Ovulation Induction in Women With Clomiphene Citrate Resistant PCOS

Study Overview
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Brief Summary
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Polycystic ovary syndrome (PCOS) affects 5-10% of women in childbearing age. Hyperinsulinemia contributes to chronic anovulation commonly encountered in women with PCOS. The first choice therapy is clomiphene citrate (CC). In CC resistant cases, the American College of Obstetrics and Gynecology (ACOG) recommends the use of insulin sensitizer metformin. Other insulin sensitizing agents include rosiglitazone and pioglitazone. Pioglitazone is said to improve fertility and ovulation in patients with PCOS.CC may be associated with poor endometrial thickening due to its antiestrogenic effect. Letrozole may improve this condition. In this study we will compare the effect of combined letrozole-metformin-pioglitazone with that of combined CC-metformin-pioglitazone in ovulation induction in CC-resistant PCOS women.

Detailed Description
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Polycystic ovary syndrome (PCOS) affects 5-10% of women in childbearing age. Hyperinsulinemia contributes to chronic anovulation commonly encountered in women with PCOS. The first choice therapy is clomiphene citrate (CC). In CC resistant cases, the ACOG recommends the use of insulin sensitizer metformin. Other insulin sensitizing agents include rosiglitazone and pioglitazone. Pioglitazone is said to improve fertility and ovulation in patients with PCOS.CC has a long half-life (2 weeks), and this may have a negative effect on the cervical mucus and endometrium, leading to discrepancy between ovulation and conception rates. There has been a search for a compound capable of inducing ovulation but devoid of the adverse antiestrogenic effects of CC. recent studies have suggested that letrozole, an aromatase inhibitor, does not possess the adverse antiestrogenic effects of CC and is associated with higher pregnancy rates than CC treatment in patients with PCOS. In this study we shall compare the effect of combined letrozole-metformin-pioglitazone with that of combined CC-metformin-pioglitazone in ovulation induction in CC-resistant PCOS women.This will be a prospective comparative clinical trial in which 2 groups of women will be generated (groups A and B) using the sealed envelopes randomization method.Group A (40 women) will receive: letrozole 2.5 mg/day from 3rd day of the cycle for 5 days and (pioglitazone 15 mg + metformin 850 mg) once daily from 1st day of the cycle for 10 days. Group B (40 women) will receive clomiphene citrate 100 mg/day from 3rd day of the cycle for 5 days and (pioglitazone 15 mg + metformin 850 mg) once daily from 1st day of the cycle for 10 days. Ovulation will be monitored by vaginal ultrasound and serum estrogen and progesterone.

Official Title
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Combined Letrozole-metformin-pioglitazone Versus Combined Clomiphene Citrate-metformin-pioglitazone in Clomiphene Citrate-resistant Women With Polycystic Ovary Syndrome

Conditions
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Polycystic Ovary Syndrome, Infertility

Intervention / Treatment
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* Drug: induction of ovulation using letrozole-pioglitazone-metformin
* Drug: induction of ovulation using clomiphene citrate-pioglitazone-metformin
* Radiation: transvaginal ultrasound
* Other: body mass index (BMI) calculation
* Other: day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone
* Other: pretreatment blood urea and serum creatinine
* Other: serum estradiol (E2) on day 12
* Other: serum progesterone on day 21
* Other: blood urea and serum creatinine every month


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 20-40 years old PCOS infertile women resistant to CC for3 cycles Exclusion Criteria: presence of medical disorders as diabetes, hypertension, cardiac problems, liver or kidney diseases, hyperprolactinemia or thyroid dysfunction. use of gonadotropins before previous ovarian drilling presence of urinary symptoms especially bloody urine

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: arm 1:letrozole-pioglitazone -metformin group<br>Arm 1 will receive letrozole 2.5 mg/day starting from the 3rd day of the cycle and for 5 days and (combined pioglitazone 15 mg+ metformin 850 mg) once daily from the first day of the cycle for 10 days. | Drug: induction of ovulation using letrozole-pioglitazone-metformin<br>* induction of ovulation will be done for arm 1 for 3 consecutive cycles unless pregnancy occured.<br>Radiation: transvaginal ultrasound<br>* transvaginal ultrasound will be done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle<br>Other: body mass index (BMI) calculation<br>* BMI will be calculated for all women by dividing the weight in kilograms by the height in meters squared<br>Other: day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone<br>* baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) will be done for all women.<br>Other: pretreatment blood urea and serum creatinine<br>* blood urea and serum creatinine will be assayed before stating induction of ovulation to have baseline levels.<br>Other: serum estradiol (E2) on day 12<br>* serum E2 will be assayed on day 12 of the cycle for all women.<br>Other: serum progesterone on day 21<br>* serum progesterone will be assayed on day 21 for all women to monitor ovulation.<br>Other: blood urea and serum creatinine every month<br>* blood urea and serum creatinine will be assayed every month during the treatment period to find out any hazards on kidney functions<br>|
| Active Comparator: arm 2: clomiphene citrate-pioglitazone-metformin<br>Arm 2 will receive clomiphene citrate 100 mg/day starting from the 3rd day of the cycle for 5 days and (combined pioglitazone 15 mg + metformin 850 mg) once daily from the first day of the cycle for 10 days. | Drug: induction of ovulation using clomiphene citrate-pioglitazone-metformin<br>* induction of ovulation for arm 2 will be done in 3 consecutive cycles unless pregnancy occured.<br>Radiation: transvaginal ultrasound<br>* transvaginal ultrasound will be done starting from day 10 and every 48 hours until finding a follicle of > 18 mm or till day 20 of the cycle<br>Other: body mass index (BMI) calculation<br>* BMI will be calculated for all women by dividing the weight in kilograms by the height in meters squared<br>Other: day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone<br>* baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) will be done for all women.<br>Other: pretreatment blood urea and serum creatinine<br>* blood urea and serum creatinine will be assayed before stating induction of ovulation to have baseline levels.<br>Other: serum estradiol (E2) on day 12<br>* serum E2 will be assayed on day 12 of the cycle for all women.<br>Other: serum progesterone on day 21<br>* serum progesterone will be assayed on day 21 for all women to monitor ovulation.<br>Other: blood urea and serum creatinine every month<br>* blood urea and serum creatinine will be assayed every month during the treatment period to find out any hazards on kidney functions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ovulation Rate |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Follicles>18mm. |  | 3 months | 
| Endometrial Thickness |  | 3 months | 
| Pregnancy Rate |  | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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letrozole, clomiphene citrate, pioglitazone, metformin, ovulation induction, PCOS