Ovulation induction From shot in the dark a

Ovulation induction: From shot in the dark, a flat staircase and beyond Zeev Shoham Dep. Of OB/GYN Kaplan Hospital, Rehovot, Israel

Developments in Reproductive Health • Move toward all biosynthetic gonadotrophins. • Increase treatment success rates. • Enhance safety of stimulation regimens. • Simplify treatment regimens.

Simplifying procedure - improving results • Replacing Laparoscopy with Transvaginal ultrasound. • Using Gn. RH-a for down-regulation. • Simplifying monitoring. • S. C. administration for selfadministration. • Administration of Gn. RH-antagonists.

Ovarian Hyperstimulation Syndrome Multiple pregnancy Prevention ?

OHSS A Mystery

Strategies for prevention Withholding h. CG administration Reduced dose of h. CG Administration of native Gn. RH or Gn. RH-a Administration of rec-LH Freeze the embryos

Differentiation Angiogenesis Proteolysis Luteinization Demise of the CL Apoptotic process

…. . Ovarian. VEGF - Production (Basic & clinical studies) Capillary permeability Angiogenesis Endothelial cell proliferation

Ovarian renin-angiotensin system Ovarian Prorenin h. CG Active Renin Angiotensin I ACE Angiotensin II PG’s Steroidogenesis Angiogenesis Hyperpermeability

Patients at Risk PCOD h. CG (Exo/Endo) High serum E 2 Multiple follicles Younger age <32 Lean Habitus Gn. RH-a Protocols

Human Albumin Pathogenesis h. CG mediated factor produced by the corpus luteum which increases capillary permeability

Human Albumin Maintains plasma oncotic pressure (70 to 80%) Carrier protein (Hormone, Drugs, Glucorticoids, Fatty acids, Aldosterone, Bilirubin) Tullis. Am J Med Assoc 1977

Human Albumin Administration of 50 g. Increase blood volume within 15 min. > 800 m. L Half-life 14 days Luteal Phase

Human Albumin Sterile Solution Process of Manufacturing FDA Approved plasma Cold ethanol fractionation Fraction IV or V paste Ion exchange chromatography Diafiltration & concentration Pasteurization Viral Safe Hepatitis C antibody Hepatitis B surface antigen HIV-1 antibody HIV-2 antibody

h. MG h. CG Ovary Ovulation Corpus luteum Factor X Capillary permeability Leak Syndrome Albumin loss Hypovolemia Oliguria Renal Failure Thromboembolic events Hemoconcetration

h. MG h. CG Activation Renin-Angiotensin Ovary Ovulation Plasma Renin Activity Corpus luteum Factor X Endothelial cell contraction Angiotensin II “like substance” Promote Angiogenesis Capillary permeability Binding capacity in plasma Free/Biologically Active Factor? Leak Syndrome Albumin loss Hypovolemia Oliguria Renal Failure Thromboembolic events Hemoconcetration

Release Angiotensin Converting Enzyme ATI h. MG h. CG Activation Renin-Angiotensin Ovary Ovulation Plasma Renin Activity Corpus luteum ATII Factor X Endothelial cell contraction Promote Angiogenesis Capillary permeability Aldosterone Release Binding capacity in plasma Free/Biologically Active Factor? Leak Syndrome Albumin loss Oncotic Pressure Hypovolemia Ascites Angiotensin II “like substance” Oliguria Renal Failure Thromboembolic events Hemoconcetration

Authors Study Type Asch et al. Hum. Reprod. 1993 Prospective (25 g x 2) Shoham et al. Fertil Steril 1994 Prospective (50 g) Randomized Placebo-controlled Ng et al. Hum. Reprod. 1995 Cohot study (50) Retrospective-control Shalev et al. Hum. Reprod. 1995 Prospective (20 g) Randomized Controlled-group Alb/OHSS Cont/OHSS 36/0 p<0. 043 16/0 14/4 49/2 158/10 22/0 18/4 p<0. 008 Prospective (10 g) Eur J OB/GYN Reprod Biol 1996 Randomized 27/0 28/5 p<0. 05 Shaken et al. Fertil Steril 1996 13/0 163/2 231/23 Isik et al. Prospective (40 g x 2) Randomized

Intra-venous albumin for preventing severe ovarian hyperstimulation syndrome Reviewers' conclusions: This review shows a clear benefit from administration of intra-venous albumin at the time of oocyte retrieval in prevention of severe OHSS in high-risk cases. Cochrane Liberary 1999

Hydroxyethyl Starch Solution High molecular weight Increase plasma oncotic pressure Half-life of 10 h Graf et al. Hum Reprod 12: 2599, 1998

Prophylactic intravenous hydroxethyle starch solution A prospective, randomized, double-blind, placebocontrolled study. 1000 cc 6% HES vs. 1000 cc Na. Cl Konig et al. Hum Reprod 13: 2421, 1999

Treat Group Control Group No. of Pat. 51 50 Moderate OHSS 1 6 Severe OHSS 0 1 Mod+Sev OHSS 1 7 p<0. 031 Konig et al. Hum Reprod 13: 2421, 1999

Treat Group No. of Pat. Control Group 100 82 No. of Pregnancy 28 24 Moderate OHSS 10 32 p<0. 000001 Severe OHSS 2 7 Graf et al. Hum Reprod 12: 2599, 1998

Lessons For The Future * Markers for detection of patients at risk. * Develop strategies to decrease neovascularization and hyperprmeability

Multiple Gestation From curiosity to epidemic

Septuplets following Ovulation induction; Miracle in Iowa?

Multiple Gestation Rate Japan 6. 7/1000 U. S/Europe 11/1000 Africa 40/1000 Monozygous 3. 5/1000 O. I. /ART 37%

Complications Maternal Fetal Miscarriages IUGR Hypertension Congenital anomalies Operation Hydroamnios Postpartum hemorrhage Birth asphyxia Postpartum stress Neonatal death

Multiple birth rate in Ovulation Induction and ART Unacceptable high. Triplet and higher order is a major medical problem. Twins are also a medical problem. Can only be overcome by carefull management of O. I. and reducing number of embryos transferred.

Twins born in Western Australia 1991 4 times more likely to be stillborn. 5 times more likely to dies as neonates. 16 times more likely to weight less 1500 g at birth. CP 8 times more often than a singeltone. Required neonatal intensive care 8 times more often than singleton.

Multiple pregnancy rate related to the number of follicles > 16 mm on h. CG day No. of Clinical No. of Birth follicles on cycles clinical pregnancy birth rate day h. CG pregnancy rate (%) No. of Multiple twins birth rate (%) 1 foll. 277 47 17. 09 39 14. 18 2 5. 13 2 foll. 77 20 25. 97 17 22. 08 2 11. 76 3 foll. 32 11 34. 38 10 31. 25 2 20. 00 >3 foll. 19 5 26. 32 4 21. 05 2 50. 00 Overall 405 83 20. 60 70 17. 37 8 11. 4

FSH Administration Regimen Chronic Low Dose (CLD): S. Franks et al. 75 IU Days 7 14 h. CG 150 IU 112. 5 IU 75 IU 21 28 Step Down (SD): B. Fauser et al. 150 IU 112. 5 IU 75 IU h. CG Foll. 10 mm Sequential (SE): J. N. Hugues et al. 150 IU 112. 5 IU 75 IU 6 ½ 75 IU 12 Foll. 14 mm h. CG

How to minimize the risk of multiple birth Strict criteria for h. CH administration. Replacing h. CG with rec-LH or Gn. RH-a Optimize Follicular Development? The use of different doses of rec-LH

How to minimize the risk of multiple birth and still achieve a good pregnancy rate/ started stimulation? Adjust the No. of embryos transferred depending on risk factors for multiple gestation. Age. A good freezing program

Complications Embryo reduction Miscarriage 4 -5 % Premature labor 75 % Traumatic experience

Conclusion Identify groups who will benefit from having one blastocyst only. We have to adopt a strategy where we try to retrieve as many oocytes as possible, replace one blastocyst and freeze the others.

Physician obligations are: Do no harm. Assessing the balance between risk and benefit.

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.