letrozole in assisted reproduction , usama m. fouda
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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).
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