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YayınlayanCeyhan Tarhan Değiştirilmiş 9 yıl önce
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The Role of Aromatase Inhibitors in Assisted Reproductive Technologies Ulun ULUG, M.D. Bahceci IVF Centers, Istanbul
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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
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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
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Aromatase Enzyme Sources: –Granulosa cells of Ovary –Endometrial cells –Placenta –Subcutaneous fat –Liver –Muscle –Brain –Normal breast –Breast cancer
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Aromatase Enzyme Premenopausal women –Ovarian source Postmenopausal women –Adipose tissue Aromatase transcription regulated by: –Cytokines –Cyclic nucleotides –Gonadotropins –Glucocorticoids –Growth factors
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Aromatase Inhibitors
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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 1000-10,000 fold more effective Oral administration More selective for aromatase
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Dosage 1.Letrozole 2.5mg/5mg daily from day 3 to day 7 of menses 2.Letrozole 20mg single dose on day 3
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A Randomized Trial of Superovulation with Two Different Doses of Letrozole Al-Fadhli et al 2006 Unexplained Infertility
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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%)
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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
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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)
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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
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Letrozole co-treatment in infertile women 40 years old and older receiving controlled ovarian stimulation and intrauterine insemination Mohamed A. Bedaiwy, et al 2009
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Management of Poor Responders: Can Outcomes Be Improved with a Novel Gonadotropin-Releasing Hormone Antagonist/Letrozole Protocol? Schoolcraft et al. 2008
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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: 166 20 hasta
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Daha önceden GnRH agonisti (uzun protokol) + 375 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
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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)38502980<0.05 Cancellation (%)28.68.6<0.05 Pregnancy rates (%)2025.8NS Cost (USD)1758411560<0.05
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Bahçeci Kliniği Letrozol Deneyimi 2009 yılı GnRH antagonist siklusları 1328 siklus Seçilmemiş hasta grubu (infertilite faktörü, yaş, ovaryen rezerv, sperm orijini-(TESE, MESA, Ejakülat))
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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 + 150 IU (5 gün) 3.Önde giden follikül >13mm veya 6.gün 4.Önde giden en az 2 adet >19mm: hCG enjeksiyonu
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AntagonistLetrozole OPU Siklus (n)727601 Embiryo Transfer (n)526465 Yaş32.733.8 0.002 İptal Oranı (%)27.622.6 0.03
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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)
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AntagonistLetrozole Gonadotropin (IU)2618.41639.3 0.0001 Peak Estradiol (pg/ml)2081.91298.5 0.0001 Endometrium kalınlık (mm) 9.88.6 0.001 Total Oosit15.49.7 0.0001 ET2.72.4 0.0001
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P:0.09P: 0.0002
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P: 0.05P:0.1
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Biyokimyasal Gebelik P:0,1
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Pregnancy Outcome After the Use of an Aromatase Inhibitor for Ovarian Stimulation Mitwally et al.2005
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Congenital Malformations Among 911 Newborns Conceived After Infertility Treatment with Letrozole or Clomiphene Citrate Tulandi et al. 2006
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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%0.2 0.02
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Does addition of AI increase pregnancy rates ? Needs further evidence
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Does addition of AI reduce cost ? yes
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Does addition of AI augment ovarian response ? Needs further evidence
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