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
T he 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
Severe renal impairment (Requena et al , 2008).
Side effects of letrozole therapy
Hot flashes (11%),
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)
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).