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 AROMATASEAromatase is the rate limiting step in the

conversion of androstenedione and testosterone to estrone and estradiol

Suppression of plasma estrogen levelsAromatase

– 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

3rd Generation Aromatase Inhibitors

Type 1: Exemestane– t½= 27h

Type 2: Anastrozole and Letrozole– t½= 48h, once daily dosing

99% inhibition of aromatase enzyme1000-10,000 fold more effectiveOral administrationMore 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%)

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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)

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Clomiphene Citrate - ProblemsLong tissue half-life (2 weeks)

prolonged central ER depletionHigh multiple pregnancy rate Peripheral anti-estrogenic effects Thin endometrium (Gonen et al, 1990)Unfavorable cervical mucusReduced uterine blood flow Lower pregnancy rate than expected from

the high ovulatory rate

Letrozole co-treatment in infertile women 40 years oldand older receiving controlled ovarian stimulation and

intrauterine inseminationMohamed 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: 16620 hasta

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

Use of aromatase inhibitors in poor-responder patients receiving GnRH antagonist protocolsOzmen et al, 2009RCT of 70 poor responder patients

FSH (450 IU) FSH (450IU)+ AI

Gonadotropin consumption (IU) 3850 2980 <0.05

Cancellation (%) 28.6 8.6 <0.05

Pregnancy rates (%) 20 25.8 NS

Cost (USD) 17584 11560 <0.05

Bahçeci Kliniği Letrozol Deneyimi

2009 yılıGnRH antagonist siklusları1328 siklusSeçilmemiş hasta grubu (infertilite

faktörü, yaş, ovaryen rezerv, sperm orijini-(TESE, MESA, Ejakülat))

Protokoller

Antagonist1. 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

Letrozol1. 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

Antagonist Letrozole

OPU Siklus (n) 727 601

Embiryo Transfer (n) 526 465

Yaş 32.7 33.8 0.002

İptal Oranı (%) 27.6 22.6 0.03

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)

Antagonist Letrozole

Gonadotropin (IU) 2618.4 1639.3 0.0001

Peak Estradiol (pg/ml) 2081.9 1298.5 0.0001

Endometrium kalınlık (mm)

9.8 8.6 0.001

Total Oosit 15.4 9.7 0.0001

ET 2.7 2.4 0.0001

P:0.09 P: 0.0002

P: 0.05 P: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 %0.2 0.02

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