Impact of Different Doses and Routes of Exogenous Progesterone Administration on Endometrial Receptivity Parameters

Study Overview
=================
Brief Summary
-----------------
After so many years conducting artificial endometrial preparation cycles for embryo transfer, there is no clear indication about which is the optimal dose of exogenous progesterone in this scenario to optimize the outcome. Taking into account that the luteal phase can be controlled by measuring serum P levels (not done until now), the next step is to find out which is the best dose and route of administration of exogenous progesterone for luteal phase in artificial cycles. Therefore, the aim of this experimental study is to compare the endometrial function and structure, as well as the serum P levels according to the use of different types of exogenous progesterone available on the market depending on their doses and route of administration (vaginal, subcutaneous or intramuscular). The endometrial receptivity status will be compared in the different artificial cycles with the one observed in a natural cycle, without exogenous progesterone (only the endogenous one) as a control group. Endometrial receptivity will be analysed by means of endometrial function and structure, but not by pregnancy outcome as in this study an embryo cannot be replaced in the uterus because an endometrial biopsy needs to be done to do this type of research.

Official Title
-----------------
Exploratory Study on the Impact of Different Doses and Route of Administration of Exogenous Progesterone in Artificial Endometrial Preparation Cycles on Endometrial Structure and Function

Conditions
-----------------
Infertility, Female, ENDOMETRIAL RECEPTIVITY

Intervention / Treatment
-----------------
* Drug: Progesterone
* Other: Artificial Cycle (no intervention)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria All women with no history of infertility who agree to participate in the study: Age: 18-35 years old, both inclusive Regular menstrual cycles In good health and not suffering from any mental or medical condition(s) that would preclude participation in the study. Exclusion Criteria Subjects who meet one or more of the following will not be considered eligible to participate in the pilot study: Simultaneous participation in other clinical studies that, at the researcher's criteria, could interfere with the results of this study. Taking oral contraceptives in the three months prior to signing informed consent. Presence of uterine pathology (submucosal or intramural myomas >4 cm deforming cavity, endometrial polyps or müllerian anomalies) or adnexal pathology (communicating hydrosalpinx). Background of thrombosis, breast cancer, systemic diseases. Those unable to comprehend the investigational nature of the proposed study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Exploratory, unicentric, with blind evaluators, randomized to six parallel arms in ratio 1:1:1:1:1:1 clinical trial conducted in healthy volunteers under an artificial endometrial preparation cycle and luteal phase support with exogenous progesterone administered by different doses and routes or natural menstrual cycles.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: I: Artificial endometrial preparation cycle<br>Artificial endometrial preparation cycle with estrogens and vaginal natural micronized progesterone 400mg/12h | Drug: Progesterone<br>* Subjects will undergo an artificial cycle with hormone replacement therapy (HRT) with the aim of comparing the endometrial gene expression profile in the different types of exogenous progesterone with different doses and routes of administration.<br>|
| Experimental: II: Artificial endometrial preparation cycle<br>Artificial endometrial preparation cycle with estrogens and subcutaneous natural progesterone 25mg/24h | Drug: Progesterone<br>* Subjects will undergo an artificial cycle with hormone replacement therapy (HRT) with the aim of comparing the endometrial gene expression profile in the different types of exogenous progesterone with different doses and routes of administration.<br>|
| Experimental: III: Artificial endometrial preparation cycle<br>Artificial endometrial preparation cycle with estrogens and subcutaneous natural progesterone 25mg/12h | Drug: Progesterone<br>* Subjects will undergo an artificial cycle with hormone replacement therapy (HRT) with the aim of comparing the endometrial gene expression profile in the different types of exogenous progesterone with different doses and routes of administration.<br>|
| Experimental: IV: Artificial endometrial preparation cycle<br>Artificial endometrial preparation cycle with estrogens and a combination of subcutaneous natural progesterone 25mg/24h + vaginal natural micronized progesterone 400mg/24h | Drug: Progesterone<br>* Subjects will undergo an artificial cycle with hormone replacement therapy (HRT) with the aim of comparing the endometrial gene expression profile in the different types of exogenous progesterone with different doses and routes of administration.<br>|
| Experimental: V: Artificial endometrial preparation cycle<br>Artificial endometrial preparation cycle with estrogens and intramuscular natural progesterone 50mg/24h | Drug: Progesterone<br>* Subjects will undergo an artificial cycle with hormone replacement therapy (HRT) with the aim of comparing the endometrial gene expression profile in the different types of exogenous progesterone with different doses and routes of administration.<br>|
| Active Comparator: Natural menstrual cycle<br>Natural menstrual cycle (without any exogenous steroid hormone Treatment) | Other: Artificial Cycle (no intervention)<br>* Control group of 15 subjects in the context of a natural cycle with only endogenous progesterone present<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endometrial gene expression profile | Determination of gene expression | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histological dating of endometrial biopsies | Endometrial classification using Noyes criteria | 12 months | 
| Histological analysis of the endometrial tissue using electron microscopy | Presence or Absence of Pinopodes | 12 months | 
| Progesterone concentration in the endometrium | Endometrial progesterone values | 12 months | 
| Serum Progesterone concentrations | Blood serum progesterone values | 12 months | 
| Correlation between progesterone levels in blood and uterus. | Presence or Absence of correlation | 12 months | 
| Correlation between serum and uterine levels with endometrial transcriptome and histological dating | Presence or Absence of correlation | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Luteal phase, Artificial endometrial preparation cycle, Progesterone, Endometrial gene expression, Endometrial receptivity