PCOD Critical analysis of medical and surgical management

PCOD: Critical analysis of medical and surgical management Zeev Shoham M. D. Dep. Of OB/GYN Kaplan Hospital, Rehovot, Israel

PCOD: Various treatment modalities Pharmacological Treatment CC Gonadotropins h. MG u. FSH HP-FSH rec-FSH Surgical Treatment Hyperinsulinemia? Insulin sensitizer Gn. RH-analogs Wedge resection Electro cauterization

Cycle evaluation during CC treatment LH FSH E 2 PRL T DHEA U/S Menses LH FSH U/S E 2 LH PCT U/S P 4 Foll. Endo. h. CG 5, 000 IUI CC 100 mg/d h. CG 10, 000 Day 5 to 9 Day 13 -14 HSG Ov. Endo. 36 h 5 days

Anovulatory infertility in PCOS | 50 -80% will ovulate on CC | Only 40 -50% will conceive

FSH administration regimens 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

Ovarian Hyperstimulation Syndrome Multiple pregnancy Prevention ?

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

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 all embryos

Prevention of OHSS Replacing h. CG with rec-LH or Gn. RH-a

IU/L Spontaneous LH surge Endogenous surge triggered by Gn. RH-a Periovulatory phase (hrs) h. CG

LH Serum Concentration versus Time 400 IU/kg IV 10 Normalized LH serum level (I/L) r-LH u-LH 1 p-LH 0. 1 0. 001 0 12 24 36 48 Time 60 72 84 96 Parameter p-h. LH r-h. LH u-h. LH Initial half-life 0. 6+0. 02 10+0. 7 0. 8+0. 2 11+0. 9 0. 7+0. 2 9+0. 8 Terminal halflife le Cotonnec and Porchet 1993

Multiple Gestation From curiosity to epidemic

Multiple Gestation Rate Japan 6. 7/1000 U. S/Europe 11/1000 Africa 40/1000 Monozygous 3. 5/1000 O. I. /ART 370/1000

How to minimize the risk of multiple gestation Optimize Follicular Development? Strict criteria for h. CG administration.

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

How to minimize the risk of multiple birth Strict criteria for h. CH administration. Optimize Follicular Development? The use of different doses of rec-LH

The use of rec-LH to facilitate monofollicular development European r-h. LH Research Group

United Kingdom Holland Italy Israel

Study design To assess the efficacy of two doses of r-h. LH 225 450 Given at the late follicular phase to FSH treated PCOS patients if 4 foll. 8 -13 mm

17 PCOS patients enrolled Placebo r-h. LH 225 IU/day r-h. LH 450 IU/day : : : 5 patients 4 patients 8 patients

PRIOR TO STUDY: patients received FSH stimulation. If met following criteria: > 4 follicles with diameter 8 mm and 13 mm Endometrium thickness 8 mm randomization FSH 450 IU r-h. LH 225 IU r-h. LH (7 days max) Placebo (Coasting) When at least one follicle of 18 mm and 3 follicles of 11 mm => h. CG 5’ 000 IU

Mean total number of follicles at baseline ( 8 -13 mm) and on day of h. CG ( 14 mm) No. of follicles 14 10 6 2 225 IU rh. LH Placebo 450 IU rh. LH 9. 75 18 8. 88 14 8 -13 5. 6 3. 8 3. 75 2. 25 1. 25 >11 >14 8 -13 mm 11 mm 14 mm

Summary • This study supports the ‘hypothesis’: adding high dose LH during the late follicular phase, induces atresia of growing follicles.

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

Conclusion Identify patients who will benefit from single blastocyst transfer. We have to adopt a strategy where we try to retrieve multiple oocytes, replace one blastocyst and freeze the others.

Insulin resistance Compensatory Hyperinsulinemia ? Androgens Ovary Cause-and-effect relationship Serum insulin

Impact of insulin secretion on ovarian response to FSH stimulation in PCOS Relationship between: Circulating insulin levels Follicular growth Ovarian hormone secretion Fulghesu et al. , J Clin Endocrinol Metab 1997

Clinical Data Normoinsulinemic patients 14 No. of pat. Obese 3 BMI. SHBG FAI (Tx 100)/SHBG Lean 11 Hyperinsulinemic patients 20 Obese Lean 14 6 P<0. 05 27. 8+5. 3 48. 47+29. 3 P<0. 001 23. 29+8. 2 P<0. 005 11. 39+5. 4 23. 2+4. 12+1. 9 Fulghesu et al. J. C. E. M. 1997

Treatment protocol h. CG 5, 000 amps. 4 FSH 1 E 2 18 14 8 Menses 4 12 Fulghesu et al. J. C. E. M. 1997

Stimulation outcome Normoinsulinemic patients Hyperinsulinemic patients No. of Cy. 21 31 Dose/BMI 57. 7+18. 7 54+18 FSH dose 1395+472 1507+727 Ovul. rate 85. 7% 83. 8% OHSS 23. 8% Pregnancy 28. 5% 16% Abortion 16. 6% 20% P<0. 05 64. 5% Fulghesu et al. J. C. E. M. 1997

Estradiol (pmol/L) P<0. 01 Days from h. CG injection Fulghesu et al. J. C. E. M. 1997

Number of follicles Diameter >12 mm and < 16 mm P<0. 01 Days from h. CG injection Fulghesu et al. J. C. E. M. 1997

Conclusion: Insulin resistance may be an important marker for poor outcome and for high risk for development of the ovarian hyperstimulation syndrome.

Hyperinsulinemic PCOS patients: management ]Weight loss: diet, exercise, life-style changes ]Insulin lowering agents ]Induction of ovulation

Metformin Dimethylbiguanide Multiple mechanisms of action: v. Inhibition of gluconeogenesis in the liver v. Enhanced peripheral uptake of glucose v. Increased intestinal use of glucose v. Decreased fatty acid oxidation

61 women with BMI >28 USA Venezuela Italy PCOS 26 women received - Placebo 1 ovulated P<0. 001 35 women received - Metformin 1500 mg/day 1 14 28 14 ovulated 35 Prog. >25 nmol/L Nestler et al. , New Engl J Med 1998

CC 50 mg 25 women received - Placebo 2 ovulated 21 women received - Metformin 1500 mg/day 1 5 10 P<0. 001 19 ovulated 18 Area under the curve (mic. U/ml/min) 75 g of glucose (0, 60, 120 min) Pre- Post Metformin 6598+1267 3479+455 Placebo 6558+1030 5100+55 P<0. 03 Nestler et al. , New Engl J Med 1998

Conclusions: Effects of metformin on gonadotropin-induced ovulation in PCOS v. Reduction of # follicles > 15 mm in diameter v. Reduction in E 2 levels on h. CG day v. Reduction in cycle cancellation (h. CG withholding) v. Lower incidence of OHSS De Leo et al. , Fertil Steril 1999; 72: 282 -5

A major challenge for every physician is to balance the immediate gain of a pregnancy against the potential long term negative impact of the treatment, mainly OHSS and multiple gestation.