1. Stimulation of Ovarian Function MONITORING Zeev Shoham, M.D. Department of Obstetrics and Gynecology, Kaplan Hospital, Rehovot, Israel rec-hFSH

2. The art of Science

3. Monitoring serves what? Helps the physician to choose the most suitable protocol, to obtain best possible outcome, avoid complications Adds to the common pool of information, which increase our knowledge and understanding of human reproduction

4. MONITORING Close continuos observation Patient’s initial parameters Ovarian response to ovulation induction Completion of therapy Kaplan Medical Center, Rehovot, Israel

5. Increase patient comfort. Avoiding the development of OHSS. Reduce rate of multiple pregnancies. Taking advantage of significant improvements that have been achieved in embryology and laboratory science. Addressing the economic considerations. What do we have to consider? Kaplan Medical Center, Rehovot, Israel

6. The mortality rate for twins in England and Wales (late fetal death up to age of 1 year) is nearly 3 to 7.8 times greater than for single birth. Doyle et al. J Epidemiol Commun Health 1991 Multiple gestatiuons Kaplan Medical Center, Rehovot, Israel

7. Age Preg. rate Age and pregnancy rate following Leyendecker et al. Gynecol Endocrinol 1995

8. Simplifying treatment protocols remains a most important objective Reduce the cost Reduce time commitments Kaplan Medical Center, Rehovot, Israel

9. The administration of GnRH-a Reduce rates of cycle cancellation. Increased number of oocytes. Improves clinical pregnancy rates. A prolonged treatment cycle. Necessity for higher gonadotropin dosage. Greater expense and patient inconvenience. However: Kaplan Medical Center, Rehovot, Israel

10. Serum LH < 2 Serum Estradiol < 50 pg/ml Absence of ovarian cyst GnRH-a Protocol Criteria of Pituitary suppression Kaplan Medical Center, Rehovot, Israel

11. Endometrial thickness as a predictor of pituitary down-regulation following gonadotropin-releasing hormone analog administration in an IVF program IVF Unit, Dep. Ob/Gyn, Kaplan Medical Center, Rehovot, (Affiliated with the Hadassah-Hebrew University Medical School Jerusalem), Israel Kaplan Medical Center, Rehovot, Israel

12. Hypothesis Shulman et al. (Hum Reprod 1989) Morcos et al. (Fertil Steril 1991) Ultrasonographic assessment of the endometrium has been suggested as a predictor of estrogen status in amenorrheic patients. Endometrial thickness - a reliable bioassay of the patient’s estrogenic status. Kaplan Medical Center, Rehovot, Israel

13. Objective Prediction of pituitary down-regulation by sonographic assessment of endometrial thickness only. Kaplan Medical Center, Rehovot, Israel

15. n = 183 Endometrial thickness vs. Estradiol Kaplan Medical Center, Rehovot, Israel

17. Conclusion Transvaginal sonographic measurement of endometrial thickness of  6 mm predicts pituitary down-regulation in over 95% of cases. The baseline sonographic scan may provide additional relevant information Kaplan Medical Center, Rehovot, Israel

18. A. Weissman, A. Barash, M. Manor, A. Ben-Arie, I. Granot, Z. Shoham Acute changes in endometrial thickness following aspiration of gonadotropin-releasing hormone analog-related baseline ovarian cysts I VF Unit, Dep. Ob/Gyn, Kaplan Medical Center, Rehovot, (Affiliated with the Hadassah-Hebrew University Medical School Jerusalem), Israel

19. The reported incidence varies between 6-39%, according to the protocol used, and time of administration of the GnRH-a. Kaplan Medical Center, Rehovot, Israel

20. This condition is usually characterized by: # A functional ovarian follicle/cyst, usually > 15-20 mm in diameter. # High serum estradiol levels, usually >200 pmol/L # Increased endometrial thickness, usually > 7 mm Kaplan Medical Center, Rehovot, Israel

21. Management of this condition is controversial Ultrasound-guided transvaginal aspiration This procedure is usually followed by a sharp decline in serum estradiol concentration Continue follow-up and GnRH-a treatment Kaplan Medical Center, Rehovot, Israel

22. Study Protocol 20 IVF patients on the long GnRH-a protocol All scheduled for cyst aspiration following measurement of endometrial thickness. Serum estradiol > 180 pmol/L Ovarian follicle > 20 mm Kaplan Medical Center, Rehovot, Israel

23. Follow up Evaluation 2 days post-procedure Ovarian morphology Serum estradiol concentration Endometrial thickness Kaplan Medical Center, Rehovot, Israel

24. Results Endometrial Thickness After: 5.9 + 2.4 mm Before: 9.6 + 2.0 mm p< 0.0001 Serum estradiol concentration After: 184.0 + 271.1 pmol/L Before: 739.8 + 493.0 pmol/L p< 0.0001

25. Serum hormone concentration Before aspiration After aspiration P LH FSH 1 2 3 nmol/L IU/L IU//L

26. Aspiration of a functional GnRH-a related ovarian cyst Observed in 19/20 patients No vaginal bleeding reported Acute reduction in serum estradiol concentration Acute decline in endometrial thickness Kaplan Medical Center, Rehovot, Israel

27. Shaken et al. Fertil Steril 1996 Prospective (40g x 2) Randomized Asch et al. Hum. Reprod. 1993 Prospective (25g x 2) 36/0 Authors Study Type Alb/OHSS Cont/OHSS p<0.043 p<0.05 p<0.008 231/23 163/2 Kaplan Medical Center, Rehovot, Israel Shoham et al. Fertil Steril 1994 Prospective (50g) Randomized Placebo-controlled 14/4 16/0 Ng et al. Hum. Reprod. 1995 Cohot study (50) Retrospective-control 158/10 49/2 Shalev et al. Hum. Reprod. 1995 Prospective (20g) Randomized Controlled-group 18/4 22/0 Isik et al. Eur J OB/GYN Reprod Biol 1996 Prospective (10g) Randomized 28/5 27/0 13/0 13/0

28. Kaplan Medical Center, Rehovot, Israel Mukherjee et al. Fertil Steril 1995 2 Case Reports Orvieto et al. Hum. Reprod. 1996 2 pat. out of 30 treated “ Letter to the Editor” Lewit et al. Fertil Steril 1996 Case reports 5/4 OHSS Ronen et al. J Assist Reprod 1995 2 Case Reports Authors Study Type

29. Conclusion Avoidance of E2 blood tests may simplify IVF protocols, thus increasing cost-effectiveness and patient convenience. Induction of ovulation and IVF protocols can be monitored successfully by measuring endometrial thckness and ovarian follicles. Kaplan Medical Center, Rehovot, Israel

30. A major challenge for every physician is to balance the immediate gain of a pregnancy against the potential long-term negative impact of multiple gestation. Conclusion Kaplan Medical Center, Rehovot, Israel

31. Conclusion It might be possible that by introducing a new technology and replacing only few number of instead of we will be able to achieve significantly lower rate of multiple pregnancies. large numbers of Kaplan Medical Center, Rehovot, Israel