Infertility, Polycystic Ovary Syndrome
Conditions
Keywords
letrozole, clomiphene citrate, pioglitazone, metformin, ovulation induction, PCOS
Brief summary
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
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.
Interventions
DRUGinduction of ovulation using letrozole-pioglitazone-metformin
induction of ovulation will be done for arm 1 for 3 consecutive cycles unless pregnancy occured.
DRUGinduction of ovulation using clomiphene citrate-pioglitazone-metformin
induction of ovulation for arm 2 will be done in 3 consecutive cycles unless pregnancy occured.
RADIATIONtransvaginal ultrasound
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
OTHERbody mass index (BMI) calculation
BMI will be calculated for all women by dividing the weight in kilograms by the height in meters squared
OTHERday 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone
baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) will be done for all women.
OTHERpretreatment blood urea and serum creatinine
blood urea and serum creatinine will be assayed before stating induction of ovulation to have baseline levels.
OTHERserum estradiol (E2) on day 12
serum E2 will be assayed on day 12 of the cycle for all women.
OTHERserum progesterone on day 21
serum progesterone will be assayed on day 21 for all women to monitor ovulation.
OTHERblood urea and serum creatinine every month
blood urea and serum creatinine will be assayed every month during the treatment period to find out any hazards on kidney functions
Sponsors
Cairo University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 40 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Ovulation Rate | 3 months |
Secondary
| Measure | Time frame |
|---|---|
| Number of Follicles>18mm. | 3 months |
| Endometrial Thickness | 3 months |
| Pregnancy Rate | 3 months |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety of Pioglitazone as Regards Serum Creatinine | 3 months | serum creatinine was measured at the end of the study period (after 3 months) in both groups. |
Countries
Egypt
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1:Letrozole-pioglitazone -Metformin Group Arm 1 received 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.
induction of ovulation using letrozole-pioglitazone-metformin: induction of ovulation was done for arm 1 for 3 consecutive cycles unless pregnancy occurred.
transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of \> 18 mm or till day 20 of the cycle
body mass index (BMI) calculation: BMI was calculated.
day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women.
serum estradiol (E2) was done on day of hCG administration for all women.
serum progesterone on day 21 was done for all women. | 50 |
| Arm 2: Clomiphene Citrate-pioglitazone-metformin Arm 2 will received 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.
induction of ovulation using clomiphene citrate-pioglitazone-metformin: induction of ovulation for arm 2 was done in 3 consecutive cycles unless pregnancy occured.
transvaginal ultrasound: transvaginal ultrasound was done starting from day 10 and every 48 hours until finding a follicle of \> 18 mm or till day 20 of the cycle
body mass index (BMI) calculation: BMI was calculated.
day 3: follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), total testosterone: baseline hormonal assay (day 3 FSH, LH, TSH and total testosterone) were done for all women.
serum estradiol (E2) was done on day of hCG administration for all women.
serum progesterone on day 21 was done for all women. | 50 |
| Total | 100 |
Baseline characteristics
| Characteristic | Arm 1:Letrozole-pioglitazone -Metformin Group | Total | Arm 2: Clomiphene Citrate-pioglitazone-metformin |
|---|---|---|---|
| acne | 7 participants | 11 participants | 4 participants |
| Age, Continuous | 25.8 years STANDARD_DEVIATION 3.62 | 26.19 years STANDARD_DEVIATION 3.29 | 26.58 years STANDARD_DEVIATION 2.9 |
| BMI | 26.45 kg/m^2 STANDARD_DEVIATION 2.84 | 26.51 kg/m^2 STANDARD_DEVIATION 2.75 | 26.57 kg/m^2 STANDARD_DEVIATION 2.7 |
| diastolic blood pressure | 69.6 mmHg STANDARD_DEVIATION 5.31 | 69.02 mmHg STANDARD_DEVIATION 5.61 | 68.44 mmHg STANDARD_DEVIATION 5.89 |
| E2 | 49.83 Pmol/dL STANDARD_DEVIATION 7.31 | 48.24 Pmol/dL STANDARD_DEVIATION 8.56 | 47.75 Pmol/dL STANDARD_DEVIATION 10.02 |
| free T4 | 13.78 nmol/L STANDARD_DEVIATION 0.84 | 13.68 nmol/L STANDARD_DEVIATION 0.68 | 13.58 nmol/L STANDARD_DEVIATION 0.45 |
| free testosterone | 3.87 Pmol/dL STANDARD_DEVIATION 0.61 | 3.99 Pmol/dL STANDARD_DEVIATION 0.94 | 4.12 Pmol/dL STANDARD_DEVIATION 1.17 |
| FSH | 5.71 mIU/L STANDARD_DEVIATION 1.34 | 5.7 mIU/L STANDARD_DEVIATION 1.35 | 5.68 mIU/L STANDARD_DEVIATION 1.38 |
| hirsutism | 11 participants | 21 participants | 10 participants |
| infertility period | 2.67 years STANDARD_DEVIATION 1.62 | 2.87 years STANDARD_DEVIATION 1.5 | 3.07 years STANDARD_DEVIATION 1.46 |
| LH | 9.81 mIU/L STANDARD_DEVIATION 3.16 | 10.18 mIU/L STANDARD_DEVIATION 3.21 | 10.55 mIU/L STANDARD_DEVIATION 3.25 |
| ovarian volume | 14.17 ml STANDARD_DEVIATION 0.76 | 14.19 ml STANDARD_DEVIATION 0.98 | 14.58 ml STANDARD_DEVIATION 1.42 |
| prolactin | 15.52 ng/ml STANDARD_DEVIATION 4.84 | 14.9 ng/ml STANDARD_DEVIATION 5.24 | 14.3 ng/ml STANDARD_DEVIATION 5.6 |
| Region of Enrollment Egypt | 50 participants | 100 participants | 50 participants |
| Sex: Female, Male Female | 50 Participants | 100 Participants | 50 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| systolic blood pressure | 106.08 mmHg STANDARD_DEVIATION 8.81 | 106.56 mmHg STANDARD_DEVIATION 8.86 | 107.04 mmHg STANDARD_DEVIATION 8.97 |
| total testosterone | 1.19 nmol/L STANDARD_DEVIATION 0.25 | 1.16 nmol/L STANDARD_DEVIATION 0.23 | 1.13 nmol/L STANDARD_DEVIATION 0.2 |
| TSH | 3.42 mIU/L STANDARD_DEVIATION 0.61 | 3.47 mIU/L STANDARD_DEVIATION 0.53 | 3.51 mIU/L STANDARD_DEVIATION 0.44 |
| waist/hip ratio | 0.838 ratio STANDARD_DEVIATION 0.02 | 0.837 ratio STANDARD_DEVIATION 0.037 | 0.837 ratio STANDARD_DEVIATION 0.04 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 50 | 0 / 50 |
| serious Total, serious adverse events | 0 / 50 | 0 / 50 |
Outcome results
Primary
Ovulation Rate
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1:Letrozole-pioglitazone -Metformin Group | Ovulation Rate | 93 percentage of all cycles |
| Arm 2: Clomiphene Citrate-pioglitazone-metformin | Ovulation Rate | 108 percentage of all cycles |
Secondary
Endometrial Thickness
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1:Letrozole-pioglitazone -Metformin Group | Endometrial Thickness | 10.56 mm | Standard Deviation 1.79 |
| Arm 2: Clomiphene Citrate-pioglitazone-metformin | Endometrial Thickness | 9.68 mm | Standard Deviation 1.39 |
Secondary
Number of Follicles>18mm.
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1:Letrozole-pioglitazone -Metformin Group | Number of Follicles>18mm. | 1.44 follicles | Standard Deviation 0.16 |
| Arm 2: Clomiphene Citrate-pioglitazone-metformin | Number of Follicles>18mm. | 1.5 follicles | Standard Deviation 0.86 |
Secondary
Pregnancy Rate
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1:Letrozole-pioglitazone -Metformin Group | Pregnancy Rate | 28 participants |
| Arm 2: Clomiphene Citrate-pioglitazone-metformin | Pregnancy Rate | 24 participants |
Other Pre-specified
Safety of Pioglitazone as Regards Serum Creatinine
serum creatinine was measured at the end of the study period (after 3 months) in both groups.
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1:Letrozole-pioglitazone -Metformin Group | Safety of Pioglitazone as Regards Serum Creatinine | 0.62 mg/dL | Standard Deviation 0.04 |
| Arm 2: Clomiphene Citrate-pioglitazone-metformin | Safety of Pioglitazone as Regards Serum Creatinine | 0.57 mg/dL | Standard Deviation 0.03 |