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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.

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.

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

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

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.

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

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

1. Bulun et al (1999): Successfully treated unusually aggressive form of recurrent endometriosis in a postmenopausal women using an aromatase inhibitor

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%)

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

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}.

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)).

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).

Dose 2.5 mg/ day on day 3 to 7 or Single dose of 20 mg on day 3

(Mitwally & Casper,2001).

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

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

3. The largest study done by Elnashar et al (2002): 44 patients with CC resistant PCOS

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 nonresponders.

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.

Table-4:Characteristics of Letrozole responders and non-responders:

Variable
1-A ge (years) 2-P eriod of infertility(y) 3- BM I (K g/m 2 ) 4-W aist (Cm ) 5-W /H ratio 6-M ens trual p attern: Oligom enor.:N o(% ) A m enorrhea:N o(% ) 7-Hirsutism :No(% ) 8-LH ( IU /ml) 9-FSH ( IU /ml) 10-LH /FSH ratio

Responde Non respon- Signifi rs (n=24) ders(no=20) cance

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) N S (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.

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

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

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.

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%)

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.

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%

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.

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%)

CONTRAINDICATIONS OF LETROZOLE

1. Hypersensitivity to Letrozole

2. Pregnancy 3. Lactation 4. Severe renal impairment.

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

Benha University Hospital, EGYPT E-mail: elnashar@hotmail.com