Letrozole ovulation presented in NARCHI Annual conference 2008

1. Letrozole in Ovulation
Induction
Dr. Meenakshi Sharma
MBBS, MD (Obs & Gynae)
2008

2. Ideal Ovulation Induction Drug
 Oral Administration
 Minimal monitoring of cycle
 No hostile effect on endometrium & cervical
mucus
 Better ovulation rate & pregnancy rate
 Less risk of OHSS & multiple pregnancy

3. Ovulation induction
 WHO group II patient-current treatment
 CC
 Discrepancy between ovulation and
pregnancy
 Higher incidence of miscarriage
 20-25% women are resistant to CC
 Long half life- longer depletion of ER
 Antiestrogenic effect on cervical mucus &
endometrial lining

4. Ovulation induction
 Gonadotrophins
 Costly
 Parentral administration
 Requires intensive monitoring
 Higher rate of multiple pregnancies
 Higher rate of miscarriage
 Higher OHSS

5. Letrozole
 Oral administration
 Unifollicular development
 Short half life
 No depletion of ER
 No antiestrogenic effect on cervical mucus &
endometrial thickness

6. Pharmacology and
Endocrinology

7. Pharmacology
 Inhibit or inactivate
Aromatase
 Aromatase
 Cytochrome P-450
superfamily
 CYP19 gene
 Rate-limiting step in
estrogen production

8. estradiol
progesterone
LH
FSH
LH
FSH
GnRH
inhibin/activin
estradiol
progesterone
Ovaries
Uterus
Hypothalmus
Pituitary
estradiol/progesterone
Hypothalamic-Pituitary-Ovarian
Axis
•Decreased estradiol production
•Decreased –ve feedback on HPO
axis increased FSH
•Ovarian follicular stimulation &
sensitivity to FSH
(Vendola et al,1998).
(Mitwally & Casper, 2001).

9. Aromatase Inhibitors

10. 3rd
Generation Aromatase
Inhibitors
 Type 2: Anastrozole and Letrozole (t½= 48h)
 1000-10,000 fold more effective
 Oral administration
 More selective for aromatase
 No effect on aldosterone or corticosterone levels
 No effect on plasma levels of 17-OHP, TSH, LH,
FSH, androstenedione,

11. Scientific Evidence

12. Letrozole in Anovulatory
patients
Author/yr N Type of
study
OR PR ET Comments
Mitwally
MF, 2001
12
L-2.5mg
prospe
ctive
9(75%) 3(25%) 8.1 Better ET &
PR
Begum
MR, 2006
35 prospe
ctive
90% 25.94%
Badaway
A, 2007
438
L-5mg
CC100mg
Rando
mized 67.5%
70.9%
15.1%
17.9%
8.1mm
9.2mm
As effective as
CC
Begum
MR, 2008
64
L 7.5mg
CC 150
Rando
mized 20(62.5%)
12(37.5%)
13(40.63%
)
6(18.75%)
10.37m
m
9.03mm
Better OR &
PR than CC

13. Letrozole in Ovulatory patients
Author N Type of
study
Folli
cle
S E2
pmol/l
PR ET
mm
Comments
Mitwally
MF, 2001
10
L-2.5mg
Prospective 2.3 719 1(10%) 8
Al Fozan
H, 2004
154
L- 7.5mg
CC-
100mg
Randomized
0.7
1.1
11.5%/cyc
8.9%/cyc
7.1
8.2
comparable
Bayar U,
2006
74
L-38
CC-36
Prospective
randomized 1
1
189
386(p<
.001)
9%/cyc
12%/cyc
8
8
comparable
Topipat
C,2008
22
L
CC
Crossover
randomized
No. mature
follicle, E2 &
p less in L,
no diff in ET

14. Letrozole compared with
clomiphene
 Shorter half life
 Get negative feedback returning
 Monofollicular development
 Preovulatory estradiol (E2) levels lower
 AI increase the intrafollicular androgen conc &
increase in ovarian follicular FSH receptor mRNA
 No antiestrogenic effects on endometrium & cervical
mucus
Garcia-Velasco, 2005
Bedaiwy MA, 2007

15. Letrozole in Gonadotrophin
induction
 Letrozole improved ovarian response to FSH
 Letrozole significantly reduced FSH Dose
during COS similar to CC
Mitwally MF, 2002, Healey S, 2003
 Beneficial effect on endometrial thickness &
better Pregnancy rate
 Addition of Letrozole to Gonadotrophins
increased the number of preovulatory follicles
without any negative effect on pregnancy
Healey S, 2003

16. Letrozole in Gonadotrophin
induction
Author N Study FSH (IU)
dose/cycle
ET (mm) PR
Mitwally MF,
2002
12
L-2.5 +
FSH,14cycle
FSH-20cycle
Prospective
616
1590(.001)
8.8
8.9
21%
Mitwally MF,
2003
36 L+FSH
18 CC+FSH
56 FSH
Prospective 465
619
1114(.001)
9.1
8
10
22.2%
11.1%
18.7%
Healey S, 2003 60cy L+FSH
145cy FSH
Retrospective 600
940(.001)
9.4
8.5
21.6%
20.9%
Bedaiwy MA,
2007
630 L+FSH
166cy FSH
Prospective 420
1351p(.001)
8.5
9.0
30.04%
22.04%
Gregoriov O,
2007
CC R 50
r-FSH
L
RCT
8.6
7.1
36%
24%
Barroso G,
2006
41
L+ FSH
CC+ FSH
RCT
9.5
7.3
23.8%
20%
Jee BC, 2006 60, L+hMG
27,CC+hMG
Prospective No diff 18.2%
25.9%

17. Letrozole in Gonadotrophin
induction
 Significant reduction in follicular phase E2
levels
 Significant decrease in serum progesterone
concentrations in the late follicular phase
 Approximately 33% reduction in the number
of follicles
 Significantly lower multiple pregnancy rate
compared with the FSH-only group
Bedaiwy MA, 2007

18. AI in ART
 Decrease dose of FSH for superovulation
 Improve response to FSH in poor
responders
 Improve implantation by ↓ E2 levels
 Prevent premature LH surge

19. Letrozole in IVF
 Randomized, controlled, single-blind trial
 Incorporation of letrozole may be an effective low cost
IVF protocol in poor responders
N 38 FSH
Dose
No.
follicles
E2 ET PR/cycl
e
13
L+FSH
25
GnRHag
+ FSH
150
2865
(p<.001)
1.8
2.3
227
380(p<.001)
8.5
7.4
23%
24%
Goswami SK,2004

20. Letrozole in IVF
 Efficacy of a microdose GnRH agonist flare (MF)
with a GnRH antagonist/letrozole (AL) protocol
before IVF-ET in poor responders
 Significantly lower with the AL protocol
 Total Gonadotrophin dose & duration
 E(2) level on the day of hCG administration
 Number of oocytes retrieved
 Fertilization rate and the rate of at least one top-
quality embryo transferred were higher with the AL
compared with the MF protocol
Yarali H,2008

21. Letrozole in luteal phase
 Randomized, placebo-controlled trial (n30).
 Letrozole during the luteal phase after oocyte retrieval
in IVF/(ICSI) cycles.
 Reduces serum E(2) levels
 Faster recovery of LH concentration
 This may be of interest for egg donors at high risk of
OHSS who freeze all their embryos or who cancel
hCG administration to reduce the potential risk that
high E(2) levels pose.
Garcia-Velasco JA,2008

22. Adverse Effects

23. Letrozole and Birth Defects
 An Abstract presentation
 150 infants compared to control of 3600
infants low risk pregnancies
 Cardiac anomalies - 2 AS
 Bone anomalies – 3
 Control population was younger
Biljan MM, Fertil Steril 2005

24. Letrozole and Clomiphene
Birth Defects
 There is no increase in birth
defects for letrozole or
clomiphene if used when
not pregnant in 911 births
after ovulation induction.
 Letrozole associated with
fewer birth defects than
clomiphene but this is not
statistically significant.
Tulandi T. Fertil Steril 85:1761, 2006
Letrozole(n-
514)
Clomiphene
(n-397)
Congenital
malformatio
n &
Chromosom
al
anomalies
14(2.4%) 19(4.8%)
Major
malformatio
n
6(1.2%) 12(3%)
Cardiac
anomalies
1(0.2%) 7(1.8%)
VSD 1(0.2%) 4(1.0%)

25. Conclusion

26. Advantages of Aromatase
Inhibitors in COH
 Simplicity of CC cycles
 No anti-estrogenic effects on endometrium
and mucus
 As effective as clomiphene citrate in
ovulation induction
 Lower incidence of multiple pregnancy than
CC
 Decreased tendency for premature
luteinization

27. Conclusion
 Letrozole reduces the dose of FSH required
for optimal follicle recruitment and improve
the response to FSH in poor responders
 Letrozole may be considered before
gonadotrophin therapy, or when clomiphene
therpy has been associated with a thin
endometrial lining
 Role in ART needs further exploration

28. Thank you