Clinical Trials Logo

Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT03901170
Other study ID # 201810102MINC
Secondary ID
Status Active, not recruiting
Phase Phase 4
First received
Last updated
Start date April 25, 2019
Est. completion date April 8, 2021

Study information

Verified date April 2020
Source National Taiwan University Hospital
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


Description:

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.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 300
Est. completion date April 8, 2021
Est. primary completion date June 30, 2020
Accepts healthy volunteers No
Gender Female
Age group 20 Years to 45 Years
Eligibility Inclusion Criteria:

- Women aged from 20 to 45 years old

- Receive IVF treatment due to infertility

- Plan to have fresh embryo transfer

- Total ovarian follicle number from 8 to 15 before oocyte retrieval

- Plan to have letrozole in IVF treatment routine

Exclusion Criteria:

- Systemic disease, such as diabetes mellitus, hypertension, heart disease, hypothyroidism, liver or renal disease, cancer, autoimmune disease, etc.

- Treatment cycle with pre-implantation genetic screening (PGS)/ pre-implantation genetic diagnosis(PGD)

- Oocyte recipient

- Poor ovarian responders according to Bologna criteria

- Patients who have risk of Ovarian Hyperstimulation Syndrome (OHSS)

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Letrozole 2.5mg
oral administration of letrozole 2.5mg/tab, 1tab once per day from stimulation Day 7 to hCG Day.

Locations

Country Name City State
Taiwan National Taiwan University Hospital Taipei

Sponsors (1)

Lead Sponsor Collaborator
National Taiwan University Hospital

Country where clinical trial is conducted

Taiwan, 

References & Publications (3)

Chen SU, Chou CH, Chen MJ, Chen TH, Yang YS, Yang JH. Apoptotic effects of high estradiol concentrations on endometrial glandular cells. J Clin Endocrinol Metab. 2014 Jun;99(6):E971-80. doi: 10.1210/jc.2013-3794. Epub 2014 Feb 19. — View Citation

Kyrou D, Popovic-Todorovic B, Fatemi HM, Bourgain C, Haentjens P, Van Landuyt L, Devroey P. Does the estradiol level on the day of human chorionic gonadotrophin administration have an impact on pregnancy rates in patients treated with rec-FSH/GnRH antagon — View Citation

Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer in nor — View Citation

Outcome

Type Measure Description Time frame Safety issue
Other cumulative pregnancy rate The sequential frozen-thaw embryo transfer cycle if the patient fail at fresh embryo transfer cycle within three months after failure to achieve pregnancy in fresh embryo transfer cycle
Primary pregnancy rate 16 days after oocyte retrieval
Primary implantation rate intra-uterine gestational sac/total transfer embryo number 23 days after oocyte retrieval
Primary miscarriage rate pregnancy loss before gestational weeks 12 gestational weeks 12
Secondary live birth rate live birth with newborn from gestational weeks 24 to 42
See also
  Status Clinical Trial Phase
Recruiting NCT05442125 - First Live Birth Rate With eSET After Preimplantation Methylome Screening (PIMS) Versus Conventional In-vitro Fertilization N/A
Withdrawn NCT00767611 - Molecular Markers of Human Sperm Function N/A
Completed NCT04549649 - The Effect of Dual Trigger for Final Oocyte Maturation on IVF/ICSI Outcomes in Patients With Suboptimal Ovarian Response N/A
Completed NCT02457481 - An Alternative Culture Medium to Better Support Preimplantation Embryo Development in Vitro N/A
Completed NCT02567552 - Clinical Trial Comparing Endometrial Transformation With Subcutaneous Progesterone Versus Intramuscular Progesterone Phase 4
Completed NCT00518141 - Use of Acetyl Salicylic Acid and Terbutalin in Assisted Reproductive Techniques (ART) N/A
Terminated NCT01071200 - Study to Evaluate if the Addition of r-hLH (Luveris®) to FSH From Day 8 of Ovarian Stimulation is Able to Decrease Total FSH Dose and to Improve Cycle Outcome in Infertile Women Undergoing ART, Who Required High FSH Dose in a Previous Cycle Phase 3
Recruiting NCT02516462 - In Vitro Maturation of Human Eggs N/A
Recruiting NCT05473039 - Effect of a Multivitamin Supplement With Probiotic (Seidivid Ferty4®) on Oocyte Retrieval and Quality N/A
Recruiting NCT04124913 - Oral Dydrogesterone vs. Micronized Vaginal Progesterone for Luteal Phase Support in Frozen-thawed Embryo Transfer Cycles Phase 4
Completed NCT02381821 - Endometrial Volume and Sub-endometrial Vascularity as Predictors of In-vitro Fertilization Success N/A
Recruiting NCT02625519 - Efficacy of Urinary Vs Recombinant FSH in Oocyte Donors Based on Receptor N680S FSH Gene Polymorphism (Genodon Trial) Phase 4
Active, not recruiting NCT02625532 - Early Follicular Phase vs Lutheal Phase Ovarian Stimulation in Bologna Criteria IVF/ICSI Cycles (LUTEAL Trial) N/A
Completed NCT04458454 - "Study of the Effects of Serum and Follicular Fluid Relaxin Levels on Ovarian Function in IVF Cycles"