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Ovarian Reserve Disorders: Molecular Mechanisms and Regulation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 10742

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Special Issue Editor

Prof. Dr. Saad Amer

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Guest Editor

Division of Medical Science and Graduate Entry Medicine, School of Medicine, Royal Derby Hospital Centre, University of Nottingham, Room 4115, Derby DE22 3DT, UK
Interests: reproductive medicine; reproductive biology; ovarian pathophysiology; polycystic ovary syndrome (PCOS)
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Special Issue Information

Dear Colleagues,

Ovarian reserve is a term used to reflect the total number of the remaining primordial follicles, which determine woman’s fertility potential and reproductive life span. Since its emergence in the late 1980s, the concept of ovarian reserve has continued to gain more significance as reflected by the exponentially growing number of publications. Ovarian reserve disorders such as Diminished Ovarian Reserve (DOR) and Premature Ovarian Insufficiency (POI) are common and represent a real dilemma in young women. They are often associated with reduced fecundity and significant long-term health risks. Although several aetiologies of ovarian reserve disorders have been recognised including genetic, autoimmune, pathological, and iatrogenic mechanisms, most cases are idiopathic. Currently, there is no treatment for ovarian reserve disorders owing to the lack of full understanding of the underlying mechanisms. Therefore there is a need for more research into the molecular mechanisms and regulations of ovarian reserve and its disorders.

This Special Issue of the International Journal of Molecular Sciences (IJMS) aims to rapidly publish contributions on all aspects of molecular, cellular, biochemical, and genetic research into ovarian reserve. We encourage the submission of manuscripts that provide novel and mechanistic insights and papers that report significant advances in the fields. This special issue welcomes original research as well as in-depth review articles addressing this hot topic.

Prof. Dr. Saad Amer
Guest Editor

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Keywords

ovarian reserve
diminished ovarian reserve
early ovarian aging
premature ovarian insufficiency
poor ovarian reserve
primary ovarian insufficiency
premature menopause

Published Papers (5 papers)

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Research

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15 pages, 10585 KiB

Open AccessArticle

Classification of Atretic Small Antral Follicles in the Human Ovary

by Fu Wei, Xueying Fan, Julieta S. del Valle, Joyce D. Asseler, Lotte E. van der Meeren, Hui Cheng, Bernard A. J. Roelen, Leoni A. Louwe, Gonneke S. K. Pilgram, Lucette A. J. van der Westerlaken, Norah M. van Mello and Susana M. Chuva de Sousa Lopes

Int. J. Mol. Sci. 2023, 24(23), 16846; https://doi.org/10.3390/ijms242316846 - 28 Nov 2023

Cited by 1 | Viewed by 1325

Abstract

The reproductive lifespan in humans is regulated by a delicate cyclical balance between follicular recruitment and atresia in the ovary. The majority of the small antral follicles present in the ovary are progressively lost through atresia without reaching dominance, but this process remains largely underexplored. In our study, we investigated the characteristics of atretic small antral follicles and proposed a classification system based on molecular changes observed in granulosa cells, theca cells, and extracellular matrix deposition. Our findings revealed that atresia spreads in the follicle with wave-like dynamics, initiating away from the cumulus granulosa cells. We also observed an enrichment of CD68+ macrophages in the antrum during the progression of follicular atresia. This work not only provides criteria for classifying three stages of follicular atresia in small antral follicles in the human ovary but also serves as a foundation for understanding follicular degeneration and ultimately preventing or treating premature ovarian failure. Understanding follicular remodeling in the ovary could provide a means to increase the number of usable follicles and delay the depletion of the follicular reserve, increasing the reproductive lifespan. Full article

(This article belongs to the Special Issue Ovarian Reserve Disorders: Molecular Mechanisms and Regulation)

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20 pages, 3799 KiB

Open AccessArticle

A Cross-Species Analysis Reveals Dysthyroidism of the Ovaries as a Common Trait of Premature Ovarian Aging

by Marco Colella, Danila Cuomo, Valeria Nittoli, Angela Amoresano, Alfonsina Porciello, Carla Reale, Luca Roberto, Filomena Russo, Nicola Antonino Russo, Mario De Felice, Massimo Mallardo and Concetta Ambrosino

Int. J. Mol. Sci. 2023, 24(3), 3054; https://doi.org/10.3390/ijms24033054 - 3 Feb 2023

Viewed by 2002

Abstract

Although the imbalance of circulating levels of Thyroid Hormones (THs) affects female fertility in vertebrates, its involvement in the promotion of Premature Ovarian Aging (POA) is debated. Therefore, altered synthesis of THs in both thyroid and ovary can be a trait of POA. We investigated the relationship between abnormal TH signaling, dysthyroidism, and POA in evolutionary distant vertebrates: from zebrafish to humans. Ovarian T3 signaling/metabolism was evaluated by measuring T3 levels, T3 responsive transcript, and protein levels along with transcripts governing T3 availability (deiodinases) and signaling (TH receptors) in distinct models of POA depending on genetic background and environmental exposures (e.g., diets, pesticides). Expression levels of well-known (Amh, Gdf9, and Inhibins) and novel (miR143/145 and Gas5) biomarkers of POA were assessed. Ovarian dysthyroidism was slightly influenced by genetics since very few differences were found between C57BL/6J and FVB/NJ females. However, diets exacerbated it in a strain-dependent manner. Similar findings were observed in zebrafish and mouse models of POA induced by developmental and long-life exposure to low-dose chlorpyrifos (CPF). Lastly, the T3 decrease in follicular fluids from women affected by diminished ovarian reserve, as well as of the transcripts modulating T3 signaling/availability in the cumulus cells, confirmed ovarian dysthyroidism as a common and evolutionary conserved trait of POA. Full article

(This article belongs to the Special Issue Ovarian Reserve Disorders: Molecular Mechanisms and Regulation)

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12 pages, 1779 KiB

Open AccessArticle

The Role of PEDF in Reproductive Aging of the Ovary

by Luba Nemerovsky, Hadas Bar-Joseph, Anat Eldar-Boock, Rana Tarabeih, Cindy Elmechaly, Ido Ben-Ami and Ruth Shalgi

Int. J. Mol. Sci. 2022, 23(18), 10359; https://doi.org/10.3390/ijms231810359 - 8 Sep 2022

Viewed by 1791

Abstract

Reproductive aging is characterized by a decline in ovarian function and in oocytes’ quantity and quality. Pigment epithelium-derived factor (PEDF), a pivotal player in ovarian angiogenic and oxidative balance, was evaluated for its involvement in reproductive aging. Our work examines the initial stage of reproductive aging in women and mice, and the involvement of PEDF in the process. Granulosa cells from reproductively-aged (RA) women and mice (36–44 years old and 9–10 months old, respectively) indicated an increase in the level of PEDF mRNA (qPCR), with yet unchanged levels of AMH and FSHR mRNAs. However, the PEDF protein level in individual women showed an intra-cellular decrease (ELISA), along with a decrease in the corresponding follicular fluid, which reflects the secreted fraction of the protein. The in vitro maturation (IVM) rate in the oocytes of RA mice was lower compared with the oocytes of young mice, demonstrated by a reduced polar body extrusion (PBE) rate. The supplementation of PEDF improved the hampered PBE rate, manifested by a higher number of energetically-competent oocytes (ATP concentration and mtDNA copy number of individual oocytes). Our findings propose PEDF as an early marker of reproductive aging, and a possible therapeutic in vitro agent that could enhance the number of good-quality oocytes in older IVF patients. Full article

(This article belongs to the Special Issue Ovarian Reserve Disorders: Molecular Mechanisms and Regulation)

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Graphical abstract

12 pages, 2225 KiB

Open AccessArticle

High Housing Density-Induced Chronic Stress Diminishes Ovarian Reserve via Granulosa Cell Apoptosis by Angiotensin II Overexpression in Mice

by Jihyun Kim and Sooseong You

Int. J. Mol. Sci. 2022, 23(15), 8614; https://doi.org/10.3390/ijms23158614 - 3 Aug 2022

Cited by 2 | Viewed by 1921

Abstract

Repeated and prolonged stress causes hypothalamic-pituitary-adrenal (HPA) dysregulation. Excessive hypothalamic-pituitary-adrenal axis activity has been linked to inadequate activation of the hypothalamus-pituitary-ovarian axis, which controls the growth and development of ovarian follicles and oocytes. Therefore, we assessed the ovarian reserve under high-housing-density-induced prolonged stress, and investigated the mechanisms underlying diminished ovarian reserve in this study. Eight-week-old female C57BL/6 mice were housed for 10 weeks under different housing densities. We then assessed hormone levels, performed histology and immunohistochemistry analyses of ovarian follicles, evaluated ovarian mRNA expression, and measured angiotensin II-mediated apoptosis in vitro. More densely housed mice presented increased corticosterone levels and decreased follicle-stimulating and luteinizing hormone levels. Moreover, mice exposed to prolonged ordinary stress showed a reduced level of serum anti-Müllerian hormone and an increased number of atretic ovarian follicles. Stressed mice showed increased levels of angiotensinogen and angiotensin II in the ovaries and serum. Furthermore, our in vitro study confirmed that high-housing-density-related stress induced granulosa cell apoptosis, resulting in diminished ovarian reserves. Collectively, our findings highlight the importance of women managing everyday stress to maintain their reproductive health. Full article

(This article belongs to the Special Issue Ovarian Reserve Disorders: Molecular Mechanisms and Regulation)

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Review

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30 pages, 469 KiB

Open AccessReview

Ovarian Reserve Disorders, Can We Prevent Them? A Review

by Limor Man, Nicole Lustgarten Guahmich, Nina Vyas, Shelun Tsai, Laury Arazi, Debra Lilienthal, Glenn Schattman, Zev Rosenwaks and Daylon James

Int. J. Mol. Sci. 2022, 23(23), 15426; https://doi.org/10.3390/ijms232315426 - 6 Dec 2022

Cited by 6 | Viewed by 2907

Abstract

The ovarian reserve is finite and begins declining from its peak at mid-gestation until only residual follicles remain as women approach menopause. Reduced ovarian reserve, or its extreme form, premature ovarian insufficiency, stems from multiple factors, including developmental, genetic, environmental exposures, autoimmune disease, or medical/surgical treatment. In many cases, the cause remains unknown and resulting infertility is not ultimately addressed by assisted reproductive technologies. Deciphering the mechanisms that underlie disorders of ovarian reserve could improve the outcomes for patients struggling with infertility, but these disorders are diverse and can be categorized in multiple ways. In this review, we will explore the topic from a perspective that emphasizes the prevention or mitigation of ovarian damage. The most desirable mode of fertoprotection is primary prevention (intervening before ablative influence occurs), as identifying toxic influences and deciphering the mechanisms by which they exert their effect can reduce or eliminate exposure and damage. Secondary prevention in the form of screening is not recommended broadly. Nevertheless, in some instances where a known genetic background exists in discrete families, screening is advised. As part of prenatal care, screening panels include some genetic diseases that can lead to infertility or subfertility. In these patients, early diagnosis could enable fertility preservation or changes in family-building plans. Finally, Tertiary Prevention (managing disease post-diagnosis) is critical. Reduced ovarian reserve has a major influence on physiology beyond fertility, including delayed/absent puberty or premature menopause. In these instances, proper diagnosis and medical therapy can reduce adverse effects. Here, we elaborate on these modes of prevention as well as proposed mechanisms that underlie ovarian reserve disorders. Full article

(This article belongs to the Special Issue Ovarian Reserve Disorders: Molecular Mechanisms and Regulation)

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