Benha University Hospital,

EGYPT

ABOUBAKR ELNASHAR

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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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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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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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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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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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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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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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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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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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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:Anstrazole

1-2 mg/day

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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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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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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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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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2. Letrozole Vs anstrazole:

No difference as regard the pregnancy rate (Cochrane library, 2005)

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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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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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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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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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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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Al-Fozan et al (2004)

The pregnancy rates were similar but the miscarriage rate was higher with CC.

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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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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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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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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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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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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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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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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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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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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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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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3. {Reducing FSH dose & estrogen levels}, reduce

the risk of OHSS during ART cycles

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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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5. Fertility preservation via embryo cryopreservation

in endometrial cancer

(Oktay et al,2003)

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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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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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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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CONTRAINDICATIONS OF LETROZOLE

1. Hypersensitivity to Letrozole

2. Pregnancy

3. Lactation

4. Severe renal impairment.

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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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•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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CONCLUSION

Current uses of AIs in infertility are

Endometriosis,

Induction of ovulation,

Unexplained infertility,

Reducing FSH dose &

Improving response to FSH in poor responders

ABOUBAKR ELNASHAR

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