Invited Lecture delivered by Dr Sujoy Dasgupta in the "Dream City Meet"- the East Zone Conference of Endometriosis Society of India, held on 24 December 2019 at Durgapur

1. Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
Advanced ART Course for Clinicians (NUHS, Singapore)
Consultant: Reproductive Medicine, Genome Fertility Centre, Kolkata
• Managing Committee Member, Bengal Obstetric & Gynaecological
Society (BOGS)- 2019-20
• Secretary, Subfertility and Reproductive Endocrinology Committee,
BOGS- 2019-20
• Faculty and Organizer: Spectrum MRCOG Course
• Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress,
London, 2019
A Good Old friend-
GnRH Agonist in Endometriosis

2. Old is Gold

4. Old is Gold

5. GnRH- Basic Chemistry

6. Mechanism of action of GnRHA
• GnRHA have similar structure to native GnRH and a
great affinity to the GnRH receptors.
• Initially cause Gonadotrophin release (flare-up effect).
• After several days of continuous administration, this is
followed by a dramatic drop in the circulating
concentrations of FSH and LH, through a desensitization
mechanism.
• Presence of a different, yet unknown signaling pathway
activated in the ovary by GnRHA.

7. Commonly available GnRHA

8. Safety profile of GnRHA
• Levels of serum estrogens and
androgens decrease significantly.
• The most common adverse effects of GnRH
agonists are hot flashes, vaginal dryness and
insomnia
• A decrease in bone mineral density has been
demonstrated in the LS spine. However, the
bone mineral density appears to recover
completely 1 to 2 years after cessation of
therapy.

9. Case 1
• 18 year-old girl presented with severe
dysmenorrhoea and 2 cm endometrioma

10. Presented with Pain only,
fertility is not an immediate concern
NSAIDs
Pain NOT resolved
Hormonal treatment
Pain Not resolved
Ovarian endometrioma ≥3 cm
Laparoscopy
Pain resolved
Follow up
Pain resolved
Follow up

11. G.A.J. Dunselman, N. Vermeulen, C. Becker, C. Calhaz-Jorge, T. D'Hooghe, B. De Bie, O.
Heikinheimo, A.W. Horne, L. Kiesel, A. Nap, A. Prentice, E. Saridogan, D. Soriano, W. Nelen, ESHRE
guideline: management of women with endometriosis , Human Reproduction, Volume 29, Issue
3, March 2014, Pages 400–412

12. Brown J, Pan A and Hart RJ. Gonadotrophin-releasing hormone analogues for
pain associated with endometriosis. Cochrane Database Syst Rev
2010:CD008475.
• The results suggest that GnRHa is more
effective than placebo but inferior to the LNG-
IUS or oral danazol.
• The review found a worse side effect profile
for GnRHa in all studies.

13. • Leuprolide depot 11.25 mg intramuscular injection every
3 months, plus oral norethindrone acetate 5 mg daily or
oral norethindrone acetate 5 mg daily and oral conjugated
equine estrogens 0.625 mg daily.
• Subjects believed that GnRHa used with add-back was
effective and would recommend it to others, despite
significant side effects. Those who received 2-drug add-
back reported more success than those who received
standard add-back. A subset of patients reported side
effects they consider to be irreversible.

14. Case 2
• Mrs PS, 28, Newly married, presented with
severe dysmenorrhoea, dyschezia and dysuria.
There was 5 cm unilateral endometrioma and
MRI scan suggested the possibility of
rectosigmoid endometriosis
• She wanted to defer surgery for 4 months
because of professional commitments

15. • There was no evidence of a benefit of preoperative
medical therapy on the outcome of surgery.
• From a patient perspective, medical treatment should be
offered before surgery to women with painful symptoms
in the waiting period before the surgery can be
performed, with the purpose of reducing pain BEFORE,
NOT AFTER, surgery.
• In clinical practice, surgeons prescribe preoperative
medical treatment with GnRH analogues as this can
facilitate surgery due to reduced inflammation,
vascularisation of endometriosis lesions and adhesions.
However, there are no controlled studies supporting this.
Furness S, Yap C, Farquhar C and Cheong YC. Pre and post-operative medical therapy
for endometriosis surgery. Cochrane Database Syst Rev 2004:CD003678. [New search
for studies, and content updated (no change to conclusions), published in Issue 1,
2011.]

16. GnRHA in deep Endometriosis
• As an adjunct to surgery
for deep endometriosis
involving the bowel,
bladder or ureter,
consider 3 months of
GnRH agonists before
surgery.

17. Case 2 (Contd.)
• Mrs PS finally underwent laparoscopy. Grade
IV endometriosis was found, ovarian
cystectomy, adhesiolysis, removal of all visible
implants and bowel-resection-anastomosis
done.
• She is not planning for pregnancy in next 2-3
years

18. Postoperative hormonal therapies
 Do not prescribe adjunctive hormonal
treatment after surgery, as it does not
improve the outcome of surgery for pain
Short Term (<6 months)

19. Postoperative hormonal therapies
 there are limited data
 After cystectomy for ovarian endometrioma in women not
immediately seeking conception, prescribe hormonal
contraceptives
 Deep endometriosis- prescribe postoperative use of a LNG-
IUS or a COC (continuous/ cyclic) for at least 18–24
months, as one of the options for the secondary prevention of
endometriosis-associated dysmenorrhea, but not for non-
menstrual pelvic pain or dyspareunia
 postoperative pain recurrence is not different in women
receiving GnRH agonists, danazol or MPA or pentoxifylline,
when compared to placebo
Long term (>6 months)- Secondary Prevention

20. • This prospective cohort study analyzed 52 reproductive-aged women who
underwent surgery for ovarian endometrioma and received postoperative
medical treatment with either COC after GnRH agonist (n = 20) or DNG
(n = 32) for 24 months. Changes in quality-of-life (QOL) and bone mineral
density (BMD) were compared according to treatment.
• During 24 months of treatment, no differences in any component of QOL were
found between the two groups. BMD at the LS Spine significantly decreased
after the first 6 months of treatment in both COC after GnRH agonist (−3.5%)
and DNG (−2.3%) groups, but the groups did not differ statistically. After 6
months, further decrease in BMD was not observed until 24 months in both
groups.
• long-term use of COC after GnRH agonist plus add-back therapy is
comparable to dienogest as a long-term postoperative medical treatment for
endometriosis.

21. Case 3
• Mrs AB, 30, P0+0, had been trying to conceive
for one year. She is having severe
dysmenorrhoea not responding to NSAID.
There was 4 cm endometrioma in right ovary.
• Husband’s semen, HSG, AMH all are normal
24

22. Choice of treatment- Surgical
Peritoneal Endometriosis-
• Both ablation and excision improve the chance of spontaneous conception in
ASRM stage I/II endometriosis (CO2 laser vaporization > monopolar
electrocoagulation)
Endometrioma-
• ≥3 cm- cystectomy preferred to drainage and coagulation/ CO2 laser vaporization
• controversial if cumulative pregnancy rate is more after surgery but time to
achieve the first pregnancy in infertile patients was significantly shorter
• A small added risk of requiring an oophorectomy
Deep Endometriosis-
• radical excision of endometriosis combined with bowel segmental resection and
anastomosis was associated with a higher postoperative spontaneous pregnancy
rate

23. Hormonal therapies
•Pregnancy is not
possible/contraindicated
during hormonal therapy
•hormonal treatment for
suppression of ovarian
function does not improve
the chance of natural
conception
•Only indicated- if wants to
delay Laparoscopy/ IVF and
the pain is severe

24. Postoperative hormonal therapies
27
 Do not prescribe adjunctive hormonal
treatment after surgery, in women trying for
pregnancy

25. Case 3 (Contd.)
• Mrs AB underwent laparoscopy- ovarian
cystectomy and ablation of superficial
peritoneal endometriosis were done. Tubal
patency was confirmed.
28

26. Next Step
• GnRh Agonist?
• OI/ IUI

27. Case 3 (Contd.)
• Mrs AB tried IUI 6 times but failed. She
presented to you 18 months after the initial
laparoscopy. She wants to try IVF.
• Now there is 6 cm endometrioms in right
ovary. However, her dysmenrrhoea is well
controlled with NSAID.
30

28. 31

29. Medical treatment before ART
32

30. How to administer GnRH Agonists
• Ultralong protocol
• Antagonist protocol → freeze embryos → give
GnRH agonist depot 3-6 → FET
• GnRH antagonist protocol may be not inferior
to GnRH agonist protocol in women with
minimal to mild endometriosis and
endometrioma. (ESHRE, 2015)
33

31. Case 4
• Mrs DH underwent laparoscopy. There was
grade IV endometriosis. Tubes were difficult to
identify. Dyes tests were negative B/L. The
surgeon felt adhesiolysis was not safe.
• During post operative discussion, she decided
for IVF
• She received 2 doses of injection (Leuprolide
acetate depot 3.75) IM before referral to the
IVF clinic

32. She does not want to defer IVF
anymore
• Start stimulation, utilizing the long agonist
protocol

33. IVF in Endometriosis
39

38. Conclusion
• GnRh Agonist is an acceptable and
effective treatment modality
• Effective in pain management
• Significantly improves pregnancy rate
in IVF