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

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

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

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

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

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

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

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)

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

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

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

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

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

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

Follicular diameter: 16-18mm E pg/ml / per dominant foll. Doz  IU Early HCG -atresia, LUF Late HCG -postmaturity HCG timing

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

Clomiphene Citrate(CC)

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

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

Absorbation  GIS tract.

Anti-estrogenic activity uterus cervix vagina

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

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

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

CC- YAN ETKİLER CC-Side effects Hot flushes Abdominal tenderness Nausea/vomitting Breast tenderness Visual disturbance Head ache Hair loss Dermatid, Depretion, %

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

When HCG Follicular diameter  18-20mm, hours later  ovulation

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

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

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

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

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

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

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

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

Tamoxifen TAMOXIFEN HIPOTALAMIC E2 RESEPTORS Endometrial stimulation  FSH OVERIAN STIMULATION

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.

Aromatase Inhibitors (AI)

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

AndrostenedionTestosteron EstronEstradiol AromataseAromatase

ANDROGENS AROMATASE ESTROGENS  HYPOTALAMUS FSH    Overian Stimulation

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

AİGenerationNon-steroidSteroid(Non-reversibl)IAminoglutetimid IIRoglitimidFadrozolFormestan IIIAnastrozolLetrozolVorozolEksemestan

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

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

Aİ Contrendications Hipersensitivity Pregnancy Laktation Renal insufficiency

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

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%)

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

LOW-DOSE STEP-UP 75 IU /g IU/g 150 IU/g IU/g

Gonadotrophins Overian Failure Hiperprolactinemia No cooperation with patient CONTRENDICATIONS

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