Aromatase inhibitors in infertility

1. Benha University Hospital,
EGYPT
ABOUBAKR ELNASHAR

2. Aromatase enzyme
•Responsible for:
The conversion of androstenedione & testosterone to
estrone & estradiol
Localized primarily in:
1.Ovarian granulosa cells in premenopausal women,
2. Other tissues: liver, brain.
3. After menopause: adipose tissue is the principle
source of estrogens.
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3. 3rd generation Aromatase Inhibitors (AIs)
•offer increased potency, specificity and better tolerability than the
former compounds.
•Type I: Steroidal derivatives: Testolactone (Teslac)
Type II: Non-Steroidal
imidazole derivatives: Fadrozole.
triazole derivatives:
Anastrazole (Arimidex)
Letrozole (Femara)
Both are approved in USA for the treatment of breast cancer.
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4. Mechanism of action
AIs suppress ovarian & peripheral (e.g. adipose
tissue) estrogen production.
Absorption & metabolism
• Letrozole is rapidly and completely absorbed from
the gastrointestinal tract.
•The elimination half-life: 2 days
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5. Uses of aromatase inhibitors in infertility
(Elnashar AM. M E F S J;2003)
I. Endometriosis
II. Induction of ovulation
III. Unexplained infertility
IV. Reducing the FSH dose needed to achieve
optimum COH
V. Improving response to FSH in poor responders
VI. Oligozoospermia
VII. Future applications
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6. 1-Endometriosis
Mechanism
*Estrogen is produced by 3 pathways
1. Hypothalamic-pituitary-ovarian pathway
2. Peripheral conversion
3. Locally within endometriosis.
*GnRH analogue stops only the first pathway
AIs stop all 3 pathways
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7. 1. Anstrazole/ Agonist Vs Agonist in severe
endometriosis
(Scarpellini & Sbracia, 2000):
GnRH agonist (Goserelin, 3.6 mg SC every 28 days)
plus Anastazole (1 mg daily) for 6 months Vs GnRH
agonist alone
•Side effects are similar
•In anstrazole-agonist group:
Relapse is less (10% Vs 38%)
Pregnancy rate is higher (47% Vs 17%)
Medical therapy alone is of no benefit in treating the
infertility associated with endometriosis
(Vercillini et al, 2003) .
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8. 2. In the long protocol of COH of IVF in severe
endometriosis
(Krasnopol & Kaluina, 2002)
: addition of anstrazole (1 mg/d from the start of the
agonist to the beginning of HMG).
•In anstrazole-agonist group:The pregnancy rates
were higher (21.7 % Vs 4.3%).
{The lowest E2 just before HMG administration}.
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9. II. Induction of ovulation
Mechanism
1. Release the pituitary/hypothalamic axis from the
estrogenic negative feedback, increase Gnt
secretion, stimulate ovarian follicle development
(Mitwally & Casper, 2001).
2. locally in the ovary: increase the follicular
sensitivity to FSH
(Vendola et al,1998).
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10. Advantages
1. No adverse antiestrogenic effect on the
endometrium or cervical mucus
a. absence of estrogen receptor depletion.
b. Rapid elimination from the body (half-life of 45
hours)
2. Limited number of mature follicles (decrease
OHSS & multiple pregnancy).
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11. Dose
• Letrozole:
-2.5, 5, 7.5 mg daily from day 3 to 7
5 mg daily is more effective than 2.5 mg
(Biljan et al, 2002)
-Single dose of 20 mg on day 3
Single dose is comparable to the 5-day regimen with
the advantage of increased safety {rapid clearance
from the body}
(Mitwally & Casper, 2005)
The ideal dose remains unknown & further studies
are needed
(Al-Fozan et al, 2004)
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12. :Anstrazole
1-2 mg/day
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13. A- Induction of ovulation in anovulatory
infertility
1. Letrozole Vs CC
(Metawie, 2001)
Letrozole was significantly more effective in
induction of ovulation than CC.
• Ovulation rate: 85% in the CC group
92.5% in the Letrozole group
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14. 2. Anstrazole Vs CC
(Park et al, 2004)
•No difference in:
ovulation rate,
number of dominant follicles & pregnancy rate.
•The endometrial growth was more desirable with
anstrazole
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15. B- Induction of ovulation in CC-resistant PCOS
1.Letrozole:
a. Mitwally and Casper (2001); Al-Omari et al (2001) :
ovulation rate 75% and
pregnancy rate 25%.
Letrozole is effective for ovulation induction in
CC resistant PCOS
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16. b. The largest study (44 patients) done by
Elnashar et al (MEFS J; 2004):
Induction of ovulation with Letrozole in CC R PCOS
is associated with ovulation rate (54.6%) and
pregnancy rate (25%)
No significant difference between letrozole
responders & non-responders as regards the age,
period of infertility, BMI, W.C., LH, FSH or LH/FSH
(Elnashar et al , 2005).
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17. 2. Letrozole Vs anstrazole:
No difference as regard the pregnancy rate
(Cochrane library, 2005)
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18. 3. Letrozole Vs FSH
a. Amin (2002); Ghosh et al (2004):
compared letrozole (2.5 mg/d) & Low dose r-FSH (50 IU/d)
• No significant differences in ovulation or pregnancy rates.
• Both are safe but letrozole is cheaper & more accepted by
the patient
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19. 4. Letrozole, FSH, CC/FSH:
(Mittal et al, 2004)
Base line E2 (pg/ml)
<20: FSH (75 IU daily)
25-35: CC plus 2 doses FSH on D 3 & D8
>40: Letrozole
Letrozole is effective in CR PCOS with elevated
baseline E2.
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20. 5. Letrozole plus metformin
(Shirazee et al, 2003)
Letrozole 5 mg from day 3-7 & metformin 1000 mg
daily continuously
Ovulation rate 59.4% & pregnancy rate 18.8%.
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21. III. Unexplained (ovulatory) infertility
1. Letrozole
Mitwally and Casper (2000):
Letrozole is effective for increasing follicle
recruitment in ovulatory infertility
Cortinez et al (2005)
E2 levels similar
higher midluteal P,
in-phase endometrial development of
pinopodes
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22. 2. Letrozole Vs CC
Sammour et al (2001):
The pregnancy rate in letrozole group was 3
times higher that with CC (16.7% Vs
5.6%).
Elhelw et al (2002):
letrozole single dose Vs CC
In letrozole group:
The pregnancy rate was higher
(18.2% Vs11.5%)
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23. Al-Fozan et al (2004)
The pregnancy rates were similar but the
miscarriage rate was higher with CC.
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24. IV. Reducing FSH dose
1. Letrozole plus FSH Vs FSH
a. Tulandi et al (2002);Casper (2003)
letrozole group:
number of FSH amps was less
number of follicles was higher but
the pregnancy rate was similar
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25. 2. Letrozole plus FSH Vs Anstrazole plus FSH
(Ho et al, 2003)
The pregnancy rates were similar but the required
FSH dose was less in the letrozole/FSH protocol
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26. V. Improving response to FSH in poor responders
1. Letrozole plus FSH
(Mitwaly & Casper, 2002)
Significant reduction in the FSH dose and
an improvement in ovarian response to FSH.
2. Letrozole/FSH Vs long protocol
(Goswami et al ,2004)
The number of follicles,
endometrial thickness&
the pregnancy rates are similar.
The letrozole/FSH protocol is cheaper
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27. 3. Letrozole /antagonist
a. Garcia-Velasco et al (2005)
Letrozole/antagonist Vs antagonist
Letrozole group:
significant increase in intrafollicular testosterone
(80.3 pg/mL Vs 43.8 pg/mL)& androstenedione
(57.9 mg/ml Vs 37.4 mg/mL)
increase the expression of the FSH receptor, and
thus improve the ovarian response
more oocytes retrieved (6.1 Vs 4.3)
higher implantation rate (25% Vs 9.4%)
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28. b. Tsirigotis et al (2002):
Letrozole /antagonist Vs short protocol
In letrozole-antagonist group:
FSH dose & cycle cancellation were lower:
10% Vs 23%
Pregnancy rate was higher:
16.7% Vs 7.7%
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29. c. Kalifa (2002):
Letrozole /antagonist Vs long protocol
In Letrozole-antagonist protocol:
HMG amps & cancellation rate were lower.
The implantation & pregnancy rates were higher.
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30. d. Kahraman et al (2003)
Letrozole/antagonist,
CC /antagonist
Short protocol
Using CC or letrozole can provide better pregnancy
results with using fewer amps of FSH
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31. VI. Oligozospermia with low T/E2
Itoh et al, (1991); Raman & Schlegel (2002)
Anstrazole 1 mg/d or testolactone 100 mg/d for 3
mo.
An increase in T/E2 (from 7 to 18) Improvement in
semen parameters
{E2 is suppressive to spermatogenesis}
TT: 250-1000 ng/dl E2: 10-50 pg/dl
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32. VII Other applications
1. Improving implantation rate in ART {reducing the
supraphysiologic levels of estrogen associated
with COH., believed to have deleterious effects on
the embryos or on the endometrium}
(Mitwalley & Casper, 2002)
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33. The use of AIs in ovulation induction cycles has a
positive effect on endometrium & embryo in both
preimplantation & implantation periods
(Karaer et al, 2004)
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34. 2. {Reducing estrogen levels during ART cycles},
preventing the occurrence of premature LH surge
making the use of GnRH agonists or antagonist
unnecessary
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35. 3. {Reducing FSH dose & estrogen levels}, reduce
the risk of OHSS during ART cycles
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36. 4. Development of multiple small ovarian follicles in
the early part of aromatase inhibitor –stimulated
menstrual cycles to aid in vitro maturation
procedures
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37. 5. Fertility preservation via embryo cryopreservation
in endometrial cancer
(Oktay et al,2003)
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38. 6. Endometrial preparation for frozen embryo transfer
(Shiraze et al,2004)
Letrozole from D3-7 with FSH (75 IU) on D3 & 8
It is a cost effective protocol with minimum amount of
FSH
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39. SIDE EFFECTS
generally well tolerated
(Lamb Adkins,1998)
Headache (6.9%)
Nausea (6.3%),
Peripheral edema (6.2%),
Fatigue (5.2%),
Hot flushes (5.2%),
Bone and back pain (4.8%),
Hair thinning and rash (3.4%)
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40. Future structure
•Simpson & Dowest (2002) suggested that the
development of tissue-specific inhibitors of
aromatase could be one of the approaches to reduce
the risk of side effects i.e. selective aromatase
modulators (SAMs).
•New studies are needed to develop SAMs that can
be widely used in gynecologic problems with fewer
side effects
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41. CONTRAINDICATIONS OF LETROZOLE
1. Hypersensitivity to Letrozole
2. Pregnancy
3. Lactation
4. Severe renal impairment.
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42. Pregnancy outcome after the use of
letrozole for ovulation induction
•Information on teratogenic capacity in
human is lacking, but animal studies have
shown that low doses of letrozole induce
noxious effects in developing conceptus
(Tiboni,2004).
•Although extrapolation of animal data to
human is a complex process, these findings
suggest that letrozole might have the capacity
to elicit teratogenesis also in the human
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43. •Pregnancies conceived after letrozole Vs other
ovarian stimulation treatments
(Mitwally et al, 2005).
-Similar miscarriage and ectopic pregnancy rates.
-a significantly lower rate of multiple gestation in
letrozole group
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44. CONCLUSION
Current uses of AIs in infertility are
Endometriosis,
Induction of ovulation,
Unexplained infertility,
Reducing FSH dose &
Improving response to FSH in poor responders
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45. ABOUBAKR ELNASHAR