In vitro activation of ovarian cortex and autologous transplantation: A novel approach to primary ovarian insufficiency and diminished ovarian reserve

Abstract

Background: Primary ovarian insufficiency (POI) and diminished ovarian reserve are two conditions that affect women's fertility. Oocyte donation remains an option for these patients; however, the development of certain novel technologies, such as in vitro activation of ovarian cortex (IVA), enables the possibility of activating the pool of resting primordial follicles, increasing the chance of pregnancy.

Objective and rationale: Here, we review the main pathways (PI3K and Hippo signaling) that govern the activation of primordial follicles and its application through the development of culture systems that support ovarian cortex for autologous transplantation. We also review the available data from case reports regarding outcomes of pregnancy and live birth rates with IVA.

Search methods: A PubMed search was conducted using the PubMed-NCBI database to identify literature pertinent to the pathways involved in the activation of primordial follicles and the outcomes of IVA techniques from 2013 to the present.

Outcomes: Women with POI have around a 5% chance of spontaneous pregnancy. Recently, novel techniques involving the activation of primordial follicles through molecular pathways have been developed, thus increasing the odds of these patients. More recently, the introduction of a drug-free IVA technique has shown to increase the number of antral follicles with successful oocyte maturation after gonadotropin treatment, reaching pregnancy rates over 30%, either through spontaneous conception or by the implementation of assisted reproductive technology.

Limitations: The evidence of this review is based on a few small series, so data should be interpreted with caution, and only randomized controlled trials could estimate the real magnitude and success of the procedure.

Reasons for caution: IVA technique remains an experimental strategy, with limited available data and the requirement of invasive procedures. Moreover, possible carcinogenic effects not yet determined after transplantation require special caution.

Wider implications: In view of the results achieved, IVA could provide a promising option for the preservation of fertility in some cancer patients and prepuberal girls where the only alternative is tissue cryopreservation.

Study funding/competing interests: The authors received no specific funding for this work and declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Keywords: invitro activation/ primary ovarian insufficiency/ diminished ovarian reserve/ 38 PI3K pathway/ Hippo pathway/ dormant primordial follicle/ growth factors/ 39 autotransplantation.

Figure 1.

The PI3K pathway. 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; AKT, protein kinase B; AP-1, activating protein-1; Cjun, proto-oncogene; FOXO3A, forkhead box protein O3 transcription factor; GSK-3, glycogen synthase kinase 3; JNK, c-Jun N-terminal kinase; mTORC1, rapamycin-sensitive mTOR complex 1; P, phosphorylation; P110, PI3K catalytic subunit; P27, cyclin-dependent kinase inhibitor; P85, PI3K regulatory subunit; PDK1, 3´-phosphoinositide-dependent kinase-1; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; rpS6, ribosomal protein S6; RTK, tyrosine kinase receptor; S6K1, P70 S6 kinase 1-ribosomal protein S6; TSC2, tuberous sclerosis complex 2 or tuberin.

Figure 2.

The Hippo pathway. BIRC, baculoviral IAP repeat containing proteins; CTGF/CCN2, connective tissue growth factor; CYR61/CCN, cysteine-rich protein 61; LATS 1/2, large tumor suppressor; MST 1/2, serine/threonine mammalian Ste-20 like kinases; NOV/CCN3, nephroblastoma overexpressed; SAV1, protein salvador homolog 1; TAZ, transcriptional coactivator with PDZ-binding motif; TEAD, transcriptional enhanced associate domain; YAP, YES-associated protein.