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.

Overview

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.

Interventions

• Procedure Ovarian puncture
  Egg collection
• Other Hormonal blood Test
  AMH (ng/ml), FSH (IU/mL), E2(pg/mL), P4(ng/mL), LH (IU/mL)
• Diagnostic test Transvaginal ultrasound
  Doppler of arteria ovarica. Resistance index

Primary outcome measures

• Follicle growth above 4 mm [Time frame: 1 day]
• Anti-Müllerian hormone evaluation after intervention. [Time frame: 1 day]
• Follicle-stimulating hormone evaluation after intervention. [Time frame: 1 day]
• Luteinizing hormone evaluation after intervention. [Time frame: 1 day]
• Estradiol hormone evaluation after intervention. [Time frame: 1 day]
• Progesterone hormone evaluation after intervention. [Time frame: 1 day]
• Spontaneous menstruation. [Time frame: 1 day]
• Arteria ovarica doppler results. [Time frame: 1 day]

Secondary outcome measures (5)

• Number of follicles [Time frame: 1 day]
• Number of oocytes retrieved [Time frame: 1 day]
• Fertilization rate [Time frame: 1 day]
• Blastulation rate [Time frame: 1 day]
• Aneuploidy rate [Time frame: 1 day]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United Arab Emirates · 1 center

• ART Fertility Clinics LLC — Abu Dhabi

Publications

• 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. PMID 31376814
• 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. PMID 30541396
• 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. PMID 27022685
• Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost. 2011 May;105 Suppl 1:S13-33. doi: 10.1160/THS10-11-0720. Epub 2011 Apr 11. PMID 21479340
• Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008 May 15;453(7193):314-21. doi: 10.1038/nature07039. PMID 18480812
• Lacci KM, Dardik A. Platelet-rich plasma: support for its use in wound healing. Yale J Biol Med. 2010 Mar;83(1):1-9. PMID 20351977
• Sfakianoudis K, Simopoulou M, Nitsos N, Rapani A, Pantou A, Vaxevanoglou T, Kokkali G, Koutsilieris M, Pantos K. A Case Series on Platelet-Rich Plasma Revolutionary Management of Poor Responder Patients. Gynecol Obstet Invest. 2019;84(1):99-106. doi: 10.1159/000491697. Epub 2018 Aug 22. PMID 30134239
• 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. PMID 29486615

Identifiers

NCT: NCT04390308 · 2004-ABU-005-LM

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗