Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations

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.

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Mechanisms of Ovarian Aging

Reproduction ◽

10.1530/rep-21-0022 ◽

2021 ◽

Author(s):

Selena Park ◽

Leann Walsh ◽

Karen M. Berkowitz

Keyword(s):

Ovarian Reserve ◽

Molecular Mechanisms ◽

Spindle Assembly Checkpoint ◽

Gene Mutations ◽

Diminished Ovarian Reserve ◽

Contributing Factors ◽

Ovarian Insufficiency ◽

Ovarian Aging ◽

Metabolic Dysregulation

Ovarian aging in women correlates with the progressive loss of both the number and quality of oocytes. When these processes occur early or are accelerated, their clinical correlates are diminished ovarian reserve and/or premature ovarian insufficiency. Both these conditions have important consequences for the reproductive and general health of women, including infertility. Although there are many contributing factors, the molecular mechanisms underlying many of the processes associated with ovarian aging have not been fully elucidated. In this review, we highlight some of the most critical factors that impact oocyte quantity and quality with advancing age. We discuss chromosomal factors including cohesion deterioration and mis-segregation, errors in meiotic recombination, and decreased stringency of the spindle assembly checkpoint. DNA damage, telomere changes, reactive oxygen species and mitochondrial dysfunction as they relate to ovarian aging, and well-known gene mutations associated with primary ovarian insufficiency and diminished ovarian reserve are also discussed. Additionally, studies investigating recently acknowledged cytoplasmic factors associated with ovarian aging including protein metabolic dysregulation and microenvironmental alterations in the ovary are presented. We use both mouse and human studies to support the roles these factors play in physiologic and expedited ovarian aging, and we propose directions for future studies. A better understanding of the molecular basis of ovarian aging will ultimately lead to diagnostic and therapeutic advancements that would provide women with information to make earlier choices about their reproductive health.

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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.

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Fragile X premutation carriers with mid-range CGG repeat size and reduction in AGG interruptions demonstrate more profoundly diminished ovarian reserve

Fertility and Sterility ◽

10.1016/j.fertnstert.2017.07.172 ◽

2017 ◽

Vol 108 (3) ◽

pp. e54

Author(s):

J. Lekovich ◽

L. Man ◽

K. Xu ◽

D. Lilienthal ◽

N. Pereira ◽

...

Keyword(s):

Ovarian Reserve ◽

Fragile X ◽

Diminished Ovarian Reserve ◽

Cgg Repeat ◽

Fragile X Premutation ◽

Repeat Size ◽

Agg Interruptions

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Primary ovarian insufficiency in an adolescent population: clinical phenotype and diagnostic approach

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0083 ◽

2019 ◽

Vol 32 (9) ◽

pp. 979-985

Author(s):

Alfonso Hoyos-Martinez ◽

Luis R. Hoyos ◽

Metee Comkornruecha ◽

Alejandro Diaz

Keyword(s):

Clinical Phenotype ◽

Fragile X ◽

Clinical Information ◽

Rare Condition ◽

Primary Ovarian Insufficiency ◽

Diagnostic Approach ◽

Ovarian Insufficiency ◽

Adolescent Population ◽

Autoimmune Conditions ◽

Reproductive Counseling

Abstract Background Primary ovarian insufficiency (POI) can be seen in adolescents secondary to genetic or autoimmune conditions, or gonadotoxic therapies. Often times, its underlying cause is not identified. It is a rare condition in pediatrics, but a thorough evaluation is required for a timely diagnosis and optimizing outcomes. Objectives We aim to describe the clinical phenotype of idiopathic POI in an adolescent population seen in a referral center, and evaluate its diagnostic approach. Methods All patients evaluated between 2012 and 2018 were identified using the diagnostic codes for POI. Medical records were manually reviewed and clinical information was extracted. Cases were excluded from the final sample if they were found to have incomplete diagnostic information, Turner syndrome, eating disorders, gonadal surgeries and/or a history of oncological conditions or treatments. Results Forty-eight patients with POI were identified, and only seven met the established criteria. Anti-ovarian and anti-thyroid antibodies were evaluated in 100% and 86%, respectively, while only 29% were tested for anti-adrenal autoimmunity. The karyotype was obtained consistently, while the fragile X mental retardation 1 (FMR1) gene expansion was only assessed in approximately a third of the patients. Finally, only 29% of patients received reproductive counseling or referral to a fertility specialist. Conclusions Diagnostic evaluation for POI appears to be challenging to pediatric providers. Anti-ovarian antibodies are frequently obtained despite the lack of their clinical significance in POI, while anti-adrenal antibodies, which are the preferred diagnostic test, are not commonly obtained. Reproductive orientation or referral is seldom provided to the adolescent population.

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