1. Ovulation Induction Prof. Dr. Cem FICICIOGLU Yeditepe University Hospital Obstetrics and Gynecology

2. Foliculogenesis 60 days14 days 1mm. 4-6 mm. 20 mm. Gougeon, 1982

3. Ovulation Atresia FSH Baird DT: J Steroid Biochem 27: 15-23, 1987 FSH Treshold

4. Ovulation Induction -alone, -Prior to an IUI ( =< 2 follicles) -Prior to an IVF (>5 follicles)

5. Factors 1.Demographical ( age, weight…..). 2.Causes: OI+Coit IUI IVF / ICSI.

6. Preparation Treatmen of the causes ( weight loses, PCO + Obesity ) BMI should be 20-25 kg/m2 General health status ( anemia ) Folic support, Spermiogram/HSG Hormonal profile

7. Methods Hormonal Chemical SurgeryMedical hmgCC/ TamoxifenOvarian drilling Weight loss FSH (pure)CC+Metformin GnRH (puls) Bromocriptin Rec.FSHAromatase Inhibitors

8. Ovulation Problems Group I Hipogonadotropik hipogonal anovulasyon ( %10 ) Group II Normogonadotropik normoöstrojenik anovulasyon- PCO (%70) Group III Hipergonadotropik hipoöstrojenik anovulasyon (%10) Group IV Hiperprolaktinemik anovulasyon (%10)

9. Group III Anovulation FSH , LH N , E2  Premature Ovarian Failure Overian Resistans

10. Ovulation Follow up Methods Old Gynecologic Exam Vaginal smear Basal Body Temp Progesterone New Basal body temp Serial Ultrasonography E2 levels LH kit

11. Starting to the treatment No ovarian cyts Thin endometrium ESTRADIOL <50 PG/ML PROGESTERON <1.6 NG/ML

12. OI for IUI Aim  Monofollicular development. Close up follow up. Dosage should be adjusted based on response.

13. 1.CC (clomiphene Citrate). 2.CC ± FSH veya ± HMG. 3.Aromatase Inhibitors 4.Gn. Standard step-up protokol. 5.Gn. Low dose step-up protokol. 6.Gn. Low dose step-up, step-down protokol. For < 4 folficular development

14. Cycles Cancellation >3 Dominant Follicles ESTRADİOL (E 2 )>1500 PG/Ml DOMİNANT Follicule ( - )

15. Follicular diameter: 16-18mm E2 150-250 pg/ml / per dominant foll. Doz  2.000-10.000 IU Early HCG -atresia, LUF Late HCG -postmaturity HCG timing

16. SERMs Binding to Er  ve Er  receptor – Clomiphene –Tamoxifen –Raloxiphene –Bazedoxifene

17. Clomiphene Citrate(CC)

18. CC 2 stereoisomer –zu-clomiphene (38 %)(sis) –en-clomiphene (62 %)(trans),

19. En-clomiphene  rapid degradation, zu-clomiphene  long half life Both isomere have estrogenic and antiestrogenic activity Zu-clomiphene has much more estragenic activity

20. Absorbation  GIS tract.

21. Anti-estrogenic activity uterus cervix vagina

22. CC HYPOTALAMIC E2 RESEPTORS Endometrium and cervical (mukus)Inhibition  FSH OVERIAN STIMULATION

23. CC - Endications Normogonadotrophic, normoprolactinemic anovulation PCOS - Anovulation Unexplained Infertility Prior IUI Hipotalamo-hipofizer aks sağlam olmalı!

24. CC Contrendications E2< 40 pg/ml Liver dysfunction Pregnancy Overian cyts Age>35 FSH>11 IU

25. CC- YAN ETKİLER CC-Side effects Hot flushes Abdominal tenderness Nausea/vomitting Breast tenderness Visual disturbance Head ache Hair loss Dermatid, Depretion, % 11 7 2 1.5 0.3

26. CC - Treatment Day 3-5. of the menstruel cycle, 50 mg/g; 5 days Hiperresponders  25 mg/g No ovulation> 50 > 100 > 150 > 200 > 250 mg/g

27. When HCG Follicular diameter  18-20mm, 34-40 hours later  ovulation

28. Ovulation: USG Findings Disappearnece of the follicles Shrinkage of the follicles Corpus Luteum Fluids in the Douglas

29. Ovulation:Midluteal Progesterone >= 5 ng/ml  ovulation >= 9 ng/ml  pregnancy?

30. CC-Results Ovulation: %60-80 Pregnancy: %20-40 Multiple Pregnancy: %10 Abortion : %20

31. 3 cycles, max dosage CC (150 mg)  No ovulation No pregnancy after successful 6 treatment cycles CC Failure

32. CC Resistans Alternative Treatments Weight loss (BMI) İnsülin sensitizer agents + CC (metformin 3x500mg, 2x850mg) Corticosteroids (Deksametazon 0.5 mg/gün) + CC (DHEAS ) Prolaktin inhibating agent + CC Aromatase inhibitors Gonadotrophins + CC Gonadotrophins IUI + CC

34. Insulin Sensitisizer Drugs Folliküler gelişimin artan androjen düzeyi ile negatif etkilenmesi CC cevabının bozulması Hiperinsulinemia

35. Metformin Glucose decreases Hepatic production ↓ Bowel Absorbtion ↓  LH ve Androgens ↓ Normal blood glucose does not decrease with Metformin

36. Metformin Side Effects Anorexia,Nausea, Vomitting Diarrheae, constipation, Vit. B12 levels ↓ Aplastic anemia, Hemolitic anemia, Trombositopenia, Agranülositosis Laktic asidoz

37. Tamoxifen TAMOXIFEN HIPOTALAMIC E2 RESEPTORS Endometrial stimulation  FSH OVERIAN STIMULATION

38. Tamoxifen Pregancy rates looks like CC Spontanous abortion rate  lower than CC No side effect to the cervical mucus Pts with breast cancer can use this for OI.

39. Aromatase Inhibitors (AI)

40. Aromataz Aromatase, an enzyme Ovarium, Adipouse tissue, Muscles, Liver, Breast has Aromatase enzyme Aromatase transforms androgens to estrogens (with FSH stimulation)

41. AndrostenedionTestosteron EstronEstradiol AromataseAromatase

42. ANDROGENS AROMATASE ESTROGENS  HYPOTALAMUS FSH    Overian Stimulation

43. Aromatase Inhibitors Blocks the E2 reseptors (reversible) No negative effects on Endometrium and Cervical muucus. Multiple Pregnancy and OHSS risks are low

44. AİGenerationNon-steroidSteroid(Non-reversibl)IAminoglutetimid IIRoglitimidFadrozolFormestan IIIAnastrozolLetrozolVorozolEksemestan

45. AIDozage Aromataz inhibition (%) Anastrozol Arimidex, 28 tb, 1 mg/g97.3 Letrozol Femara, 30 tb, 2.5 mg/g>99.1

46. 1.CC resistans PCOS 2.Poor responders 3.Breast cancer AI-Endications

47. Aİ Contrendications Hipersensitivity Pregnancy Laktation Renal insufficiency

48. 2.5 – 5 (1-2 ) mg / day 3-7 Aİ - Dosage

49. AI Side effects Headache (6.9%) Nausea (6.3%), Periferal Edema (6.2%), Fatigue (5.2%), Hot flushes(5.2%), Bone and back ache(4.8%), Rash (3.4%)

50. WHO-Grup IIWHO-Grup I Gonadotrophin Treatments Hipogonadotrophic patients Normogonadotrophic patients ART

51. LOW-DOSE STEP-UP 75 IU /g 112.5 IU/g 150 IU/g 187.5 IU/g 1 14 21 28 35

52. Gonadotrophins Overian Failure Hiperprolactinemia No cooperation with patient CONTRENDICATIONS

53. Kibar olanın her zaman kazanır