Letrozole Versus Gonadotropins in Clomiphene Citrate Resistance

Letrozole Versus Gonadotropins for Ovulation Induction in Clomiphene Citrate Resistance: A Randomized Controlled Study

Clomiphene citrate resistance (CCR) occur in 15-40% in women with PCOS. Several studies have shown that letrozole is superior to CC regarding side effects, ovulation, and pregnancy rates. Letrozole or gonadotropins use for ovulation induction in CCR is not well established which is superior and most safe.

Study Overview

• Status: Completed
• Conditions: Ovulation Induction; Clomiphene Citrate Resistance; Letrozole; Gonadotropins
• Intervention / Treatment: Drug: Letrozole 2.5mg; Drug: Gonadotropin

Detailed Description

This study included 70 patients enrolled according inclusion and exclusion criteria. The inclusion criteria were (a) Infertility lasting one year or more in presence of regular intercourse, (b) Patients' age between 20-35years (c) Normal semen analysis according to WHO 2010 (d) Patent fallopian tubes (e) Normal prolactin and TSH. (e) Anovulatory cycles confirmed by mid-luteal progesterone ≤ 3 ng/ml and (f) Clomiphene citrate resistance for 3 cycles of 150mg. Exclusion Criteria were (a) Any hormonal disturbances eg. hyperprolactinemia, (b) Immunological causes of infertility, (c) Coital errors, (d) Metabolic disorders and (e) Poor patient compliance.

Sample size calculation: The minimum sample size calculated using Epi info program version 7 for unmatched case control study; 80% power and 95% Confidence interval was 22 for each group. For better accuracy and validity of results the sample size was increased by 10%=3 in each group. The total number of cases was 50 and 25 for each group.

Randomization and allocation: It was a prospective quesi-randomization. Based on the attendance order, patients with odd numbers were considered group I (Letrozole group) and those with even numbers were considered group II (Gonadotropin group). Allocation was equal 1:1.

Intervention:

Group I (Letrozole Group n=25): These patients were treated with letrozole (Femara®, Novartis New York, NY, USA) in a dose 2.5 mg (one tablet daily) orally began on the 3rd day to the 7th day of the cycle. If ovulation is not achieved dose is increased by 2.5 mg in next cycle till 3 cycles. If hyperstimulation occurred, the cycle was cancelled and the patients were excluded from the study.

Group II (Gonadotropin Group n=25) These patients were given urofollitropin (fostimon ®, IBSA, Lugano, Switzerland) in a dose of 75 IU/mL I.M from day 3rd to day 7th of the cycle beginning by one ampoule per day and the dose had been modulated according to response. If hyperstimulation occurred, the cycle was cancelled and the patients were excluded from the study.

Methods:

Proper history taking including age, gravidity, parity, infertility duration, history of laparoscopic surgery, previous induction of ovulation in the last 6 months. Examination was done to assess weight, height (BMI), signs of androgen excess, thyroid gland and breast examination.

Serum FSH, LH, testosterone level, prolactin level and thyroid stimulating hormone on day 3 of spontaneous menstrual cycle were done. Serum Progesterone (P4) was done on day 22 (midluteal) to confirm ovulation if ≥ 10ng/ml.

Basal transvaginal U/S on day3 of the cycle to detect criteria of PCOS and count number of antral follicles in both ovaries and to exclude of any basal ovarian cyst. Transvaginal ultrasound was also used to follow follicular growth and endometrial thickness starting on day 8 and then every other day till assuming good ovulatory response when one or more follicles is ≥ 18mm and endometrial thickness ≥ 6mm.

Human Chorionic Gonadotropin (choriomon®, IBSA, Lugano, Switzerland) 10.000IU/I.M was administered when good ovulatory response was assumed. The intercourse was advised on the day of HCG injection and every other day for 4 days after injection HCG.

Number and size of Dominant follicles, endometrial thickness were recorded. Clinical pregnancy was detected by serum pregnancy test and by presence of intrauterine gestational sac with fetal pulsation.

Outcome measures: Primary outcomes was ovulation rate. Secondary outcomes were pregnancy rate.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• Egypt
  • Gharbia
    • Tanta, Gharbia, Egypt, 31111
      • Ayman Shehata Dawood

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Infertility lasting one year or more in presence of regular intercourse,
• Patients' age between 20-35years
• Normal semen analysis according to WHO 2010
• Patent fallopian tubes (e) Normal prolactin and TSH.
• Anovulatory cycles confirmed by mid-luteal progesterone ≤ 3 ng/ml and
• Clomiphene citrate resistance for 3 cycles of 150mg.

Exclusion Criteria:

• Any hormonal disturbances eg. hyperprolactinemia,
• Immunological causes of infertility,
• Coital errors,
• Metabolic disorders and
• Poor patient compliance.

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
Experimental: Letrozole; These patients were treated with letrozole (Femara®, Novartis New York, NY, USA) in a dose 2.5 mg (one tablet daily) orally began on the 3rd day to the 7th day of the cycle. If ovulation is not achieved dose is increased by 2.5 mg in next cycle till 3 cycles.	Drug: Letrozole 2.5mg; These patients were treated with letrozole (Femara®, Novartis New York, NY, USA) in a dose 2.5 mg (one tablet daily) orally began on the 3rd day to the 7th day of the cycle. If ovulation is not achieved dose is increased by 2.5 mg in next cycle till 3 cycles
Active Comparator: Gonadotropins; These patients were given urofollitropin (fostimon ®, IBSA, Lugano, Switzerland) in a dose of 75 IU/mL I.M from day 3rd to day 7th of the cycle beginning by one ampoule per day and the dose had been modulated according to response.	Drug: Gonadotropin; These patients were given urofollitropin (fostimon ®, IBSA, Lugano, Switzerland) in a dose of 75 IU/mL I.M from day 3rd to day 7th of the cycle beginning by one ampoule per day and the dose had been modulated according to response.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ovulation rate	Number of mature follicles in each ovary>18mm	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pregnancy rate	Number of pregnant women evidenced by serum HCG and gestational sac inside the uterus	6 months

Collaborators and Investigators

• Sponsor: Tanta University
• Investigators: Principal Investigator: Ayman Dawood, MD, assistant professor

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2019
• Primary Completion (Actual): October 31, 2019
• Study Completion (Actual): October 31, 2019

Study Registration Dates

• First Submitted: April 4, 2021
• First Submitted That Met QC Criteria: April 4, 2021
• First Posted (Actual): April 8, 2021

Study Record Updates

• Last Update Posted (Actual): April 8, 2021
• Last Update Submitted That Met QC Criteria: April 4, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

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

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: on request
• IPD Sharing Time Frame: 3 months
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No