This document discusses the use of recombinant luteinizing hormone (rLH) in assisted reproduction. It begins by asking if an appropriate patient population has been defined that could benefit from rLH supplementation. It then discusses LH and FSH action on follicles, the LH therapeutic window concept, and how central nervous system influence can cause hypothalamic-pituitary-hypogonadism. The document presents studies showing improved follicular development and outcomes like pregnancy rates with the addition of rLH for poor responders and women over 35 undergoing fertility treatments. It also discusses dose-finding studies that identified a safe and effective dose of 75IU/day rLH. In conclusion, the risks of rLH supplementation are addressed as

1. Lh in assisted Reproduction Dr G A RAMA RAJU. KRISHNAIVF VISAKHAPATNAM.

2. Dr.Subhasmukherjee http://drsubhasmukhopadhyay.blogspot.com/ I dedicate this lecture

3. LH

4. Is there a need for recombinant luteinizing hormone? Has the appropriate patient population been defined? Has a safe and effective dose been identified? 75 IU/day Is the composite primary endpoint of follicular development an appropriate endpoint to assess efficacy in this patient population? 4

5. Luveris® (lutropin alfa for injection)

6. Agenda

7. LH and FSH Action on the Follicle E2 A Theca externa cells FSH receptors on granulosa cells Theca interna cells LH receptorson theca cells Granulosa cells FSH Follicular antrum Zona pellucida Oocyte Cumulus Oophorus cells LH Capillary network Basement membrane 7

9. Follicular atresia (nondominant follicles)

10. Premature luteinization (preovulatory follicle)

12. Inadequate androgen (and estrogen) synthesis

13. No full oocyte maturationBalasch J, Fábreques F. Curr Opin Obstet Gynecol 2002, 14:265-274 8

14. CNS Influence GnRH LH FSH Steroidal and Nonsteroidal Feedback 9 HH Can Be Caused by Hypothalamic Disorders, Pituitary Disease or Both Hypothalamus Pituitary Ovary

15. HH Treated with r-hFSH Alone 9 0 r-hFSH 15 Follicle Follicle Size (mm) and FSH(IU/L) Estradiol (pg/ml) 10 Serum FSH 5 Estradiol 100 50 0 0 5 10 15 20 Days Endometrial Thickness (mm) Shoham Z et al. Fertil Steril 1993; 59:738 10

16. HH Treated with r-hFSH and r-hLH Follicle 20 400 350 15 300 Follicle Size (mm) and FSH(IU/L) 250 10 200 Serum FSH 150 5 100 Estradiol 50 0 0 0 5 10 15 20 Days Endometrial Thickness (mm) 9 0 r-hFSH r-hLH Estradiol (pg/ml) Serono data Study 6253 11

17. 12 Follicular Development in HH Give back what’s missing

18. Beneficial effect of LH supplementation in ART > 5 < .5

19. LH 14

20. Beneficial effect of LH supplementation in ART

21. Women > 35 years: 16

22. Poor responders: 10-15% of IVF patients have an inadequate response to FSH stimulation by day 8 De Placido et al, 2001, 2004 Women showing a hypo-responsive response in IVF down regulated cycles had asignificant increase in pregnancy and implantation rates with the addition ofrecombinant LH (40.7% vs. 22%) Ferraretti et al, 2004 Prospective randomised controlled trial rLH supplementation is more effective than increasing the dose of rFSH inpatients with an initial inadequate ovarian response to r FSH alone De Placido et al, 2005 Multicenter, prospective, randomised controlled trial

23. Beneficial effect of LH supplementation in ART

24. How did an optimal dose found. Dose Finding Studies LH Controlled ovarian stimulation and HH 19

25. Percentage of Patients with Follicular Development Trend Test* p = 0.004 1/9 2/8 7/11 7/10 p = 0.467 p = 0.020 p = 0.012 p-values vs 0 IU LH * Statistically significant and robust 20

26. 21 Risks Known complications of gonadotropins in infertility treatment Ovarian Hyperstimulation Syndrome (OHSS) Multiple births Other minimal/transient treatment-related adverse events (minor) Risks mitigated with proper diagnosis, dosing and observation

27. 22 Risks vs. Benefits

28. ASIA PACIFIC LH ADBOARD.

29. ASIA PACIFIC LH ADBOARD.

30. Indian study :krishnaivf LH study submitted for publication

31. Adding Lh 26

32. Thank u 27