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This randomized clinical trial evaluates two different endometrial preparation protocols-hormone replacement therapy (HRT) and natural cycle-for frozen embryo transfer (FET) in infertile women undergoing assisted reproductive technology (ART). The goal is to compare implantation, clinical pregnancy, and ongoing pregnancy outcomes.
This prospective, randomized controlled clinical trial is conducted on women aged 18 to 42 years undergoing frozen embryo transfer (FET) during in vitro fertilization (IVF) cycles. Eligible participants meet the inclusion criteria and provide written informed consent.
Participants are randomized into two groups using a permuted block method:
HRT Group (Control): Estradiol valerate is initiated at 4 mg/day on day 2 of the menstrual cycle and is adjusted to 8 mg/day based on endometrial thickness. Once the endometrial thickness reaches ≥8 mm, progesterone supplementation is started (400 mg vaginal suppositories twice daily and 50 mg intramuscular injections daily) for 5 days before blastocyst transfer.
Natural Cycle Group: A transvaginal ultrasound is performed on cycle day 2 or 3 to rule out ovarian cysts and confirm an endometrial thickness <5 mm. If eligible, patients are monitored from day 8 onward. Ovulation is tracked by assessing dominant follicle growth (≥15 mm), LH surge (≥17 IU/L), and serum progesterone (>1.5 ng/mL). Once ovulation is confirmed and endometrial thickness reaches ≥7 mm, FET is scheduled for 6 days post-LH surge or 5 days post-follicle collapse. Serum progesterone is measured one day before transfer; if <10 ng/mL, 400 mg/day progesterone is administered.
Embryos are cultured in Blastocyst medium (Origio, Denmark) and assessed daily. High-quality embryos (Grade A) are defined by a 4-cell stage on day 2, a 7-8 cell stage on day 3, uniform cell size, and <20% fragmentation. Blastocyst grading follows Gardner's criteria. One or two top-quality embryos are transferred using a Cook catheter under abdominal ultrasound guidance. If no blastocyst is available by day 5, the most advanced embryo is transferred.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| natural cycle group | No Intervention | A transvaginal ultrasound is performed on cycle day 2 or 3 to rule out ovarian cysts and confirm an endometrial thickness <5 mm. If eligible, patients are monitored from day 8 onward. Ovulation is tracked by assessing dominant follicle growth (≥15 mm), LH surge (≥17 IU/L), and serum progesterone (>1.5 ng/mL). Once ovulation is confirmed and endometrial thickness reaches ≥7 mm, FET is scheduled for 6 days post-LH surge or 5 days post-follicle collapse. Serum progesterone is measured one day before transfer; if <10 ng/mL, 400 mg/day progesterone is administered | |
| Hormone Replacement Therapy (HRT) | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| hormone replacement therapy (HRT) group | Drug | Estradiol valerate is initiated at 4 mg/day on day 2 of the menstrual cycle and is adjusted to 8 mg/day based on endometrial thickness. Once the endometrial thickness reaches ≥8 mm, progesterone supplementation is started (400 mg vaginal suppositories twice daily and 50 mg intramuscular injections daily) for 5 days before blastocyst transfer. |
| Measure | Description | Time Frame |
|---|---|---|
| Clinical pregnancy rate | presence of gestational sac on ultrasound at 6 weeks | 6 weeks post-transfer |
| Chemical pregnancy rate | Positive BHCG test greater than 25 mIU/ml after 12-16 days of embryo transfer | 12-16 days post embryo transfer |
| Measure | Description | Time Frame |
|---|---|---|
| Ongoing Pregnancy Rate | Pregnancy sustained beyond 20 weeks gestation | At 20 weeks after embryo transfer |
| Early Miscarriage Rate | loss of a fetus before 12 weeks of gestation |
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Inclusion Criteria:
Regular menstrual cycles
Maternal age between 18 and 42 years
Normal intrauterine cavity confirmed by pretreatment ultrasound or hysteroscopy
Body Mass Index (BMI) less than 30 kg/m²
No ovulation disorders
Exclusion Criteria:
No embryos available for transfer (no embryo thawing)
Withdrawal of patient consent to continue treatment
Failure of dominant follicle development (in natural cycle group)
Inadequate endometrial response for transfer
No endometriosis grade 3 or higher
The participant provided written informed consent
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Malihe Mahmoudinia, Prof | Contact | 09153047813 | mahmoudiniam@mums.ac.ir |
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| ID | Term |
|---|---|
| D020249 | Hormone Replacement Therapy |
| D044382 | Population Groups |
| ID | Term |
|---|---|
| D004358 | Drug Therapy |
| D013812 | Therapeutics |
| D003710 | Demography |
| D011154 | Population Characteristics |
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|
| Up to 12 weeks after embryo transfer |
| Late Miscarriage Rate | loss of a fetus after 12 weeks and before 24 weeks | up to 24 weeks gestation |
| Live Birth Rate | Birth of at least one live neonate after 24 completed weeks of gestation | At delivery, After 24 weeks gestation |
| Cycle Cancellation Rate | Proportion of treatment cycles canceled before embryo transfer | Up to the day of embryo transfer |
| Pregnancy Complications | Incidence of pregnancy-related complications, including: Preeclampsia: Onset of hypertension after 20 weeks of gestation, Gestational Diabetes, Placental Abruption,Placenta Previa | through study completion, an average of 1 year |