Is There A Role For Mechanical Stimulation In Ovarian Follicular Activation?

Study Overview
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Brief Summary
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Premature ovarian failure (POI) is a loss of normal function before age 40, leading to infertility and hypoestrogenism. About 1% of women younger than 40 years old and 0.1% before 30 are affected. Most patients already had impaired or complete loss of fecundity when diagnosed. Hence, the treatment of POI is particularly tough. Currently, no optimal regimen exists to ameliorate ovarian function.

Detailed Description
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In women, the non-growing population of follicles that comprise the ovarian reserve is determined at birth and serves as the reservoir for future fertility. This reserve of dormant, primordial follicles and the mechanisms controlling their selective activation which constitute the committing step into folliculogenesis are essential for determining fertility outcomes in women. While POI is sometimes called premature menopause, it is not identical with menopause. Women with POI may still have occasional irregular periods and may even occasionally achieve a pregnancy. Symptoms of POI include irregular menses or amenorrhea, infertility, hypoestrogenic symptoms and decreased libido. POI may be caused by chromosomal defects such as mosaic Turner's syndrome, exposure to toxins (chemotherapy or radiation), autoimmunity, genetic factors (FMR1) and other unknown factors. Recently, new promising approaches have emerged for infertility treatment in patients with POI, which are based on arousing the still available primordial follicle pool. It is supposed that these techniques activate dormant primordial follicles using a combination of mechanical signaling and biochemical factors. The hypothesis that mild local ovarian injury, such as ovarian puncture, which is a usual procedure in an IVF center with minimal side effects, might exert a similar favorable effect in women with POI arouses our curiosity. Different groups have published case series of ovarian procedures, injecting substances in the ovaries (A-PRP) or ovarian biopsies / scratch in infertile patients with low ovarian reserve (LOR) or/and patients with POF. However, those studies were underpowered, including not enough number of cases, with variable inclusion criteria and reporting results with very low scientific evidence. Furthermore, the mechanical effect of injecting the ovary should be taken into consideration during the evaluation of these patients, yet it might improve the ovarian function as well. There are no previous randomized controlled trials considering a procedure as ovarian puncture, which is easier and accessible at any fertility center.

Official Title
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Is There A Role For Mechanical Stimulation In Ovarian Follicular Activation? A Randomized Control Trial.

Conditions
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Infertility, Female, Premature Ovarian Failure, IVF

Intervention / Treatment
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* Procedure: Ovarian puncture
* Other: Hormonal blood Test
* Diagnostic Test: Transvaginal ultrasound


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent Women 40 years of age and younger with documented primary ovarian insufficiency (12). Normal Karyotype BMI </= 35 kg/m2 Oligo/amenorrhea for at least 4 months FSH > 25 IU/mL AMH </= 0,1 ng/ml No evidence of follicles > 4mm Must have two ovaries of approximately equal volume. Willingness to undergo further fertility treatment, including IVF if there is evidence of response A transvaginal scan including Doppler for arteria ovarica will be performed previously to the surgical procedure. Exclusion Criteria: Premature ovarian failure due to a genetic origin, such as Turner's Syndrome or chromosomal abnormality. Oncological diseases (specially, skeletal system and blood). Autoimmune diseases, for example, lupus erythematosus, etc. Previous treatments including radiotherapy or chemotherapy. Other conditions not suitable for surgical procedures and/or anesthesia. Anticoagulant or antiaggregant treatment. Acute and chronic infectious diseases. Active substance abuse or dependence. Major Mental health disorder.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Intervention<br>The cortex of selected ovary will be punctured up to ten times. In the surgical report, the surgeon will state how many punctures have been done. | Procedure: Ovarian puncture<br>* Egg collection<br>Other: Hormonal blood Test<br>* AMH (ng/ml), FSH (IU/mL), E2(pg/mL), P4(ng/mL), LH (IU/mL)<br>Diagnostic Test: Transvaginal ultrasound<br>* Doppler of arteria ovarica. Resistance index<br>|
| Control<br>No intervention | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Follicle growth above 4 mm | One or more follicles evaluated by transvaginal ultrasound. Defined by number of follicles growing, quantitative variable. | 1 day | 
| Anti-Müllerian hormone evaluation after intervention. | Anti-Müllerian hormone evaluation after intervention. | 1 day | 
| Follicle-stimulating hormone evaluation after intervention. | Follicle-stimulating hormone evaluation after intervention. | 1 day | 
| Luteinizing hormone evaluation after intervention. | Luteinizing hormone evaluation after intervention. | 1 day | 
| Estradiol hormone evaluation after intervention. | Estradiol hormone evaluation after intervention. | 1 day | 
| Progesterone hormone evaluation after intervention. | Progesterone hormone evaluation after intervention. | 1 day | 
| Spontaneous menstruation. | Spontaneous menstruation. | 1 day | 
| Arteria ovarica doppler results. | Arteria ovarica doppler results. Resistance index. | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of follicles | Number of follicles | 1 day | 
| Number of oocytes retrieved | Number of oocytes retrieved | 1 day | 
| Fertilization rate | percentage of 2PN embryos per oocyte injected | 1 day | 
| Blastulation rate | percentage of blastocysts per 2PN embryos | 1 day | 
| Aneuploidy rate | percentage of aneuploid blastocysts per total blastocyst biopsied | 1 day |