Ovulation Induction for Fertility: Methods and Treatments

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

2. Foliculogenesis 60 days 14 days 14 days 1mm. 4-6 mm. 20 mm. Gougeon, 1982

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

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

5. Factors • Demographical ( age, weight…..). • 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

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

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. For < 4 folficular development • CC (clomiphene Citrate). • CC ± FSH veya± HMG. • Aromatase Inhibitors • Gn. Standard step-up protokol. • Gn. Low dose step-up protokol. • Gn. Low dose step-up, step-down protokol.

14. Cycles Cancellation • >3 Dominant Follicles • ESTRADİOL (E2 )>1500 PG/Ml • DOMİNANT Follicule ( - )

15. HCG timing • 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

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-clomiphenehas much more estragenic activity

20. Absorbation GIS tract.

21. Anti-estrogenic activity • uterus • cervix • vagina

22. HYPOTALAMIC E2 RESEPTORS CC  FSH Endometrium and cervical (mukus) Inhibition 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-Side effects CC- YAN ETKİLER Hot flushes Abdominal tenderness Nausea/vomitting Breast tenderness Visual disturbance Head ache Hair loss Dermatid, Depretion, % 11 7 2 2 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. CC Failure • 3 cycles, max dosage CC (150 mg) No ovulation • No pregnancy after successful 6 treatment cycles

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

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

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

35. MetforminSide Effects Anorexia,Nausea, Vomitting Diarrheae, constipation, Vit. B12 levels↓ Aplastic anemia, Hemolitic anemia, Trombositopenia, Agranülositosis Laktic asidoz

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

37. 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.

38. Aromatase Inhibitors (AI)

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

40. Androstenedion Testosteron Aromatase Aromatase Estron Estradiol

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

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

43. Aİ

45. AI-Endications • CC resistans PCOS • Poor responders • Breast cancer

46. Aİ Contrendications Hipersensitivity Pregnancy Laktation Renal insufficiency

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

48. AISide 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%)

49. Gonadotrophin Treatments ART WHO-Grup I WHO-Grup II Normogonadotrophic patients Hipogonadotrophic patients

50. Gonadotrophins CONTRENDICATIONS • Overian Failure • Hiperprolactinemia • No cooperation with patient