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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
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
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
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
1. Bulun et al (1999): Successfully treated unusually
aggressive form of recurrent endometriosis in a
postmenopausal women using an aromatase inhibitor
ABOUBAKR ELNASHAR
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
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
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
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)
ABOUBAKR ELNASHAR
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
Dose
• 2.5 mg/ day on day 3 to 7 or
• Single dose of 20 mg on day 3 •(Mitwally & Casper,2001).
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
•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.
ABOUBAKR ELNASHAR
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-P eriod of infert ility(y)
3-BMI (K g/m2)
4-W aist (Cm)
5-W/H ratio
6-Mens trual p attern:
· 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)
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
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
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
ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
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
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
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
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
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
CONTRAINDICATIONS OF LETROZOLE
1. Hypersensitivity to Letrozole
2. Pregnancy
3. Lactation
4. Severe renal impairment.
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR