Effect of ALA Combined With Letrozole on Polycystic Ovary Syndrome Clinical Outcome in Infertile Females

Eligible participants will be randomly allocated to the control group or the intervention group with a ratio of 1:1 after obtaining informed consent.

The two study groups will be as follows:

Control group: this group will include 75 PCOS participants who will receive the standard treatment letrozole and the other commonly provided PCOS care (lifestyle modification, diet and exercise education, any other non-pharmacological method of management) according to the PCOS guidelines.

Treatment with letrozole will begin after the baseline visit, and for three cycles, the administration will start after a spontaneous or progesterone-induced menstruation. In the first cycle, "2.5" mg letrozole will be taken for 5 days starting from day 3 to 7 of the menses, if no pregnancy was detected, letrozole dose will be increased to "5 mg" in the next cycle, and finally, "7.5 mg" letrozole will be administered during the third cycle if the patient is still unable to conceive.

Interventional group: this will include 75 PCOS participants who will receive the standard treatment as letrozole with the same schedule as the control group and the other commonly provided PCOS care as previously described in addition to ALA, (Thiotacid®, EVAPHARMA, Egypt) in a dose of one tablet "600 mg" three times per day Each patient in the test group will start the ALA from day 3 of the menstrual period, then daily until the day of human chorionic gonadotropin (HCG) injection.

Baseline assessment:

After enrollment, baseline data and demographics will be obtained from each participant including:

• Age and body mass index will be calculated in Kg/m^2.
• Serum FSH, LH, TSH, prolactin, androgens, including free and total testosterone and SHBG.
• Ultrasound measurements including antral-follicles count and detection of Polycystic ovaries "defined as either 12 or more follicles measuring 2 to 9 mm in diameter or an increased ovarian volume >10 cm^3.".
• Menstrual cyclicity, presence of first degree relatives with diabetes mellitus , smoking status, comorbidities, medication history .
• All subjects will be educated about their diet and physical activity, and they will be asked not to start any new medications during the study without informing the principal investigator.

Patients monitoring and follow-up. All the participants included in the study after a spontaneous or progesterone-induced menstrual cycle will be randomly assigned to either Control group or Interventional group and will be monitored by trans-vaginal ultrasound to assess follicular diameter and endometrial thickness on the 10th day of the cycle, then on 12th , 14th and the 20th days of the cycle for assessment of dominant follicle ( ≥ 18 mm) on TVUS. The number of dominant follicles and the endometrial thickness will be documented for each menstrual cycle.

• When at least one dominant follicle is detected, participants will receive an intramuscular injection of 10 000 IU human chorionic gonadotropin (HCG) (Choriomon, IBSA).
• An HCG injection will be given when at least one follicle measuring at least 18 mm is observed.
• Ovulation will also be confirmed by the evaluation of serum progesterone each cycle between cycle days 20-22 ( > 5 ng/mL) and the test will be repeated 1 week later if the initial progesterone level is below the threshold to confirm ovulation.
• Couples will be instructed to have timed intercourse 36 hours after the HCG injection.
• Serum HCG will be determined 2 weeks after HCG injection in the absence of menstruation for the detection of pregnancy.
• Pregnant women will be required to stop all medication.
• Patients who do not have any dominant follicles, will start a new ovulation induction cycle in the following month.
• Treatment of the next cycle will start if menses occurs either spontaneously or by induction. The first day of the menses is considered the first day of the cycle and this is repeated for up to a total of 3 treatment cycles.
• For those who fail to achieve a dominant follicle, alpha lipoic acid will be stopped and restarted in the next cycle as before.

Inclusion criteria

• Female patient aged 18-35
• Willing to conceive
• PCOS, diagnosed according to the revised 2003 Rotterdam consensus criteria. " Oligo- or anovulation secondary to PCOS and at least one of the remaining two criteria: hyperandrogenism or polycystic ovarian morphology on ultrasound .
• Anovulation and/or infertility ≥ 1 year.
• At least one patent fallopian tube
• Normal uterine cavity
• Male partner with sperm concentration of at least 14 million/mL in at least one ejaculate.

Exclusion criteria

• Other causes for the infertility (male factor, tubal factor).
• Intake of hormonal or other drugs that can potentially influence the ovulation.
• Causes of anovulation or hyperandrogenism other than PCOS such as uncontrolled thyroid dysfunction or hyperprolactinemia.
• Contraindication to pregnancy
• Myo-inositol use < 3 months prior to study enrollment
• Concomitant metformin use. Previous use is allowed with last use at least 6 weeks prior to randomization.