The influence of preovulatory and postovulatory progesterone on the outcome of the in vitro fertilization (IVF)

This study is a prospective cohort study. 400 stimulated patients in IVF treatment will be prospectively analyzed by determining progesterone (P4) and estradiol (E2) on the day of hCG administration. Patients with a normal preovulatory P4 (less than or equal to 4.77 nmol/l) will be in a control group (300 women), while patients with elevated P4 (>4.77 nmol/l) will represent a study group (100 women). The study group will be further divided into two subgroups; normal responder patients will be in the first subgroup (85 women), while the other subgroup (15 women) will be represented with high responder patients. All the patients will be paired according to their age, BMI, stimulation protocol, gonadotropin dosage and the number of retrieved oocytes and transferred embryos. Ovulation stimulation among patients will be conducted with GnRH analogues in the ovulation induction. Gonadotropin dosage and their selection (single drug or drug combination) as well as the overall duration of the intervention period for each participant will be adjusted according to patients' age, FSH, AFC (antral follicle counts), BMI and previous IVF procedure. Drugs that will be used in this research are Follitropine Alfa (Gonal F, MerckSerono, Germany), Follitropine Beta (Puregon, Organon, Netherland), Triptorelin (Decapeptyl SR, Ferring Pharmaceuticals, Switzerland), Cetrorelix acetate (Cetrotide, MerckSerono, Germany), Choriogonadotropin Alfa (Ovitrelle, MerckSerono, Germany), Menotropin (Menopur, Ferring Pharmaceuticals, Switzerland). Every drug will be administered as a subcutaneous injection. Follitropine Alfa can be used as a single drug or in combination with GnRH agonists. If we use Follitropine Alfa as a single drug, it will be used from the second day of the cycle till the 10th day of the cycle (9 days in total). The initial dose will be 225 IU (3 ampoules of 75 IU) for the first 3-4 days of the treatment of the patients and the later dose will be 150 IU (2 ampoules of 75 IU). Follitropine Beta will be used from the second day of the cycle till the 10th day of the cycle (9 days in total). The initial dose will be 200 IU (4 ampoules of 50 IU) for the first 3-4 days of the treatment of the patients and the later dose will be 150 IU (3 ampoules of 50 IU). On the 10th day, Choriogonadotrophin Alfa will be administered in a single dose of 250 micro g. If we use the combination of Follitropine Alfa and GnRH agonists, the treatment will start on the second day of the cycle (short protocol) with single daily dose of Triptorelin of 0,1mg and its duration will be till the 10th day of the cycle (9 days in total). Long protocol with Triptorelin can also be used with a single daily dose of 0,1mg from the 21st day of the previous cycle till the 10th day of the cycle (18 days in total). Cetrorelix acetate will be used in a daily dose of 0,25mg starting on the 6th or the 7th day of the cycle till the 10th day of the cycle (4-5 days in total). If we use the single dose of the Cetrorelix acetate, we will administer 3mg of Cetrorelix acetate on the 7th day of the cycle. Choriogonadotropin Alfa will be administered in a single dose of 250 micro g when more than 3 follicles in diameter of 17 mm and more are registered on the ovaries on the ultrasound examination. Menotropin will be administered for at least 5 days starting on the second day of the cycle and the duration of the treatment must not be more than 20 days. The daily dose of Menotropin will be 225 IU (3 ampoules of 75 IU). Folliculogenesis will be monitored by ultrasound examination and by determination of E2 serum levels. When more than 3 follicles in diameter of 17 mm and more are registered on the ovaries on the ultrasound examination, hCG will be given to the patients and 36 hours later transvaginal follicle aspiration will be performed. All patients will receive the luteal support in form of micronized vaginal P4 (Utrogestan, Besins Laboratories International, France), which will be used for 12 days in a dose of 600mg a day (3 doses of 200mg). Since all the patients will receive Utrogestan, micronized P4 will not affect the results of the study of preovulatory P4. Considering the possibility that different populations have different levels of P4 after the ovulation on the 5th day, the mean P4 on the 5th day will be determined in the control group. The obtained value of P4 on the 5th day of the control group would be the discriminatory border on which will the study patients be classified for the frozen/thawed embryo transfer (FET) or blastocyst embryo transfer (BET). In the study subgroup, among normal responders who have higher values of P4 on the 5th day as compared to the mean P4 value on the 5th day obtained in the control group, FET will be made, while at lower values of P4 as compared to the mean P4 value on the 5th day obtained in the control group, BET will be conducted. In high responders with elevated preovulatory and postovulatory P4 a randomized fresh or delayed blastocysts transfer is planned. The overall duration of the intervention period for each participant would be 28 days (single 28 day cycle). The duration of the study will be maximum 2 years.