Letrozole in Ovarian stimulation protocol for IVF

Usama M. Fouda

Lecturer of Obstetrics and Gynecology , Cairo University

Aromatase enzyme

• It is a member of Cytochrome P-450 superfamily.

• It catalyzes the rate-limiting step in estrogen synthesis, that is, the

conversion of androgens (androstenedione and testosterone) into

estrogens (estrone and estradiol, respectively).

• Its activity is demonstrated in the ovaries, adipose tissue brain,

osteoblasts and breast.

Aromatase Inhibitors

• A large number of aromatase inhibitors have been developed over the

past five decades.

• The third-generation aromatase inhibitors were developed after the

clinical failure of the earlier generations of aromatase inhibitors.

• The third-generation aromatase inhibitors were licensed for suppressing

estrogen synthesis in postmenopausal women with breast cancer .

Letrozole (Femara)

Therapeutic uses of aromatase inhibitors

• Breast cancer (hormone receptor positive)

• Induction of ovulation (Mitwally and Casper,2001)

• Endometrial carcinoma & endometrial stromal sarcoma

• Endometriosis (Sasson and Taylor ,2009).

• Induction of abortion in combination with misopristol (Lee et al

2011).

Induction of ovulation with aromatase inhibitors

• In 2001, Mitwally and Casper introduced letrozole as new ovulation

induction agent in clomiphene citrate resistant patients with polycystic

ovary syndrome (PCOS).

• Subsequent studies confirmed the effectiveness of letrozole as an

alternative to clomiphene citrate in induction of ovulation in

anovulatory women with PCOS and in augmentation of ovulation in

women with unexplained infertility or mild endometriosis (Requena et

al ,2008) .

• Several studies revealed that the use of letrozole as an adjuvant

for gonadotropins in patients undergoing superovulation ± IUI

was associated with less total dose of gonadotropins

administered and more or at least equivalent number of

mature follicles (Healey et al ,2003; Pritts ,2010).

• These promising results have encouraged the use of letrozole

as an adjuvant for gonadotropins in poor responders

undergoing IVF-ET (Goswami et al ,2004).

Mechanisms of ovulation induction with aromatase inhibitors

• The decrease in the circulatory estrogens (production by the ovary

and adipose tissues ) and locally produced estrogens in the brain

releases the hypothalamic-pituitary axes from the estrogenic

negative feedback and therefore increases gonadotropin

secretion and ovarian follicular development (Mitwally and Casper

,2001).

• Furthermore , the temporary accumulation of androgens in the

ovary enhances the expression of FSH receptor and therefore

increases the sensitivity of the growing follicles to FSH

stimulation (Weil et al , 1999).

• In contrast to clomiphene citrate , letrozole is rapidly eliminated

from the body and does not deplete estrogen receptors and

therefore has no adverse effect on endometrium or endocervix

(Mitwally and Casper, 2001).

Doses of letrozole

• 2.5 mg /day from cycle day 3 to 7 (Mitwally and Casper,2001 ).

• 5 mg/day from cycle day 3 to 7 (Al-Fadhli et al ,2006).

• 20 mg once on cycle day 3 (Mitwally and Casper,2005).

• 2.5 mg/day from cycle day 1 to 10 (Badawy et al,2009).

Contraindication of letrozole therapy

• Hypersensitivity to Letrozole

• Pregnancy

• Lactation

• Severe renal impairment(Requena et al , 2008).

Side effects of letrozole therapy

• Hot flashes (11%),

• Nausea (7%)

• Fatigue (5%)

• Alopecia and vaginal bleeding

• Complications occur more frequently in breast cancer patients

than in women treated for ovulation induction due to differences

in the duration of treatment (Requena et al , 2008).

Role of aromatase inhibitors in different types of

infertility

1) Anovulatory women with PCOS

• A pooled analysis of four early randomized trials has shown a

significantly higher pregnancy rate in women treated with letrozole or

anastrozole compared with CC (Table1).

• On the other hand , a large randomized trial failed to detect any

significant difference in the pregnancy rate between both

management options (Badawy et al.. 2007).

Table 1.letrozole versus CC in anovulatory women with PCOS(Polyzos et al. 2009)

Effect of letrozole on ovulation rate per cycle in PCOS (Requena et al , 2008)

Effect of letrozole on pregnancy rate per cycle in PCOS (Requena et al , 2008)

ESHRE/ASRM-sponsored PCOS consensus workshop group(2007)

• Initial preliminary reports suggest that letrozole appears to be as effective as

CC for induction of ovulation in anovulatory patients with PCOS .

• Further studies should demonstrate efficacy and safety of aromatase

inhibitors .

2) Unexplained infertility

• Five trials compared aromatase inhibitors versus CC and four

trials compared aromatase inhibitors plus gonadotropins versus

CC plus gonadotrophins (Table 2) .

• Pregnancy rate was comperable between both management

options (Polyzos et al .2009).

Table 2.Aromatase inhibitors versus CC in patients with unexplained infertility

3) Clomiphene citrate resistant PCOS

• Twelve CC-resistant women with PCOS received letrozole 2.5 mg

/day from cycle day 3 to 7 . Ovulation occurred in 75% of

patients and pregnancy rate was 25% (Mitwally and Casper,

2001).

• In another study, 44 CC-resistant women with PCOS received

letrozole 2.5 mg /day from cycle day 3 to 7, ovulation occured in

54.6% of patients and pregnancy rate was 25% (Elnashar et al.,

2006).

4) Letrozole + gonadotrophins Vs gonadotropins in

poor responders undergoing IUI and in women with

unexplained infertility

• In most of the trials, the number of mature follicles and the pregnancy

rates were comparable between both management options(Table3) .

• Moreover, the required gonadotrophin dose was significantly lower in the

arms receiving letrozole + gonadotrophins (Polyzos et al .2009).

Table. 3, Letrozole + gonadotrophins Vs gonadotropins in poor responders undergoing IUI and

in women with unexplained infertility (Polyzos et al. 2009)

Effect of letrozole on pregnancy rate per cycle in intrauterine insemination

5) Aromatase inhibitors for IVF

• In theory, the low estradiol level in letrozole / FSH regimen

could result in a favourable endometrium, and a high

implantation rate.

• Furthermore , there should be lower incidence of ovarian

hyperstimulation syndrome and premature luteinization.

• Moreover, aromatase inhibitors increases the sensitivity of the

growing follicles to FSH stimulation.

a) Patients with poor response to COH undergoing

IVF

• Several studies revealed that the use of letrozole as an adjuvant to

FSH or FSH-GnRHant protocol improved the ovarian response and

reduced the total gonadotropins dose administered (Table 4,5) .

• On the other hand , other studies revealed that microdose flare

protocol has superior efficacy as compared with letrozole/ FSH-

GnRHant protocol (Table 6).

b)Use of letrozole for fertility preservation in oncological patients

• Embryo cryopreservation is a well established technique to

preserve fertility in oncological patients .

• There is a potential risk that the supraphysiological estradiol

levels resultant of the ovulation induction with gonadotropins

may promote the growth of estrogen sensitive tumours( breast

and endometrial cancer ).

• Recent studies have described the use of aromatase inhibitors in

combination with gonadotropins for superovulation to freeze

embryos in patients with estrogen sensitive tumours.

• The main advantage of this regimen is that the peak estradiol levels

are closer to estradiol levels observed in natural cycles.

• In a prospective controlled study including 60 patients with

breast cancer , the embryo yield was significantly higher in

letrozole plus low-dose FSH (Let/FSH/ IVF) and tamoxifen plus

low-dose FSH (Tam/FSH/IVF) groups than in tamoxifen alone

group (Tam/IVF) (5.3±0.8, 3.8±0.8 and 1.3±0.2, respectively)

(Oktay et al ,2005).

• Peak estradiol levels were lower in Let/FSH/IVF and Tam/IVF

groups that in Tam/FSH/IVF group (380±57, 419±39, and

1182±271 pg/ml, respectively) (Oktay et al ,2005).

• In another prospective study including 215 patient with breast

cancer , 79 patients underwent COH with letrozole/FSH regimen

and 136 patients served as control.

• The hazard ratio for recurrence after IVF was 0.56 [95% (CI),

0.17–1.9], and the survival was not compromised compared

with the control patients(P=0.36)(Azim et al , 2008).

• Letrozole/FSH regimen was also used safely in endometrial

cancer patients(Azim and Oktay,2007).

• Anstrazole/FSH regimen was associated with higher estradiol

level than letrozole/FSH regimen in patients with breast cancer

(Azim et al , 2007).