Comparison Between Two Ovulation Induction Therapies and LOD on Clinical Outcomes in CC-Resistant PCOS Women

NCT ID: NCT06486870

Last Updated: 2024-07-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 183 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-01
• Study Completion Date: 2024-01-31

Brief Summary

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting 4-8% of reproductive-aged women and is a leading cause of infertility due to oligo-anovulation (1). Studies suggest a higher prevalence of 17.8-19.9% based on Rotterdam diagnostic criteria. PCOS is diagnosed by the presence of at least two out of three criteria: oligo- and/or anovulation, hyperandrogenism, and polycystic ovaries, with other etiologies excluded (2). Clomiphene citrate (CC), a selective estrogen receptor modulator, has been the first-line treatment for inducing ovulation in anovulatory women with PCOS for decades. Approximately 80% of women resume ovulation with CC, but only 35-40% achieve pregnancy. About 15-40% of women are resistant to CC, defined as failure to ovulate after receiving a maximum dosage of 150 mg per day for 5 days starting on the third day of the menstrual cycle. For CC-resistant women, metformin, an insulin sensitizer, has been explored but shows limited effectiveness except in combination with CC. Gonadotropins are the standard treatment for CC-resistant PCOS but come with risks of multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) (3). Letrozole, an aromatase inhibitor, is another treatment option that prevents the conversion of androgens to estrogen, thereby increasing gonadotropin-releasing hormone (GnRH) secretion and promoting ovulation. Letrozole has shown superior ovulation and live birth rates compared to CC and is now recommended as the first-line treatment for anovulation in women with PCOS. It has comparable rates of OHSS and miscarriage to CC, but fewer relevant studies have compared it directly to laparoscopic ovarian drilling (LOD) (4). LOD is an alternative to gonadotropins for inducing ovulation in CC-resistant PCOS. It involves surgical intervention, which can be either unilateral or bilateral, and is effective without the risks of multiple pregnancies or OHSS. LOD also increases ovarian responsiveness to CC. Despite minimal morbidity, LOD can lead to tubo-ovarian adhesions and premature ovarian failure, although these risks are reduced by careful technique (5).

Detailed Description

### Materials and Methods

**Design:** A randomized clinical study to evaluate and compare the effects of gonadotropins, Letrozole, and unilateral laparoscopic ovarian drilling in infertile women with PCOS. Conducted at Kasr El Aini Maternity Hospital, Cairo University, gynecological and infertility clinics.

**Patients:** The study includes infertile women aged 20-35 years with PCOS referred to the gynecology and infertility clinics of the Department of Obstetrics and Gynecology, Kasr Ainy Hospital, Cairo University. Women diagnosed with PCOS based on the Rotterdam criteria (ovulatory disturbance, hyperandrogenism, and the presence of more than 12 follicles, 2-9 mm in diameter, in each ovary by ultrasound examination) are randomly assigned to one of three groups: Letrozole (G1), Gonadotropin (G2), or Laparoscopic Unilateral Ovarian Drilling (G3), based on a computer-generated random number sequence. Side effects for each intervention are registered.

**Treatment Protocol:**

• Group I (G1): Letrozole 2.5 mg oral tablets, administered from the fifth day of menses for 5 days, repeated for up to six cycles.
• Group II (G2): Human menopausal gonadotropin (hMG) starts on cycle day three, 75 IU every other day, aiming for mono-ovulation. Monitoring through transvaginal ultrasound begins on cycle day nine. The hMG dose is adjusted based on follicular response. Cycles are cancelled for under or over-response.
• Group III (G3): Laparoscopic ovarian drilling with electrocautery (mixed current, monopolar electrosurgical needle, 4-point cauterization, each for 4 seconds, 40 W, 3 mm diameter, 4 mm depth) on one ovary.

**Follow-Up:** Patients will be monitored for six months post-intervention. Hormonal profiles will be reassessed at the end of the study period. Statistical analyses will be performed using Microsoft Excel 2007 and IBM SPSS version 22. A p-value <0.05 will be considered statistically significant.

Conditions

PCOS (Polycystic Ovary Syndrome) of Bilateral Ovaries

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

gonadotropin

Human menopausal gonadotrophin (hMG) is given starting on cycle day three in a dose of 75 IU alternate days. The aim of treatment is to achieve mono-ovulation. Monitoring of treatment is achieved by serial transvaginal ultrasound scanning every other day starting from cycle day nine. Size and number of follicles is recorded in patients follow up sheets. The dose of hMG is reviewed around stimulation day 10 and if follicular development is unsatisfactory, the dose is increased to 75 IU daily .If a good response is not achieved day16 ; the cycle is cancelled. A new cycle is commenced with a higher starting dose of hMG (75 IU per day). When one follicle reached a size of \> =18 mm a single dose of 10,000 IU human chorionic gonadotrophin (hCG, Pregnyl, Epifasi, Choriomon) is given.

Group Type: EXPERIMENTAL

Gonadotropin

Intervention Type: DRUG

Human menopausal gonadotrophin (hMG) is given starting on cycle day three in a dose of 75 IU alternate days. The aim of treatment is to achieve mono-ovulation. Monitoring of treatment is achieved by serial transvaginal ultrasound scanning every other day starting from cycle day nine. Size and number of follicles is recorded in patients follow up sheets. The dose of hMG is reviewed around stimulation day 10 and if follicular development is unsatisfactory, the dose is increased to 75 IU daily .If a good response is not achieved day16 ; the cycle is cancelled. A new cycle is commenced with a higher starting dose of hMG (75 IU per day). When one follicle reached a size of \> =18 mm a single dose of 10,000 IU human chorionic gonadotrophin (hCG, Pregnyl, Epifasi, Choriomon) is given.

letrozole

: 5 mg LE oral tablets are administered on the fifth day of menses and then every day for 5 days. Treatment is repeated for up to six cycles

Group Type: EXPERIMENTAL

Letrozole

Intervention Type: DRUG

5 mg LE oral tablets are administered on the fifth day of menses and then every day for 5 days. Treatment is repeated for up to six cycles

unilateral laparoscopic ovarian drilling

Laparoscopic ovarian drilling will be done according to the following:

Electrocautery using a mixed current in monopolar electrosurgical needle will be into introduced through the ovarian ipsilateral parts and applied up to 4 point cauterisation of the ovarian capsule, each for 4 second, at 40 W and for a diameter of 3mm and a depth of 4 mm in the antimesentric surface . (Amer et al 2003, Sawant S et al 2019) ,the procedure will be applied for one ovary .

The patient under the study will be followed up to six months of continuous marital life after the procedure

Group Type: EXPERIMENTAL

laparoscopic ovarian drilling

Intervention Type: PROCEDURE

Laparoscopic ovarian drilling will be done according to the following:

Electrocautery using a mixed current in monopolar electrosurgical needle will be into introduced through the ovarian ipsilateral parts and applied up to 4 point cauterisation of the ovarian capsule, each for 4 second, at 40 W and for a diameter of 3mm and a depth of 4 mm in the antimesentric surface . (Amer et al 2003, Sawant S et al 2019) ,the procedure will be applied for one ovary .

The patient under the study will be followed up to six months of continuous marital life after the procedure

Interventions

Gonadotropin

Human menopausal gonadotrophin (hMG) is given starting on cycle day three in a dose of 75 IU alternate days. The aim of treatment is to achieve mono-ovulation. Monitoring of treatment is achieved by serial transvaginal ultrasound scanning every other day starting from cycle day nine. Size and number of follicles is recorded in patients follow up sheets. The dose of hMG is reviewed around stimulation day 10 and if follicular development is unsatisfactory, the dose is increased to 75 IU daily .If a good response is not achieved day16 ; the cycle is cancelled. A new cycle is commenced with a higher starting dose of hMG (75 IU per day). When one follicle reached a size of \> =18 mm a single dose of 10,000 IU human chorionic gonadotrophin (hCG, Pregnyl, Epifasi, Choriomon) is given.

Intervention Type: DRUG

Letrozole

5 mg LE oral tablets are administered on the fifth day of menses and then every day for 5 days. Treatment is repeated for up to six cycles

Intervention Type: DRUG

laparoscopic ovarian drilling

Laparoscopic ovarian drilling will be done according to the following:

Electrocautery using a mixed current in monopolar electrosurgical needle will be into introduced through the ovarian ipsilateral parts and applied up to 4 point cauterisation of the ovarian capsule, each for 4 second, at 40 W and for a diameter of 3mm and a depth of 4 mm in the antimesentric surface . (Amer et al 2003, Sawant S et al 2019) ,the procedure will be applied for one ovary .

The patient under the study will be followed up to six months of continuous marital life after the procedure

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Age 20 to 35 years
• Infertile woman diagnosed to have PCO according to Rotterdam criteria as ovulatory distrbance, hyperandrogenism and presence of more than 12 follicles, 2- 9 mm in diameter in each other by ultrasound examination
• Resistance to clomiphene citrate i.e failed to respond to clomiphene citrate dose up to 150 mg per day for at least 3 cycles
• BMI from18-30
• High LH/FSH ratio≥1.5 , LH level ≥10IU/l)

Exclusion Criteria

• Extremes of age less than 20 years old or more than 35 years old
• Hormonal therapy and oral contraception for the past 3cycle
• Other causes of infertility including tubal , uterine and male causes .
• Pre-existing endocrine disease including thyroid disorder, cushing's syndrome and congenital adrenal hyperplasia
• Any previous version surgery
• Obese patients with BMI >35
• Low ovarian reserve by AMH serum level measurement (AMH < .5-1.1 ng/ml).

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Cairo University

OTHER

Sponsor Role: lead

Responsible Party

ahmed nagy shaker ramadan

lecturer

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mamdouh Sheeba, MD

Role: STUDY_DIRECTOR

kasr alainy, Cairo university

Locations

faculty of medicine, Kasr el ainy hospital, Cairo university

Cairo, , Egypt

Countries

Egypt

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Other Identifiers

AA-2024-2

Identifier Type: -

Identifier Source: org_study_id