The Role of Aromatase Inhibitors in Assisted Reproductive Technologies Ulun ULUG, M.D. Bahceci IVF Centers, Istanbul

1.Does addition of AI increase pregnancy rates ? 2.Does addition of AI reduce cost ? 3.Does addition of AI augment ovarian response ? 4.Does addition of AI during luteal phase decrease OHSS risk 5.ART in breast ca survivors

Pharmacology  Inhibit or inactivate AROMATASE  Aromatase is the rate limiting step in the conversion of androstenedione and testosterone to estrone and estradiol  Suppression of plasma estrogen levels  Aromatase –Cytochrome P-450 superfamily

Aromatase Enzyme  Sources: –Granulosa cells of Ovary –Endometrial cells –Placenta –Subcutaneous fat –Liver –Muscle –Brain –Normal breast –Breast cancer

Aromatase Enzyme  Premenopausal women –Ovarian source  Postmenopausal women –Adipose tissue Aromatase transcription regulated by: –Cytokines –Cyclic nucleotides –Gonadotropins –Glucocorticoids –Growth factors

Aromatase Inhibitors

3 rd Generation Aromatase Inhibitors  Type 1: Exemestane –t½= 27h  Type 2: Anastrozole and Letrozole –t½= 48h, once daily dosing  99% inhibition of aromatase enzyme  ,000 fold more effective  Oral administration  More selective for aromatase

Dosage 1.Letrozole 2.5mg/5mg daily from day 3 to day 7 of menses 2.Letrozole 20mg single dose on day 3

A Randomized Trial of Superovulation with Two Different Doses of Letrozole Al-Fadhli et al 2006 Unexplained Infertility

Side effects of Letrozole usage :  Headache (6.9%)  Nausea (6.3%)  Peripheral eodema (6.2%)  Fatigue (5.2%)  Hot flushes (5.2%)  Skin reactions (3.4%)

11 Hypothesis Aromatase inhibition decreases estrogenic negative feedback centrally Increased FSH Short half-life and no ER effects (no depletion) Intact central feedback loop for estrogen & FSH (Normal feedback mechanisms centrally) Avoids the undesirable peripheral anti-estrogen effects of CC = ( no –ve effect on endometrium) Result in predominantly mono-ovulation when used alone Ovarian intrinsic accumulation of A, increases GC-FSH sensitivity

 Androgens increase FSH receptor expression on granulosa cells (Weil et al. 1998)  Androgens increases ovarian paracrin factors such as IGF-1 and augments FSH activity (Vendola et al. 1999)

14 Clomiphene Citrate - Problems  Long tissue half-life (2 weeks)  prolonged central ER depletion  High multiple pregnancy rate  Peripheral anti-estrogenic effects  Thin endometrium (Gonen et al, 1990)  Unfavorable cervical mucus  Reduced uterine blood flow  Lower pregnancy rate than expected from the high ovulatory rate

Letrozole co-treatment in infertile women 40 years old and older receiving controlled ovarian stimulation and intrauterine insemination Mohamed A. Bedaiwy, et al 2009

Management of Poor Responders: Can Outcomes Be Improved with a Novel Gonadotropin-Releasing Hormone Antagonist/Letrozole Protocol? Schoolcraft et al. 2008

IVF/ICSI planlanan hastalarda 2. günden itibaren rFSH (150 IU/gün) rFSH (150 IU/gün) + ilk 5 günde letrozol (2.5 mg/gün) 6. günden itibaren ganireliks (0.25 mg/gün) Aromatase Inhibitors in Ovarian Stimulation for IVF/ICSI: A Pilot Study Verpoest et al. RBM Online 2006; 13: hasta

Daha önceden GnRH agonisti (uzun protokol) IU/gün gonadotropin tedavisi ile  4 folikül geliştirdikleri için siklusları iptal edilen IVF hastaları ¨ OK sonrası, 3. günden itibaren; ¨ 375 IU/gün gonadotropin (n=76) ¨ 375 IU/gün gonadotropin (n=76) + ilk 5 günde letrozol 2.5 mg/gün (n=71) ¨ 14 mm’den itibaren GnRH antagonisti (ganireliks 0.25 mg/gün) The Aromatase Inhibitor Letrozole Increases the Concentration of Intraovarian Androgens and Improves in Vitro Fertilization Outcome in Low Responders: A Pilot Study Garcia-Velasco et al. Fertil Steril 2005; 84: 82

Use of aromatase inhibitors in poor-responder patients receiving GnRH antagonist protocols Ozmen et al, 2009 RCT of 70 poor responder patients FSH (450 IU)FSH (450IU)+ AI Gonadotropin consumption (IU) <0.05 Cancellation (%) <0.05 Pregnancy rates (%)2025.8NS Cost (USD) <0.05

Bahçeci Kliniği Letrozol Deneyimi  2009 yılı  GnRH antagonist siklusları  1328 siklus  Seçilmemiş hasta grubu (infertilite faktörü, yaş, ovaryen rezerv, sperm orijini-(TESE, MESA, Ejakülat))

Protokoller Antagonist 1.Siklusun 2. günü 2.Serbest başlangıç dozu (150 IU 450 IU) 3.Önde giden follikül >13mm veya 6.gün 4.Önde giden en az 2 adet >19mm: hCG enjeksiyonu Letrozol 1.Siklusun 2. günü 2.Letrozole 5 mg IU (5 gün) 3.Önde giden follikül >13mm veya 6.gün 4.Önde giden en az 2 adet >19mm: hCG enjeksiyonu

AntagonistLetrozole OPU Siklus (n) Embiryo Transfer (n) Yaş İptal Oranı (%)

ET İptal Nedenleri: 1.Başarısız OPU 2.Total fertilizasyon 3.Bölünmeme 4.Kötü embiryo kalitesi 5.OHSS önlemi için total freezing 6.TESE’de sperm bulunmaması 7.Endometrial faktörler (polip, septum)

AntagonistLetrozole Gonadotropin (IU) Peak Estradiol (pg/ml) Endometrium kalınlık (mm) Total Oosit ET

P:0.09P:

P: 0.05P:0.1

Biyokimyasal Gebelik P:0,1

Pregnancy Outcome After the Use of an Aromatase Inhibitor for Ovarian Stimulation Mitwally et al.2005

Congenital Malformations Among 911 Newborns Conceived After Infertility Treatment with Letrozole or Clomiphene Citrate Tulandi et al. 2006

CC Letrozol p Toplam anomali%4.8 %2.4 NS Minor anomali %1.8 %1.2 NS Major anomali %3.0%1.2 NS Kardiak anomali%1.8%

Does addition of AI increase pregnancy rates ? Needs further evidence

Does addition of AI reduce cost ? yes

Does addition of AI augment ovarian response ? Needs further evidence