Reproductive Techniques, Assisted
Conditions
Keywords
endometrial receptivity, endometrial predecidualization, endometrial genomics, endometrial receptivity array
Brief summary
Study the endometrial predecidualization by using subcutaneous progesterone 25 mg/day versus intramuscular progesterone 50 mg/day, to determine whether there are differences in the endometrial transformation and endometrial receptivity.
Detailed description
The aim of this study is to compare predecidualization and endometrial receptivity as gene expression by using subcutaneous progesterone 25 mg/day versus intramuscular progesterone 50 mg/day in healthy women of childbearing age. Both, the two drugs and the doses administered in this clinical trial, are routine clinical practice. A controlled ovarian stimulation will be previously performed and following routine clinical practice for 10-12 days at standard doses of subcutaneous FSH 150-225 IU/day, according to BMI and number of antral follicles. A GnRH antagonist shall be administered, being initiated according to donor's follicular growth from greater or equal14 mm diameter follicles. Final maturation shall be performed with a bolus of GnRH agonist when there exist at least 3 follicles greater or equal17 mm diameter, and therefore performing follicular puncture 36 hours after the bolus of agonist has been administered. If the donor meets the inclusion criteria, she will be informed of the study and, if she agrees, she will sign the informed consent. Randomization shall be performed in 2 arms; arm 1 will be administered subcutaneous progesterone 25 mg/day (Prolutex; Angelini, Spain), and arm 2, intramuscular progesterone 50 mg/day (Prontogest IBSA, Italy). In each arm 12 donors (ITT population) will be included. The randomization to a treatment group shall be performed the day the follicular puncture has been programmed. To that purpose, a randomized consecutive sampling will be used by means of assignment tables. The medication will be administered by a person not involved in the assessments and responsible for group assignment, data centralization and drug assignment. At day 5 (5 days after follicular puncture):endometrial thickness measurement by means of transvaginal ultrasound and perform endometrial biopsy and take two samples: 1 sample to Anatomical Pathology and 1 sample to Endometrial Receptivity Array (ERA).
Interventions
subcutaneous progesterone 25 mg/day
intramuscular progesterone 50 mg/day
Sponsors
IVI Barcelona
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Masked samples for histological evaluation and assessment of gene expression
Intervention model description
Parallel Assignment
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 34 Years
Healthy volunteers
Yes
Inclusion criteria
* Female aged between 18 and 34 years * BMI between 18 and 28 kg/m2 * Endometrial thickness \> 7 mm the day of progesterone treatment initiation (day of follicular puncture) * Follicular maturation with a single bolus of GnRH agonist * Egg donors who undergo a cycle of ovarian stimulation in the IVI Barcelona Centre * Egg donors selected in accordance with the requirements of Law 14/2006 of 26 May 2006 on Assisted Human Reproduction Techniques * Informed consent has been signed and dated
Exclusion criteria
* Known allergy to progesterone formulations or their excipients * Known allergy to estrogens * Known thrombophilias * Alcohol, drug or psychotropic medication dependence * Concurrent participation in another study * Concomitant medication that may interfere with the study medication and ovarian stimulation * Failure to comply with the requirements for egg donors in accordance with Law 14/2006 of 26 May 2006 on Assisted Human Reproduction Techniques
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endometrial Gene Expression Difference | 5 days | Genes with a significantly high gene expression difference (adj-p-value \< 0.05, Fold Change\>3) |
| Predecidual Transformation | 5 days | Histologic dating of the endometrium at day 5: early secretory phase, media secretory phase or late secretory phase |
| Decidualization of Stromal Cell | 5 days | Rate of transformation of endometrial stromal fibroblasts into specialized secretory decidual cells (three categories: less than 25%, between 26% and 50%, and over 50%) |
| Endometrial Maturation Using Noyes' Criteria | 5 days | Endometrial dating of luteal phase days according to the Noyes criteria |
| Endometrial Gene Expression | 5 days | Gene expression profile of endometrial |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Endometrial Thickness | 5 days | Endometrial thickness measurement by means of transvaginal ultrasound. |
| Blood Estradiol Level | day 0 | Blood estradiol level on the day of follicular puncture |
| Blood Progesterone Level | day 0 | Blood progesterone level on the day of follicular puncture |
| Blood LH Level | day 0 | Blood Luteinizing hormone level on the day of follicular puncture |
| Number of Participants With Side Effects During the Study | 5 days | Number of Participants with side effects during the study |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prolutex Subcutaneous progesterone
Subcutaneous progesterone: subcutaneous progesterone 25 mg/day | 12 |
| Prontogest Intramuscular progesterone
Intramuscular progesterone: intramuscular progesterone 50 mg/day | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Prolutex | Prontogest | Total |
|---|---|---|---|
| Age, Continuous | 26.92 years STANDARD_DEVIATION 5.32 | 25.58 years STANDARD_DEVIATION 2.39 | 26.25 years STANDARD_DEVIATION 4.09 |
| Blood Estradiol Level | 2020.35 pg/ml STANDARD_DEVIATION 998.36 | 2464.33 pg/ml STANDARD_DEVIATION 1144.19 | 2262.52 pg/ml STANDARD_DEVIATION 1078.94 |
| Blood LH level | 1.25 pg/ml STANDARD_DEVIATION 0.45 | 1.24 pg/ml STANDARD_DEVIATION 0.91 | 1.25 pg/ml STANDARD_DEVIATION 0.7 |
| Blood Progesterone Level | 1.31 ng/ml STANDARD_DEVIATION 0.85 | 1.44 ng/ml STANDARD_DEVIATION 0.77 | 1.37 ng/ml STANDARD_DEVIATION 0.79 |
| Body Mass Index | 21.76 kg/m^2 STANDARD_DEVIATION 2.88 | 23.12 kg/m^2 STANDARD_DEVIATION 2.79 | 22.44 kg/m^2 STANDARD_DEVIATION 2.86 |
| Endometrial Thickness | 8.88 mm STANDARD_DEVIATION 1.98 | 9.58 mm STANDARD_DEVIATION 1.61 | 9.23 mm STANDARD_DEVIATION 1.8 |
| Height | 166.75 cm STANDARD_DEVIATION 5.1 | 162.08 cm STANDARD_DEVIATION 3.5 | 164.42 cm STANDARD_DEVIATION 4.9 |
| Sex: Female, Male Female | 12 Participants | 12 Participants | 24 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight | 61.00 Kg STANDARD_DEVIATION 10.05 | 61.00 Kg STANDARD_DEVIATION 8.55 | 61.00 Kg STANDARD_DEVIATION 9.12 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 5 / 12 | 4 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Decidualization of Stromal Cell
Rate of transformation of endometrial stromal fibroblasts into specialized secretory decidual cells (three categories: less than 25%, between 26% and 50%, and over 50%)
Time frame: 5 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Prolutex | Decidualization of Stromal Cell | <25% of stromal cell | 3 participants |
| Prolutex | Decidualization of Stromal Cell | 25-50% of stromal cell | 3 participants |
| Prolutex | Decidualization of Stromal Cell | > 50% of stromal cell | 6 participants |
| Prontogest | Decidualization of Stromal Cell | 25-50% of stromal cell | 7 participants |
| Prontogest | Decidualization of Stromal Cell | <25% of stromal cell | 2 participants |
| Prontogest | Decidualization of Stromal Cell | > 50% of stromal cell | 2 participants |
p-value: 0.1523Chi-squared
Primary
Endometrial Gene Expression
Gene expression profile of endometrial
Time frame: 5 days
Population: We assessed the gene expression of 238 endometrial genes to detect differences in gene expression between treatments.~This analysis could not be performed in 1 patient of the prolutex group because of the poor quality of the sample collected
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Prolutex | Endometrial Gene Expression | differential expressed genes | 28 Endometrial genes |
| Prolutex | Endometrial Gene Expression | the same trend of gene expression | 210 Endometrial genes |
| Prontogest | Endometrial Gene Expression | differential expressed genes | 28 Endometrial genes |
| Prontogest | Endometrial Gene Expression | the same trend of gene expression | 210 Endometrial genes |
Primary
Endometrial Gene Expression Difference
Genes with a significantly high gene expression difference (adj-p-value \< 0.05, Fold Change\>3)
Time frame: 5 days
Population: We assessed the expressed genes with a significantly high gene expression difference between treatments (adj-p-value \< 0.05, Fold Change\>3) This analysis could not be performed in 1 patient of the prolutex group because of the poor quality of the sample collected
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Prolutex | Endometrial Gene Expression Difference | expressed genes with fold change > 3 | 4 Endometrial genes |
| Prolutex | Endometrial Gene Expression Difference | expressed genes without or with fold change < 3 | 234 Endometrial genes |
| Prontogest | Endometrial Gene Expression Difference | expressed genes with fold change > 3 | 4 Endometrial genes |
| Prontogest | Endometrial Gene Expression Difference | expressed genes without or with fold change < 3 | 234 Endometrial genes |
Primary
Endometrial Maturation Using Noyes' Criteria
Endometrial dating of luteal phase days according to the Noyes criteria
Time frame: 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prolutex | Endometrial Maturation Using Noyes' Criteria | 9.08 days | Standard Deviation 2.23 |
| Prontogest | Endometrial Maturation Using Noyes' Criteria | 7.64 days | Standard Deviation 2.01 |
Comparison: comparison between groupsp-value: 0.1189t-test, 2 sided
Primary
Predecidual Transformation
Histologic dating of the endometrium at day 5: early secretory phase, media secretory phase or late secretory phase
Time frame: 5 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Prolutex | Predecidual Transformation | early secretory phase | 1 participants |
| Prolutex | Predecidual Transformation | media secretory phase | 7 participants |
| Prolutex | Predecidual Transformation | late secretory phase | 4 participants |
| Prontogest | Predecidual Transformation | early secretory phase | 2 participants |
| Prontogest | Predecidual Transformation | media secretory phase | 8 participants |
| Prontogest | Predecidual Transformation | late secretory phase | 1 participants |
p-value: 0.3395Chi-squared
Secondary
Blood Estradiol Level
Blood estradiol level on the day of follicular puncture
Time frame: day 0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prolutex | Blood Estradiol Level | 1384.06 pg/mL | Standard Deviation 1122.8 |
| Prontogest | Blood Estradiol Level | 1208.58 pg/mL | Standard Deviation 502.96 |
p-value: 0.6262t-test, 2 sided
Secondary
Blood Estradiol Level
Blood estradiol level 5 days after progesterone treatment
Time frame: 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prolutex | Blood Estradiol Level | 257.88 pg/mL | Standard Deviation 150.65 |
| Prontogest | Blood Estradiol Level | 246.45 pg/mL | Standard Deviation 106.9 |
p-value: 0.8371t-test, 2 sided
Secondary
Blood LH Level
Blood Luteinizing hormone level 5 days after progesterone treatment
Time frame: 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prolutex | Blood LH Level | 1.30 pg/mL | Standard Deviation 0.6 |
| Prontogest | Blood LH Level | 2.92 pg/mL | Standard Deviation 5.36 |
p-value: 0.3107t-test, 2 sided
Secondary
Blood LH Level
Blood Luteinizing hormone level on the day of follicular puncture
Time frame: day 0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prolutex | Blood LH Level | 2.32 pg/mL | Standard Deviation 0.89 |
| Prontogest | Blood LH Level | 2.75 pg/mL | Standard Deviation 2.08 |
p-value: 0.5118t-test, 2 sided
Secondary
Blood Progesterone Level
Blood progesterone level 5 days after progesterone treatment
Time frame: 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prolutex | Blood Progesterone Level | 3.16 ng/mL | Standard Deviation 1 |
| Prontogest | Blood Progesterone Level | 11.04 ng/mL | Standard Deviation 5.21 |
p-value: <0.0001t-test, 2 sided
Secondary
Blood Progesterone Level
Blood progesterone level on the day of follicular puncture
Time frame: day 0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prolutex | Blood Progesterone Level | 14.40 ng/mL | Standard Deviation 6.63 |
| Prontogest | Blood Progesterone Level | 10.92 ng/mL | Standard Deviation 6.88 |
p-value: 0.2301t-test, 2 sided
Secondary
Endometrial Thickness
Endometrial thickness measurement by means of transvaginal ultrasound.
Time frame: 5 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prolutex | Endometrial Thickness | 8.46 mm | Standard Deviation 2.66 |
| Prontogest | Endometrial Thickness | 9.61 mm | Standard Deviation 1.24 |
p-value: 0.2042t-test, 2 sided
Secondary
Number of Participants With Side Effects During the Study
Number of Participants with side effects during the study
Time frame: 5 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prolutex | Number of Participants With Side Effects During the Study | 5 participants |
| Prontogest | Number of Participants With Side Effects During the Study | 4 participants |
p-value: 0.5Fisher Exact