Drug-free in-vitro activation of follicles and fresh tissue autotransplantation as a therapeutic option in patients with primary ovarian insufficiency

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.

Download Full-text

Primary ovarian insufficiency: from basis of pathogenesis to treatment perspectives

Voprosy ginekologii akušerstva i perinatologii ◽

10.20953/1726-1678-2021-5-100-107 ◽

2021 ◽

Vol 20 (5) ◽

pp. 100-107

Author(s):

E.N. Andreeva ◽

◽

Yu.S. Absatarova ◽

R.R. Akhmatova ◽

E.V. Sheremetieva ◽

...

Keyword(s):

Early Diagnosis ◽

Ovarian Tissue ◽

Reproductive Potential ◽

Primary Ovarian Insufficiency ◽

Cochrane Library ◽

Ovarian Insufficiency ◽

Autoimmune Pathology ◽

In Vitro Activation ◽

Selection Of

The review of literature data on primary ovarian insufficiency (POI), its autoimmune aspect, determination of markers for early diagnosis of the disease, treatment options and implementation of reproductive plans was carried out. Autoimmune and genetic aspects of pathogenesis, markers of autoimmunity in ovarian tissue, which may be promising for early diagnosis in risk groups of patients with autoimmune pathology, were considered; information on the incidence of nosology in other autoimmune diseases, which will also allow to identify POI at early stages, was provided. This article provides information about a new direction in reproductive surgery – drug-free in vitro activation based on primordial follicle activation by modulating biological signaling pathways. This procedure may have a long-term perspective for realizing reproductive potential without the use of donor eggs. The literature search was performed in domestic (eLibrary, CyberLeninka.ru) and international (PubMed, Cochrane Library) databases in Russian and English. The selection of sources was made within a limited period from 2016 to 2021. However, given the insufficient knowledge of the chosen topic, the selection of sources was dated from 2009. Key words: autoimmune oophoritis, hypergonadotropic hypogonadism, primary ovarian insufficiency, in vitro activation

Download Full-text

In Vitro Follicular Activation and Stem Cell Therapy as a Novel Treatment Strategies in Diminished Ovarian Reserve and Primary Ovarian Insufficiency

Frontiers in Endocrinology ◽

10.3389/fendo.2020.617704 ◽

2021 ◽

Vol 11 ◽

Author(s):

Francesc Fàbregues ◽

Janisse Ferreri ◽

Marta Méndez ◽

Josep María Calafell ◽

Jordi Otero ◽

...

Keyword(s):

Ovarian Reserve ◽

Therapeutic Option ◽

Treatment Strategies ◽

Ovarian Response ◽

Primary Ovarian Insufficiency ◽

Diminished Ovarian Reserve ◽

Hippo Signaling ◽

Ovarian Insufficiency ◽

Novel Treatment Strategies

Usually poor ovarian response (POR) to gonadotropins reflects a diminished ovarian reserve (DOR) that gives place to few recruitable follicles despite aggressive stimulation. The reduction in the quantity and quality of the oocytes with advanced age is physiological. However, some women experience DOR much earlier and become prematurely infertile, producing an accelerated follicular depletion towards primary ovarian insufficiency (POI). Up to now, egg donation has been commonly used to treat their infertility. In the last thirty years, specialists in assisted reproduction have focused their attention on the final stages of folliculogenesis, those that depend on the action of gonadotrophins. Nevertheless, recently novel aspects have been known to act in the initial phases, with activating and inhibiting elements. In vitro activation (IVA) combining the in vitro stimulation of the ovarian Akt signaling pathway in ovarian cortex fragments with a method named Hippo-signaling disruption. Later, a simplification of the technique designated Drug-Free IVA have shown encouraging results in patients with POI. Another innovative therapeutic option in these patients is the infusion of bone marrow-derived stem cells (BMDSC) in order to supply an adequate ovarian niche to maintain and/or promote follicular rescue in patients with impaired or aged ovarian reserves. In this review, for the first time, both therapeutic options are addressed together in a common clinical setting. The aim of this review is to analyze the physiological aspects on which these innovative techniques are based; the preliminary results obtained up to now; and the possible therapeutic role that they may have in the future with DOR and POI patients.

Download Full-text