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.

The Trends and Hotspots in Premature Ovarian Insufficiency Therapy from 2000 to 2022

“…After 2018, there was a shift from hormone replacement therapy to more innovative treatment strategies. In vitro activation (IVA) of the ovarian cortex combined with autologous transplantation is one of the novel approaches to primary ovarian insufficiency and diminished ovarian reserve [ 40 ]. Later, a simplification of the technique designated “Drug-Free IVA” has shown encouraging results in patients with POI [ 41 , 42 ].…”

In Vitro Activation Early Follicles: From the Basic Science to the Clinical Perspectives

“…Thus, they represent a finite source of ovarian follicles and their recruitment is an indispensable step as it determines reproductive lifespan [ 23 , 24 ]. The activation of EFs is modulated strictly to ensure only a small number of PFs can be activated [ 10 , 25 ]. Subsequently, they undergo continuous folliculogenesis to develop to later stages of development until the ovulation occurs.…”

“…The development of EFs is a complicated process governed by a number of signaling pathways and components [ 25 , 95 , 96 ]. Recent computational studies revealed that these components interact in different ways to promote the transition from PFs to the primary stage [ 83 ].…”

“…Recent computational studies revealed that these components interact in different ways to promote the transition from PFs to the primary stage [ 83 ]. Additionally, it is reported that more than 1000 genes are involved in EFs’ survival and development [ 25 , 95 , 97 ]. These findings suggested that there should be additional possible future therapeutic targets for the IVA approach.…”

Oocyte Vitrification for Fertility Preservation in Women with Benign Gynecologic Disease: French Clinical Practice Guidelines Developed by a Modified Delphi Consensus Process

“…They specifically rejected ovarian tissue cryopreservation for this indication. Some authors propose this ovarian tissue cryopreservation with the aim of in vitro activation of ovarian cortex before autologous transplantation [25]. However, this innovative method must be interpreted cautiously and deserves further well-conducted studies.…”