Benha University

Hospital, EGYPT

ABOUBAKR ELNASHAR

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.

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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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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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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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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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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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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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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%)

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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

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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}.

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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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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

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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.

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•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

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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.

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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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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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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

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