1. Aromatase inhibitors like letrozole are used to treat breast cancer and endometriosis by suppressing estrogen production. 2. Letrozole has been shown to effectively induce ovulation, with limited follicular development and no adverse effects on the endometrium. It achieves ovulation rates of 50-90% and pregnancy rates of 15-25% for conditions like PCOS and infertility. 3. When used as an adjunct to FSH for poor responders, letrozole lowers FSH doses and cycle cancellation rates while improving ovarian response and pregnancy rates compared to standard protocols.

1. Benha University
Hospital, EGYPT
ABOUBAKR ELNASHAR

2. Aromatase enzyme
•Responsible for:
The conversion of androgens to estrogens
•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.
ABOUBAKR ELNASHAR

3. 3rd generation Aromatase Inhibitors
offer increased potency, specificity and better tolerability
than the former compounds. They are classified into:
i-Steroidal derivatives: Exemestane (Aromasin)
approved in USA.
ii-Non-Steroidal imidazole derivatives: Fadrozole.
iii-Non-Steroidal triazole derivatives:
Anastrazole (Arimidex)
Letrozole (Femara)
Both are approved in USA for the treatment of breast
cancer.
ABOUBAKR ELNASHAR

4. Mechanism of action
• Aromatase inhibitors suppress ovarian and 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. CURRENT USES OF AROMATASE INHIBITORS
1. BREAST CANCER
2. Endometrial carcinoma & endometrial stromal
sarcoma
3. ENDOMETRIOSIS
4. INDUCTION OF OVULATION
5. UNEXPLAINED INFERTILITY
6. POOR RESPONDERS
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6. 1-Breast cancer
In 2001, FDA approved Letrozole as a first-line
treatment for postmenopausal women with
1. Hormone receptor positive or unknown breast
cancer
2. Advanced or metastatic breast cancer. Letrozole
was more effective than tamoxifen
(Mouridsen et al,2001).
3. Letrozole is also used for pre-operative therapy
where it is given for 4 months before surgery to
reduce tumor size.
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7. 2. Endometrial carcinoma & endometrial stromal sarcoma
• Bershtein et al (2001): letrozole decrease pain &
secretion before surgery for endometrial carcinoma
(estrogen dependant tumor)
• Malouf et al (2001): Letrozole is effective in low grade
endometrial stromal sarcoma with positive estrofen
receptors
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8. 3-Endometriosis
*Aromatase activity is necessary for growth of
ectopic endometrial tissue but not for eutopic
endometrium
(Fang et al,2001).
*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
AI stop all three pathways
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9. 1. Bulun et al (1999): Successfully treated unusually
aggressive form of recurrent endometriosis in a
postmenopausal women using an aromatase inhibitor
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10. 2. Scarpellini & Sbracia (2000): class IV endometriosis
compared
GnRH agonist ( Goserelin, 3.6 mg SC every 28 days)
plus Anastazole (1 mg daily) for 6 months &
GnRH agonist alone
•Side effects are similar
In anstrazole-agonist group:
Relapse is less (10% Vs 38%)
Pregnancy rate is higher (47% Vs 17%)
ABOUBAKR ELNASHAR

11. 3. Muderris (2002): severe pelvic pain of endometriosis.
compared anstrazole (1mg daily) &
Goserelin (3.6 mg, SC) for 6 mo
•Side effects & relapse after 1 year were similar
ABOUBAKR ELNASHAR

12. 4. Krasnopol & Kaluina (2002): evaluated the addition of
anstrazole (1 mg/d from the start of the agonist to the
beginning of HMG) in the long protocol of COH, for IVF,
severe endometriosis.
•In letrozole-agonist group:The pregnancy rate per cycle
& per transfer were higher (21.7 & 23.8 % Vs 3.6% &
4.3%). {The lowest E2 just before HMG administration}.
ABOUBAKR ELNASHAR

13. 4-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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14. 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 OHS
& multiple pregnancy).
ABOUBAKR ELNASHAR

15. Dose
• 2.5 mg/ day on day 3 to 7 or
• Single dose of 20 mg on day 3
•(Mitwally & Casper,2001).
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16. A-Induction of ovulation in anovulatory infertility;
• 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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17. B- Induction of ovulation in CC-resistant PCOS
1.Mitwally and Casper (2001) selected 12 patients:
ovulation rate75% and pregnancy rate 25%.
2. Al-Omari et al (2001) selected 22 women:
similar results.
They concluded that, Letrozole is effective for ovulation
induction in CC resistant PCOS
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18. 3. The largest study done by Elnashar et al (2002):
44 patients with CC resistant PCOS
Aim:
1. To evaluate the efficacy of Letrozole, in induction of
ovulation in cases of C.C. resistant PCOS
2. To compare between Letrozole responders and non-
responders.
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19. •Examination: general, abdominal and local.
Weight, height, waist and hip circum.
TVS
Letrozole: 2.5mg/day for 5 days from D3.
• TVS: folliculometry.
When D. follicle 18-24 mm
Cervical mucus score
Endometrial thickness
HCG: 10.000 U IM and timed S.I.
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20. ABOUBAKR ELNASHAR

21. Table-4:Characteristics of Letrozole
responders and non-responders:
Variable Responde
rs (n=24)
Non respon-
ders(no=20)
Signifi
cance
1-Age (years)
2-Period of infertility(y)
3-BMI (K g/m2
)
4-W aist (Cm)
5-W/H ratio
6-Menstrual pattern:
· Oligom enor.:N o(%)
· A menorrhea:N o(%)
7-Hirsutism :No(%)
8-LH (IU /ml)
9-FSH (IU /ml)
10-LH/FSH ratio
26.7±4.21
4.56±3.29
30.07±3.23
99±9.5
0.89±0.04
16(66.6%)
8(33.33%)
15(62.5%)
16.7±3.21
6.5±1.62
2.68±0.48
28.35±4.36
5.05±2.29
29.06±3.59
101±8.41
0.90±0.04
14(70%)
6(30%)
13(65%)
17.9±3.65
6.8±1.81
2.66±0.45
NS(a)
NS(a)
NS(a)
NS(a)
NS(a)
NS(b)
NS(b)
NS(b)
NS(a)
NS(a)
NS(a)

22. A- Induction of ovulation with Letrozole in CC resistant
PCOS is associated with
1- Limited number of mature follicles.
2- No adverse effect on the endometrium or cervix.
3- Ovulation rate (54.6%) and pregnancy rate (25%)
B- No significant difference between letrozole
responders & non-responders as regard
1. Age, period of infertility, hirsutism
2. BMI or W.C.
3. LH, FSH or LH/FSH.
ABOUBAKR ELNASHAR

23. Letrozole is an orally effective, inexpensive &
safe drug for stimulating foliccular
development in CC resistant PCOS & should
be tried before gonadotropins & laparoscopic
drilling.
ABOUBAKR ELNASHAR

24. 4. Amin (2002): compared
letrozole (2.5 mg/d) &
Low dose r-FSH (50 IU/d)
•No significant difference in ovulation: (71.4% Vs 80%)
Both are safe but letrozole is cheaper & more accepted
by the patient
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25. 5-Unexplained (ovulatory) infertility
1. Mitwally and Casper (2000): Letrozole is effective for
increasing follicle recruitment in ovulatory infertility
2. Sammour et al (2001): The pregnancy rate in
letrozole group was 3 times higher that with CC
(16.7% Vs 5.6%).But the sample size was not large
enough to reach statistical significance
Letrozole could replace CC, at least in some patients,
with unexplained infertility undergoing ovulation
induction and IUI.
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26. 3. Elhelw et al (2002): compred
20 mg letrozole as a single dose on D3 with
100 mg CC from D3-7.
•In letrozole group:The pregnancy rate was higher
(18.2% Vs11.5%)
ABOUBAKR ELNASHAR

27. 6- Adjunctive therapy with FSH in poor
responders
1. Mitwaly & Casper (2001) examined the use of
Letrozole with FSH for poor responders (< 3
dominant follicles) undergoing ovarian
superovulation and IUI.
Letrozole ( 2.5 mg /day from day 3 to day 7 ) was
used with FSH (50-225 IU/ day starting on day 7)
•Significant reduction in the FSH dose and
an improvement in ovarian response to FSH.
ABOUBAKR ELNASHAR

28. 2. Tsirigotis et al (2002): compared
short protocol (GnRH agonist & FSH) with a letrozole,
FSH & GnRH antagonist
•In letrozole-antagonist group:
FSH dose was significantly lower.
Cycle cancellation was lower: 10% Vs 23%
Pregnancy rate was higher: 16.7% Vs 7.7%
ABOUBAKR ELNASHAR

29. 3. Kalifa (2002): compared
low dose agonist (buserelin 0.25 mg/d) long protocol
with
letrozole ( 5 mg from D2-6), 5 amps. HMG/d from D3
& cetrorelix (0.25 mg/d) when the follicle 14 mm.
•In Letrozole-antagonist protocol:
HMG amps & cancellation rate were lower.
The implantation & pregnancy rates were higher.
ABOUBAKR ELNASHAR

30. SIDE EFFECTS OF LETROZOLE
Letrozole is 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%)
ABOUBAKR ELNASHAR

31. CONTRAINDICATIONS OF LETROZOLE
1. Hypersensitivity to Letrozole
2. Pregnancy
3. Lactation
4. Severe renal impairment.
ABOUBAKR ELNASHAR

32. CONCLUSION
A. Current uses of aromatase inhibitors are breast
cancer, endometriosis, induction of ovulation,
unexplained infertility & adjunctive therapy with FSH in
poor responders
B. Induction of ovulation with letrozole is associated
with
1- limited number of mature follicles.
2- no adverse effect on the endometrium or cervix.
3- significant rates of ovulation & pregnancy
C. Letrozole is well tolerated
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33. ABOUBAKR ELNASHAR