lipoprotein conc’. unlike those associated
with danazol or high dose progestins.
7. Dienogest provides similar efficacy, but better
tolerability than GnRH-a

57. Clinical tips:
* In endometriosis treatment, all options should
be administered for a minimum of 3
months, with evaluation of efficacy at
the end of the trial.
Evidence indicates – ‘No one medical treatment is best’.
Treatment decisions must be individualized
considering severity of symptoms, extent of
disease, desire for future pregnancy, age, side
effects & costs.