TAQI Consultant OB/ GYN,Infertility,IVF Operative laparoscopy,and Ultrasonography.

1. Ovulation induction TAQI Consultant OB/GYN,Infertility,IVF Operative laparoscopy,and Ultrasonography. AS-SALMA Hospital

2. Over the years Patient Expectations have not changed… ‘to become Pregnant and to have a healthy Baby’

3. What are our chances of having a baby?

4. Objective • To highlight the rationale, principles and different protocols of ovarian stimulation in cases of I.V.F

5. There is no golden standards, guidelines or protocol. • Any of the following slides is packed up with hundreds of reputed studies. • But …..still can be logically criticized • As there is no golden rule,inuction of ovulation depends largely on the provider experience and patients merits. • Think twice before starting induction, and avoid the routine.

6. Taylor made for perfect individualization 1st step for success: Take the exact measurements From “one size fits all” to taylor made COS

7. Many variables can impact treatmentsuccess • Patient characteristics • Age • Type of infertility • Psychological stress • Oocyte / EmbryoCompetence • Laboratory Conditions • Embryotransferprocedure • Type of stimulation regimen • Type of gonadotrophinpreparation Keck RBM Online , 2005

8. Aim of COH Regulated superovulation by turning off the patient’s own HPO system (down regulation) followed by stimulation. • Recruiting multiple follicles • Control timing of ovulation (eggs can be surgically retrieved before they are ovulated) • Prevention of premature LH surge • To time the insemination • Increase the pregnancy rate

9. Monitoring • To time HCG injection • Decreases OHSS • Decreases multiple pregnancy • Follicular monitoring from D9 • S. estradiol levels did not give any additional information in various studies

10. Monitoring ovarian stimulation Transvaginal ultrasound scanning : . No. & size of follicles . Pattern & thickness of endometrium  Estrogen blood level

11. Traditional COH • HMG or FSH300 IU on 2° day cycle • HCG10.000 IU on leading follicle >17 mm and at least two follicles >15 mm • Pick-upafter 33-36 h • P450 mg i.m. for luteal supplementation

12. Traditional COH • FSH remain elevated • recruitment and growth of ovarian follicles continues throughout treatment This FSH serum pattern profoundly diverges from the spontaneous menstrual cycle * Filicori M: Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle . J ClinEndocrinolMetab. 1986;62:1136–1144

13. Traditional COH • heterogeneous size cohorts of follicles are often found at hCG day • the optimal outcome of COH would be the selective attainment of numerous large mature homogeneous follicles. * Arnot AM , Vandekerckhove P , DeBono MA , Rutherford AJ . Follicular volume and number during in-vitro fertilization (association with oocyte developmental capacity and pregnancy rate) . Hum Reprod . 1995;10:256–261

14. Gn-RH-a protocols long protocol short (“flare-up”) protocol ultrashort protocol microdose flare protocol

15. Long protocol: • Avoid pre-menses FSH surge • Follicles timing • Avoid premature LH surge • Higher follicular recruitment (synchronization) • Improvement immune attitude • Expensive cost High responders PCOS

16. short protocols • follicles timing • avoid premature LH surge • lower follicular recruitment • make procedures easier Poor responders

17. PR/transfer in Gn-RH-a FIV nel periodo 92-96 (da FIV-NAT ’97) sec. Barrière et al. 1999

18. Gn-RH-a Long protocol 1 • Gn-Rh-adepot 3.75 mg in one dose on 21stdayonlyofpreviouscycle or • Gn-Rh-alow-dosedaily on the 21stdayofpreviouscicleto HCG day: • Buserelin (Suprefactfl 5.5 ml) 0.3 ml fl s.c. • Buserelinnasally 1 buff x 3/d (300 μg) • Leuproreline (Enantonediefl s.c.) 0.2 ml/day • Triptoreline (Decapeptyldiefl s.c.) 0.2 ml or • on anydaywhen: • LH <0.5 • E2 <30 • No ovariancyst >10 mm

19. Gn-RH-a long protocol 2 • FSH/HMG 300-650 IU/day on 2nd cycle day to HCG day • HCG 10.000 IU on the leasttwofollicles >18 mm • Pick-up after 33-36 hours • P4 supplementation • HCG 5.000 IU sixdaysafter E-T

20. Short (flare-up) protocol • Gn-RH-a 3.75 mg depot ½ fl i.m. on 2° cycle day only • FSH 225-600 IU/d on 3th day (step-down regimen) • HCG 10.000 IU (18 mm + 15-16) • Pick-up after 33-36 h • HCG (+ P4)

21. Gn-RH-a flare low dose protocol • EE-P for 1-2 cycles • on 1st cycle day at HCG day: • Triptoreline (decapeptyl die) 0.2 ml (0.1 mg) s.c. daily • Leuproreline acetate (enantone die) 0.2 ml (1 mg) s.c. daily • Buserelin (Suprefact flac 5.5 ml) 0.3 ml s.c. • Buserelin nasally 3 buff/day (300 μg) or • on any day when: • LH <0.5 • E2 <30 • No ovarian cyst >10 mm • r-FSH/HMG 300-650 UI/d on 3rd cycle day

22. Antagonists protocol • on 1° days Gn stimulation • on 5°-6° days • one leading follicle ≥14 mm • HMG or FSH + LH added Fixed and early start of the antagonist is probably more effective than an individualized and late start.

23. advantages: Prevention surge LH larger cohort of follicles Avoidance of adverse effects of agonists More friendly stimulation protocol  OHSS disavantages  peak E2 on HCG day  mature follicles  oocytes  embryos  PR Gn-RH Antagonist

24. Luteal supplementation in agonists/antagonists protocols • Pituitary depletion • Pituitary desensitization • Negative estrogen feed-back • Compulsory supplementation E/P HCG supplementation absolutely necessary !!!

25. P4 secretion *P4 serum level:4 ng/ml is low level; 40 ng/ml is high

26. Luteal E2 supplementation • E2 orally 2-6 mg/d (Progynova cpr 2 mg) * • Start on: • E-T day or • 7 days after E-T • Increases implantation rate • Increases pregnancy rate In IVF cycles, the levels of E2 and P4 drop in the mid-late luteal phase Lower E2 at 11 days after pick-up is associated with lower pregnancy rate * Lukaszuk K: Fertil Steril 2005;83:1372-1376

27. poorrespondersprotocols

28. Poor responders • diminished ovarian reserve • A lower expression of FSH receptor in the granulosa cells • Advanced maternal age • E2 < 500 pg/mL on day of hCG • <4 de Graaf follicles on HCG day • lower fertilization rates • lower cleavage rates • lower resulting embryos • Lower implantation rate • lower pregnancy rates “occult ovarian failure” 10–25% of the ART population* * Keay et al., 1997 ; Karande and Gleicher, 1999 ; Fasouliotis et al., 2000 ; Tarlatzis et al., 2003

29. increase Gn dose • first and simplest approach • limited benefit to 450 IU per day • 300 IU FSH +hMG 150 IU • beyond this amount little or no improvement Murat Arslan: Fertil Steril 2005; 84,3:555-569

30. Luteal estradiol protocol * * Frattarelli J, et al: “A luteal estradiol protocol for expected poor-responders improves embryo number and quality” Fertil Steril 2008;89,5:1118-22

31. High respondersprotocol • CC 100 mg/d 3°-7° days • FSH 150 UI s.c. on cycle day 9 at HCG day • antagonist 0.25 mg/d delayed regimen • Aspirin 100 mg/d on 1° at 45° cycle day

32. High respondersprotocol 2 • Gn 225 UI/d on 2° cycle days • step-down regimen • antagonist 0.25 mg/d on 2° day up HCG day Doxycycline* 80 mg/Kg/day (inhibits vascular leakage) * Folkman HJ: fertil Steril 2007;88,S1:O14 *Bassado cpr 100 mg

33. FSH 225 IU/d on the 2° cycleday (step-downregimen) antagonist 0.25 mg/d on the 2° cycle at HCG day Agonist (0.50 mg) as HCGtrigger to achieveanendogenous LH surge when E2 ≥ 3.700 pg/ml (range 3.000-7.500) 0% OHSS AA high responders III

34. Gn-RH-a: HCG 10.000 UI Agonist vs. HCG as trigger mature oocytes premature oocytes implantation rate clinical pregnancy ongoing pregnancy OHSS            

35. OHSS/Coasting • Until drop of estrogen level <3.000 pg/ml • Coasting >3 days no affects on Pr Egbase PE , Al Sharhan M , Berlingieri P , Grudzinskas JG . Serum oestradiol and progesterone concentrations during prolonged coasting in 15 women at risk of ovarian hyperstimulation syndrome following ovarian stimulation for assisted reproduction treatment . Hum Reprod . 2000;15:2082–2086

36. PCOS Protocol • Pre-treatment with metformin ≥6 months • 2.000 mg/day • Improvment in menstrual cyclicity • Long-protocol agonist • Higher pregnancy outcome • Essah et al Fertil Steril 2006;86,1:230-232

37. The core of an assisted reproduction program is oocyte quality • Recognition of the right maturation state of oocytes obtained from stimulated cycles remains the major problem • Polar body extrusion indicates only meiotic or nuclear maturation

38. Acquisition of developmental competence “cytoplasmic maturation”, is a fundamental event that render the oocyte competent to be fertilized and able to support the embryo cleavage • Insufficient or incomplete cytoplasmic maturation of the oocyte has a negative effect on IVF outcome

39. Although nuclear and cytoplasmic maturation can proceed as an independent processes, developmental competence of oocytes is conferred only when the two processes are closely integrated. • Meiotic and cytoplasmic maturation of oocytes collected in stimulated cycle is asynchronous (Sundstrom and Nilson 1988).

40. Estradiol and cytoplasmic maturation • There are evidencesthatestradiolexerts a directeffect on oocytecytoplasmicmaturation via a non genomiccalcium-mediatedmechanismwhichcontributetooocytecompetence • Tesarik 1995 and 1997 • Revelli 1998 • Zheng 2003

41. Considerations • Over 30 years passed since the first IVF success, but the implantation rate did not substantially improved. • Although a great improvements in ART technologies and ovarian stimulation regimens, around 80% of produced embryos does not implant • The number of oocytes per pregnancy/birth remains high if not increased. • Increasing number of harvested oocytes • Lower oocyte utilization rate

42. The efficiency of oocyte utilization has not improved significantly since the early 1980s irrespective to the improved level of ovarian stimulation, the problem continue to lie with finding and identifying the “right oocyte”

43. The pregnancy rate per retrieved oocyte remains far too low (Nayudu et al 1989b Inge et al. 2005) The major limiting factor is oocyte quality Oocytes developmental competence is mainly acquired during folliculogenesis However: Despite the impressive improvements and innovations in human assisted reproduction treatment:

44. GV MI MII Oocyte maturation assessment Retrieved eggs were immediately denuded and assessed for their maturity, and then inseminated by ICSI Immature oocytes Slightly immature oocytes Mature oocytes

45. Embryo grading Embryos were scored on the basis of morphological appearance: size of blastomeres and degree of fragmentation

46. SUMMARY • Controversies on gonadotropins • Controversies on analogues • Controversies on E-P pills • Controversies on LH added Arslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Controlled ovarian hyperstimulation protocols for in vitro fertilization : two decades of experience after the birth of Elizabeth Carr”Fertil Steril 2005;84,3: 555-569

47. Conclusion(s) • Ovarian stimulation is a critical step in in vitro fertilization therapy. • A variety of controlled ovarian hyperstimulation regimens are available and efficacious, • but individualization of management is essential and depends on assessment of the ovarian reserve. • Identification of the etiologies of poor ovarian response constitutes a formidable challenge facing reproductive endocrinologists. Arslan MA, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S: “Controlled ovarian hyperstimulation protocols for in vitro fertilization : two decades of experience after the birth of Elizabeth Carr”Fertil Steril 2005;84,3: 555-569

48. Conclusion • Ovarian stimulation is the fundamental tool of subfertility treatment • Different options pose challenges • Choice depends on doctors expertise and patients condition, choice • Increases the pregnancy rate • Judicious monitoring to avoid complications

50. P0INT TO REMENBER ONE SATISFIED PATIENT IS WORTH THOUSANDS OF GUIDELINES AND PROTOCALS