This document discusses the role of aromatase inhibitors (AIs) in assisted reproductive technologies. It addresses several key questions: 1. Whether the addition of AIs increases pregnancy rates, which needs further evidence. 2. That the addition of AIs does reduce costs by decreasing the amount of gonadotropins needed. 3. Whether the addition of AIs augments ovarian response, which also needs more evidence. The document provides background on AIs and their pharmacology. It reviews studies on the use of letrozole in ovarian stimulation protocols and outcomes like pregnancy rates, cost savings, and safety.

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

2. 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

3. 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

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

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

6. Aromatase Inhibitors

7. 3rd 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

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

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

10. 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. 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

13. 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. 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

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

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

20. 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

22. 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

25. 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) 3850 2980 <0.05
Cancellation (%) 28.6 8.6 <0.05
Pregnancy rates (%) 20 25.8 NS
Cost (USD) 17584 11560 <0.05

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

30. 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

31. 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

32. 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)

33. 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

34. P:0.09 P: 0.0002

35. P: 0.05 P:0.1

36. Biyokimyasal Gebelik
P:0,1

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

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

40. ●
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

41. Does addition of AI increase pregnancy
rates ?
Needs further evidence

42. Does addition of AI reduce cost ?
yes

43. Does addition of AI augment ovarian
response ?
Needs further evidence