Ovulation Induction Prof Dr Cem FICICIOGLU Yeditepe University

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

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

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

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 20 -25 kg/m 2 • General health status ( anemia ) • Folic support, • Spermiogram/HSG • Hormonal profile

Methods Hormonal Chemical hmg CC/ Tamoxifen Ovarian drilling Weight loss FSH (pure) CC+Metformin Gn. RH (puls) Bromocriptin Rec. FSH Aromatase Inhibitors Surgery Medical

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 , E 2 • Premature Ovarian Failure • Overian Resistans

Ovulation Follow up Methods • • Old Gynecologic Exam Vaginal smear Basal Body Temp Progesterone • • New Basal body temp Serial Ultrasonography E 2 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.

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

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

HCG timing • • • Follicular diameter: 16 -18 mm E 2 150 -250 pg/ml / per dominant foll. Doz 2. 000 -10. 000 IU Early HCG -atresia, LUF Late HCG -postmaturity

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 E 2 RESEPTORS Endometrium FSH and cervical (mukus) Inhibition OVERIAN STIMULATION

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

CC Contrendications • E 2< 40 pg/ml • Liver dysfunction • Pregnancy • Overian cyts • Age>35 • FSH>11 IU

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

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 -20 mm, • 34 -40 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 :

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

CC Resistans Alternative Treatments • Weight loss (BMI) • İnsülin sensitizer agents + CC (metformin 3 x 500 mg, 2 x 850 mg) • • • Corticosteroids (Deksametazon 0. 5 mg/gün) + CC (DHEAS ) Prolaktin inhibating agent + CC Aromatase inhibitors Gonadotrophins + CC Gonadotrophins IUI + CC

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

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. B 12 levels ↓ Aplastic anemia, Hemolitic anemia, Trombositopenia, Agranülositosis Laktic asidoz

Tamoxifen TAMOXIFEN HIPOTALAMIC E 2 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)

Androstenedion Testosteron Aromatase Estron Estradiol

ANDROGENS AROMATASE ESTROGENS HYPOTALAMUS FSH Overian Stimulation

Aromatase Inhibitors • Blocks the E 2 reseptors (reversible) • No negative effects on Endometrium and Cervical muucus. • Multiple Pregnancy and OHSS risks are low

Aİ Generation Non-steroid Steroid (Non-reversibl) I Aminoglutetimid II Roglitimid Fadrozol Formestan III Anastrozol Letrozol Vorozol Eksemestan

AI Anastrozol Arimidex, 28 tb, Letrozol Femara, 30 tb, Dozage Aromataz inhibition (%) 1 mg/g 97. 3 2. 5 mg/g >99. 1

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

Aİ Contrendications Hipersensitivity Pregnancy Laktation Renal insufficiency

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

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%)

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

LOW-DOSE STEP-UP 112. 5 IU/g 75 IU /g 1 14 21 150 IU/g 28 187. 5 IU/g 35

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

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