Clinical trial NCT04390308: Is There A Role For Mechanical Stimulation In Ovarian Follicular Activation?
Official title: Is There A Role For Mechanical Stimulation In Ovarian Follicular Activation? A Randomized Control Trial.
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Infertility, Female
Premature Ovarian Failure
IVF
Lead sponsor: ART Fertility Clinics LLC
Sponsor class: OTHER
First posted: 2020-05-15
Enrollment: 70
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Adult women with primary or secondary infertility with a diagnosis of POI, willing to perform an IVF treatment

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Follicle growth above 4 mm
timeFrame: 1 day
measure: Anti-Müllerian hormone evaluation after intervention.
timeFrame: 1 day
measure: Follicle-stimulating hormone evaluation after intervention.
timeFrame: 1 day
measure: Luteinizing hormone evaluation after intervention.
timeFrame: 1 day
measure: Estradiol hormone evaluation after intervention.
timeFrame: 1 day
measure: Progesterone hormone evaluation after intervention.
timeFrame: 1 day
measure: Spontaneous menstruation.
timeFrame: 1 day
measure: Arteria ovarica doppler results.
timeFrame: 1 day
Secondary outcomes:
measure: Number of follicles
timeFrame: 1 day
measure: Number of oocytes retrieved
timeFrame: 1 day
measure: Fertilization rate
timeFrame: 1 day
measure: Blastulation rate
timeFrame: 1 day
measure: Aneuploidy rate
timeFrame: 1 day
Other outcomes:
measure: Clinical pregnancy by blood test
timeFrame: 12 weeks
measure: Implantation rate (%)
timeFrame: 4 weeks
measure: Clinical pregnancy by ultrasound
timeFrame: 12 weeks
Locations:
city: Abu Dhabi
country: United Arab Emirates
facility: ART Fertility Clinics LLC
Study officials:
affiliation: ART Fertility Clinics LLC
name: Laura Melado, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ford EA, Beckett EL, Roman SD, McLaughlin EA, Sutherland JM. Advances in human primordial follicle activation and premature ovarian insufficiency. Reproduction. 2020 Jan;159(1):R15-R29. doi: 10.1530/REP-19-0201.
citation: Zhang X, Han T, Yan L, Jiao X, Qin Y, Chen ZJ. Resumption of Ovarian Function After Ovarian Biopsy/Scratch in Patients With Premature Ovarian Insufficiency. Reprod Sci. 2019 Feb;26(2):207-213. doi: 10.1177/1933719118818906. Epub 2018 Dec 12.
citation: Kawamura K, Kawamura N, Hsueh AJ. Activation of dormant follicles: a new treatment for premature ovarian failure? Curr Opin Obstet Gynecol. 2016 Jun;28(3):217-22. doi: 10.1097/GCO.0000000000000268.
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citation: Sills ES, Rickers NS, Li X, Palermo GD. First data on in vitro fertilization and blastocyst formation after intraovarian injection of calcium gluconate-activated autologous platelet rich plasma. Gynecol Endocrinol. 2018 Sep;34(9):756-760. doi: 10.1080/09513590.2018.1445219. Epub 2018 Feb 28.
citation: Sills ES, Li X, Rickers NS, Wood SH, Palermo GD. Metabolic and neurobehavioral response following intraovarian administration of autologous activated platelet rich plasma: First qualitative data. Neuro Endocrinol Lett. 2019 Jan;39(6):427-433.
citation: Sills ES, Rickers NS, Svid CS, Rickers JM, Wood SH. Normalized Ploidy Following 20 Consecutive Blastocysts with Chromosomal Error: Healthy 46, XY Pregnancy with IVF after Intraovarian Injection of Autologous Enriched Platelet-derived Growth Factors. Int J Mol Cell Med. 2019 Winter;8(1):84-90. doi: 10.22088/IJMCM.BUMS.8.1.84. Epub 2019 May 15.
citation: European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI; Webber L, Davies M, Anderson R, Bartlett J, Braat D, Cartwright B, Cifkova R, de Muinck Keizer-Schrama S, Hogervorst E, Janse F, Liao L, Vlaisavljevic V, Zillikens C, Vermeulen N. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016 May;31(5):926-37. doi: 10.1093/humrep/dew027. Epub 2016 Mar 22.