Reproductive Techniques, Assisted Clinical Trial
Official title:
Does Use of Letrozole in Controlled Ovarian Stimulation in Normal Ovarian Responder in Fresh Embryo Transfer IVF/ICSI Cycle Improve the Pregnancy Rate?
Letrozole (Femara), is an aromatase inhibitor which is used in the treatment of
hormonally-responsive breast cancer after surgery. It is a good target for selective
inhibition because estrogen production is a terminal step in the biosynthetic sequence.
Aromatase inhibitors are widely used as adjuvant endocrine therapy for postmenopausal women
with breast cancer. They have been used off-label in the treatment of patients for increasing
the number of ovarian follicles recruited in ovulatory women undergoing controlled ovarian
hyperstimulation (COH). A shorter half-life (48 hours) which would predict a lower risk of
teratogenicity. No direct antiestrogenic adverse effects on the endometrium, due to an
absence of peripheral estrogen receptor blockade and the shorter half-life.
For ovarian normal responders, instead of hCG (human chorionic gonadotropin), luteal support
with exogenous progesterone supplementation is the standard protocol for patients who
received fresh embryo transfer for avoiding the risk of OHSS. In other normal responders who
have increasing risk of OHSS, the strategy of freezing all embryos are more favored.
In previous studies, high estrogen-induced endometrial gland cells apoptosis might account
for the defective endometrial receptivity in women with excessively high estrogen
concentrations after ovarian hyperstimulation in IVF cycles. Since letrozole can reduce the
serum level of estrogen due to its pharmacological properties, which in turn reduces the
adverse effects of high estrogen on the endometrium and improve the endometrial receptivity
for embryo implantation.
The investigators anticipate that infertility patients will receive short-term oral
administration of letrozole (2.5 mg/tab) once a day when estrogen is elevated in the late
stage of ovulation stimulation when receiving ovulation stimulation for two to three days.
And transvaginal ultrasound was performed every two to three days for growth of ovarian
follicles until two days before oocyte retrieval. Observing whether taking the drug can
improve the maturity of the oocyte, pregnancy rate, implantation rate, miscarriage rate,
ongoing pregnancy rate and live birth rate of the fresh embryo transfer cycle.
Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor which is
used in the treatment of hormonally-responsive breast cancer after surgery. Aromatase is a
microsomal cytochrome P450 hemoprotein-containing enzyme that catalyzes the rate-limiting
step in the production of estrogens: the conversion of androstenedione and testosterone via
three hydroxylation steps to estrone and estradiol, respectively. It is a good target for
selective inhibition because estrogen production is a terminal step in the biosynthetic
sequence. Aromatase activity is present in many tissues, including the ovaries, brain,
adipose tissue, muscle, liver, and breast. The investigators use letrozole as routine for
patients of breast cancer who want to keep chance of fertility in the future before receiving
chemotherapy which may do damage to their ovarian function. After they complete the treatment
protocol of breast cancer, they can practice the fertility plan with these frozen embryos or
oocytes.
Aromatase inhibitors are widely used as adjuvant endocrine therapy for postmenopausal women
with breast cancer. They have been used off-label in the treatment of patients for increasing
the number of ovarian follicles recruited in ovulatory women undergoing controlled ovarian
hyperstimulation (COH).
A shorter half-life (48 hours) which would predict a lower risk of teratogenicity. No direct
antiestrogenic adverse effects on the endometrium, due to an absence of peripheral estrogen
receptor blockade and the shorter half-life. In a previous report, the addition of letrozole
to gonadotropins (compared with gonadotropins alone) during IVF resulted in a greater number
of oocytes and blastocysts, similar pregnancy rates, and no increased risk of ovarian
hyperstimulation syndrome.
According to the current guidelines for the treatment course of IVF in NTUH (National Taiwan
University Hospital), fresh embryo transfer (ET) cycle is considered for patients who have
poor ovarian response because of its low risk of ovarian hyperstimulation syndrome (OHSS).
Patients who have high response to ovarian stimulation with freezing all the embryos should
be the best policy for avoiding high risk of OHSS and have the advantage of increasing the
cumulative pregnancy rate. For ovarian normal responders, instead of hCG, luteal support with
exogenous progesterone supplementation is the standard protocol for patients who received
fresh embryo transfer for avoiding the risk of OHSS. In other normal responders who have
increasing risk of OHSS, the strategy of freezing all embryos are more favored.
In a prospective study had shown that in the population of ovarian normal responder, the
cryopreservation group has a higher clinical pregnancy rate per ET transfer (84% vs 54.7%)
compared to fresh ET group. The implantation rates were 70.8% and 38.9%, respectively. The
ongoing pregnancy rates per transfer (at 10 weeks' gestation) were 78.0% and 50.9%,
respectively. The attributable risk percentage of implantation failure due to reduced
endometrial receptivity in the fresh group was 64.7%.
The estrogen serum level is about 200~300pg/mL in a normal menstrual period. In previous
studies, high estrogen-induced endometrial gland cells apoptosis might account for the
defective endometrial receptivity in women with excessively high estrogen concentrations
after ovarian hyperstimulation in IVF cycles. Since letrozole can reduce the serum level of
estrogen due to its pharmacological properties, which in turn reduces the adverse effects of
high estrogen on the endometrium and improve the endometrial receptivity for embryo
implantation.
In IVF cycles, the data regarding coadministration of gonadotropins and letrozole for 5 days
(days 2-6 or 3-7) in normal and high responders are quite limited. Favorable outcomes related
to letrozole have been reported, including lower doses of gonadotropin consumed which
decreased the cost of the IVF and increased the number of oocytes and mature oocytes while
achieving the same pregnancy rate compared with conventional stimulation.
The investigators anticipate that infertility patients will receive short-term oral
administration of letrozole (2.5 mg/tab) once a day when estrogen is elevated in the late
stage when receiving ovulation stimulation for two to three days. Other follow-up
examinations and general IVF treatments are exactly the same with control group, that is, the
whole course of treatment takes about two to three days. Blood test is taken four to five
times to check the concentration of hormones: including estrogen, luteinizing hormone,
follicle stimulating hormone, progesterone, etc. (about 5 cc each time) And transvaginal
ultrasound was performed every two to three days for growth of ovarian follicles until two
days before oocyte retrieval. Observing whether taking the drug can improve the maturity of
the oocyte, pregnancy rate, implantation rate, miscarriage rate, ongoing pregnancy rate and
live birth rate of the fresh embryo transfer cycle.
The first endpoint of our study was to demonstrate higher implantation rates, pregnancy
rates, ongoing pregnancy rates and live birth rates in the group of using letrozole. The
second endpoint: the investigators want to discover the cut-off value for upper limit of
estrogen serum level in fresh ET cycle which does not make significant difference in
pregnancy rate between natural estrogen level and in letrozole cycle.
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