Letrozole /GnRH Antagonist Protocol in Women Over 40 Years Undergoing ICSI Cycle

Impact of Adding Letrozole to Gonadotrophin-Releasing Hormone Antagonist Protocol in Women Over 40 Years Undergoing ICSI Cycle

The aim of this study To compare the clinical and laboratory outcomes of two ovarian stimulation protocols (standard GnRH antagonist protocol and aromatase inhibitor/ antagonist protocol) in women (40-44) years undergoing ICSI cycle.

Study Overview

• Status: Completed
• Conditions: Ovarian Stimulation
• Intervention / Treatment: Drug: Letrozole 2.5mg tablet

Detailed Description

Fertility is known to decline significantly in women after the age of 35 years, and fecundity is almost completely lost after the age of 45 . As age increases the natural fecundity and pregnancy rates after assisted reproduction decrease .This reduction in fecundity is thought to be due to ovarian aging mainly, which is defined as a decline in both the quantity and quality of the ovarian follicle pool .The increase in patient's age is associated with poor ovarian response, as represented by smaller ovarian volume, lower antral follicle count and poor stromal vascularity. In addition to the reduction in fecundity, there is an increase in spontaneous abortion rates in this group of women .It has been reported that about 19% of all women undergo ART are 40 years, and they could be considered as expected poor responders .Various protocols of ovarian stimulation have been proposed to optimize IVF results in this age group, however, satisfactory results remain a challenge . The lack of initial central down-regulation in early follicular phase and adequate prevention of premature luteinizing hormone (LH) surge in late follicular phase provide GnRH antagonist protocol as a potentially proper option .The use of aromatase inhibitors in a GnRH antagonist protocol was suggested by some studies [Mit. Yarali and colleagues demonstrated that adjuvant therapy with letrozole could improve the response [Yarali et al., 2009]. Meanwhile, in another study, adding letrozole to ovarian stimulation has no positive effect on the likelihood of pregnancy . Letrozole is a selective, non-steroidal third generation aromatase inhibitor. Letrozole causes a reduction in conversion of androstenedione and testosterone to estrone and estradiol by inhibiting the aromatase enzyme activity . According to some published studies, the decline in early follicular phase estrogen levels, and consequently decrease in negative feedback of estrogen on FSH release in hypothalamic-pituitary axis cause an increase in endogenous gonadotropin secretion and stimulation of ovarian follicular growth. In addition, an increase in intraovarian androgens secondary to aromatase inhibition, augments the follicular sensitivity to FSH stimulation and follicular growth . Letrozole has no antiestrogenic effect over the endometrium . These reports prompted us to hypothesize that use of letrozole as a co-treatment agent in GnRH antagonist protocol might enhance cycle outcomes.

I

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Egypt
  • Menoufia
    • Shibīn Al Kawm, Menoufia, Egypt, 11111
      • Menoufia University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women between 40- 44-years undergoing ICSI cycle with FSH less than 15 and AMH more than 0.30.

Exclusion Criteria:

• Azoospermia in male partner,
• Previous ovarian surgery,
• Severe endometriosis,
• Uterine cavity lesion
• Metabolic or endocrine disorders including hyperprolactinemia and ypo/hyperthyroidism.
• Previous failed ICSI cycle.
• BMI more than 30.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: standard GnRH antagonist protocol; Gonadotropins (300-450 IU) IM start on cycle day 2 then the dose modulated according to response	Drug: Letrozole 2.5mg tablet; letrozole (femara, Novartis) orally in a dose of 2.5 mg daily, on day 2 of cycle for 5 days and gonadotropins (300-450 IU) IM start on cycle day 3. then the dose modulated according to response; Other Names: Gonadotropins units
Active Comparator: Aromatase inhibitor/flexible antagonist protocol; letrozole orally in a dose of 2.5 mg daily, on day 2 of cycle for 5 days and gonadotropins (300-450 IU) IM start on cycle day 3. then the dose modulated according to response	Drug: Letrozole 2.5mg tablet; letrozole (femara, Novartis) orally in a dose of 2.5 mg daily, on day 2 of cycle for 5 days and gonadotropins (300-450 IU) IM start on cycle day 3. then the dose modulated according to response; Other Names: Gonadotropins units

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
live birth rate	deliveries ≥22 weeks gestation with heartbeat and breath	1 year after embryo transfer

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
positive hCG	serum β-hCG ≥10 mIU/mL	2 weeks after FET
clinical pregnancy	presence of intrauterine gestational sac by trans-vaginal ultrasound at gestational weeks.	5 weeks' gestation
Total gonadotropin /cycle (IU),	number of gonadotropin units needed per cycle	two weeks
Duration of stimulation (Day),	number of days needed for stimulation	two weeks
Endometrial thickness (mm)	measure endometrial thickness	two weeks
serum E2 levels	measuring E2 level during stimulation	two weeks
Follicles number	number of follicles during stimulation	two weeks

Collaborators and Investigators

• Sponsor: Menoufia University

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2021
• Primary Completion (Actual): February 10, 2025
• Study Completion (Actual): February 10, 2025

Study Registration Dates

• First Submitted: December 8, 2021
• First Submitted That Met QC Criteria: December 8, 2021
• First Posted (Actual): December 22, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 10, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Estrogen Antagonists; Aromatase Inhibitors; Letrozole
• Other Study ID Numbers: 12/2021OBSGN 1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No