1. RECOMBINANT VS. URINARY FSH IN IUI J. Serna MD PhD

2. QUESTIONS Is it necessary multiple follicle development for IUI? IUI vs. TI? Best medication?

3. QUESTIONS Is it necessary multiple follicle development for IUI? – –Balance risk/benefits – –Difficult to draw clear conclusions from studies in subfertile couples

4. PRs IN IUI EtiologyNon StimulatedClomiphenehMG Male Factor4.65.911.2 Unexplained6.017.321.6 Endometriosis--10.4 Anovulation-18.215.6 Cervical--12.1 PR: Natural cycle:4.6% CC: 11.8% Gonadotropins17.7%

5. IUI: Ovarian Stimulation DrugDiagnosisPregnancy RateP Martinez 90CCMale NC MFD 3/30 5/35 NS OR 0.78 Arici 94CC Unexplained NC MFD 1/20 6/23 <.05 Male NC MFD 1/26 NS Cohlen 98GonadotropinsMale NC MFD 13/153 21/153 NS OR 2 Nulsen 93Gonadotropins Unexplained NC MFD 1/41 11/57 <.05 Male NC MFD 1/41 7/54 <.05 Duran HE Hum Reprod Update 2002 Male factor: CC do not  PR, but gonadotropins does Unexplained: CC and gonadotropinas  PR vs. NC

6. IUI-D: Ovarian Stimulation Remohí 1996 Ovarian StimulationNatural Cycle Number of cycles 1009420 Number of pregnancies 205 (20.3)48 (11.4) Cumulative PR77.1 ± 3.351.0 ± 3.5

7. IUI-D: Ovarian Stimulation Lashen 1999 PR/CyclePR/Patient Natural cycle13%32% CC10%18% Gonadotropins21%53%

8. QUESTIONS Is it necessary multiple follicle development for IUI? IUI vs. TI? Best medication?

9. Metaanalysis: MFD + TI vs. MFD + IUI PR/cycle > double vs. NC and > 5 times FSH + IUI vs. NC OR 2.37 FSH + IUI Hughes E, Hum Reprod 1997; 12(9): 865-72

10. In most cases it is better MFD vs. natural cycle Gonadotropins are better than CC in most non-PCO patients TI yields worst results than IUI

11. QUESTIONS Is it necessary multiple follicle development for IUI? IUI vs. TI? Best medication?

12. Drugs for ovarian stimulation - Clomiphene citrate - Gonadotropins - hMG - FSH ( uFSH vs rFSH)

13. Gonadotropins Menotropin Urofollitropin – –Almost no LH rFSH – –Highest purity – –Batch to batch consistency – –Potentially allergenic urinary proteins

14. Urinary Highly Purified Human FSH (uhpFSH) Active FSH Immunoselection (anti-FSH Ab) Metrodin ® HP: 95 % purity LH activity 0,1 UI/mg FSH activity 9000 UI/mg < 5 % other proteins Less batch to batch variability Better control intersubject variability Lunenfeld B. Reprod Biomed Online 2002; 4 supp 1: 11-17

15. Evidence of urinary prion excretion in asymptomatics animals and humans Not able to develop the disease after CNS injection Shaked GM. J Biol Chem 2001; 276: 31479-82 Theoretical risks: Urinary products: infected donors Recombinant products: hamster cells, bovine serum Reichl H. Hum Reprod 2002; 17: 2501-8 Debate: Absence of data do not exclude the risk of CJD transmission. Matorras R. Hum Reprod 2002; 7: 1675 Main problem: price, activity Crosignani PG. Hum Reprod 2002; 7: 1676. There is no demonstrated infective reason to interrupt urinary products, nor absolute security with recombinant counterparts. Balen A. Hum Reprod 2002; 7: 167-9 Prionic risk

16. Constantly Looking for Quality and Consistincy 1930 1950198019952004 Purity Specific activity Consistency Safety Efficacy Efficiency Side Effects PMSG Porcine FSH hCG Pituitary FSH hMG uFSH rFSH rLH rHCG rFSH- fbm Modified Gn ImmunereactionsSide EffectsCreutzfeld-Jacob Lunenfeld B. Reprod Biomed Online 2002; 4 supp 1: 11-17

17. AIM To compare the results of ovulation induction in couples undergoing IUI with uhpFSH vs. rFSH

18. Isaza V, Requena A, García-Velasco J, Martínez-Salazar J, Remohí J, Pellicer A, Simón C. Recombinant vs. Urinary Follicle-Stimulating Hormone in Couples Undergoing Intrauterine Insemination: A Randomized Study Journal of Reproductive Medicine, 2002 IVI MADRID

19. Material and Methods Prospective Randomized June 1999 to May 2000 108 women 224 cycles

20. Inclusion criteria Infertility more than 1 year 18 and 38 y.o. At least one normal patent tube MSC > 5 Mill/mL after swim-up No previous OI, TI or IUI No PCOs Institutional review board approval + IC

21. Pretreatment work-up HSG and/or laparoscopy TVU scan D3 Serum FSH, LH, E2, PRL and TSH D22 Progesterone Semen analysis WHO + MSC

22. Diagnostic groups Endometriosis Ovulatory Dysfunction Male Factor Unexplained infertility

23. Distribution of etiologies Male Factor 39% Ovulatory dysfunction 20% Endometriosis 6% Unexplained infertility 35%

24. Stimulation Protocol TVUS on 1 st to 3 rd cycle day Ovulation induction started on D3 with – –rFSH 100 IU – –uFSH 150 IU Randomly assigned by even/odd file record number Patients with several cycles received the same medication

25. 5000 UI hCG 100 UI rFSH 150 UI uFSH MENS rFSH uFSH 123456 TVS IA TVS

26. Stimulation Protocol TVUS Ovarian monitoring started on D5 No dose adjustment 5,000 IU hCG with a 18 mm leading follicle + E2 +12 & +36 h IUIs

27. Cancellations No ovarian response 5 or more follicles Luteal phase support 400 mg bid micronized vaginal progesterone Serum hCG 12 days after 2 nd IUI Clinical pregnancy defined as HB 22-25 days after the positive result

28. Outcomes measures Main – –Total number of follicles > 12 mm Secondary – –Follicles >17mm and 12-16 – –Number of cycles with 2- 4 follicles >17mm – –Duration of gonadotropin treatment – –Total FSH dose – –Serum E2 on hCG – –Ration E2/follicle > 17mm – –E2/units of FSH

29. RESULTS Characteristics rFSH (n =118 cycles, 55 couples) uFSH (n =106 cycles, 53 couples) P Age (yr) 33.1 ± 0.332.4 ± 0.2 NS BMI (Kg/m 2 ) 22.3 ± 2.623.7 ± 2.3 NS Duration of infertility (mo) 40.5 ± 3.5636.4 ± 1.9 NS Infertility diagnosis Male Factor 22 (40%)23 (43.4%) NS Ovulatory dysfunction 11 (20%)10 (18.9%) NS Endometriosis 3 (5.5%)3 (5.7%) NS Unexplained infertility 19 (34.5%)17 (23.1%) NS Hormone levels on day 3 FSH (mIU/mL) 6.2 ± 0.36.0 ± 0.2 NS LH (mIU/mL) 6.2 ± 0.56.2 ± 0.4 NS E2 (pg/mL) 42.3 ± 2.952.0 ± 4.4 NS

30. rFSH groupuFSH group IUI cycle 118 Cycles (55 couples Cumulative pregnancy rate (%) 106 cycles (53 couples) Cumulative pregnancy rate (%) 1 st 11/5520.011/5320.7 2 nd 8/3936.47/3735.7 3 rd 4/1850.63/1153.2 4 th 2/667.11/562.6 P > 0.05 in each group RESULTS

31. Parameter rFSH (n = 118 cycles) uFSH (n = 106 cycles)P No. of days of stimulation 7.4 ± 0.18.1 ± 0.02<.005 FSH dose (IU)799.1 ± 20.71293.0 ± 148.0<.001 Total no. of follicles (>12 mm) 2.9 ± 0.13.7 ± 0.1<.001 No. of follicles > 17mm2.2 ± 0.12.0 ± 0.1NS No. of follicles 12-16 mm0.7 ± 0.11.7 ± 0.1<.001 E2 at hCG (pg/mL)679.6 ± 52.4813.0 ± 54.1NS E2/IU of FSH0.9 ± 0.020.6 ± 0.01<.001 E2/follicle > 17 mm308.9 ± 15.1406.5 ± 24.1<.001 RESULTS

32. 7 7,2 7,4 7,6 7,8 8 8,2 rFSHuFSH DAYS OF STIMULATION 0 200 400 600 800 1000 1200 1400 rFSHuFSH FSH dose (IU) 0 0,5 1 1,5 2 2,5 3 3,5 4 rFSHuFSH Total no. of follicles (>12 mm) 1,9 1,95 2 2,05 2,1 2,15 2,2 rFSHuFSH No. of follicles > 17mm

33. RESULTS 0 0,5 1 1,5 2 rFSHuFHS No. of follicles 12-16 mm 600 650 700 750 800 850 rFSHuFSH E2 at hCG (pg/mL) 0 0,2 0,4 0,6 0,8 1 rFSHuFSH E2/IU of FSH 0 100 200 300 400 500 rFSHuFSH E2/follicle > 17 mm

34. OutcomerFSH (n = 118 cycles, 55 couples) uFSH (n = 106 cycles, 53 couples) P PR/cycle (%)25/118 (21.2%)22/106 (20.8%)NS PR/couple (%)25/55 45.5%22/53 (41.5%)NS Cumulative PR 4 cycles (%)66.7%65.8%NS Miscarriage rate (%)2/25 (8.0%)3/22 (26.3%)NS Multiple PR (%)5/23 (21.7%)5/19 (26.3%)NS Cancellation rate (%)2/118 (1.7%)2/106 (1.9%)NS RESULTS

35. Shorter duration of stimulation Less total FSH doses Less total number of follicles More follicles >17 mm Less follicles 12-16 Better optimization of the results CONCLUSION

36. Similar Pregnancy Rates, Miscarriage Rates There was a trend towards a less Multiple Rate CONCLUSION