Letrozole-resistant PCOS: Prevalence, Further Options and Course of Fertility Treatment- ESHRE presentation

Dr Sujoy Dasgupta delivered a lecture to present the research paper on "Letrozole-resistant PCOS: Prevalence, Further Options and Course of Fertility Treatment" in the Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), 2024 held at Amsterdam, The Netherlands.

Total nine speakers from India were selected to deliver lecture in the ESHRE, 2024 at Amsterdam held between 7 and 10 July, 2024.

This study was carried out in the Genome Fertility Centre, which showed that some women with PCOS won't respond to the oral medicine Letrozole and some of them can be benefitted from another oral medicine Clomiphene citrate. If still Clomiphene citrate fails, then Gonadotropin injection should be offered. Many women conceive with these regimes without requiring IUI or IVF.

1. Letrozole -resistant PCOS: Prevalence, Further Options and Course of Fertility Treatment Sujoy Dasgupta MS, DNB, MRCOG, MSc Consultant, Reproductive Medicine, Genome Fertility Centre, Kolkata, India

2. Conflict of interest I declare that I have no commercial or financial interests pertaining to the subject of this presentation or its content.

3. Background Polycystic ovary syndrome (PCOS) is a heterogenous reproductive and metabolic disorder→ hyperandrogenism , menstrual irregularities and polycystic ovaries 1-3 Lifestyle changes→ first line of management 1-3 70% of them have anovulation / oligo -ovulation→ Infertility 1 Rababa'h AM, et al. A. Heliyon . 2022 Oct 10;8(10):e11010. Cunha A, Póvoa AM. Porto Biomed J. 2021 Jan 26;6(1):e116. Teede HJ, et al Fertil Steril . 2018 Aug;110(3):364-379.

4. Ovulation Induction (OI) in PCOS Cornerstone in managing PCOS-associated infertility 1,2,3,4 Clomiphene citrate (CC)- used as first line of agent for long time 3,4 Rababa'h AM, et al. A. Heliyon . 2022 Oct 10;8(10):e11010. Cunha A, Póvoa AM. Porto Biomed J. 2021 Jan 26;6(1):e116. NICE Clinical Guideline CG 156. Fertility problems: assessment and treatment. 2013 Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Hum Reprod . 2008 Mar;23(3):462-77. Clearly defined- No response to 150 mg of CC 1,2,3,4 Prevalence- 15-20% 1,2 Options- 1. Clomiphene + Metformin 2. Laparoscopic ovarian drilling (LOD) 3. Gonadotrophins 1,2,3,4

5. Letrozole in PCOS Letrozole - now the preferred agent 1-4 Management of letrozole -resistant PCOS → largely undocumented Cunha A, Póvoa AM. Porto Biomed J. 2021 Jan 26;6(1):e116. Teede HJ, et al Fertil Steril . 2018 Aug;110(3):364-379. Legro RS, et al. N Engl J Med. 2014; 371:119. Franik S, et al. Cochrane Database Syst Re.v 2018. (5):CD010287.

6. Aims and Objectives To identify the prevalence of letrozole -resistance in women with PCOS and infertility To find out the course of clinical management for such women

7. Materials and Methods

8. Study Design- Prospective Observational Study Study Population- Women with PCOS and Infertility Study Setting- Genome Fertility Centre, Kolkata, India Study Duration- April 2018 to March 2023 (five years) Approved by Institutional Human research Ethics Committee (IEC/ 2018/G-3/1)

9. Inclusion Criteria Women having PCOS, defined by modified Rotterdam criteria 1 Trying for pregnancy for more than one year Age 21-35 Not received any forms of OI (medical or surgical) before At least one fallopian tube patent Normal semen analysis report of the partners Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Fertil Steril . 2004 Jan;81(1):19-25.

10. Exclusion Criteria Sexual dysfunction (in women or their partners) Other causes of hyperandrogenism (adrenal or ovarian origin) Hyperprolactinaemia ( Prolactin >30 ng /ml) Overt hypothyroidism (TSH >10 mU /L) Known/ suspected endometriosis Known diabetes Uncontrolled hypertension, liver or kidney disease Known/ suspected genital tract/ breast cancer

11. Evaluation Teede HJ, et al Fertil Steril . 2018 Aug;110(3):364-379.

12. R. Homberg . Ovulation Induction and Controlled Ovarian Stimulation. 2014; 80-84. 1

13. Atay V, et al. J Int Med Res. 2006 Jan-Feb;34(1):73-6. Mitwally MF, Casper RF. Fertil Steril . 2001 Feb;75(2):305-9. Seckin B, et al. Arch Gynecol Obstet. 2016 Apr;293(4):901-6.

14. R. Homberg . Ovulation Induction and Controlled Ovarian Stimulation. 2014; 80-84

15. Sellami I, et al. Médecine de la Reproduction. 2021;23(3):199-212. R. Homberg . Ovulation Induction and Controlled Ovarian Stimulation. 2014; 87-94

16. Further course Huang S, et al. Eur J Obstet Gynecol Reprod Biol. 2018 Dec;231:117-121. Seckin B, et al. Arch Gynecol Obstet. 2016 Apr;293(4):901-6.

17. Cycle cancellation policy If more than 2 follicle ≥ 14 mm developed with any of the drugs Cycle was cancelled Or Option for conversion to IVF was offered Teede HJ, et al Fertil Steril . 2018 Aug;110(3):364-379. ACOG Committee Opinion No. 719.   Obstet Gynecol. 2017; 130(3):670-671. The ESHRE Capri Workshop Group’ Hum Reprod . 2000; 15(8):1856-1864

18. Statistical analysis

19. Results

20. Prevalence of Letrozole resistant PCOS 2.7% (50)

21. Response to CC in Letrozole -resistant women N= 50

22. Outcome of women responded to CC N= 19

23. Clinical characteristics as per response to CC N= 50

24. Laboratory characteristics as per response to CC N= 50

25. Course in women resistant to both Letrozole and CC

26. Response to Gonadotrophins (GT) N= 24

27. Gonadotrophin Stimulation- Dose nd Duration (First Cycle)

28. Outcome of women receiving Gonadotrophins N= 24

29. Outcome of all women resistant to letrozole N= 50

30. Pregnancy between women responding to clomiphene citrate and gonadotrophin

31. Endometrial thickness between women responding to clomiphne citrate and gonadotrophin

32. Live birth in letrozole -resistant women N= 16

33. Multiple pregnancy in letrozole -resistant women N= 16

34. Preterm birth in letrozole -resistant women N= 11

35. Other obstetric complications

36. Summary of findings

37. Discussion

38. Dose of Letrozole in OI 2.5 mg conventionally- dose used in postmenopausal breast cancer 1,2 Short-term use in reproductive age women- ? 2 7.5 mg used in CC resistant women with PCOS. 3,4 10-12.5 mg- in a retrospective study 1 Pritts EA, et al. ISRN Obstet Gynecol. 2011;2011:242864. R. Homberg . Ovulation Induction and Controlled Ovarian Stimulation. 2014; 80-84 Begum MR, et al.. Fertil Steril . 2009 Sep;92(3):853-857 Al- Fozan H, et al. Fertil Steril . 2004 Dec;82(6):1561-3.

39. Starting dose of Letrozole in OI

40. Letrozole - Ovulation rate in PCOS

41. Our study- 97.3% responded to letrozole 2.7% did not respond to the maximum dose (10 mg) 2.7%→ “ Letrozole -resistant” “ Letrozole -resistance” in the study by Gayam et al. 1 53.3% with dose 2.5 mg 36.67% with dose 5 mg Gayam S, et al.  Obs Gyne Review J Obstet Gynecol. 2020;6(4):72-78.

42. Letrozole in CC resistant cases If not responding to 150 mg/day of CC 1-5 Mitwally MF, Casper RF..  Fertil Steril . 2001;75:305–309.  Begum MR, et al. Fertil Steril . 2009 Sep;92(3):853-857 Al- Fozan H, et al. Fertil Steril . 2004 Dec;82(6):1561-3. Rababa'h AM, et al. Heliyon . 2022 Oct 10;8(10):e11010. Cunha A, Póvoa AM. Porto Biomed J. 2021 Jan 26;6(1):e116

43. CC in Letrozole -resistant cases No evidence in the literature Concern about thin endometrium ? 1,2 Our study Endometrial thickness- not significantly lower 38% women resistant to letrozole responded to CC 37% of them conceived 72% of them had live birth Multiple pregnancy- only 2 cases Did not prolong time to pregnancy Gadalla MA, et al. Ultrasound Obstet Gynecol.2018. 51:64. Weiss, N.S, et al. Hum. Reprod . 2017; 32: 1009–1018

44. Gonadotrophins Conventionally used as “second line” in CC-resistant PCOS 1-4 We recommend- as third line Letrozole → CC → Gonadotrophins Mentioned in the literature 2-4 Supporting evidence? NICE Clinical Guideline CG 156. Fertility problems: assessment and treatment. 2013. Teede HJ, et al. J Clin Endocrinol Metab . 2023 Sep 18;108(10):2447-2469. Cunha A, Póvoa AM. Porto Biomed J. 2021 Jan 26;6(1):e116. Costello MF, et al. Hum Reprod Open. 2019;2019:hoy021.

45. Cautions with Gonadotrophins Extremely sensitive- very narrow therapeutic range Promote development of a single follicle→ just break “FSH threshold” 1 No difference between urinary/ recombinant products 1-3 Recombinant FSH- easy to handle, purer 4 Low-dose step-up – minimum risk of OHSS and multiple pregnancy 1-4 Our study with rFSH - Low dose step up One case of multifollicular development One case of multiple pregnancy Cunha A, Póvoa AM. Porto Biomed J. 2021 Jan 26;6(1):e116. NICE Clinical Guideline CG 156. Fertility problems: assessment and treatment. 2013 Teede HJ, et al. J Clin Endocrinol Metab . 2023 Sep 18;108(10):2447-2469. R. Homberg . Springer International Publishing Switzerlanfd . 2014; 87-94

46. Conclusion In letrozole -induced cycle, follicular study should be done to confirm ovulation In resistant PCOS, clomiphene citrate (CC) should be tried first → no significant adverse effect, no “loss of time” If CC fails, low-dose gonadotrophins should be tried for ovulation induction

47. Limitations of the study Small sample size Single center-experience Not randomized Cannot comment on role of LOD Significant loss to follow up

48. Wider implications of the study Correct identification of “ letrozole -resistant” PCOS → timely management Needs adequately powered randomized trials 1. using different arms 2. in different population

49. Acknowledgement Mr Abhyuday Chanda , Quartesian Clinical Research Dr Raunque Singh, Stat VConsult Dr Vishal S Dave, Intas Pharmaceuticals Ltd Staffs of Genome Fertility Centre All the participants in the study Team ESHRE 2024

50. Mail ID- [email protected] ORCID ID- 0000-0002-8116-9312